Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([NH2:14])[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[O:16])=[O:8])=[CH:4][N:3]=[CH:2]1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[OH-].[Na+].C(Cl)Cl>[NH:1]1[C:5]([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([NH:14][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[O:16])=[O:8])=[CH:4][N:3]=[CH:2]1
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cc2cnc[nH]2)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](NCc2ccccc2)CN1C(=O)Cc1cnc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A flask was charged with (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (150 mg, 0.302 mmol), benzaldehyde (0.031 mL, 0.30 mmol), methylene chloride (5 mL), acetic acid (0.140 mL, 2.45 mmol) and sodium triacetoxyborohydride (22 mg, 0.45 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then diluted with 2N sodium hydroxide (10 mL). The dilution was extracted with ethyl acetate (20 mL) and the extract was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 173, (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (47 mg, 0.091 mmol, 30%), as an off-white solid. 1H-NMR (400 MHz, DMSO-D6): 11.94 (s, 1H), 10.09 (s, 1H), 7.60 (d, 2H), 7.34-7.28 (m, 4H), 7.25-7.17 (m, 3H), 7.03-6.96 (m, 6H), 4.48 (t, 1H), 3.60-3.32 (m, 7H), 2.12-1.99 (m, 2H). MS (EI) for C29H28FN5O3. found 513.9 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=2)[N:4]([CH3:19])[CH:3]=1.[O:20]=[C:21]1[NH:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH3:30])=[O:28])[CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[CH3:19][N:4]1[C:5]2=[N:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]2[C:2]([N:26]2[CH2:25][CH2:24][N:23]([C:27]([O:29][CH3:30])=[O:28])[CH2:22][C:21]2=[O:20])=[CH:3]1
Reactant: Cn1cc(Br)c2ccc(OCc3ccccn3)nc21
Reactant: COC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)N1CCN(c2cn(C)c3nc(OCc4ccccn4)ccc23)C(=O)C1
Temperature: 100 °C
Yield: 80.3 %

Procedure:
To a solution of 3-bromo-1-methyl-6-(2-pyridylmethoxy)pyrrolo[2,3-b]pyridine (0.5 g, 1.57 mmol) in 1,4-dioxane (10 mL) is added methyl 3-oxopiperazine-1-carboxylate (0.271 g, 1.88 mmol) and potassium phosphate (0.467 g, 2.20 mmol). The mixture is degassed with nitrogen for 15 minutes, then copper(I) iodide (0.060 g, 0.31 mmol) and N,N′-dimethylethylenediamine (0.055 g, 0.63 mmol) are added. The reaction vessel is sealed and heated at 100° C. for 16 h. The reaction is cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue is purified by column chromatography on neutral alumina, eluting with 1% MeOH in DCM. The resultant product is triturated with Et2O/pentane (1:1) to afford the title compound (0.5 g, 1.26 mmol) as an off white solid. MS (m/z): 396 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 3.66 (s, 3H), 3.68 (s, 3H), 3.75 (m, 4H), 4.14 (s, 2H), 5.49 (s, 2H), 6.66 (d, 1H), 7.30-7.33 (m, 2H), 7.50 (d, 1H), 7.77-7.82 (m, 2H), 8.56 (d, 1H).
