Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>C(O)C>[CH3:11][N:9]1[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[CH3:17])[CH2:10]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: CC1CCCN1
Solvent: CCO
Product: CC1CCCN1CCC1CN(C)C(=O)c2cccnc2O1
Yield: 35.7 %

Procedure:
To a solution of 3.5 g (0.0145 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one in ethanol (15 ml) was added 2-methyl pyrrolidine (5.0 g, 0.063 mole). The solution was heated to reflux for 3 hours with stirring. The ethanol was removed by rotary evaporation (water aspirator, 80° C.). The residual oil was partitioned between dilute aqueous sodium hydroxide (50 ml) and chloroform (50 ml). The organic layer was saved and the aqueous layer extracted with chloroform (2×30 ml). All the chloroform layers were combined, dried over anhydrous sodium sulfate and concentrated by rotary evaporation (water aspirator, 70° C.). The residual oil was then distilled at 200° C. and low vacuum (vacuum pump) giving 1.5 g (36.7%) of a clear oil.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].Cl[CH2:29][CH:30]([OH:33])[CH2:31][OH:32]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 57.5 g of sodium 4-(n-hexadecylamino)benzoate and 55.0 g of 3-chloro-1,2-propanediol in 350 ml of hexamethylphosphoramide is treated in the manner described in Example 3 to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate melting at 112°-113° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:13]([C@@:16]1([CH3:42])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:18]([C@@H:36]([CH2:39][CH3:40])[CH:37]=[O:38])[C:17]1=[O:41])[CH:14]=[CH2:15]>C1COCC1.C(OCC)(=O)C>[CH2:13]([C@@:16]1([CH3:42])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:18]([C@H:36]([CH:37]([OH:38])[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:39][CH3:40])[C:17]1=[O:41])[CH:14]=[CH2:15]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CCCO[Si](C)(C)C(C)(C)C)C1=O
Reaction time: 2 h

Procedure:
The Grignard reagent derived from of (3-bromopropoxy)(tert-butyl)dimethylsilane was prepared on 1.8 mmol scale according to Minguez, et al. Biorg. Med. Chem. 11, 3335, 2003 as a gray solution in THF (˜3 mL). About 1.5 mL of the Grignard regent was added slowly to a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (100 mg, 0.22 mmol; Example 91, Step C) in THF (1 mL) at ambient temperature. After 2 h, the reaction was diluted in ethyl acetate and washed with saturated ammonium chloride solution followed by sat. aq. NaCl solution. The organic layer was dried over sodium sulfate and concentrated. Purification by silica chromatography eluting with ethyl acetate/hexane provided the title compound as a mixture of diastereomers.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH3:25][C:24]1[C:23](=[O:26])[O:22][CH2:21][C:20]=1[N:4]1[CH2:3][C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:5]1=[O:19]
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=C(N2CC(=O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Reaction time: 1.5 h

Procedure:
To tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (see example I-37A and I-37B, Step C, racemate prior to chiral HPLC separation)(200 mg, 0.546 mmol) in DCM (2.8 mL) was added sodium bicarbonate (68.8 mg, 0.819 mmol) and Dess-Martin periodinane (347 mg, 0.819 mmol). The reaction mixture was vigorously stirred for 1.5 h, then quenched with 10% Na2S2O3 and NaHCO3 aqueous solutions, and stirred for 20 min. The aqueous layer was extracted with DCM, and the organic layers were washed with brine, dried, and concentrated to give tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4-dioxo-2,8-diazaspiro[4.5]decane-8-carboxylate. LCMS: [(M+1)]+=365
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(Br)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(Br)cc1
Reaction time: 8 h
Yield: 10.1 %

