Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C1COCC1>[C:16]1([C@H:22]([NH:24][CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](NC1CCCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
A mixture of 4-oxoazepane-1-carboxylic acid tert-butyl ester (90 g, 422 mmol) and (R)-1-phenylethanamine (56.4 g, 465 mmol) in THF (1000 mL) was stirred at rt for 15 min and STAB (107.4 g, 510 mmol) was added. The mixture was cooled to 0° C. in an ice bath, then acetic acid (26.7 g, 450 mmol) was added. The mixture was stirred overnight at rt then concentrated in vacuo, residue dissolved in DCM (800 mL) and washed with sat. NaHCO3 sol. (2×300 mL), dried (Na2SO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (gradient 0% to 3% MeOH in DCM) to give tert-butyl 4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (90 g, 67.0%) as a mixture of two diastereoisomers.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:14][N:15]=1)[CH3:10])=O)(C)(C)C.[ClH:26]>C1COCC1.O1CCOCC1>[ClH:26].[NH2:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:14][N:15]=1)[CH3:10]
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)OCc2ccccc2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(N)c1ncc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of benzyl 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylate (0.55 g, 0.55 mmol) in THF (2 mL) was added 4M HCl in dioxane (0.5 ml). The reaction solution was stirred at room temperature overnight. The solution was concentrated to dryness to afford a colorless oil (0.45 g, 100%). LC-MS: (FA) ES+ 263.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:16]3[CH:9]([CH2:10][C:11](=[O:17])[C:12]=3[C:13]=1[O:14][CH3:15])[NH:8][CH2:7][CH2:6]2.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[C:26]([O:30][C:31](=[O:38])[NH:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.C(OCC)(=O)C.O>[C:26]([O:30][C:31](=[O:38])[NH:32][CH2:33][CH2:34][CH2:35][CH2:36][N:8]1[CH2:7][CH2:6][C:5]2[C:16]3[CH:9]1[CH2:10][C:11](=[O:17])[C:12]=3[C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: COc1cc2c3c(c1OC)C(=O)CC3NCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c3c(c1OC)C(=O)CC3N(CCCCNC(=O)OC(C)(C)C)CC2
Reaction time: 8 h
Yield: 44 %

Procedure:
Over a suspension of 7,8-Dimethoxy-2a,3,4,5-tetrahydro-2H-3-aza-acenaphthylen-1-one (0.950 g, 4.1 mmol), K2CO3 (1.89 g, 13.6 mmol) and NaI (0.061 g, 0.4 mmol) in DMF (20 ml) is slowed added (4-Bromo-butyl)-carbamic acid tert-butyl ester (1.09 g, 4.32 mmol) and the mixture is stirred overnight. Then, water (40 ml) and ethyl acetate (40 ml) are added and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×40 ml). The organic layers are collected and washed with water (3×40 ml). After drying with Na2SO4, filtration and vacuum concentration, a brown oil is obtained, which is purified by silicagel chromatography using a gradient of CH2Cl2/methanol (from 100% to 98% CH2Cl2) to obtain a brown solid (0.730 g, 45% yield)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].CS[C:18](SC)=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[C:20]1=[O:41]>C1(C)C=CC=CC=1>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[C:20](=[O:41])[C:19]=1[C:18]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=2[S:7](=[O:8])(=[O:9])[N:10]=1
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(N2C(=O)c3ccccc3C2=O)C1=O
Solvent: Cc1ccccc1
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N3C(=O)c4ccccc4C3=O)c1=O)N2
Yield: 61.1 %

