Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][NH:41][CH2:42][CH2:43][CH2:44][N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: NCCCn1ccnc1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CNCCCn4ccnc4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.6 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 1-(3-aminopropyl)imidazole (0.034 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 1-(3-aminopropyl)imidazole (0.1 mL) and sodium triacetoxyborohydride (0.086 g, 0.40 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 14.0-15.7 min was collected, concentrated, and lyopholyzed to afford N1-(4-{4-amino-1-[4-{([3-(1H-1-imidazolyl)propyl]amino}methyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.040 g, 0.061 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.40 (2H, m), 8.16 (2H, d, J=7.6 Hz), 7.99 (1H, t, J=7.6 Hz), 7.89 (1H, d, J=10.0 Hz), 7.75 (1H, d, J=8.4 Hz), 7.59 (1H, s), 7.52 (2H, d, J=3.8 Hz), 6.45 (1H, s), 7.40 (1H, d, J=8.0 Hz), 7.16 (1H, s), 6.87 (1H, s), 4.04 (2H, t, J=7.0 Hz), 3.96 (3H, s), 3.77 (2H, s), 2.45-2.46 (2H, m), 1.91 (3H, s), and 1.86-1.90 (2H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.28 min. MS: MH+ 660.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:2][OH:1]
Reactant: N#Cc1cccc(CO)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccc(CO)c1
Yield: 40 %

Procedure:
A solution of 3-(hydroxymethyl)benzonitrile in THF was slowly added to a refluxing solution of LiAlH4 in THF with vigorous stirring, maintained under nitrogen atmosphere. The solution was heated at reflux overnight and water was thereafter slowly added dropwise to quench the reaction (until no further evolution of H2 was apparent). The THF was evaporated under reduced pressure and ether/acidified water was added. The ether phase was discarded. The aqueous phase was washed with ether and the organic phase was discarded. NaOH was added until the pH of the aqueous phase reached pH 7. The solution was extracted with THF three times, dried over MgSO4 and evaporated under reduced pressure to furnish a slightly yellow residue which was purified by chromatography on a silica gel column using a gradient eluent starting from ethyl acetate and ending with a mixture of 1:1 ethyl acetate:MeOH), to give the intermediate in a 40% yield.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].C.C[O:9][C:10]([C@@H:12]1[C@H:16]([CH3:17])[CH2:15][CH2:14][N:13]1[C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])=O.Cl>C1(C)C=CC=CC=1>[CH3:17][C@@H:16]1[CH2:15][CH2:14][N:13]([C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C@@H:12]1[C:10]([NH2:6])=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1[C@H](C)CCN1[C@@H](C)c1ccccc1
Agent: C
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Trimethylaluminum in toluene (2 M, 3.23 mL) was added dropwise to a mixture of ammonium chloride (0.346 g, 6.47 mmol) in toluene (3.2 mL) at 0° C. under an argon atm., with the formation of methane gas. The RM was then allowed to warm to rt, and stirred at rt for a further 15 min. before (2S,3R)-3-methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (prepared as described in Tetr. Lett. 1997, 38 (1), 85-88; 1.6 g, 6.47 mmol) was slowly added. The RM was stirred at it for 56 h, 1 M HCl was then added with cooling and the RM washed 3× with DCM. The aqueous phase was basified with Na2CO3, extracted 3× with DCM and the combined organic layers dried over Na2SO4. Evaporation gave the title compound as a yellowish oil. MS: M+H=233.2. HPLC: tR 3.17 min (method D). 1H-NMR (d6-DMSO, 600 MHz): 7.37-7.33 (m, 2H), 7.30 (t, 2H), 7.25 (s, br,1H), 7.21 (t, 1H), 7.12 (s, br,1H), 3.55 (q, 1H), 3.40 (d, 1H), 2.71 (t, 1H), 2.28-2.22 (m, 1H), 2.21-2.16 (m, 1H), 1.71 (qt, 1H), 1.38-1.31 (m, 1H), 1.21 (d, 3H), 0.90 (d, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(CCC)=O)[N:19]=2)[CH2:3]1.Cl.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)=[O:35])[CH3:32].C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:20]2[N:19]=[C:18]([N:13]3[C:14]4[C:10](=[C:9]([O:8][CH2:7][CH:4]5[CH2:5][CH2:6][S:2](=[O:29])(=[O:1])[CH2:3]5)[CH:17]=[CH:16][CH:15]=4)[CH:11]=[CH:12]3)[CH:23]=[CH:22][N:21]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CCCS(=O)c1nccc(-n2ccc3c(OCC4CCS(=O)(=O)C4)cccc32)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCC5CCS(=O)(=O)C5)cccc43)n2)CC1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