Procedure:
To a solution of 1-(4-bromobenzyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.10 g, 0.25 mmol) in CH2Cl2 (15 mL) at 0° C. under nitrogen was added boron tribromide (1.47 mL, 1.47 mmol). The reaction was allowed to reach RT. After 8 hours, the reaction was poured into water (10 mL) and neutralized with saturated sodium bicarbonate. Additional CH2Cl2 (25 mL) was added, the organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was then chromatographed (SiO2, 2:1, hexanes/ethyl acetate) to provide the title compound (0.010 g, 10% yield): 1H NMR (CDCl3) 7.33 (d, 2H), 7.24 (dd, 2H), 6.97 (d, 1H), 6.88 (d, 2H), 6.80 (d, 2H), 6.75 (dd, 2H), 6.66 (m, 1H), 6.27 (s, 1H), 4.78 (t, 1H), 3.53 (m 2H), 3.13 (dd, 1H), 2.96 (m, 2H), 2.62 (m, 1H); ES−MS (m/z) 392 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:21])[C:17]([OH:20])=[CH:18][CH:19]=3)[S:13][C:6]=12.Br[CH2:30][CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:33][CH2:32][CH2:31][CH2:30][O:21][C:16]1[CH:15]=[C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:30][CH2:31][CH2:32][Cl:33]
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)c(O)c4)sc23)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(OCCCCl)c(OCCCCl)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a stirred solution of 332 (140 mg, 0.35 mmol) in anhydrous DMF (5 ml) were added 1-bromo-3-chloropropane (553 mg, 3.51 mmol) and cesium carbonate (573 mg, 1.76 mmol), respectively. The reaction mixture was stirred for 2 hrs at room temperature, diluted with AcOEt, and successively washed with water, sat. ammonium chloride, water, and concentrated. The crude material was adsorbed on silica gel and purified by flash column chromatography (eluents AcOEt/CH2Cl2: 10/90 to 20/80) to afford title compound 333 (120 mg, 62% yield) as a yellow solid. MS (m/z): 551.0 and 553.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[Li]CCCC.CCCCCC.[C:33](OC)(=[O:38])[C:34]([O:36][CH3:37])=[O:35].S(=O)(=O)(O)O>C1COCC1>[CH2:12]([N:9]1[CH2:8][C@H:7]([CH3:14])[N:6]2[C:2]([C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]([O:15][CH3:16])=[C:5]2[C:10]1=[O:11])[CH3:13]
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)[C@@H](C)CN(CC)C2=O
Reactant: COC(=O)C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OC)c2n(c1C(=O)C(=O)OC)[C@@H](C)CN(CC)C2=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of ethyl (4S)-6-bromo-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-carboxylate (8.51 g, 23.7 mmol) in anhydrous THF (800 mL) under an atmosphere of dry nitrogen, a solution of n-BuLi in hexane (10.5 mL, 26.3 mmol, 2.5 M) was added. The resultant mixture was stirred at −78° C. for 20 minutes. A solution of dimethyl oxalate (6.4 g, 53.8 mmol; dried from concentration from benzene under vac) in anhydrous THF (30 mL) was added. The reaction mixture was stirred at −78° C. for 1 hour and cannulated into a mixture of aqueous sulfuric acid (240 mL, 2M) and THF (200 mL) maintained between at −5 to −35° C. The mixture was extracted with ethyl acetate (3 times). The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 40 to 100% ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])C.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[C:9]3[NH:10][C:11]4[C:16]([C:8]=3[CH2:7][CH:5]([C:4]([O:3][CH3:1])=[O:17])[NH:6]2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(O)cc1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)cc2)N1

Procedure:
The same method but starting from racemic tryptophan ethyl ester and 4-hydroxybenzaldehyde gave the title compound as pale yellow crystals 1H NMR (DMSO) δ (ppm): 10.3 (s, 1H, NH-indole) 9.4 (s, 1H, OH); 7.8-7.5 (m, 8H, H aromatic); 5.1 (brs, 1H, H-1); 3.9 (m, 1H, H-3); 3.75 (s, 3H, CO2CH3) 3.1 (m, 1H, H-4); 2.8 (m, 1H, H-4).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]2)=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: C[C@H]1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C(=O)OC(C)(C)C
Yield: 81.5 %