Reaction SMILES: C[N:2]([C:4]1[CH:9]=CC=CN=1)C.[CH3:10][CH2:11][S:12]([C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[C:16](C1NC=CC=1)=[O:17])=O>C1(C)C=CC=CC=1>[CH:4]1[N:2]2[C:11]([S:12][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]2=[O:17])=[CH:10][CH:9]=1
Reactant: CN(C)c1ccccn1
Reactant: CCS(=O)c1ccccc1C(=O)c1ccc[nH]1
Solvent: Cc1ccccc1
Product: O=c1c2ccccc2sc2cccn12
Reaction time: 29 h
Yield: 54.7 %

Procedure:
Dimethylaminopyridine (0.123 g, 1 mmol, 0.1 eq), 2-(2-ethylsulfinyl)benzoyl pyrrole (2.5 g, 10.1 mmol) and toluene (115 mL) are combined and refluxed with stirring in a flask covered with foil (to exclude light) for 29 hours, at which time the solvent is removed, in vacuo. The resulting crude solid is chromatographed to give 110 mg of comprising pyrrolo(2,1-b)-(1,3)benzothiazin-9-one (20 percent), 514 mg of pyrrolo(1,2-b)-(1,2)benzo-thiazin-10-one (46 percent) and 1.11 g of unreacted starting material. A small amount of 1H, 9H-(1)benzothiopyrano(3,2-b)pyrrol-9-one is detected by thin-layer chromatography but was not isolated. The pyrrolo(1,2-b)-(1,2)benzothiazin-10-one is recrystallized with EtOAc and hexanes to give an analytically pure yellow-orange solid (mp 100-102° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:17].C([O-])(O)=O.[Na+].Cl[CH2:24][C:25](Cl)=[O:26].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C.CCOC(C)=O>[C:11]1([S:8]([C:6]2[CH:5]=[CH:4][C:3]3[O:17][CH2:24][C:25](=[O:26])[NH:1][C:2]=3[CH:7]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(S(=O)(=O)c2ccccc2)ccc1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(S(=O)(=O)c3ccccc3)cc2N1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
2-Amino-4-benzenesulfonyl-phenol (2.064 g, 8.2 mmol) was dissolved in 15 mL of methyl ethyl ketone, and NaHCO3 (1.39 g, 9.1 mmol) was added to this solution. The reaction mixture was cooled to 0° C., and 2-chloroacetyl chloride (0.215 mL, 9.0 mmol) was added dropwise while stirring. The reaction mixture was stirred for 2 hours, after which K2CO3 (1.37 g, 9.95 mmol) was added, and the reaction was brought to reflux for three hours. The reaction mixture was cooled and 150 mL of EtOAc was added. The organic layer was washed three times with 50 ml water, once with 50 mL saturated brine, dried (Na2SO4) and concentrated in vacuo to yield a crude solid, which was purified by flash chromatography (10-30% EtOAc in hexanes), to afford 6-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one (2.176 g, 7.52 mmol, 92%). MS: 290 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:40]1[CH:41]=[CH:42][C:37]([CH2:36][NH:35][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:38][CH:39]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (15.4 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (30 μL) was added followed by 4-aminomethylpyridine (14 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.8 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 19 h then eluted directly on silica gel column (2-10%MeOH in CH2Cl2) to yield 8.9 mg of the title compound. 1H NMR (500 MHz, CDCl3,partial): δ 8.56 (m, 2H); 8.46 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.96 (s, 1H); 7.81 (d, J=7.9 Hz, 1H); 7.71 (d, J=7.8 Hz, 1H); 7.63 (d, J=7.8 Hz, 1H); 7.47 (t, J=7.7 Hz, 1H); 7.24 (d, J=5.9 Hz, 1H); 6.79 (d, J=5.5 Hz, 1H); 6.64 (br s, 1H); 5.77 (br s, 1H); 5.5.24 (br s, 1H); 4.65 (m, 2H); 1.66 (d, J=7.1 Hz, 3H). Mass Spectrum (ESI): m/e 450.2 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]2=[O:17])=[C:5]1[C:27]([O:29]C)=[O:28])[CH:2]=[CH2:3].C[N+]1([O-])CC[O:35]CC1.O>CC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13](=[O:14])[N:4]3[CH2:1][CH:2]([CH2:3][OH:35])[O:29][C:27](=[O:28])[C:5]3=2)[C:10]1=[O:17]
Reactant: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.20 g, 0.46 mmol), N-methylmorpholine N-oxide (67 mg, 0.58 mmol), water (0.2 mL), and osmium tetroxide (0.75 mL, 0.08 M in t-butanol) in acetone (1 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ncn(-c2ccccn2)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2ncn(-c3ccccn3)n2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2-(3-Bromo-1H-1,2,4-triazol-1-yl)pyridine (0.25 g, 1.12 mmol) and 3-chlorophenylboronic acid (0.35 g, 2.23 mmol) were dissolved in toluene (20 mL) and methanol (2 mL), then deoxygenated via argon bubbling for 10 min. Potassium carbonate (0.23 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium (129 mg, 0.11 mmol) were added to this stirred solution. The reaction container was fitted with a reflux condenser and stirred at 90° C. for 16 h, after which time it was cooled to ambient temperature and poured into a separatory funnel containing EtOAc (100 mL). The EtOAc solution was washed with H2O (2×100 mL), then brine (100 mL) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was chromatographed on silica gel eluting with hexanes:EtOAc (8:2) to afford 2-[3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl]pyridine as a white powder which was dissolved in dichloromethane (10 mL) and precipitated as the hydrochloride salt (M.p.