Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:38][CH2:37]2)=[C:32](Cl)[N:31]=1)=[O:29].[Cl:40][C:41]1[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:42]=1[NH2:43].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:38][CH2:37]2)=[C:32]([NH:43][C:42]2[CH:44]=[CH:45][C:46]([Cl:48])=[CH:47][C:41]=2[Cl:40])[N:31]=1)=[O:29]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(C2CC2)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1
Reaction time: 20 h
Yield: 39 %

Procedure:
A solution of palladium(II)acetate (4.24 mg, 18.9 μmol) and 2-(dicyclohexylphosphino) biphenyl (13.2 mg, 37.8 μmol) in dioxane (1.9 ml) under an argon atmosphere was stirred for 10 min at ambient temperature and subsequently added to a suspension of 6-chloro-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester (100 mg, 472 μmol), 2,4-dichloroaniline (76.6 mg, 472 μmol) and potassium carbonate (1.31 g, 9.45 mmol) in dioxane (3.24 ml) under an argon atmosphere. The yellow suspension was heated to reflux and stirred for 20 h. The reaction mixture was poured into 20 mL ice/brine and extracted with i-PrOAc (2×50 mL). The combined organic layers were washed with ice/brine (1×50 mL), dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography (silica gel, 4 g, 0% to 10% heptane/iPrOAc) to give the title compound (62 mg, 39%) as light brown liquid, MS (EI): m/e=337.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:19].[H-].[Na+]>C1COCC1>[N:14]([C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]1[O:17][CH3:19])=[N+:15]=[N-:16]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.6 %

Procedure:
To a stirred mixture of 146A (320 mg, 1.32 mmol) and iodomethane (0.25 mL, 3.96 mmol) in 4 mL of dry THF at room temperature under nitrogen was added 95% NaH (40.0 mg. 1.58 mmol). This mixture was stirred at room temperature for 15 h and then quenched by addition of 30 mL of water. The aqueous solution was extracted with EtOAc (2×40 mL). The combined EtOAc extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to give 310 mg (Yield: 92%) of 247A. It had an analytical HPLC retention time=2.86 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++Na=279.
Reaction SMILES: [C-]#N.[K+].[CH2:4]([O:11][C:12]1[CH:30]=[CH:29][C:28]2=[CH:31][C:13]=1[CH2:14][C@H:15]([NH:55][C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])[C:16](=[O:54])[NH:17][C@@H:18]([CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:19](=[O:39])[N:20]([CH3:38])[C@H:21]([C:34](OC)=[O:35])[CH2:22][C:23]1[CH:32]=[C:27]2[CH:26]=[CH:25][C:24]=1[F:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[NH2:67][CH2:68][CH2:69][NH2:70]>>[NH2:67][CH2:68][CH2:69][NH:70][C:34]([C@H:21]1[N:20]([CH3:38])[C:19](=[O:39])[C@H:18]([CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:45])[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:17][C:16](=[O:54])[C@@H:15]([NH:55][C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])[CH2:14][C:13]2[CH:31]=[C:28]([CH:29]=[CH:30][C:12]=2[O:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:27]2=[CH:32][C:23](=[C:24]([F:33])[CH:25]=[CH:26]2)[CH2:22]1)=[O:35]
Reactant: COC(=O)[C@@H]1Cc2cc(ccc2F)-c2ccc(OCc3ccccc3)c(c2)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N1C
Reactant: NCCN
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CN1C(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(F)c(c2)C[C@H]1C(=O)NCCN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.46 mg (0.007 mmol) of potassium cyanide are added to a solution of 30 mg (0.036 mmol) of methyl (8S,11S,14S)-17-(benzyloxy)-14-{[(benzyloxy)carbonyl]amino}-11-(3-{[(benzyloxy)-carbonyl]amino}propyl)-5-fluoro-9-methyl-10,13-dioxo -9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaene-8-carboxylate (Example 23O) in 0.6 ml of 1,2-diaminoethane. The mixture is stirred at RT for 16 h. Water is added to the mixture. The precipitated solid is filtered off and dried under high vacuum.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10]CC)=O.O.[NH2:14][NH2:15]>CC(O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH:14][NH2:15])=[O:10]
Reactant: NN
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1O
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a one-liter four-necked flask were added 102.5 g (595 mmol) of ethyl (R,R)-2-hydroxycyclohexanecarboxylate and 400 mL of 2-propanol and stirring was started. Hydrazine monohydrate (44.7 g; 893 mmol) was dropped thereinto at 13° C. taking 30 minutes. After the dropping, the mixture was stirred at 80° C. for 9.5 hours. Followed by, heating was stopped and the mixture was cooled to room temperature to precipitate the crystals. The crystals were filtered and washed with a small amount of 2-propanol. The resulting crystals were dried to give 30.10 g of the title compound. The yield was 32%.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].B([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C#N)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C#N)ccc1-c1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 67.4 %

