Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:30])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11](=[O:30])[C:10]=1[C:8]#[N:7]
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccc(F)cc1
Yield: 47 %

Procedure:
A solution of Compound 19 (5 g, 12.24 mmol) in 30 mL neat phosphorus oxychloride was heated at 100° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.90 g (47%) of yellow solids. M.P. 206° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 5.52 (s, 2H), 7.12-7.15 (m, 2H), 7.30-7.33 (m, 2H), 7.46 (d, J=8.7 Hz, 1H), 7.64 (dd, J=1.2, 8.7 Hz, 1H), 7.89 (d, J=1.2 Hz, 1H). EIMS m/z 327 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+].Cl>O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2cccc(C(=O)O)c2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cnn1-c1cccc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
The mixture of 3-(5-amino-4-ethoxycarbonylpyrazol-1-yl)benzoic acid (5.9 g) and sodium hydroxide (2.1 g) in water (15 ml) was stirred for 2 hours at 80° C. To the reaction mixture was added water and the mixture was adjusted to pH 3.5 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration washed with water and dried to give 3-(5-amino-4-carboxypyrazol-1-yl)benzoic acid (5.1 g).
Reaction SMILES: [NH2:1][C:2]1([CH2:7][O:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:16]1([CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:8][CH2:7][C:2]2([NH:1][CH2:29][CH2:28][C:27]3[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC1(COC(c2ccccc2)c2ccccc2)CCCC1
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCNC2(COC(c3ccccc3)c3ccccc3)CCCC2)cc1

Procedure:
The title compound was prepared as described in Example 1 using 1-amino-1-diphenylmethoxymethylcyclopentane (see Preparation 4) and 4-methoxyphenethyl bromide. The title compound was obtained as a pale brown oil which was characterised as a hydrate (0.50 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.N[CH:19]1C2C(=CC=CC=2)[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:29][CH2:22][NH:21][C:20](=[O:35])[CH2:19]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2ccccn2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1CCCCCNC(=O)C1

Procedure:
Following General Procedure B above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-8-octanelactam (i.e., 2-oxo-1-azacyclononane prepared as described in General Procedure 5-C), the title compound was prepared as a solid having a melting point of >220° C.
Reaction SMILES: C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1.[C:31](=[O:33])=[O:32]>O1CCCC1>[Br:22][C:23]1[C:24]([C:31]([OH:33])=[O:32])=[C:25]([F:30])[C:26]([F:29])=[CH:27][CH:28]=1
Reactant: O=C=O
Reactant: Fc1ccc(Br)cc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(Br)ccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of 1.6M butyllithium in hexane (60 mL, 96 mmol) was diluted with tetrahydrofuran (180 mL) under an argon atmosphere, and cooled to −78° C. To the solution, were added dropwise 2,2,6,6-tetramethylpiperidine (16.2 g, 116 mmol) and subsequently 4-bromo-1,2-difluorobenzene (15.4 g, 80 mmol), and the mixture was stirred at the same temperature for 2 hours. The solution was carefully poured onto crushed dry ice, and the mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure, and the residue was poured into water. After the solution was washed with diethylether, the aqueous layer was made acidic by the addition of 6N hydrochloric acid, and organic matter was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (10.8 g, 57% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH2:21])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:21][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(S(=O)(=O)N2CCc3cccc(N)c32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCc3cccc(NC(=O)c4ccncc4)c32)cc1
Yield: 82 %

Procedure:
To a stirred mixture of 19 (0.2 g, 0.52 mmol), isonicotinoyl chloride hydrochloride (0.18 g, 1.04 mmol), and cesium carbonate (0.68 g, 2.08 mmol) in acetonitrile (20 ml) was heated to reflux for 16 h. The reaction mixture was quenched with ice water and extracted with CH2Cl2. The combined organic layer was dried over MgSO4 and evaporated to give a residue that was purified by silica gel flash column chromatography (EtOAc:n-hexane :NH3(aq)=3:2:1%) and recrystallized (CH2Cl2/EtOAc) to afford compound 26, yield 82%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[CH3:16][N:17]1[C:21](=[O:22])[C:20]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][C:20]3([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:18][N:17]([CH3:16])[C:21]3=[O:22])[CH2:23][CH2:24]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Yield: 50 %

Procedure:
A mixture of 4.8 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5.6 parts of 3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride, 7.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 4-methyl-2-pentanone. The solid product is filtered off and dried, yielding 4.1 parts (50%) of 8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 186° C.
Reaction SMILES: [NH2:1][C:2]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:17][O:18][C:19]([CH2:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[O:20]>>[CH3:17][O:18][C:19]([CH2:21][CH:22]([CH3:26])[C:23]([NH:1][C:2]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:24])=[O:20]
Reactant: COC(=O)CC(C)C(=O)O
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Product: COC(=O)CC(C)C(=O)NC1(C(=O)OCc2ccccc2)CCCC1

