Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[CH2:18][S:17][C:16](=[N:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]3[CH2:13][C:14]=2[CH:15]=1.[ClH:26]>O>[Cl:26][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[CH2:18][S:17][C:16](=[N:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]3[CH2:13][C:14]=2[CH:15]=1
Reactant: Cl
Reactant: Nc1ccc2c(c1)CN1C(=Nc3cccnc3)SC[C@@H]1C2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(c1)CN1C(=Nc3cccnc3)SC[C@@H]1C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium nitrite (3.1 g.) in distilled water (10 cc.) is added slowly to a solution, at 0° C., of (S)-7-amino-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (13 g.) in 4N hydrochloric acid (25 cc.). The mixture is stirred for 15 minutes at 0° C., and the solution obained is then added to a suspension of cuprous chloride (6 g.) in concentrated hydrochloric acid (d = 1.18; 25 cc.). The mixture is allowed to return to 20° C., and is then heated for 30 minutes at 70° C. After cooling to 20° C., distilled water (200 cc.), methylene chloride (250 cc.) and then N sodium hydroxide solution (100 cc.) are added. After filtration, the organic phase is recovered by decanting and is dried over magnesium sulphate, filtered and concentrated to dryness at 40° C., under reduced pressure (20 mm.Hg). The residue obtained is purified by chromatography on silica gel (200 g.) contained in a column of 3 cm. diameter, elution being carried out with methylene chloride containing 1% v/v of methanol (5,000 cc.), and 1 litre fractions being collected. Fractions 2 to 4 are combined and then concentrated to dryness. The residue obtained is recrystallised from a mixture of isopropanol (70 cc.) and heptane (100 cc.). (S)-7-Chloro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (5.5 g.), melting at 125° C., is thus obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:39])[CH2:26][CH2:27][C:28]3([C:33]([O:35]CC=C)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1CCOCC1>CN(C=O)C.C([Pd](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:39])[CH2:26][CH2:27][C:28]3([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)C1(CCC(=O)NCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1
Agent: c1ccc(C(c2ccccc2)(c2ccccc2)[Pd](C(c2ccccc2)(c2ccccc2)c2ccccc2)(C(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: O=C(CCC1(C(=O)O)CCCC1)NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
Allyl 1-(3-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylamino)-3-oxopropyl)cyclopentanecarboxylate (360 mg, 0.676 mmol) was dissolved in DMF (15 mL) and cooled to 0° C. under nitrogen. Tetratritylpalladium (122 mg, 0.113 mmol) and morpholine (941 mg, 10.8 mmol) were added and the mixture stirred for 2 h. Solvent was removed under reduced pressure and material was purified by reverse-phase chromatography. Recovered 1-(3-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylamino)-3-oxopropyl)cyclopentanecarboxylic acid (54.4 mg, 0.110 mmol, 16.34% yield).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([F:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([F:12])[CH2:11][NH:8][CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.3 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-fluoroazetidine-1-carboxylic acid tert-butyl ester (235 mg, 0.44 mmol) in DCM (10 mL) was added TFA (2 mL) and the resulting mixture was allowed to stir at r.t. for 3.5 h. The reaction mixture was concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was triturated with Et2O and the resulting solid dried in vacuo affording 834 (185 mg, 97%). LCMS (method I): RT 2.50 min, [M+H]+ 437.3. 1H NMR (DMSO, 400 MHz): δ 8.06-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.28-7.24 (2 H, m), 4.60-4.10 (4 H, brd s), 4.26 (2 H, dd, J=19.18, 10.17 Hz), 4.01 (2 H, dd, J=22.47, 10.23 Hz), 3.80 (4 H, t, J=4.63 Hz), 3.74-3.73 (3 H, m), 3.28-3.27 (2 H, m), 1.34 (3 H, t, J=7.43 Hz)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([C:19]2[CH:32]=[CH:31][C:22]3[C@@H:23]4[C@H:28]([CH2:29][CH2:30][C:21]=3[CH:20]=2)[NH:27][CH2:26][CH2:25][CH2:24]4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:27]3[C@@H:28]4[C@@H:23]([C:22]5[CH:31]=[CH:32][C:19]([C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)=[CH:20][C:21]=5[CH2:30][CH2:29]4)[CH2:24][CH2:25][CH2:26]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc(-c2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(-c4ccccc4)cc3CC[C@@H]21
Yield: 29 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-8-phenyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 29% of theory; TLC: rf=0.49 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[O:5][C:6]1[CH:7]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:2].[F:29][C:30]([F:35])([F:34])[C:31]([NH2:33])=[O:32].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:28])[O:5][C:6]1[CH:7]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24](=[O:27])(=[N:33][C:31](=[O:32])[C:30]([F:35])([F:34])[F:29])[CH2:23][CH2:22]2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:2]
Reactant: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCS(=O)CC1
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+3]
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCS(=O)(=NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-(1-oxo-hexahydro-1λ4-thiopyran-4-ylmethyl)-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (191 mg, 0.47 mmol), trifluoro-acetamide (104 mg, 0.92 mmol), (diacetoxyiodo)benzene (246 mg, 0.76 mmol), MgO (75 mg, 1.8 mmol) and rhodium acetate (10 mg, 0.023 mmol) in 10 ml of CH2Cl2 was stirred at room temperature for 2 h. Then, it was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel. Yield: 80 mg of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-[1-oxo-1-(2,2,2-trifluoro-acetylimino)-hexahydro-1λ6-thiopyran-4-ylmethyl]-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (isomer A, compound P1.6) as a solid, mp 91-93° C. and 40 mg of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-[1-oxo-1-(2,2,2-trifluoro-acetylimino)-hexahydro-1λ6-thiopyran-4-ylmethyl]-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (isomer B, compound P1.7) as a solid, mp 87-89° C.