Procedure:
4-bromo-3-methylbenzonitrile (5 g, 0.026 mol) was suspended in 1,2-dimethoxyethane (100 ml) and treated with 4-boronobenzoic acid (2.4 g, 0.026 mol) followed by a solution of sodium carbonate (11.65 g, 0.11 mmol) in water (100 ml). The mixture was flushed with argon and tetrakis(triphenylphosphine)palladium (0) (0.55 g) was added. The reaction mixture was then heated to reflux with stirring. After 24 h, the 1,2-dimethoxyethane was removed by evaporation under reduced pressure and the aqueous residue was washed with ethyl acetate. The aqueous layer was then acidified to pH 1 and the resultant solid was filtered off and was dried in vacuo to give the title compound as a white solid (4.16 g, 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11](=[O:12])[CH2:10][S:9][C:8]1=S.[N:14]1([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC>C1COCC1.[Hg](Cl)Cl>[N:14]1([C:20]2[CH:21]=[CH:22][C:23]([N:24]=[C:8]3[N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11](=[O:12])[CH2:10][S:9]3)=[CH:25][CH:26]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: O=C1CSC(=S)N1c1ccccn1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CSC(=Nc2ccc(N3CCOCC3)cc2)N1c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
3-(2-pyridyl)-2-thioxo-thiazolidin-4-one (1.1 g, 5.3 mmol, 1.0 equiv), prepared as described in J. Chem. Soc. (1956) 1644, was dissolved in 30 ml THF and charged with 4-morpholin-4-yl aniline (0.94 g, 5.28 mmol, 1.0 equiv) and Et3N (1.47 ml, 10.6 mmol, 2.0 equiv). Mercury (II) chloride (1.4 g, 5.28 mmol, 1.0 equiv) was added in one portion as a solid, and the heterogeneous mixture was stirred at ambient temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was partitioned between EtOAc and saturated NH4Cl. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography (40% to 100% EtOAc in hexanes, silica) afforded 0.83 g (44%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 8.70 (m, 1H), 7.90 (m, 1H), 7.37–7.44 (m, 2H), 3.99 (s, 2H), 3.84 (m, 4H), 3.11 (m, 4H); MS (ESI) m/z=355.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([CH:27]=[CH2:28])[N:20]=2)[C:12]=1[F:29])=[O:8].C1(SC2C=CC=CC=2)C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([CH2:27][CH3:28])[N:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)n1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)n1
Yield: 80.6 %