Procedure:
Following the procedures as described for compound 108c, reaction of 3,5-dibromo-1-methylpyridin-2(1H)-one (83 mg) and 107b (90 mg), gave 107c as a yellow solid (120 mg, 81%). MS: [M+H]+ 480
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:22][C:23]([F:36])([F:35])[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])=[O:25]>>[CH:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:24](=[O:25])[C:23]([F:35])([F:36])[F:22])[CH:27]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(C(=O)C(F)(F)F)c1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)c3cccc(C(=O)C(F)(F)F)c3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 3-(trifluoroacetyl)benzoic acid (Preparation 200) to afford the title compound as a white solid in 80% yield, 41 mg. LCMS (system 3): Rt=2.52 min; m/z 482 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:46]=[S:47]1(=[O:71])[NH:60][C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH:52]=2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:60]3[C:59]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:67][CH3:68])([CH2:69][CH3:70])[CH2:65][CH3:66])[CH:52]=4)[S:47]3(=[O:71])=[O:46])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: CC[Si](CC)(CC)OCCc1ccc2c(c1)-c1ccccc1NS2(=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccccc4-c4cc(CCO[Si](CC)(CC)CC)ccc4S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthrene (429 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7.3 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography , eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-[9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([NH:12][S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=1)[NH:8][C:7]([C:21]([O:23]CC)=[O:22])=[CH:6]2.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([NH:12][S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=1)[NH:8][C:7]([C:21]([OH:23])=[O:22])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(OC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
To a mixed solution of ethyl 5-methoxy-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.34 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.20 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (300 mg, yield 96%) as pale-yellow crystals. melting point>240° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(N)c(Cl)cc1Cl
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(Cl)cc1Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,4-dichloro-5-methoxyaniline (44 mg, 0.232 mmol) similar to Example 117 and isolated as a brown solid (9 mg, 11%). 1H NMR (CDCl3): 9.64–9.63 (m, 1H), 8.76–8.70 (m, 2H), 8.12 (s, 1H), 7.49 (s, 1H), 7.46–7.41 (m, 2H), 6.95 (s, 1H), 4.00 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OCC)(=O)C>O1CCOCC1>[CH2:35]([NH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2NCc2ccccc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 2-amino-5-bromo-3-[(S)-4-Boc-3-benzylpiperazinyl]pyrazine 108 (170 mg, 0.379 mmol) in anhydrous dioxane (3 mL) was added a 1 M solution of potassium t-butoxide (0.42 mL, 0.42 mmol). The reaction mixture was stirred at room temperature for 10 minutes and benzyl bromide (130 mg, 0.76 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 2-benzylamino-3-[(S)-4-Boc-3-benzylpiperazinyl]-5-bromopyrazine 112 (165 mg, 0.307 mmol).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCN1CC[C@H](O)C1=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCN1CC[C@H](OC(C)=O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 5.0 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 6.7 ml of pyridine, 0.2 g of dimethylaminopyridine and 6.7 ml of acetic anhydride was stirred in a water bath for 3 hours. The mixture was diluted with 150 ml of dichloromethane, washed in succession with water, sodium bicarbonate solution, 1N hydrochloric acid, sodium bicarbonate solution and brine, dried and concentrated, giving 6.4 g of (S)-3-(acetyloxy)-1-(2-propynyl)-2-pyrrolidinone [α]D260 =-45° (dichloromethane).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=O)[CH2:32][CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:32][CH2:31]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C1CCc2cc(OCc3ccccc3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: -78 °C
Yield: 70 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in THF) (30 mL, 30 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (5.0 mL, 30 mmol) in THF (20 mL). The reaction was maintained at −78° C. for 11 minutes and then 5-(benzyloxy)-2,3-dihydroinden-1-one (5.2) (4.0 g, 17 mmol) in 10 mL of THF was added in one portion. The resulting mixture was stirred at −78° C. and allowed to warm to room temperature overnight. EtOAc (400 mL) was added, and the mixture was washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give 5.3 in 70% yield.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])=[CH:29][CH:30]=1)#[N:24]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: N#Cc1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:32])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cc(F)cc(Cl)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.71 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.32 g, 2.1 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white solid (Yield, 0.15 g, 36%).