Reaction SMILES: [C:1]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:28][C:22]1([C:20]([NH:19][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:7][CH:6]=2)=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COc1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1
Solvent: O=CO
Product: COc1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4′-methoxybiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 20, step (i), 120 mg) was dissolved in formic acid (3 mL) and the mixture stirred at room temperature for 3 h. The mixture was evaporated to dryness, dissolved in methanol (10 mL), re-evaporated to dryness, dissolved in methanol (5.5 mL) and purified on reversed phase HPLC eluting with methanol in 0.1% aqueous TFA on a Water's SunFire column. The material was converted to free base by evaporating the relevant fractions, dissolving in ethyl acetate (20 mL) and extracted with saturated sodium bicarbonate solution (20 mL). The sodium bicarbonate solution was further extracted with ethyl acetate (20 mL). The combined ethyl acetate extracts were dried and evaporated to afford the titled compound (91 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][C:4]1=[N:15]O)[CH3:2].C(NCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:3]1([CH2:17][CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH:5]2[NH:15][CH:4]12)[CH3:2]
Reactant: CCC1(CC)C(=NO)CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCC1(CC)c2cc(OC)ccc2CC2NC21
Temperature: 0 °C

Procedure:
To a solution of 1,1-Diethyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one oxime (4.68 g, 18.96 mmol) in dry THF (100 mL) at 0° C. was added the diethylamine (4.9 mL, 47.4 mmol) and the LAH (95% powder) (2.16 g, 56.9 mmol). The mixture was stirred at 0° C. for min then heated to reflux for 3 h. The gray solution was cooled down to 0° C., quenched with brine and diluted with AcOEt. The organic layer was decanted, washed with H2O (2×), brine, dried over MgSO4, filtered then evaporated. The residue was purified by a flash chromatography (3% MeOH/CH2Cl2) (3.889 g, 89%).
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2(C(F)(F)F)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].ClC1C(OCC2CCCCC2)=C[C:32](F)=[C:33]([CH:41]=1)C(OC(C)(C)C)=O>>[CH:18]1([CH2:17][O:16][C:3]2[C:2]([CH:41]3[CH2:33][CH2:32]3)=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])=[C:5]([F:15])[CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 3 and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate with tert-butyl 5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoate, the title compound was obtained as colorless oil (13.73 g, 88%): MS (ES+) m/z 387.2 (M+39).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH3:31][N:32]([CH3:63])[C:33](=[O:62])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]2[CH2:53][C:52]3[C:47](=[C:48]([O:60]C)[C:49]([O:58][CH3:59])=[C:50]([O:56][CH3:57])[C:51]=3[O:54]C)[CH2:46]2)=[CH:36][CH:35]=1>O>[CH3:63][N:32]([CH3:31])[C:33](=[O:62])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]2[CH2:53][C:52]3[C:51](=[O:54])[C:50]([O:56][CH3:57])=[C:49]([O:58][CH3:59])[C:48](=[O:60])[C:47]=3[CH2:46]2)=[CH:36][CH:35]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)N(C)C)cc1)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N(C)C)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
A water (1.0 ml) solution of CAN (1.07 g, 1.96 mmols) was dropwise added to an acetonitrile (8.0 ml) solution of N,N-dimethyl-4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzamide (358 mg, 0.782 mmols), with cooling with ice, and stirred for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:2) followed by recrystallization (from diisopropyl ether-ethyl acetate) to obtain the entitled compound (153 mg) as crystals.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH:44]C=O)[N:39]=1)[C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:33]([OH:35])=[O:34])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25]C(OC(C)(C)C)=O)=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]>C(O)=O>[CH2:1]([O:4][N:5]=[C:6]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[N:39]=1)[C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:33]([OH:35])=[O:34])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH2:25])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1cccc(NC=O)n1
Solvent: O=CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
A solution of 7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (2.7 g) in formic acid (27 ml) was stirred for 2 hours at ambient temperature and evaporated to dryness. To the residue were added methanol (50 ml) and concentrated hydrochloric acid (0.82 g), and the mixture was stirred for an hour at ambient temperature. The solvent was evaporated and the residue was dissolved in water (50 ml), adjusted to pH 4 to 5 with an aqueous solution of sodium bicarbonate, treated with an activated charcoal and then subjected to column chromatography over nonionic adsorption resin, "Diaion HP 20" (80 ml). The column was washed with water and eluted with 50% aqueous methanol. The eluent containing a desired compound was evaporated to remove the methanol and then lyophilized to give 7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (0.6 g), mp 180° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.C(N(CC)CC)C.Br[CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56].O>CN(C)C=O>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][N:11]([CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[N:12]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(2H-tetrazol-5-yl)-amine (400 mg) is dissolved in N,N-dimethylformamide (3 ml) and thereto are added triethylamine (2 ml) and ethyl 4-bromobutyrate (278 μl) and the mixture is stirred at 50° C. for 3 hours. To reaction mixture is added water, and extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give ethyl 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyrate (360 mg) MS (m/z): 732 [M+H]+