Procedure:
A solution of 4-chloro-N-({4-chloro-3-[(4-cyano-6-ethenyl-2-pyridinyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (53 mg, 0.119 mmol), diphenylsulfide (1.979 μl, 0.012 mmol) and palladium on carbon (12.64 mg, 0.012 mmol, 10%) in MeOH (8.0 ml) and ethyl acetate (8.00 ml) was reacted under H2 (40 psi) overnight. The reaction mixture was filtered through a pad of celite and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluted with 0-5% 2M NH3 solution of MeOH in CH2Cl2 to give the title compound as a white solid (43 mg, 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.82 (1H, br. s.) 7.17-7.24 (2H, m) 7.09 (2H, d, J=5.4 Hz) 4.68 (2H, d, J=6.0 Hz) 2.61 (2H, q, J=7.5 Hz) 2.39 (3H, s) 1.07 (3H, t). LCMS: m/z 448 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:13]2[CH2:16][N:15](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14]2)[C:10]([CH3:12])=[CH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.Cl.CCOCC.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:13]2[CH2:14][NH:15][CH2:16]2)[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=C(C)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reaction time: 8 h

Procedure:
A mixture of 250 mg (0.64 mmole) of 3-[(1R)-1-(3,5-difluorophenyl)-2-methylprop-2-en-1-yl]-1-(diphenylmethyl)azetidine and 50 mg of 10% Pd/C in 10 mL methanol and 2 mL of 1M HCl in ether was shaken under 40 psi H2. After 8 h, the solution was filtered and the filtrate was concentrated. The residue was triturated with hexane to remove diphenylmethane and the residue was collected to afford the title compound as a white solid; Mass Spectrum m/e=226 (M+1)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[N:13][CH:12]=[N:11][C:10]=3[N:9](CO)[CH:8]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[N:13][CH:12]=[N:11][C:10]=3[NH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(CO)c3ncnc(N4CCOCC4)c23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1cc(-c2c[nH]c3ncnc(N4CCOCC4)c23)cn1
Reaction time: 0.5 h

Procedure:
A solution of [5-(1-methyl-1H-pyrazol-4-yl)-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methanol (C5) (material from the previous step, ≦0.48 mmol) in methanol (5 mL) was brought to a pH of >12 via addition of solid potassium carbonate. The reaction mixture was stirred for 30 minutes, filtered, and concentrated in vacuo. Purification via preparative HPLC (Column: Agella Venusil ASB C18, 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: acetonitrile; Eluent: 13% B) provided the product as a yellow solid. Yield over two steps: 90 mg, 0.32 mmol, 67%. LCMS m/z 285.1 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.96 (br s, 1H), 8.47 (s, 1H), 7.85 (s, 1H), 7.57 (s, 1H), 7.52 (d, J=2.5 Hz, 1H), 3.90 (s, 3H), 3.53-3.59 (m, 4H), 3.45-3.51 (m, 4H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([N:13]1[C:17]([CH2:18][OH:19])=[CH:16][N:15]=[C:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][CH2:11][CH3:12].O>C(#N)C>[CH2:9]([N:13]1[C:17]([CH2:18][OH:19])=[C:16]([Br:1])[N:15]=[C:14]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(CO)cnc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CCCCn1c(-c2ccccc2)nc(Br)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
N-bromo succinimide (3.56 g, 20 mmol) is added to a solution of alcohol 139 (4.60 g, 20 mmol) in 100 ml of anhydrous acetonitrile cooled to 0° C., in portions over 15 minutes. The resulting mixture is stirred at 0° C. for 60 min, water is added to quench the reaction, the acetonitrile is evaporated, and the residue dissolved in 100 ml of ethyl acetate, washed with water and brine, and dried over Na2SO4 The solvent is evaporated and the residue purified by silica gel flash chromatography (hexanes/ethyl acetate, from 6:1 to 3:1) to give 3.15 g of product 140. 1H NMR (300 MHz, CDCl3) δ 7.48–7.56 (2H, m), 7.40–7.47 (3H, m), 4.67 (2H, s), 4.07 (2H, t, J=7.60 Hz), 1.65 (2H, m), 1.24 (2H, m), 0.83 (3H, t, J=7.5 Hz). MS (+VE) m/z 309 (M+), 311 (M+2).
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])=[O:3].[NH3:14]>C(Cl)Cl>[S:2]([C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])(=[O:3])[NH2:14]
Reactant: N
Reactant: COC(=O)c1cscc1S(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cscc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 4-(chlorosulfonyl)thiophene-3-carboxylate (5 g, 20.75 mmol) was dissolved in methylene chloride (50 mL), the solution was cooled to 0° C., and ammonia gas (1.1 g, 64.7 mmol) was introduced during 20 min. After a further 2 h of stirring, the reaction mixture was washed to neutrality with 10% aqueous hydrochloric acid and then with brine. After concentration os the solvent, crude methyl 4-sulfamoylthiophene-3-carboxylate was obtained which was recrystallized from ethanol to yield 2.7 g of methyl 4-sulfamoylthiophene-3-carboxylate. MS: 220 (M−1), 221.9 (M+1), 243.8 (M+Na).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[CH3:15][CH2:16][O:17][C:18]([CH2:20][C:21]([NH2:23])=[O:22])=[O:19].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[NH2:23][C:21]([C:20](=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:8][CH:9]=1)[C:18]([O:17][CH2:16][CH3:15])=[O:19])=[O:22]
Reactant: CCOC(=O)CC(N)=O
Reactant: C[Si](C)(C)COc1ccc(C=O)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(OC[Si](C)(C)C)cc1)C(N)=O
Yield: 37 %