To a solution of 4-(1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethoxy)-1-[2-(propane-1-sulfinyl)-pyrimidin-4-yl]-1H-indole 1.2 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (1.12 g) in NMP (5 mL) was added diisopropylethylamine (1.4 mL). The mixture was heated to 80° C. for 18 hours, then cooled and poured into 75 mL water. The mixture was extracted with methylene chloride, and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 1.069 g of 4-{4-[4-(1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[H-].[K+].[CH3:8][S:9][CH2:10][S:11](=[O:13])[CH3:12].BrCCCBr>C(Cl)Cl>[CH3:8][S:9][C:10]1([S:11](=[O:13])[CH3:12])[CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9][CH2:10][S:11](=[O:13])[CH3:12]
Reactant: C1CCOC1
Agent: BrCCCBr
Agent: CSCS(C)=O
Agent: [H-]
Solvent: ClCCl
Product: CSC1(S(C)=O)CCC1
Reaction time: 17 h

Procedure:
Tetrahydrofuran (15 ml) was added to 1.01 g of potassium hydride, and with stirring under ice cooling, 1.044g of formaldehyde dimethyl mercaptal S-oxide was added dropwise. After stirring for 1 hour with ice cooling, 2.070g of 1,3-dibromopropane was added dropwise over the course of about 10 minutes. The mixture was stirred for 1 hour with ice cooling, and then for 17 hours at room temperature. Then, 100 ml. of methylene chloride was added, and the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and then separated by column chromatography (silica gel, eluted with methylene chloride, ether and methanol) to afford 1.081g of cyclobutanone dimethyl mercaptal S-oxide and 199 mg of formaldehyde dimethyl mercaptal S-oxide, both as a light yellow oil. The yield was 78%. The physical properties were as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:30](=[O:38])[C:29]([C:39](O)=[O:40])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:29]5[C:30](=[O:38])[N:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:26]([CH3:25])=[CH:27][CH:28]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.1 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (70 mg, 0.215 mmol) and 6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (59.1 mg, 0.258 mmol) in N,N-dimethylformamide (1.0 mL) were added HATU (98 mg, 0.258 mmol) and N,N-diisopropylethylamine (74 μL, 0.43 mmol), and the mixture was stirred at room temperature for 17 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give a pale-yellow solid. The obtained pale-yellow solid was washed with ethyl acetate and collected by filtration to give the title compound (66 mg, 57%) as a white solid.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:7]=[C:8]([CH2:12][S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1C=CC=CC=1>[N+:3]([C:6]1[CH:7]=[C:8]([CH2:12][S:13]([NH:2][CH3:1])(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: CN
Solvent: c1ccccc1
Product: CNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
40% aqueous methylamine (10 mL, 0.1 mol) was added to a vigorously stirred solution of (3-Nitrophenyl)methanesulfonyl chloride (2.36 g, 10 mmol) in benzene (30 mL) and allowed to stir for 2 h at room temperature. To this end, the benzene layer was separated, and the aqueous layer extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), water (30 mL), filtered over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure to give 2.07 g (90%) of (3-nitrophenyl)-N-methylmethanesulfonamide as crystals.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][O:9][C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.C(Cl)Cl>[N:18]([C@@H:6]1[CH2:11][CH2:10][O:9][C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)O[C@H]1CCO[C@@H](c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCO[C@@H](c2ccccc2)C1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