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:47])[C@H:6]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:46])=[O:38])=[CH:32][CH:31]=1)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)(=[O:18])=[O:17])=[CH:12][C:11]=1[Cl:28])=[O:9]>CO.O1CCCC1>[Cl:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([Cl:45])[C:39]=1[C:37]([NH:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C@@H:6]([C:5]([OH:47])=[O:4])[NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:28])=[O:9])=[CH:35][CH:34]=1)=[O:38]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
An aqueous 1N lithium hydroxide solution (0.25 mL) was added to a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]sulfonyl]phenyl]carbonyl]-L-phenylalanine methyl ester (51 mg; 0.0738 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.35 mL). After the reaction was stirred at room temperature for 90 minutes, the solvents were removed under reduced pressure. The crude product in the minimum amount of methanol was then applied to a column of silica eel (5 g) made up in a mixture of chloroform, methanol, acetic acid and water (15:3:1:0.6). The column was eluted with the same solvent mixture and the appropriate fractions were combined and evaporated. The residue was lyophilized from deionized water to give 36 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]sulfonyl]phenyl]carbonyl]-L-phenylalanine as an off white solid. FAB HRMS: (C30H24Cl3N3O7S) Obs. Mass 676.0482 Calcd. Mass 676.0479 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=[CH:4]1)[CH3:2].[H][H]>C(O)(=O)C.[C].[Pd]>[CH2:10]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[CH3:11]
Reactant: [H][H]
Reactant: CCC1(CC)C=CC(=O)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC1(CC)CCC(=O)CC1
Yield: 85.2 %

Procedure:
In 22 ml of acetic acid was dissolved 2.20 g of 4,4-diethyl-2-cyclohexen-1-one, to which was added 0.22 g of 5% palladium-carbon. Under a pressure of 5 atmospheres, the mixture was stirred at ambient temperature for one hour under a stream of hydrogen. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=10:1] gave 1.90 g of 4,4-diethyl-1-cyclohexanone as a colorless oily product.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:18]=[C:17]([C:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])([O-:8])=[O:7].[CH2:22]=[C:23]([CH3:25])[CH3:24]>O1CCOCC1.CCOC(C)=O>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:17]([C:19]([O:21][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:20])=[CH:18][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1[N+](=O)[O-]
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
Sulfuric acid conc (5 ml) was added to a solution of 1-methyl 2-nitroterephthalate (25.2 g, 0.112 mmol) in dioxane (120 ml) in a Parr shaker bottle and cooled to 0° C. Isobutene (100 ml) was added, the vessel was sealed, and vigorously shaken for 5 days. The crude product was dissolved in EtOAc after evaporation of the excess isobutene and washed with sat NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated leaving 23.0 g (73%) of 2-nitroterephthalic acid 4-tert-butyl ester 1-methyl ester as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([OH:32])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of 57 mg (0.11 mmol) of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step B) in DCM (359 μL) was added trifluoroacetic acid (415 μL, 5.38 mmol) at 0° C. After being stirred at 25 C for 2 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure three times. Separation of the crude product by reversed phase HPLC (45 to 70% AcCN/H2O in 30 min, 3 time runs, tR=18.52 min) provided the title compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:30][O:31][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]3=[O:29])C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:30][O:31][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]3=[O:29]
Reactant: CC(C)CCN1C(=O)C2(COc3cc(OCc4ccccc4)ccc32)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)CCN1C(=O)C2(COc3cc(O)ccc32)c2ccccc21
Reaction time: 54 h
Yield: 85.3 %

Procedure:
A suspension of 6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (7.80 g, 18.86 mmol) and 10% palladium on carbon (2.00 g, 1.88 mmol) in methanol (150 mL) was hydrogenated for 54 h. The mixture was filtered through a pad of celite, the filtrate was concentrated in vacuo, and the residue was crystallized from diethyl ether to give 6-hydroxy-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (5.20 g, 85%) as a colorless solid: mp 101-103° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.32-7.27 (m, 1H), 7.16-7.14 (m, 1H), 7.07-7.02 (m, 1H), 6.92-6.89 (m, 1H), 6.40-6.38 (m, 1H), 6.20-6.12 (m, 2H), 4.77 (AB, 2H), 3.86-3.70 (m, 2H), 1.64-1.59 (m, 3H), 0.99 (d, J=6.0 Hz, 6H); MS (ES+) m/z 324.3 (M+1).