Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][C:13]([OH:15])=O)(=O)=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCl.CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:8][CH2:11][CH2:12][C:13](=[O:15])[C:6]=2[CH:7]=1
Reactant: O=C(O)CCS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C1CCSc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
3-[(4-fluorophenyl)sulfonyl]propanoic acid (3 g, 15 mmol) was dissolved in dichloromethane (30 mL) and cooled to 0° C. in an ice bath. Oxalyl chloride (10 mL) was added slowly, dimethyl formamide (1 drop) was added and the reaction mixture was stirred at 0° C. for 0.5 hours. At which point the reaction was concentrated under reduced pressure to a residue, then resuspended in dichloromethane and cooled to 0° C. in an ice bath, CS2 (1 mL) was added and AlCl3 (4 g, 15 mmol) was added slowly. The reaction mixture was then allowed to warm to room temperature and stirred over night. Ice chips and water (250 mL) were added and stirred. Concentrated hydrogen chloride was added until pH of 2, and extracted with dichloromethane (3×150 mL). Organics were combined, washed with brine (1×100 mL) and water (1×100 mL), dried (sodium sulfate), and concentrated to a yellow solid. The solid was purified by flash column chromatography on 100 g silica gel, eluting 10% ethyl acetate in hexanes to give 6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (2.55 g, 93%). 1H NMR (CDCl3, 300 MHz): δ 7.80–7.76 (m, 1H), 7.27–7.23 (m, 2H), 7.15–7.09 (m, 1H), 3.23 (t, 2H, J=6.4 Hz), 2.97 (t, 2H, J=6.4 Hz) ppm.
Reaction SMILES: [O:1]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:29])/[CH2:18][CH2:19]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])\[CH3:13])[P:2]([O:5][P:6]([O-:9])([O-:8])=[O:7])(=[O:4])[O-:3].C/C(/CC[C@H]1[C@@]2(C)CCCC(C)(C)[C@H]2CCC1=C)=C\CO>>[CH3:13]/[C:12](/[CH2:14][CH2:15][C@H:16]1[C@@:21]2([CH3:22])[CH2:23][CH2:24][CH2:25][C:26]([CH3:28])([CH3:27])[C@@H:20]2[CH2:19][CH2:18][C:17]1=[CH2:29])=[CH:11]\[CH2:10][O:1][P:2]([O:5][P:6]([OH:9])([OH:8])=[O:7])([OH:3])=[O:4]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COP(=O)([O-])OP(=O)([O-])[O-]
Agent: C=C1CC[C@@H]2C(C)(C)CCC[C@]2(C)[C@@H]1CC/C(C)=C/CO
Product: C=C1CC[C@H]2C(C)(C)CCC[C@]2(C)[C@@H]1CC/C(C)=C/COP(=O)(O)OP(=O)(O)O

Procedure:
Chemicals. The preparation of (E,E,E)-geranylgeranyl diphosphate (GGPP), and ent- and syn-copalyl diphosphate (CPP), from the corresponding copalol stereoisomers (Yee and Coates 1992), has been previously described (Mohan et al. 1996). Unless otherwise noted, all other chemicals were purchased from Fisher Scientific (Fairlawn, N.J., USA).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:11]([S:12][CH2:13][CH:14]2[C:18]#[N:19])[CH2:10]1.[C:20]1([CH2:26][CH2:27][CH:28]=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(COC)OC.C(O)(=O)C>[O:17]=[C:16]1[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10][C@H:9]1[NH:8][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CCCc1ccccc1
Reactant: N#CC1CSC2CC(N)C(=O)N12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: COCCOC
Product: N#C[C@@H]1CS[C@H]2C[C@@H](NCCCc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 mg of (3R,6R,7aS)-(6-amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate, 0.0132 ml of 3-phenylpropionaldehyde and 0.115 ml of glacial acetic acid were heated in 1.5 ml of methylene chloride at 40° C. for 20 minutes. The mixture was then cooled to room temperature, 8.3 mg of sodium acetate, 0.5 ml of dimethoxyethane and 27.8 mg of sodium triacetoxyborohydride were added, and the mixture was stirred at RT overnight. After concentration of the mixture, the residue was purified by column chromatography (silica gel, mobile phase: ethyl acetate: n-heptane=8:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH2:15][CH3:16])([CH3:14])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH2:15][CH3:16])([CH3:14])[CH2:12][CH3:13])[NH:8]1)=[O:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(C)(CC)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCC(C)(CC)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 73.1 %