A solution of cis-2-phenyl-tetrahydro-2H-pyran-4-yl methanesulfonate (0.8 g) in DMF (10 mL) was treated with sodium azide (0.8 g) and heated at 100° C. for 4 hours. The mixture was diluted with DCM (50 mL) and washed with water and brine. The organic layer was dried and concentrated. Preparative TLC provided 0.5 g of trans-4-azido-2-phenyl-tetrahydro-2H-pyran.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[NH:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[Br:29])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl.O>CN1CCCC1=O.CO>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([O:26][CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:23]4[C:18](=[C:19]([Br:29])[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc(Br)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(OCOCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
A yellow suspension of 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 27b) (3.092 g, 6.75 mmol) in 40 mL N-methylpyrolidinone was treated with sodium hydride (60% dispersion in oil, 0.410 g, 10.24 mmol). Gas evolution and warming were observed and the suspension became light brown and almost clear. The reaction was stirred for 10 minutes at room temperature under nitrogen. Addition of the 2-(trimethylsilyl)ethoxymethyl chloride (1.6 mL, 9.1 mmol) resulted in a slightly cloudy, lighter brown solution. After 4.5 hours at room temperature, the reaction mixture was poured into 300 mL water, stirred for 15 minutes and then stored at 0° C. overnight. The solids were isolated by filtration, suspended in methanol, filtered again, and dried under high vacuum to afford the product as a yellow solid (3.190 g, 80%). 1H NMR (300 MHz, DMSO, d6) δ 10.18 (s, 1 H, C(O)NH), 7.95 (d, 1 H, Jm=2.4 Hz, ArH7), 7.83 (s, 1 H, ArH3), 7.69 (d, 2 H, Jo=9.0 Hz, ArH2′& H6′), 7.51 (d, 1 H, Jm=2.7 Hz, ArH5), 7.00 (d, 2 H, Jo=9.0 Hz, ArH3′& H5′), 5.69 (s, 2 H, OCH2O), 3.95 (s, 3 H, OCH3), 3.85 (t, 2 H, J=8.0 Hz, OCH2CH2Si), 3.75 (t, 4 H, J=4.7 Hz, OCH2CH2N), 3.10 (t, 4 H, J=4.7 Hz, OCH2CH2N), 0.94 (t, 2 H, J=8.0 Hz, OCH2CH2Si), −0.04 (s, 9 H, Si(C H3)3; Mass Spec.: calc. for [C27H34BrN3O5Si+H]+ Theor. m/z=588, 590; Obs.=588, 590.
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].Cl.C(O)(C(F)(F)F)=[O:18]>O.O.CO>[OH:18][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 66 %

Procedure:
To a 250 mL flask were added 3-chloro-2-nitrobenzoic acid (10 g, 49.6 mmol) and a potassium hydroxide solution (40 g, 727 mmol) in water (70 mL). The thick slurry was heated to reflux for 12 hours. The solution was cooled in ice and cautiously brought to pH 3 with concentrated HCl. The aqueous mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The crude product mixture was dissolved in dichloromethane and the resulting yellow precipitate was filtered to afford Intermediate A-15A (6 g, 32.8 mmol, 66.0% yield). HPLC: RT=0.85 min (H2O/MeOH with TFA, Sunfire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=206 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.56-7.35 (m, 1H), 7.23 (dd, J=7.9, 1.5 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].CN(C)C=O.C([O-])(=O)C.[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
A stirred mixture of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (0.025 g, 0.067 mmoles), (3,4-dimethoxyphenyl)-boronic acid (0.017 g, 0.093 mmoles), N,N-dimethylformamide (3 mL), potassium acetate (0.026 g) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (4 mg) was stirred at room temperature under an argon atmosphere for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (2.5 mL) and 1.0 M aqueous lithium hydroxide solution (0.5 mL), and stirred for 16 hours. The reaction mixture was acidified to pH=6 using 1M hydrochloric acid and extracted with ethyl acetate (3×25 mL). The extracts were dried, concentrated in vacuo and the residue purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 70% acetonitrile/30% water at a rate of 1%/min) to give compound 96 as a solid (15 mg). LC/MS System B; Rt=1.65 mins, m/z (ES−)=367 (M−H for C21H20O6).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:10]S(C(F)(F)F)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.N[C:32]1[CH:33]=[N:34][N:35]([CH3:38])[C:36]=1[NH2:37].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl.O>[NH2:37][C:36]1[N:35]([CH3:38])[N:34]=[CH:33][C:32]=1[NH:10][C:9]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: Cn1ncc(N)c1N