Procedure:
1-[(3-Methoxycarbonyl-2-methylpropanoyl)amino]-1-cyclopentanecarboxylic acid, benzyl ester was prepared as described in Example 3 from 10.96 g (0.050 mol) of 1-amino-1-cyclopentanecarboxylic acid, benzyl ester and 7.31 g (0.050 mol) of 3-methoxycarbonyl-2-methylpropionic acid. Crude di-ester crystallized to give 13.57 g (78%) of an off-white solid, mp: 88°-93°. This was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:16]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[CH3:14])=[CH:23][CH:22]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (138 mg, 0.72 mmole) and 4-aminoacetanilide (1.50 g, 10.0 mmole) is stirred under N2 at 200° C. for 1 h. The resulting product is chromatographed over alumina (8-10% MeOH/CH2Cl2) to give 7-amino-4-(4-acetamidoanilino)pyrido[4,3-d]pyrimidine (110 mg, 52%) as a pale yellow solid. 1H NMR (DMSO) δ 9.94, 9.79 (1H, 1H, 2 brs), 9.31 (1H, s), 8.34 (1H, s), 7.69 (2H, d, J=8.9 Hz), 7.57 (2H, d, J=8.9 Hz), 6.57 (2H, brs), 6.43 (1H, s), 2.05 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[N:9]=1.Br[CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[CH3:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:9]=1
Reactant: CCCC(Br)C(=O)OCC
Reactant: Cc1nc(-c2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
380 g (1.17 mol) of caesium carbonate are added to a solution of 200 g (1.135 mol) of 3-(5-methyl-1,2,4-oxadiazol-3-yl)phenol in 2.5 l of acetonitrile. A solution of 190 ml (1.15 mol) of ethyl 2-bromovalerate in 0.5 l of acetonitrile is subsequently added. The reaction mixture is stirred at room temperature for 24 hours and then filtered, and the filtrate is evaporated, giving ethyl 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoate as a yellowish oil; ESI 305.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1.B.C1COCC1.CO.C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(F)cc1)c1cccc(CSCCc2ccccc2)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(CCNCc2cccc(CSCCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of N-(4-fluorophenethyl)-3-(phenethylthiomethyl)benzamide (0.3 g, 0.76 mmol) in THF (5 mL) was added borane-THF complex (1 M solution in THF, 12 mL, 12 mmol). The reaction mixture was stirred at rt for overnight. To the reaction mixture was added MeOH and 2 mL of TFA, and the resulting mixture was stirred for 3 h. The resulting mixture was concentrated and the residue was diluted with saturated NaHCO3 solution and ethyl acetate. The organic layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography silica gel eluting with 20% ethyl acetate in hexanes, which contained 10% of 2 M ammonia in MeOH to give the desired product (0.18 g, 58%) as a colorless oil. 1H NMR (CDCl3) δ 7.32-7.14 (m, 11H), 7.01-6.95 (m, 2H), 3.84 (s, 2H), 3.72 (s, 2H), 2.91-2.80 (m, 6H), 2.73-2.64 (m, 2H). MS (ESI): 380.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:22]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NC[C@@H](O)CO
Product: Cn1c(=O)c(C(=O)NC[C@@H](O)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 69.4 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.140 mmol) and (2R)-3-amino-1,2-propanediol (0.03 mL, 0.42 mmol) was prepared N-[(2R)-2,3-dihydroxypropyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (39 mg, 68% yield) as a white solid. 1H NMR (DMSO-d 6)δ 10.44 (br s, 1 H), 8.53 (s, 1 H), 8.01 (s, 1 H), 7.40-7.36 (m, 2 H), 7.15-7.10 (m, 2 H), 5.06 (m, 1 H), 4.77 (m, 1 H), 4.16 (s, 2 H), 3.61-3.55 (m, 4 H), 3.39 (m, 1 H), 3.24 (m, 1 H); MS m/z 402 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:16]([Br:17])=[C:15]([N:18](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:14]3[N:35]=[CH:36][C:37]([C:38]4[CH:39]=[N:40][C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].CO.[OH-].[Na+].Cl>O>[NH2:18][C:15]1[N:14]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]4[C:46]([CH:47]=3)=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[C:16]=1[Br:17]
Reactant: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1c(Br)c(C2CCC(C(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
4-{7-[Bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (100 mg, 0.135 mmol) in 2:1 MeOH:H2O (3 mL) was treated with 2N NaOH(aq) (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with 1N hydrochloride solution (2 ml) at 65° C. for 4 h. The reaction mixture was concentrated and purified by prep-LC to afford the title compound (21.8 mg): LC/MS RT=3.57 min. Mass calculated for, M+H 466.08, observed 466.08.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:39]4[CH2:40][CH2:41][CH:36]([O:35][CH3:34])[CH2:37][CH2:38]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COC1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCC(OC)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-methoxy-piperidine. ES-MS m/e (%): 484 (M+H+, 100).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CO.[BH4-].[Na+]>C1COCC1>[OH:1][CH:2]1[C:11]2[CH:10]=[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(O)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Formula 39-1 (740 mg, 2.83 mmol) in THF (5 mL)/MeOH (5 mL) was added sodium borohydride (107 mg, 2.83 mmol) while cooled at 0° C. The solution was stirred for 1 hour and concentrated to volume in vacuo. The residue was diluted with EtOAc (40 mL) and washed with sat'd sodium bicarbonate (2×10 mL) and brine (10 mL). Organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the compound of Formula 39-2 as a solid.
Reaction SMILES: [O:1]([C@H:8]1[CH2:12][CH2:11][C@H:10]([O:13]C2CCCCO2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[O:1]([C@H:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(O[C@H]2CC[C@H](OC3CCCCO3)C2)cc1
Agent: Cl
Solvent: CO
Product: O[C@H]1CC[C@H](Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of (1S,3S)-1-phenoxy-3-tetrahydropyranyloxycyclopentane (2.16 g, 8.20 mmol) in methanol (50 ml) was added 6N aqueous hydrochloric acid (5 ml) and the mixture stirred for 2 h at room temperature. Volatiles were removed under reduced pressure and chromatographic purification of the residue {SiO2, 150 g; hexane/ethyl acetate (3:1 )} provided 1.33 g (91%) of the title compound as a colorless oil: 1H NMR δ7.35-7.20 (m, 2H), 6.98-6.82 (m, 3H), 4.97-4.88 (m, 1H), 4.60-4.50 (m, 1H), 2.32-2.01 (m, 4H), 1.97-1.83 (m, 1H), 1.75-1.40 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([O:18]C)=[O:17])=[CH:10]1.[OH-].[Na+]>CCO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]1
Reactant: COC(=O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of methyl 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (5.41 g) in a mixture of EtOH (108 mL) and THF (54 mL) was added 1 M aqueous NaOH (82 mL) at 0° C., and the mixture was stirred at the same temperature for 2 hr. The mixture was concentrated under reduced pressure and the residue was treated with 1 M HCl (160 mL). The precipitates produced were collected by filtration and dried under reduced pressure at 60° C. to give 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (4.73 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]([NH2:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][C:31]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[NH2:20][C:18]([CH:13]1[N:12]([CH2:11][CH2:10][CH2:9][CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:16][N:15]([CH2:29][CH2:30][C:31]([NH:33][C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:41])=[O:32])[CH2:14]1)=[O:19]
Reactant: NC(=O)C1CNCCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1cccc(C)c1NC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1cccc(C)c1NC(=O)CCN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 3.7 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide, 2.3 parts of 3-chloro-N-(2,6-dimethylphenyl)propanamide, 2.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water-separator. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified on triturating in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.87 parts (70.8%) of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-piperazinepropanamide; mp. 120.9° C. (compound 122)
Reaction SMILES: C[O:2][C:3]([C@H:5]1[S:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:7]([C:17](=[O:30])[CH2:18][NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)=[O:21])[C@H:6]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=[O:4].[OH-].[Na+].CO>O1CCCC1>[C:13]([O:12][C:10]([C@H:8]1[N:7]([C:17](=[O:30])[CH2:18][NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)=[O:21])[C@@H:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[C@H:5]([C:3]([OH:4])=[O:2])[S:9]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@H](C(=O)OC(C)(C)C)S[C@@H](C(=O)O)[C@@H]2c2ccccc2F)c1
Yield: 70.4 %

