Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(C)ccc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A mixture of (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.59 g, 1.77 mmol) in tetrahydrofuran (13.3 mL) and water (4.4 mL) was treated with lithium hydroxide monohydrate (89 mg, 2.13 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with water (75 mL), acidified with a 3N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.51 g, 90%) as an off-white solid: HR-ES-MS m/z calculated for C17H20NO4F [M+H]+ 322.1449, observed 322.1447; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (d, J=6.4 Hz, 3H), 0.90 (d, J=6.4 Hz, 3H), 1.44 (br. s., 1H), 1.51-1.66 (m, 1H), 1.66-1.84 (m, 1H), 2.29 (s, 3H), 4.13 (d, J=18.1 Hz, 1H), 4.25 (d, J=18.1 Hz, 1H), 4.60 (dd, J=11.3, 4.1 Hz, 1H), 4.86 (s, 1H), 7.09-7.19 (m, 1H), 7.25-7.35 (m, 2H), 12.92 (br. s., 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([C:47]([F:49])([F:50])[F:48])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1c(F)cccc1C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-(trifluoromethyl)phenyl)boronic acid gave 278. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.85-7.69 (m, 4H), 7.47 (s, 2H), 5.03-4.74 (m, 2H), 4.00-3.86 (m, 2H), 3.74 (s, 3H), 2.13 (ddt, J=14.4, 6.1, 2.8 Hz, 1H), 2.01-1.61 (m, 3H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [CH2:1]([N:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](OC)([O:24]C)[C:20]([F:23])([F:22])[F:21])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)C(O)=O.C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:28]([N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[CH:15][CH:16]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCN(CCCCCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCN(CCCCCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Yield: 78.2 %

Procedure:
N-Hexyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecylamine (353 mg, 0.63 mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4-(4,4,4-trifluoro-3-oxobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester . The residue was chromatographed on silica gel (dichloromethane/methanol 98:2 to 94:6) to afford the title compound (253 mg, 78%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20]N(CCN(C)C)C.[Li]CCCC.CI>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:20])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)CCN(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g, 12.6 mmol, 1.0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) in THF (120 mL), n-BuLi (7.5 mL, 18.9 mmol, 1.5 eq) was added at −78° C. After 3 min, CH3I (3.7 mL, 59.2 mmol, 4.7 eq) was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH4Cl (10 mL) at −78° C. EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90% in yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][C:39]([N:41]([CH2:43][CH3:44])[CH3:42])=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:37][CH2:38][C:39](=[O:40])[N:41]([CH2:43][CH3:44])[CH3:42])=[O:25]
Reactant: CCN(C)C(=O)CN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: CCN(C)C(=O)CNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-N-methyl-acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[OH:22])=[O:6]
Reactant: O=C(O)c1ccncc1Br
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1Br
Temperature: 80 °C
Yield: 23.7 %

Procedure:
A mixture of 0.69 g of 3-bromo isonicotinic acid, 0.60 g of 2-amino-4-(trifluoromethyl)phenol, 1.00 g of WSC and 6 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then concentrated. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a mixture solvent of ethyl acetate and hexane to give 0.29 g of 3-bromo-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[CH:18]=[N:17]1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH2:15][C:14]2[CH:26]=[CH:27][CH:28]=[C:12]([F:11])[CH:13]=2)[N:17]=[CH:18]3)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: Nc1ncnc(Cl)c1C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc(Nc2ccc3c(cnn3Cc3cccc(F)c3)c2)c1C=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-amino-6-chloro-pyrimidine-5-carbaldehyde (95.5 mg, 0.61 mmol) and 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine (147 mg, 0.61 mmol) in DMSO (1.5 mL) was added diisopropylethylamine (DIEA, 79 mg, 0.61 mmol). The mixture was stirred at 100° C. for 2 h, cooled to room temperature, then partitioned between ethyl acetate and H2O. The combined ethyl acetate extracts were dried over Na2SO4 and evaporated to afford a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[CH3:26][N:27]1[C:31]([S:32][CH2:1][O:2][C:3](=[O:6])[CH3:4])=[N:30][N:29]=[N:28]1
Reactant: Cn1nnnc1S
Reactant: COC(=O)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCSc1nnnn1C
Reaction time: 3 h