Procedure:
4-(Trimethylsilanylmethoxy)benzaldehyde (obtained in step 1 of Example 1) (3 g, 0.015 mol) and ethyl malonate monoamide (2.1 g, 0.016 mol) in 10 ml of dry toluene in the presence of 0.24 ml of piperidine and 0.14 g of acetic acid are refluxed for 3 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The mixture is cooled and the toluene is removed by distillation. The reaction mixture is taken up in 50 ml of diisopropyl ether. The organic phase is washed 3 times with water, dried over sodium sulfate and filtered, and the solvent is evaporated off under vacuum. The yellow gum obtained is crystallized from a diisopropyl ether/heptane mixture. 1.8 g (yield: 37%) of the derivative of Example 8 are obtained in the form of a pale yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[N:25]1[CH2:29][CH2:28][S:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.Cl>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[N:25]2[CH2:29][CH2:28][S:27][CH2:26]2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1c(N2CCSC2)nc2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1c(N2CCSC2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.8 %

Procedure:
3,5-Difluorophenylacetic acid (0.152 g, 0.88 mmol), 3-Amino-2-thiazolidin-3-yl-3H-quinazolin-4-one (0.146 g, 0.59 mmol) and HATU (0.268 g, 0.71 mmol) were dissolved in dry DMF (2.5 mL), followed by addition of 2,6-lutidine (205 μL, 1.76 mmol). The reaction mixture was stirred at RT for 48 h and then poured into 1 M HCl (20 mL). The formed precipitate was collected by filtration and washed with water and heptane, which after drying gave the title compound (0.180 g, 76%). LC-ESI-HRMS of [M+H]+ shows 403,1047 Da. Calc. 403,104028 Da.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CNCCNC.O>CS(C)=O.C1C=CC=CC=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+].[Cu+].C(OCC)(=O)C>[CH3:10][S:11]([C:5]1[N:4]=[C:3]([CH3:9])[C:2]([NH2:1])=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: Cc1nc(Br)ccc1N
Reactant: CS(=O)[O-]
Agent: [Cu+]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1nc(S(C)(=O)=O)ccc1N
Temperature: 150 °C
Yield: 50.2 %