Procedure:
The product of Example 309G (32.6 mg, 0.13 mmol) and the product of Example 350C (53 mg, 0.13 mmol) were reacted in toluene (3 mL) at 100° C. for 3 hours. The resulting precipitate was collected by filtration and washed with methanol and diethyl ether to give the title compound (45 mg, 61.5%). 1H NMR (300 MHz, DMSO-d6) δ 3.32 (s, 3 H), 4.61 (s, 2 H), 4.70 (s, 2 H), 7.28 (s, 1 H), 7.42 (m, 1 H), 7.70 (d, J=4.04 Hz, 2 H), 8.06 (m, 2 H), 8.11 (m, 2 H), 8.22 (d, J=8.09 Hz, 1 H). MS (ESI−) m/z 565 (M−H)−.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:13]1=[O:36])=O)C1C=CC=CC=1>C(Cl)Cl>[NH2:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:29][CH2:30][CH2:31][C:32]([F:34])([F:33])[F:35])[C:13]1=[O:36]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O)OCc1ccccc1
Solvent: ClCCl
Product: NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
A solution of 3-(benzoxycarbonyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.42 g, 2.87 mmol) in 50 mL of anhydrous methylene chloride was cooled to 0° C. under nitrogen. A stream of anhydrous HBr gas was slowly bubbled through the solution for 1 h. The bubbler was removed and the reaction was warmed to room temperature under nitrogen. After stirring for 1 h, the reaction was concentrated under vacuum and the residue was redissolved in 10 mL of methylene chloride. The crude HBr salt of the product was precipitated from solution using 90 mL of anhydrous ether and collected by filtration. After washing with ether, the HBr salt was dissolved in methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer was extracted with saturated sodium bicarbonate. The combined aqueous layers were then back extracted twice with methylene chloride. The combined organic layers were extracted once with water and dried over sodium sulfate. After concentration under vacuum, 1.06 g (100%) of the product was obtained as a white foam which was carried on without further purification.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:17][C@H:16]([NH:18][C:19](=[O:34])[C:20]([OH:33])([CH3:32])[C:21]([NH:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[O:22])[C:15](=[O:35])[NH:14][C:13]2[CH:36]=[CH:37][CH:38]=[CH:39][C:12]1=2)C1C=CC=CC=1>CO.[Pd]>[OH:33][C:20]([CH3:32])([C:21]([NH:23][CH2:24][C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])=[O:22])[C:19]([NH:18][C@H:16]1[CH2:17][N:11]([CH2:10][CH2:9][OH:8])[C:12]2[CH:39]=[CH:38][CH:37]=[CH:36][C:13]=2[NH:14][C:15]1=[O:35])=[O:34]
Reactant: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CCO)c2ccccc2NC1=O
Reaction time: 72 h

Procedure:
A solution of 26 mg of N-[(S)-1-(2-benzyloxy-ethyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 2.0 ml of methanol was treated with 10 mg of palladium on carbon (10%) and stirred for 3 days under an atmosphere of hydrogen. During this period of time, the catalyst was replaced three times after filtration of the reaction mixture over Dicalit. For the final working-up, the reaction mixture was filtrated over Dicalit and the solvent evaporated under reduced pressure. After separation of mainly unchanged starting material by chromatography on silica gel using a gradient of heptane/ethyl acetate=100/0 to 20/80 as the eluent, 6 mg (29% of theory) of the title compound were obtained as a white foam; MS (m/e): 469 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C(O)(=O)C.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23]>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:27][C:26]2[C:28]([CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=[CH:31][C:25]=2[CH:22]([CH3:24])[CH3:23])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Solvent: CC(=O)O
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=Nc2c(C(C)C)cccc2C(C)C)C(C)=C1C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (30.0 mL) were added dropwise acetic acid (1.0 mmol) and 2,6-diisopropylaniline (10.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,6-diisopropylphenyl)amine (3.85 g, yield 100%).
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].[OH-].[Na+]>COCCOC.O.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>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[C:33]4[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(S(C)(=O)=O)cc3)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 2.1 %