Procedure:
In a manner similar to the method described in Example 100b, [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 107a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.4 mmol), and triethylamine (2.1 mL, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (2.5 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.Br[C:22]1[C:27]([CH3:28])=[CH:26][N:25]=[CH:24][C:23]=1[CH3:29].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:1][C:22]2[C:27]([CH3:28])=[CH:26][N:25]=[CH:24][C:23]=2[CH3:29])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1cncc(C)c1Br
Reactant: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)oc2c1OC1CCCC1
Temperature: 110 °C

Procedure:
A mixture of 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (0.176 g, 0.640 mmol, Example 3, Step 1), 4-bromo-3,5-dimethylpyridine (0.108 g, 0.580 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), 2,2-dicyclohexylphosphorane triisopropylbiphenyl (55 mg, 0.12 mmol), sodium tert-butoxide (67 mg, 0.69 mmol), and dry toluene (3 mL) was heated to 110° C. under N2 for 2 h. The mixture was allowed to cool to rt, filtered through Celite, washed with EtOAc, concentrated, and purified by reverse-phase HPLC (20→100% acetonitrile:water) to give 8-(cyclopentyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.43 (s, 2H), 7.93 (d, 1H), 7.17 (d, 1H), 4.83 (m, 1H), 4.29 (s, 1H), 3.90 (s, 3H), 2.15 (s, 6H) 1.86-1.53 (m, 8H); MS (ESI): 380.9.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:19])[C:10]=3[CH:20]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([OH:18])[CH:15]([CH3:16])[CH3:17])=[C:11]([CH3:19])[C:10]=3[CH:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OCC3CC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(O)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
1-[5-(Cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (19.91 g) synthesized above was dissolved in mixed solvent of methanol (40 mL)-tetrahydrofuran (200 mL), and sodium tetrahydroborate (90%, 5.53 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (22.74 g, 100%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH:26]([CH3:28])[CH3:27]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH:26]([CH3:28])[CH3:27])[CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)n1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Yield: 23 %

Procedure:
The same procedures as in Example 137 were carried out from sodium hydroxide (2.8 g), methylene chloride (100 mL), N-tert-butoxycarbonyl-L-tryptophan (6.0 g), 2-iodopropane (9.8 mL), and tetra-n-butylammonium hydrogensulfate (0.7 g), to give the captioned compound (1.6 g, 23%) as an oily product.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[CH:3]=1.[Cu][C:17]#[N:18].C(N)CN>CN(C=O)C>[C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([C:17]#[N:18])=[CH:3][C:4]=1[F:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: NCCN
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Combine 4-bromo-N-tert-butyl-2-fluoro-benzamide (1.0 g, 3.65 mmol) and copper(I) cyanide (0.7 g, 7.29 mmol) in anhydrous DMF (10 mL) and reflux for 17 h. Cool the reaction mixture to ambient temperature and treat with 50% (v/v) aqueous ethylenediamine (20 mL). Extract the reaction mixture with diethyl ether (3×10 mL), combine the organic extracts, wash with brine (2×10 mL) and dry the organic layer over Na2SO4. Evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1, 7:3 and 3:2) to obtain the desired intermediate as a white solid (0.6 g, 77%). MS (ES+) m/z: 221 (M+H)+.
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[C:25]2[N:26]=[C:27]([N:37]([CH3:39])[CH3:38])[N:28]=[C:29]([C:30]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[O:31])[C:24]=2[S:23][CH:22]=1.C([Sn](CCCC)(CCCC)[C:45]1[O:46][CH:47]=[CH:48][CH:49]=1)CCC.[NH4+].[Cl-]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][N:37]([CH3:39])[C:27]1[N:28]=[C:29]([C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[O:31])[C:24]2[S:23][CH:22]=[C:21]([C:45]3[O:46][CH:47]=[CH:48][CH:49]=3)[C:25]=2[N:26]=1
Reactant: CN(C)c1nc(C(=O)c2cccs2)c2scc(Br)c2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)c1nc(C(=O)c2cccs2)c2scc(-c3ccco3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
A mixture of palladium(II) acetate (4.1 mg, 18.3 μmol) and triphenylarsine (22.4 mg, 73 μmol) in DMF (0.8 mL) was stirred under an atmosphere of argon at room temperature for 10 min, treated with a solution of 7-bromo-2-dimethylaminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (0.067 g, 0.18 mmol) in DMF (1.1 mL), stirred for 10 min then treated dropwise with 2-tri-n-butylstannylfuran (104 μL, 0.33 mmol). The reaction mixture was stirred at 100° C. for 117 h, cooled, poured into saturated NH4Cl (5 mL), extracted with EtOAc (4×5 mL), the combined organic phase washed with water (5 mL), dried (MgSO4), concentrated in vacuo and the resulting residue purified by chromatography [SiO2; heptane-EtOAc (100:0-95:5 gradient)] to give the title compound (57 mg, 87%) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.FC(F)(F)[C:13]([O:15]C(=O)C(F)(F)F)=[O:14]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14]
Reactant: Brc1cccc2cc[nH]c12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2c(Br)cccc12