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1ncc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethylsulfonyl)guanidine (22.3 g) in dichloromethane (100 ml) were added 4,5-diamino-1-methylpyrazole sulfuric acid salt (10 g) and triethylamine (33.2 ml) at 4° C., and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate and water. The aqueous layer was separated, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The concentrate was poured into acetonitrile, and the resulting precipitate was collected by filtration and dried in vacuo to give 5-amino-4-[2′,3′-bis(tert-butoxycarbonyl)guanidino]-1-methylpyrazole (11.62 g).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([C:8](=O)[CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:6]2.[Li].[H-].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:6]2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3cccs3)CC21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3cccs3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of N-(3-{6-methyl-3-[3-(2-thienyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl]phenyl)methanesulfonamide (Preparation 125, 200 mg, 0.49 mmol) in anhydrous tetrahydrofluran (7.5 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium alumirnium hydride (1.0M solution in tetrahydrofuran, 0.99 ml, 0.99 mmol) and the mixture was stirred at room temperature for 2 h. The rapidly stirred reaction mixture was treated sequentially with water (1.0 ml), sodium hydrogen carbonate (1.0 g) and ethyl acetate (25 ml). After 15 min the reaction mixture was filtered and concentrated in vacuo to afford a light yellow oil. This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100) to afford the title compound as a colourless oil (135 mg, 70%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=C(CN2CC(C3C=CC=CC=3)CC2=O)N2C=CC=CC=12.C([O-])(=O)C.[Na+].[C:38]([N:57]1[CH:61]=[C:60]([C:62](=O)[CH2:63][CH3:64])[N:59]=[CH:58]1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[BH3-]C#N.[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CO.CCOCC>[C:38]([N:57]1[CH:61]=[C:60]([CH:62]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:63][CH3:64])[N:59]=[CH:58]1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)CCCN
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C1CC(c2ccccc2)CN1Cc1cnc2ccccn12
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)CCCNC(CC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, ethyl 4-aminobutanoate hydrochloride al 7 (1.75 g, 0.0104 mol) is dissolved in MeOH (30 ml). Sodium acetate (1.28 g, 0.0156 mol), a solution of 1-(1-trityl-1H-imidazol-4-yl)propan-1-one x89 (0.96 g, 2.6 mmol) in a mixture of MeOH (7 ml) and Et2O (20 ml), NaBH3CN (0.15 g, 2.34 mmol) and finally Na2SO4 are added. After stirring for 48 h at room temperature, the mixture is poured on Et2O/H2O. The organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude ethyl 4-{[1-(1-trityl-1H-imidazol-4-yl)propyl]amino}butanoate x90 (0.814 g) is used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C([Li])CCC.CON(C)[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC>[C:29]([C:7]1[CH:8]=[C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:20])([CH3:19])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CN1CCN(c2ccc(NC(=O)C(C)(C)C)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(c2ccc(NC(=O)C(C)(C)C)c(C(=O)c3ccccc3)c2)CC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
A solution of 1.375 g (5 mmol) of 2,2-dimethyl-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionamide was dissolved in 25 ml tetrahydrofuran and cooled to −70° C. Under argon 7.8 ml (12.5 mmol) of a 1.6 M n-butyl lithium solution in hexane was added slowly at this temperature. The cooling bath was removed and the mixture was stirred for 3 h at room temperature. The reaction mixture was cooled down again to −70° C. and a solution of 1.234 g N-methoxy-N-methyl benzamide (7.2 mmol) in 5 ml tetrahydrofuran was added slowly at −70° C. After 10 min the cooling bath was removed and stirring was continued at room temperature for 1 hour. Water (50 ml) was added to quench the reaction and the mixture was extracted with diethylether (three times 50 ml). The organic layer was dried with magnesium sulfate and evaporated to give a brown oil, which was purified by flash chromatography with dichloromethane/methanol to yield 315 mg (17%)of the product as a light orange solid.