Procedure:
The process is performed in a similar manner to that described in Example 3, but starting with 0.35 g of tert-butyl (2S,4S,5S)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-(2-fluorophenyl)-2-thiazolidinecarboxylate dissolved in 10 ml of tetrahydrofuran and 6.6 ml of aqueous 0.1N sodium hydroxide solution. 0.24 g of (2S,4S,5R)-2-tert-butoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-(2-fluorophenyl)-5-thiazolidinecarboxylic acid is thus obtained in the form of a white solid melting at 148° C., [α]D25 =-17°±1° (c=0.504; MeOH); 1H NMR (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, 5 in ppm): 1.51 (s, 9H: CH3 of the tert-butyl); 2.25 (s, 3H: ArCH3); 3.76 and 4.04 (broad d and d respectively, J=18 Hz, 1H each: COCH2N); 4.18 (d, J=3.5 Hz, 1H: H at C5 of the ring); 5.70 (s, 1H: H at C2 of the ring); 5.97 (d, J=3.5 Hz, 1H: H at C4 of the ring); 6.73 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.06 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3)); 7.10 to 7.50 (mt, 5H: aromatic H); 8.00 (mt, 1H: aromatic H at 6 (H meta to the F)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
2′-Methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-methylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.10,(1H, t), 7.99,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.56-7.51,(3H, m), 7.22,(2H, d), 7.13,(2H, d), 4.46,(2H, d), 2.56,(3H, s), 2.31,(3H, s), 2.27,(3H, s). LCMS; retention time 3.48 min, MH+ 398.