Procedure:
(R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65, 0.15 g, 0.37 mmol), 4-(methylsulfonyl)phenylboronic acid (0.148 g, 0.74 mmol), aqueous sodium hydroxide (240 μL of 3N) and Pd(PPh3)4 (42 mg, 0.037 mmol) were dissolved in 1.2 mL of DME/H2O (5/1, v/v) and a stream of nitrogen was bubbled through the mixture for 2 minutes. The resulting solution was stirred at 90° C. for 18 h. The reaction mixture was diluted with brine, extracted with EtOAc, dried with Na2SO4 then purified by silica gel column chromatography and preparative HPLC to give to give the title compound (3.8 mg). LCMS: 481.2 m/z (M+H)+; ret. Time: 6.19 min (Analytical Method C).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[SH:11][C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:21])[N:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:8]1[C:4]2[CH:3]=[C:2]([S:11][C:12]3[NH:13][C:14]4[C:19]([N:20]=3)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=4)[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: Ic1ccc2c(c1)OCC2
Reactant: Nc1ncnc2nc(S)[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]c(Sc3ccc4c(c3)OCC4)nc12
Temperature: 80 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
To a solution of S2-2 (50 mg, 0.2 mmol) in DMF (2 mL) was added 8-mercaptoadenine (34 mg, 0.2 mmol), Cs2CO3 (99.4 mg, 0.3 mmol) and PdCl2(dppf) (33 mg, 0.02 mmol). The mixture was degassed for 5 minutes with argon and stirred at 80° C. under argon protection for 48 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (CH2Cl2:MeOH, 100:0 to 90:10) to provide S2-3 (25 mg, 44% yield) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[C:9]([CH:19]([CH3:21])[CH3:20])=[N:10][N:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[CH:13][C:12]=12)=[O:5])C.Cl>[OH-].[Na+]>[C:4]([CH2:6][O:7][C:8]1[C:9]([CH:19]([CH3:20])[CH3:21])=[N:10][N:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[CH:13][C:12]=12)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1c(C(C)C)nn2cc(CC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(OCC(=O)O)c(C(C)C)nn2c1
Temperature: 90 °C
Yield: 82.8 %

Procedure:
To 500 mg of the compound prepared in Example 6 were added 20 ml of 2N sodium hydroxide solution, and the mixture was heated for 1 hour in a water bath at 90° C. The reaction mixture was neutrallized with 2N hydrochloric acid to be acidic condition (pH 3) under cooling in an ice bath. The resulting precipitates were collected by filtration and recrystallized from a mixture of benzene and hexane to give 374 mg (83.9%) of the desired product as colorless powder, mp 118°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]1([CH3:19])[C:13]([SH:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:12]1([CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccccc1S
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: Cc1ccccc1Sc1ccc([N+](=O)[O-])cc1Cl
Yield: 31 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-toluenethiol. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give 2-chloro-4-nitrophenyl 2-tolyl sulphide in 31% yield.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:17])=[CH:12][CH:13]=3)[O:8][CH:7]=2)=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)[O:25][CH:26]=1.[I-].[Na+].[OH-].[K+]>O.CS(C)=O>[F:33][C:31]1[CH:30]=[C:29]([C:34]([F:35])([F:36])[F:37])[CH:28]=[C:27]([C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:17][C:11]3[CH:10]=[C:9]4[C:14]([C:15](=[O:16])[C:6]([C:5]5[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][CH:4]=5)=[CH:7][O:8]4)=[CH:13][CH:12]=3)[N:23]=2)[CH:32]=1
Reactant: Fc1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(OCc3coc(-c4cc(F)cc(C(F)(F)F)c4)n3)ccc12
Temperature: 60 °C