Procedure:
After glycolic acid methyl ester (300 mg, 3.33 mmol), triphenylphosphine (1050 mg, 4.00 mmol), 1-methyl-5-mercapto-1H-tetrazole (465 mg, 4.00 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (2.10 ml, 4.00 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for three hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using ethyl acetate (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 70% ethyl acetate-hexane solution) to give acetic acid (1-methyl-1H-tetrazole-5-ylsulfanyl)methyl ester containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 610 mg of a colorless oily substance. Measurement of 1H-NMR showed that 406 mg of acetic acid (1-methyl-1H-tetrazole-5-ylsulfanyl)methyl ester (yield: 65%/glycolic acid methyl ester), and 204 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][C:17](=O)[CH3:18])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].BrCC[CH2:29][CH2:30][CH2:31][CH2:32][Cl:33]>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][CH2:17][CH2:18][CH2:29][CH2:30][CH2:31][CH2:32][Cl:33])([CH3:3])[CH3:2]
Reactant: CC(=O)SCC(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: ClCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CSCCCCCCCl
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a mixture of 29.3 g of N-(2,6-diisopropylphenyl)-2-(acetylthio)acetamide and 240 ml of ethanol was added dropwise 27 ml of a 30% aqueous sodium hydroxide solution at 0° C. in an argon atmosphere. After stirring for 30 minutes, 20.0 g of 1-bromo-6-chlorohexane was added thereto, followed by stirring at room temperature for 4 hours. To the reaction mixture was added 50 ml of water to yield 36.0 g of N-(2,6-diisopropylphenyl)-2-(6-chlorohexylthio)acetamide as colorless needle crystals having a melting point (m.p.) of 86.5° to 87.5° C.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:34])[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1.[Cl:35][C:36]1[N:41]=[C:40]([Cl:42])[C:39]([CH2:43]I)=[CH:38][N:37]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:34])[CH:19]([C:20]1[CH:21]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=1)[CH2:43][C:39]1[C:40]([Cl:42])=[N:41][C:36]([Cl:35])=[N:37][CH:38]=1
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 10 minutes, a solution of 3,5-bis-trifluoromethylphenylacetic acid methyl ester (2.20 g, 7.7 mmol) (from Example 8a supra) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 10 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 2 hours then slowly allowed to warm up to −20° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 2-(3,5-bis-trifluoromethyl-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester as a colorless oil. (Yield 1.71 g, 76.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)C(CCC(=O)O)(Cc2ccccc2Cl)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Methylbenzaldehyde (3.00 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.20 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is collected and air-dried, yield 7.4 g., m.p. 120°-147°C. Recrystallization from methylcyclohexane, followed by recrystallization from n-butyl chloride, yields a white solid with m.p. 166°-168.5°C.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:42])[NH2:26])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Yield: 29 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 29% of theory, C26H26N10O (494.6); EKA mass spectrum: (M+H)+=495.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].Cl[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Reactant: ClC1CCOCC1
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OC1CCOCC1

Procedure:
Similar procedure as described in example 328 was used, starting from 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and 4-chloro-tetrahydropyran to give [1-Isopropoxy-7-methoxy-6-(tetrahydro-pyran-4-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 413(MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:7]=1.[C:28]1([CH:35]=[CH:34][CH:33]=[C:31]([OH:32])[CH:30]=1)[OH:29].Cl>C1(C)C=CC=CC=1>[OH:29][C:28]1[CH:30]=[C:31]([OH:32])[CH:33]=[CH:34][C:35]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:7]=1
Reactant: Oc1cccc(O)c1
Reactant: COc1ccc(-c2nc(Cl)nc(-c3ccc(OC)cc3)n2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reaction time: 6 h