=125–128° C.) upon treatment with 1M HCl in diethyl ether (1 mL).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]([NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1)=[O:16].O>N1C=CC=CC=1>[CH:15]([NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1)=[O:16]
Reactant: N[C@H]1CC[C@H](NC=O)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: c1ccncc1
Product: O=CN[C@H]1CC[C@H](Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3-nitrobenzotrifluoride (900 mg) in pyridine (9 mL) was added trans-4-formamidocyclohexylamine (734 mg). The mixture was stirred at 100° C. under nitrogen atmosphere for 5 hours. After cooling to room temperature, water was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 4-[(trans-4-formamidocyclohexyl)amino]-3-nitrobenzotrifluoride (1.24 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=O)=[C:16]2[CH3:26])=[CH:11][C:10]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].CO>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:29][OH:30])=[C:16]2[CH3:26])=[CH:11][C:10]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C=NO)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a stirred solution of 1-(4-benzyloxy-3-fluorophenyl)-2-methyl-1H-indole-3-carbaldehyde (0.81 g, 2.3 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol) and methanol (25 mL) was added pyridine (1 mL). The reaction mixture was heated to reflux and held for 30 min. The mixture was cooled, the methanol removed by evaporation and the residue taken up in ethyl acetate/water. The product was extracted into ethyl acetate (2×50 mL), the ethyl acetate washed with water and brine and dried over MgSO4. The solvent was evaporated, and the crude product was purified by silica gel chromatography (25% ethyl acetate-hexanes) to provide a white solid (0.7 gr, 83%): mp 167-168° C.; 1H NMR (DMSO-d6): δ 2.32 (3H, s), 5.29 (2H, s), 6.99-7.01 (1H, m), 7.10-7.17 (2H, m), 7.25-7.28 (1H, m), 7.37-7.42 (1H, m), 7.43-7.49 (3H, m), 7.49-7.54 (2H, m), 8.01-8.04 (1H, m), 8.41 (1H, s), 10.67 (1H, s); MS m/z (M+H)+ 375: Anal. for C23H19FN2O2: Calc'd: C, 73.78; H, 5.11; N, 7.48. Found: C, 73.53; H, 5.06; N, 7.32
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1.C1COCC1.[I-].[K+].[CH3:25][NH:26][CH3:27]>O>[CH3:25][N:26]([CH3:27])[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1
Reactant: CNC
Reactant: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
1-(2-Chloro-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (664 mg, 2.59 mmol) was dissolved in a 2M solution of dimethyl amine in THF (15.32 mL, 30.6 mmol) and stirred for 48 hrs at room temperature. A scoop of potassium iodide was added to the reaction flask and the mixture stirred at 75° C. for 48 hrs. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (519 mg, 76%). 1H NMR (300 MHz, CDCl3): δ 7.79 (d, 2H), 4.35 (t, 2H), 2.95 (t, 2H), 2.37 (s, 6H), 1.32 (s, 12H).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:17][O:16][CH2:15][CH:13]1[CH2:12][N:11]2[C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=[C:10]2[C:9](=[O:8])[CH2:14]1
Reactant: COCc1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCC1CC(=O)c2nc(C)c(C)n2C1

Procedure:
19.2 g of 8-benzyloxy-6-methoxymethyl-2,3-dimethylimidazo[1,2-a]pyridine, dissolved in 100 ml of methanol, are treated with 1.9 g of palladium (10% strength on activated carbon, Merck) and hydrogenated with hydrogen at 80° C. using a pressure of 50 bar. After absorption of hydrogen is complete, the catalyst is filtered off, washed with methanol and methylene chloride and the combined filtrate is concentrated to dryness in vacuo. After purification on silica gel (eluent: methylene chloride/methanol=13/1), 7.6 g of the title compound of melting point 103–104° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=2)=[CH:14][CH:15]=1)=O)C.