Procedure:
4′,7-Dihydroxyisoflavone (101.7 mg, 0.40 mmol), 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazole, prepared as described in Example 1 (111.8 mg, 040 mmol, 1.0 equiv.), sodium iodide (59.6 mg, 0.40 mmol, 1.0 equiv), and potassium hydroxide powder (22.4 mg, 0.4 mmol, 1.0 equiv) were placed in a 25 mL flask equipped with a condenser. To the flask was added dimethylsulfoxide (3 mL) at room temperature under nitrogen. The solution was heated at 60° C. for 1 hour. To the mixture were added water (30 mL) and the whole was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL) and dried with Na2SO4, to give a crude mixture as colorless oil (204.7 mg). The crude mixture was purified by column-chromatography (silica gel=25 g, eluting with hexane/ethyl acetate=7:1) to give crude product (149.3 mg) as colorless crystals. Recrystallization of this crude product gave 7-({2-[5-fluoro-3-(trifluoromethyl)phenyl]-(1,3-oxazol-4-yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4-one as a colorless powder.
Reaction SMILES: C(OC(=O)[CH2:5][O:6][C@H:7]1[CH2:10][C@@H:9]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])=[CH:21][C:20]=3[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]3[N:37]=[CH:38][N:39]=[C:12]23)[CH2:8]1)C.C[Mg]Br.Cl>O1CCCC1>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:9]2[CH2:10][C@@H:7]([O:6][CH2:5][C:7]([OH:6])([CH3:10])[CH3:8])[CH2:8]2)[C:12]2[N:13]([N:37]=[CH:38][N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2ncnn12
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
Ethyl[(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate (0.29 g) was dissolved in tetrahydrofuran (3 mL), methylmagnesium bromide (1.6 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CN[C@@H]1CCc2c(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NCC(=O)O)s2)cc1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.9 %

Procedure:
To (R)-methyl 2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate (100 mg, 0.22 mmol) in ethanol was added 2N NaOH (1.1 mL) and the mixture stirred at room temperature for 12 h. The solvent was evaporated and the residue dissolved in water and acidified with 1N HCl. The resulting solid was filtered and dried to give 60 mg (63%) of (R)-2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid 96 as yellow-green solid. LCMS-ESI (m/z) calculated for C24H23N3O3S: 433.1; found 434.2 [M+H]+, tR=2.61 min.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([OH:27])[CH3:26]>>[CH2:25]([O:27][CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6])[CH3:26]
Reactant: CCO
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC=CC(=O)c1cccnc1

Procedure:
A mixture of 0.10 mole of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one and 0.20 mole of p-toluenesulfonic acid in 150 ml of anhydrous ethanol was refluxed for 10 hours. The solvent was removed and the residue partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate and the solvent removed, giving 3-ethoxy-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].[Na+].[CH3:6][O:7][C:8]1[C:13]([CH2:14]Cl)=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.O>CS(C)=O>[CH3:6][O:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1c(CCl)cccc1Oc1ccccc1C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Powdered potassium cyanide (12.50 g) and sodium iodide (28.80 g) were added to a solution of o-tolyl 2-methoxy-3-chloromethylphenyl ether (47.50 g) in dimethylsulfoxide (100 ml) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water 3 times, dried over magnesium sulfate and then evaporated to give only 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetonitrile (44.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CCOC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)NC2CCOC2)c1
Yield: 72 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(tetrahydrofuran-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (185 mg, 0.44 mmol) in methanol (7.4 mL) and 1N sodium hydroxide aqueous solution (6.6 mL, 6.6 mmol) was heated to reflux for 1 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 1N hydrochloric acid solution to pH=6. The precipitated white solid was collected by filtration and washed with dichloromethane/ether to afford 125 mg of 3,3-dimethyl-2-(3-(tetrahydrofuran-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 70%. LC-MS (M+1)=395.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)cc3)c2CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CO)cc3)c2CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-6-(4-carboxybenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.85 g, 50% purity, 2.06 mmol) in anhydrous THF (40 mL) under nitrogen, add with stirring 1M borane in THF (4.2 mL) at 0° C. Warm to ambient temperature and stir 2-3 h. Quench by the careful addition of water (3 mL), dilute with saturated aqueous NaHCO3, extract three times with ethyl ether, dry over anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (5:1) to provide the title compound as a white solid (485 mg, 54%).