Procedure:
To a solution of 7-bromoindole (10 g, 51.0 mmol) in N,N-dimethylformamide (DMF) (100 cm3) was added trifluoroacetic anhydride (12.5 cm3, 89.6 mmol) over 5 min. The resultant solution was stirred at room temperature for 16 h. The solution was poured onto water (500 cm3) and the precipitate formed was isolated by filtration, washed with water and 4N sodium hydroxide (200 cm3) added. The suspension was heated at reflux for 1.5 h and allowed to cool before washing with diethyl ether (2×250 cm3). The aqueous layer was acidified to pH 1 with 5N hydrochloric acid and the resultant precipitate isolated by filtration, washed with water and dried over phosphorous pentoxide under reduced pressure at 60° C. for 16 h. This afforded the title compound LA) (8.94 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:16])[CH:3]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(#N)C.CN(C1C=CN=CC=1)C>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[C:4](=[O:16])[CH:3]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccn(Cc2cccc(F)c2)c(=O)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 79.8 %

Procedure:
To a solution of 4-amino-1-(3-fluorobenzyl)pyridin-2(1H)-one (0.263 g, 1.2 mmol) in acetonitrile (7 mL) was added a DMAP (ca.), triethylamine (0.25 mL, 1.8 mmol) and 4-fluorobenzoyl chloride (0.213 mL, 1.8 mmol). The reaction mixture stirred at 0° C. for 25 minutes and then filtered. The solid was washed with 10% citric acid and water to afford the desired compound (0.326 g, 79%) after drying. 1H-NMR (d6DMSO, 400 MHz) δ 7.98 (m, 2H), 7.71 (d, 1H, J=7.6 Hz), 7.35 (m, 3H), 7.08 (m, 3H), 6.98 (d, 1H, J=2.4 Hz), 6.61 (dd, 1H, J=2.4 Hz, 2.4 Hz), 5.03 (s, 2H); ESLRMS m/z 341.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10]N(C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].Cl.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[NH:28])=[CH:25][CH:24]=1.[H-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:29]=[C:27]([C:26]3[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=3)[N:28]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Product: COC(=O)NCc1cc(-c2ccnc(-c3ccc(C)cc3)n2)ccc1Cl

Procedure:
To mixture of methyl N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]-methyl]carbamate (i.e. the product of Step A, Example 4) (0.43 g, 1.44 mmol), 4-methylbenzamidine hydrochloride (0.74 g, 4.33 mmol) and sodium hydride (0.14 g, 5.8 mmol) at 0° C. was slowly added methanol (5 mL). The reaction mixture was heated at reflux overnight. A solution of saturated ammonium chloride was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.160 g).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=S)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[CH:20]([NH2:22])[CH3:21].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)CCC>[CH3:21][C:20]1[N:22]=[C:10]2[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]2[CH:19]=1
Reactant: S=C1Nc2ccccc2Nc2ccccc21
Reactant: COC(OC)C(C)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Cc1cn2c(n1)-c1ccccc1Nc1ccccc1-2
Yield: 40 %