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27].O>C1(C)C=CC=CC=1>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=4)=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(OC)cc(OC)c4)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) and 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by column chromatography) (78 mg, 0.36 mmol, 1.2 equiv) in toluene (2 mL). The reaction mixture was stirred for 1 h at rt, heated to reflux, stirred for 3 h, allowed to cool, poured onto EtOAc and H2O, and filtered through a pad of celite. The filtrate was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by reverse-phase preparative HPLC to afford 54 mg of the title compound as a pale yellow solid. Title compound: ESI-MS: 513.2 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[H-].[Na+]>N1C=CC=CC=1>[CH2:10]([O:22][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 29.4 g (0.157 mole) of dodecanol and 500 ml of pyridine is flushed with nitrogen and stirred at room temperature after which 7.55 g (0.314 mole) of sodium hydride is added. The mixture is heated to 100° C for 20 hours, then refluxed 1 hour after which 2.0 g of cuprous chloride is added. The mixture is refluxed with stirring under nitrogen for 20 hours, then poured into an ice-water-hydrochloric acid mixture with stirring and filtered. The resulting oily precipitate is extracted into ether, washed with 5% hydrochloric acid solution, water and salt water, dried over sodium sulfate, filtered, and evaporated on a steam bath replacing the ether with hexane. The solid obtained is recrystallized from methanol to give 5-dodecyloxy-2-furoic acid, M.P. 122°-123° C.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=1>[Cu]I.CS(C)=O>[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)=[CH:34][CH:35]=1)[CH3:40]
Reactant: CCc1ccc(Br)cc1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CCc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-bromo-4-ethylbenzene (596 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) and concentrated to give the title compound (117 mg) as an off-white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([CH:21]3[CH2:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[C:23](=[O:32])[CH2:22]3)=O)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:7]1([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][C@@H:21]3[CH2:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[C@H:23]([OH:32])[CH2:22]3)[CH2:17][CH2:18]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O[C@@H]1C[C@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
0.15 g (3.8 mmol) of LiAlH4 were added to a solution of 0.33 g (0.95 mmol) of (±)-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in 15 mL of dry Et2O at 0° C. and the resulting mixture was heated to reflux overnight. After cooling, the reaction was quenched by the careful addition of 0.5 mL of 2 N NaOH, the suspension was stirred 10 min and then filtered by suction on a Celite pad washing with Et2O. The solvent was removed in vacuo, yielding 0.25 g of the title compound. m.p.=48-50° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3].CCN(C(C)C)C(C)C.[F:37][CH:38]([F:41])[CH2:39][NH2:40]>O1CCCC1>[F:37][CH:38]([F:41])[CH2:39][NH:40][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)Cl)cc3)cc2C1
Reactant: NCC(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)NCC(F)F)cc3)cc2C1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-[4-(chlorocarbonyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.0 g, 2.6 mmol) and DIPEA (2.2 mL, 13 mmol) in tetrahydrofuran (10 mL) was added 2,2-difluoroethylamine (0.21 g, 2.6 mmol). The reaction mixture was stirred for 2 h and then partitioned between ethyl acetate (20 mL) and 1M hydrochloric acid (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography on silica (30% ethyl acetate in hexanes) provided 1,1-dimethylethyl 7-(4-{[(2,2-difluoroethyl)amino]carbonyl}phenyl)-2,3-dihydro-1,4-benzoxazepine-4 (5H)-carboxylate (0.95 g, 85% yield). MS (EI) for C23H26F2N2O4: 433 (MH1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.CC1C=C(NC2C3C(=CC=CC=3F)N=CN=2)C=CC=1O>>[Cl:21][C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Product: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Yield: 85 %

Procedure:
4-Chloro-5-fluoroquinazoline was reacted with 4-amino-2-chlorophenol using an analogous process to that described in Example 3 for the preparation of 2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol, to give 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol in 85% yield; NMR spectrum (DMSO-d6) 6.97 (d, 1H), 7.38 (dd, 1H), 7.42 (dd, 1H), 7.59 (d, 1H), 7.73 (d, 1H), 7.81 (dd, 1H), 8.51 (s, 1H), 9.03 (d, 1H), 10.07 (bs, 1H); Mass spectrum MH+ 290.