Procedure:
10.3 g (0.077 mol) of aluminium chloride are added at 5 C. to a mixture of 23.0 g (0.07 mol) of 2-chloro-4,6-bis(4-methoxyphenyl)-1,3,5-triazine of the formula (108a) and 8.5 g (0.077 mol) of resorcinol in 150 ml of toluene. The temperature is allowed to rise to 20 C., and the mixture is then heated at 50 C. for 6 hours and at reflux for 24 hours. The cooled mixture is poured into 150 ml of 12% hydrogen chloride solution, and the crude product is filtered, washed neutral with water and then washed with methanol and dried to give a dark yellow product of the formula ##STR22##
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18](O)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=1.[OH-].[Na+]>O>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:18]3[C:13]([N:12]=2)=[N:14][C:15]([CH3:20])=[CH:16][CH:17]=3)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Cc1ccc(O)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2oc(-c3cc(Br)cnc3N)nc2n1
Temperature: 200 °C
Reaction time: 5 h
Yield: 35.6 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-methyl-pyridin-3-ol (1.4 g) and polyphosphoric acid (10 g) was stirred at 200° C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The reaction mixture was extracted with dichloromethane/acetonitrile, the organic phase was washed with water, a saturated aqueous solution of brine, dried over magnesium sulfate and concentrated to afford the crude product 5-bromo-3-(5-methyloxazolo[4,5-b]pyridin-2-yl)pyridin-2-amine (0.500 g) as a solid. NMR Spectrum: (DMSOd6) 2.60 (s, 3H), 7.35 (d, 1H), 7.85 (bs, 2H), 8.10 (d, 1H), 8.35 (d, 1H), 8.37 (d, 1H); Mass spectrum: M+H+ 304-306.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)(O)=O.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([O:11][C:6]2[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:1][NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:5]=2[CH3:20])=[CH:13][CH:14]=1)#[N:17]
Reactant: Cc1ncc(C(=O)O)c(C)c1Oc1ccc(C#N)cc1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(C)c1Oc1ccc(C#N)cc1
Yield: 45.1 %

Procedure:
The reductive amination of 4-(5-carboxy-2,4-dimethyl-pyridin-3-yloxy)-benzonitrile (189 mg, 0.75 mmol) and 4-aminobenzonitrile (400 mg, 3.38 mmol), as described in Example 21, gave 4-{[3-(4-cyano-phenoxy)-2,4-dimethyl-pyridin-5-ylmethyl]-amino}-benzonitrile (91) (120 mg, 45% yield) as a brown oil.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>C(#N)C>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8]
Reactant: CCOC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: Cl
Solvent: CC#N
Solvent: C1CCNC1
Product: CCOC(=O)c1cccc(NC(=O)C(CS)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Ethyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]benzoate (compound of Example 68-(a)-[1]) (2.0 g) is dissolved in a 80% aqueous acetonitrile, and thereto is added pyrrolidine (0.5 g), and the mixture is stirred at room temperature for 30 minutes. The mixture is adjusted to pH 5.0 with 10% hydrochloric acid, and acetonitrile is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (50 ml). The extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure. The aqueous solution is extracted with ethyl acetate (50 ml), and the extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give the title compound (0.5 g) as an oily substance.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:30][CH2:31][CH2:32][CH2:33][N:34]=2)=[CH:21][CH:20]=1)[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C.[H][H].CO>O1CCOCC1.[Pd]>[NH2:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:34][CH2:33][CH2:32][CH2:31][N:30]=2)=[CH:23][CH:24]=1)[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)C(=O)O
Reaction time: 2 h

Procedure:
100 mg (0.2 mmol) of (2S)-2-benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid (step e) were dissolved in 15 ml of dioxane, treated with 0.012 ml of glacial acetic acid and hydrogenated at room temperature under 1 bar of hydrogen over palladium/charcoal (5%). After 2 h, 15 ml of methanol were added and the mixture was hydrogenated at room temperature under 1 bar of hydrogen for further 5 h. It was then filtered and the solvent was evaporated in vacuo. Yield: 67.4 mg (93%).