Procedure:
in a 250-ml., three-neck flask fitted with a condenser, is heated to reflux 6.25 g. of 5,10-dihydro-11H-dibenzo-[b,e][1,4]diazepine-11-thione (30.0 mmol.) and 10.8 g. of aminopropionaldehyde dimethyl acetal (90.0 mmol.) in 60 ml. of n-butanol, during 2 hours. An additional 60 ml. of n-butanol is added and the mixture is refluxed overnight (22 hours). At this point, 60 ml. of n-butanol is distilled from the reaction mixture and refluxing is maintained for an additional 18 hours. On cooling, 2.0 g. of crude starting material is obtained. This is added to the reaction mixture along with an additional 5.4 g. of aminopropionaldehyde acetal (40.0 mmol.) and heating is maintained over a weekend (65 hours). On cooling and removal of the solvent in vacuo, 10 g. of brown oil is obtained. The oil is dissolved in 80 ml. of concentrated sulfuric acid and stirred at room temperature under nitrogen for 10 hours. The reaction mixture is then poured into ice and carefully neutralized with 50% aqueous sodium hydroxide solution. The basic aqueous solution is extracted thoroughly with chloroform. The combined chloroform extracts are washed with brine, dried over anhydrous potassium carbonate and concentrated in vacuo. The resulting oil is taken up in ethyl acetate, treated with activated charcoal and filtered. On concentrating and cooling the filtered solution, 3.2 g. of 2-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine is obtained in 2 crops (yield 40%) of melting point 232°-236° C.
Reaction SMILES: [CH3:1][SH:2].[CH3:3][C:4]1[C:5]([N+]([O-])=O)=[C:6]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:3][C:4]1[C:5]([S:2][CH3:1])=[C:6]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(C)c(C)c1[N+](=O)[O-]
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)c(C)c1SC
Temperature: -10 °C
Reaction time: 72 h

Procedure:
A solution of methanethiol (22 ml) in dry dimethyl formamide was added to a mixture of ethyl 3,4-dimethyl-2-nitrobenzoate (21.54 g) and potassium carbonate (20.02 g) in dry dimethyl formamide while maintaining the temperature below -15° C. The mixture was stirred at -10° C. for 0.5 hours and at room temperature for 3 days. Water was added and the mixture was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane (8:1) to give ethyl 3,4-dimethyl-2-methylsulphenylbenzoate (21.25 g) as a clear oil, NMR (CDCl3) 1.4(t,3H), 2.3(s,3H), 2.35(s,3H), 2.55(s,3H), 4.4(q,2H), 7.1(d,1H), 7.2(d,1H).
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([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H: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.[CH3:63][O:64][C:65]1[CH:70]=[C:69]([O:71][CH2:72][CH2:73][S:74][CH3:75])[CH:68]=[CH:67][C:66]=1[NH2:76]>>[CH3:63][O:64][C:65]1[CH:70]=[C:69]([O:71][CH2:72][CH2:73][S:74][CH3:75])[CH:68]=[CH:67][C:66]=1[NH:76][C:30]([C@@H:20]1[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: COc1cc(OCCSC)ccc1N
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCSC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-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 136 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.45 g, 3.5 mmol), diphenylphosphinic chloride (0.33 g, 1.4 mmol), then reacted with 2-methoxy-4-(2-methylsulfanyl-ethoxy)-phenylamine prepared in Example 168 (0.2 g, 0.9 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(2-methylsulfanyl-ethoxy)-phenyl]-amide as a off white solid (Yield 0.2 g, 44%).
Reaction SMILES: [OH-].[C:2]1([C:10]([O:12]CC)=[O:11])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1>O.C(O)C>[CH2:8]([O:7][C:5]([C:2]1([C:10]([OH:12])=[O:11])[CH2:3][CH2:4]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of soduim hydroxide (2.15 g, 54 mmol) in water (15 ml) was added dropwise to a stirred solution of diethyl 1,1-cyclopropanedicarboxylate (10 g, 54 mmol) in ethanol (30 ml) while the temperature was maintained below 25° C. After the completion of the addition, the resulting mixture was stirred at room temperature for 60 hours. Most of ethanol was removed by evaporation in vacuo and the residue was diluted with brine, acidified with 6N hydrochloric acid and extracted with diethyl ether. The extract was dried over magnesium sulfate, filtered and concentrated. The residue was purified by distillation to give the title compound (bp 66°-9° C./0.15 mm) as a viscous oil.