Procedure:
A mixture of 3-amino-6-bromo-2-methylpyridine (ECA International Corporation, Palatine, Ill., USA; 2.0 g, 10.7 mmol), sodium methanesulfinate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 5.13 g, 42.8 mmol), copper trifluoromethanesulfonate benzene complex (598 mg, 1.07 mmol), and N,N′-dimethylethylenediamine (115 μL, 1.07 mmol) in dimethylsulfoxide (15 mL) was heated at 150° C. for 4 h. The mixture was cooled and water and ethyl acetate were added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed twice with water, and then concentrated to approximately 5 mL. This gave a precipitate which was filtered off, washed with a small amount of ethyl acetate and air dried to give 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine (1 g, 50%) as a brown powder. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.05 (s, 3H), 6.04 (br s, 2H), 6.98 (d, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.2 Hz).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:16]1[S:15][C:14]2[CH2:13][C:12]3[C:8]([C:5]4[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][NH:10][C:11]=3[C:18]=2[CH:17]=1
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cn1
Temperature: 80 °C
Yield: 95 %

Procedure:
6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.16 g, 0.5 mmol) was added with a solution of bromine in glacial acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated at 80° C. for 12 hr. The solution was cooled to room temperature and poured into ice water. The resultant precipitate was filtered, washed with water to provide the corresponding 2-Bromo-6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.18 g, 0.48 mmol) as yellow solid in 95% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2SC=C(C(OC)=O)N=2)[CH2:18][CH2:17]1)=[O:13].ClCC1[O:35][CH:36]=[CH:37][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[O:35][CH:36]=[CH:37][C:38]=2[C:39]([O:41][CH3:42])=[O:40])[CH2:18][CH2:17]1)=[O:13]
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Reactant: COC(=O)c1ccoc1CCl
Product: COC(=O)c1ccoc1CN1CCC(CNC(=O)c2n[nH]c3ccc(OC)cc23)CC1

Procedure:
Methyl 2-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}furan-3-carboxylate 14 was prepared, according to the procedure described for compound 7, using methyl 2-(chloromethyl)furan-3-carboxylate. Yield: 120 mg, 13%.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:36])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.I[CH3:38].[H-].[Na+]>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:36][CH3:38])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
tert-Butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate (0.056 g, 0.114 mmol), iodomethane (0.00858 mL, 0.137 mmol) and sodium hydride (0.00915 g, 0.229 mmol) were added to DMF (1 mL) at ambient temperature and stirred for 2 hours. The reaction was concentrated and the residue was purified on Silica gel using methanol (containing 6% NH4OH) and DCM, to yield 39 mg of the desired product (67% pure). MS ESI (+) m/z 504 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH3:9])[CH2:5][N:6]=[N+]=[N-].[ClH:11]>O1CCCC1.[Pd]>[ClH:11].[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH3:9])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](C)CN=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)CN

Procedure:
2.7 g of 3-azido-2(R)-methylpropionic acid methyl ester are hydrogenated in the presence of 1.4 g of 10% Pd/C in 50 ml of tetrahydrofuran for 4 hours at room temperature at pH 6.0 (pH-stat; 2N hydrochloric acid). The reaction mixture is filtered and concentrated by evaporation. The title compound is obtained by crystallisation from isopropanol/diethyl ether: 1H NMR (DMSO-d6), δ(ppm)=7.95(3H, bs), 3.65(3H, s), 3.12-2.78 (3H, m), 1.15 (3H, d); m.p. 122°-125° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:6]=1[C:7](=[O:20])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:14][CH:15]=1
Reactant: COCOc1ccc(C=CC(=O)c2ccc(OCOC)cc2OCOC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2ccc(OCOC)cc2OCOC)cc1
Reaction time: 2 h

Procedure:
Then, a suspension of 2.52 g of 5% palladium/carbon in 50 ml of ethyl acetate was hydrogenated for 2 hours, and a solution of 5.11 g of 2',4,4'-tris(methoxymethoxy)chalcone in 50 ml of ethyl acetate was added to the suspension and hydrogenation was carried out. After the reaction, the palladium/carbon was removed by filtration and the filtrate was concentrated under a reduced pressure to obtain 1-[2,4-bis(methoxymethoxy)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone.