Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.I[CH3:11]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:9][CH3:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(O)c(Br)c1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ncc(C)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-bromo-5-methylpyridin-2-ol (500 mg, 2.7 mmol) and silver carbonate (2.6 g, 9.6 mmol) suspended in dichloromethane (10 mL) was added iodomethane (0.83 mL, 13 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered through a pad of celite and the volatiles were evaporated to yield 3-bromo-2-methoxy-5-methylpyridine, which was used directly in the next step. ESI-MS m/z calc. 201.0. found 202.3 (M+1)+. Retention time 1.51 minutes.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a stirred solution of 21 mL (42 mmol, 2.0M in THF) of benzylmagnesium chloride at room temperature under nitrogen was added a solution of 6.80 g (50.0 mmol) of thrice-fused zinc chloride in 50 mL of THF. The resulting tan slurry was stirred for 1 hour. To this slurry was added 10.0 g (35.3 mmol) 1-bromo-4-iodobenzene and 450 mg (0.4 mmol) of tetrakis(tri-phenylphosphine)palladium in 30 mL of THF. The reaction was stirred at room temperature for 16 hours and then quenched with 50 mL of 2M hydro-chloric acid. The mixture was extracted thrice with hexanes, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (5×25 cm column, hexanes as elutent) to give 7.05 g (80%) of title compound as a colorless oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li]C.[Zn](C)C.CCCCCCC.CCOCC.[CH:26]([CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH:31]=[CH:30]1)([CH3:28])[CH3:27]>[H-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].[Cu].[Zr].C([Cu])#N>[CH:1]([CH:30]1[CH:29]([CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)C1C=CC(=O)CC1
Reactant: C#CCCCCCC
Agent: N#C[Cu]
Agent: [Cu]
Agent: [Zr+2]
Solvent: CCOCC
Solvent: CCCCCCC
Product: CCCCCCC=CC1CC(=O)CCC1C(C)C
Temperature: -78 °C
Yield: 81.3 %

Procedure:
A 10 mL round-bottom flask equipped with a stir bar was charged with zirconocene chloride hydride (0.267 g, 1.014 mmol) and sealed with a septum. The flask was evacuated with a vacuum pump and purged with argon, the process being repeated 3 times. THF (2.5 mL) was injected and the mixture stirred to generate a white slurry which was treated via syringe with 1-octyne (0.113 g, 1.01 mmol). The mixture was stirred for 15 minutes to yield a yellow-green solution which was cooled to -78° C. and treated via syringe with ethereal MeLi (0.63 mL, 1.01 mmol) to generate a dark red solution. Concurrently, CuCN (2.3 mg, 0.026 mmol) was placed in a 5 mL round-bottom flask equipped with a stir bar, and sealed under septum. The flask was evacuated and purged with argon as above and THF (0.5 mL) added via syringe. The resulting slurry was cooled to -78° C. and treated with ZnMe2 in heptane (0.43 mL, 0.52 mmol). To this slurry at -78° C. was then added MeLi in Et2O (0.355 mL, 0.57 mmol). After 5 minutes the slurry was warmed to 0° C. for 10 minutes to afford a clear, colorless two-phase mixture, which was then cooled to -78° C. The solution of the zirconocene was added via canula to the Me2Cu(CN)Li2 /ZnMe3Li solution, thereby providing a reaction mixture comprising 5 mol-% of copper per mole of zirconium. The mixture was stirred for 15 minutes at -78° C. to yield a dark red solution which was treated with 4-isopropyl-2-cyclohexenone (77 μL, 0.5 mmol) as a neat liquid over 70 minutes. After 2 hours of additional stirring the mixture was quenched with 5 mL of 10% NH4OH in saturated NH4Cl. The product was extracted with 3×20 mL of ether and dried over Na2SO4. The solution was then filtered through flitted filter paper and the solvent removed in vacuo. The resulting residue was submitted to flash chromatography on silica gel (Petroleum Ether/Ethyl Acetate, 40/1) to give an 81% yield (101.8 mg) of 3-(1-octen-1-yl)-4-isopropylcyclohexanone as a colorless oil which gave satisfactory IR, NMR, MS, and HRMS data.
Reaction SMILES: [C:1]([SiH:4]([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])=[CH2:2].C([Br:14])C=C>>[C:1]([SiH:4]([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])=[CH2:2].[C:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[Br:14])([CH3:3])=[CH2:2]
Reactant: C=CCBr
Agent: C=C(C)[SiH](C(C)C)C(C)C
Product: C=C(C)[Si](Br)(C(C)C)C(C)C
Temperature: 60 °C

Procedure:
Crude isopropenyldiisopropylsilane (2.8 g), which was prepared as described in “Preparation of Isopropenyldiisopropylsilane—Method 2”, was taken up in allyl bromide (20 mL), and purged with N2 for 15 minutes. PdCl2 (32 mg, 1 mol %) was added and the suspension was heated to 60° C. for 12 hours. The suspension was concentrated by rotary evaporation, then taken up in pentane (40 mL) and filtered through quantitative filter paper, that was then rinsed with additional pentane (40 mL). Removal of solvent yielded 3.85 g of crude isopropenyldiisopropylbromosilane as a pale brown liquid.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][CH:11]([OH:12])[C@H:9]3[O:10][C:9]([CH3:11])([CH3:7])[O:8][C@@H:7]23)[CH2:2][O:1]1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(O)[C@H]2O1
Yield: 44.3 %

Procedure:
A mixture of 50 g. of D-mannose, 1,500 ml. of anhydrous acetone and 35 ml. of concentrated sulfuric acid was agitated. D-mannose was completely dissolved after 2 to 3 hours to give a light yellow solution. The reaction mixture was then neutralized with anhydrous sodium carbonate. After filtering the reaction mixture, small amounts of active carbon and anhydrous sodium carbonate were added to the filtrate, and it was refluxed for 1 hour and was again filtered. The filtrate was concentrated to give a solid. The solid was taken out and was recrystallized from petroleum ether to give 32.0 g. of 2,3:5,6-di-O-isopropylidene-D-mannofuranose (yield: 44.3%). The melting point of the product was 122° to 123° C.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:27](N(CC)CC)C.CI>CS(C)=O.C(OCC)(=O)C>[C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[C:9]([CH3:27])([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nnnn3C)S(=O)(=O)[C@H]12
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(C)(c3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 1 h

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide (300 mg), prepared as described in PCT EP 90/02189 in dimethyl sulphoxide (3 ml), was treated at room temperature with triethylamine (0.110 ml) and methyl iodide (0.135 ml). After 1 hr, the reaction mixture was diluted with ethyl acetate, sequentially washed with a dilute solution of hydrochloric acid and brine and eventually dried over Na2SO4. Removal of the solvent and flash chromatography of the residue afforded the title compound as a white solid (160 mg).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][NH2:49]>C1COCC1>[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][NH:49][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: NNc1ccccn1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NNc1ccccn1)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of N′-pyridin-2-yl-hydrazine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 534.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:18](=O)[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:41](C(OC(C)(C)C)=O)[C:42]([O:44]C(C)(C)C)=[O:43].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:13]2[C:12]([C:18]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[C:41]([C:42]([OH:44])=[O:43])[O:16][C:14]2=[O:15])=[CH:11][C:10]=1[O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)c(C(=O)O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a solution of 5-benzyloxy-4-methoxy-2-(3,4,5-trimethoxybenzoyl)-benzoic acid (90 g) in dimethylformamide (900 MI) are added potassium carbonate (60.5 g) and di-tert-butyl bromomalonate (64.6 g), and the mixture is stirred at room temperature for three hours. To the reaction mixture are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. To the residue is added a 4M solution of hydrogen chloride in ethyl acetate (500 ml), and the mixture is stirred at room temperature for five hours. The precipitated crystals are collected by filtration, washed, dried, and dissolved in a mixture of acetic acid (40 ml) and dioxane (80 ml). The mixture is heated under reflux for five hours, and the precipitated crystals are collected by filtration. washed, and dried to give 7-benzyloxy-6-methoxy-4-(3,4,5-trimethoxyphenyl)isocoumarin-3-carboxylic acid (70.0 g) as listed in Table 59.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CO>[CH3:2][C:1]([O:5][C:6]([NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[N:13]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([OH:37])=[O:36])=[CH:16][CH:17]=1)=[O:10])=[O:28])([CH3:4])[CH3:3]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2cccc(C(=O)O)c2)c(C#Cc2ccccc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate C2d (40 mg, 0.09 mmol), 3-boronobenzoic acid (18 mg, 0.11 mmol), Dichlorobis(triphenylphosphine)palladium(II) (6.3 mg, 0.01 mmol), Na2CO3 (19 mg, 0.18 mmol), dioxane (0.9 ml), MeOH (0.2 ml) and water (0.1 ml) is stirred under argon atmosphere for 4 h at 70° C. The reaction mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 16 mg (37%). HPLC-MS: M+H=486; tR=1.49 min (*Method—5).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2C(C)(C)C)cc1

Procedure:
118 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(2,3-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[P:29](Cl)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32].C([Li])CCC>>[C:9]1([P:8]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[P:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOP(Cl)OCC
Reactant: Brc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: [Li]CCCC
Product: CCOP(OCC)c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12

Procedure:
For example, 2-bromophenol (4) is reacted with trifluoromethanesulfonic anhydride to form 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), which is then reacted with di(1-naphthyl)phosphine in the presence of a palladium complex catalyst to obtain (2-bromophenyl)[di(1-naphthyl)]phosphine (6). Next, the compound (6) is reacted with diethyl chlorophosphite in the presence of n-butyllithium to obtain diethyl 2-[di(1-naphthyl)phosphino]phenylphosphonite (7). Then, the compound (7) is reduced with lithium aluminum hydride in the presence of chlorotrimethylsilane to form [2-[di(1-naphthyl)phosphino]phenylphosphine (8). Thereafter, in the presence of n-butyllithium, the compound is reacted with dimesylate of (2R,5R)-2,5-hexanediol producible, for example, according to the method described in a literature (Tetrahedron: Asymmetry, 1991, 2, 569), whereby the aimed (S,S)-Me-UCAP-(1-Nap) (3) can be produced in a high efficiency.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][CH2:5][CH:6]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1)=[O:10])[CH3:7]>>[CH3:3][O:4][CH2:5][CH:6]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](=[O:19])[CH2:18][Br:1])[CH:16]=1)=[O:10])[CH3:7]
Reactant: COCC(C)NC(=O)c1cc(C(C)=O)cc(-c2ccc(C)cc2)c1
Reactant: BrBr
Product: COCC(C)NC(=O)c1cc(C(=O)CBr)cc(-c2ccc(C)cc2)c1
Temperature: 45 °C

Procedure:
A solution of bromine (0.074 ml, 1.5 mmol) dissolved in CCI4 (2.0 ml) was added slowly to a stirred solution of 5-acetyl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (325 mg, 1 mmol) in 3.0 ml of CCI4 at room temperature. The mixture was then heated to 45° C. for 14 hours. The solution was cooled and extracted with EtOAc, and the combined organic layers were washed with saturated aqueous Na2S2O3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude 5-(2-bromo-acetyl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was used for next step directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH2:27][CH3:28])=[CH:25][CH3:26])[C:5]2=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1
Reactant: CC=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCC(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 6 h
Yield: 36.4 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.3 g, 0.70 mmol) prepared in example 66b in ethyl acetate (30 mL) was added platinum oxide (0.35 g, 1.54 mmol). The resulting suspension was vigorously shaken under hydrogen (50 psi) for 6 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.11 g, 37.7%).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Si]([O:15][CH2:16][CH2:17][CH2:18][N:19]1[C@@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][C:36]([O:38]C)=O)[C@@H:27](C(O)=O)[C:26]2[C:21](=[CH:22][C:23]([O:45][CH3:46])=[C:24]([O:43][CH3:44])[CH:25]=2)[C:20]1=[O:47])(C(C)(C)C)(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[K+]>CO.C1COCC1.O.C(O)CO.O.C(O)(=O)C>[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:28]2[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[NH:35][C:36](=[O:38])[C:27]=2[C:26]2[CH:25]=[C:24]([O:43][CH3:44])[C:23]([O:45][CH3:46])=[CH:22][C:21]=2[C:20]1=[O:47]
Reactant: COC(=O)Nc1ccccc1[C@H]1[C@@H](C(=O)O)c2cc(OC)c(OC)cc2C(=O)N1CCCO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [K+]
Solvent: OCCO
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(=O)n(CCCO)c3c4ccccc4[nH]c(=O)c3c2cc1OC
Temperature: -10 °C
Reaction time: 0.62 h
Yield: 33.2 %

Procedure:
Trimethylsilyldiazomethane (0.12 mL, 2.0 M in diethyl ether, 0.25 mmol) was added dropwise to a suspension of 22 (110 mg, 0.19 mmol) in methanol (1 mL) and THF (3 mL) at −10 to 0° C., and the mixture was stirred at −10° C. for 30-45 min after addition. The solvent was removed under reduced pressure at 20-25° C. The residue (24, cis-trans mixture) was dissolved in anhydrous 1,4-dioxane (5 mL) and DDQ (100 mg, 0.44 mmol) was added to the solution. The reaction mixture was heated at reflux for 3-4 h. 1,4-Dioxane was evaporated under reduced pressure and chloroform (30 mL) was added to the residue. The mixture was washed with sodium bicarbonate (5%, 2×10 mL), water (15 mL), dried with sodium sulfate, and filtered through a thin layer of silica gel, eluting with chloroform. The combined filtrates were evaporated under reduced pressure. The amorphous solid containing 26 was added to a stirred solution of KOH (180 mg, 18.5 mmol) in water-ethylene glycol mixture (1+3 mL) at room temperature, and the mixture was heated at reflux on oil bath for 24 h. After the mixture was cooled to room temperature, it was diluted with water (5 mL) and acidified with acetic acid (0.5 mL). The white precipitate was collected by filtration to obtain 28 as a white powder (24 mg, 47%): mp 313° C. IR (KBr) 1650, 1604 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1 H), 9.36 (s, 1 H), 8.02 (d, J=8.3 Hz, 1 H), 7.71 (s, 1 H), 7.54 (t, J=7.6 Hz, 1 H), 7.44 (d, J=8.1 Hz, 1 H), 7.23 (t, J=7.6 Hz, 1 H), 4.51 (t, J=6.8 Hz, 2 H), 4.43 (t, J=4.8 Hz, 1 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.22 (dd, J=10.8, 5.5 Hz, 2 H), 2.05-1.81 (m, 2 H); 13C NMR (126 MHz, DMSO-d6) δ 162.82, 160.88, 152.96, 149.17, 144.41, 137.37, 130.28, 128.54, 126.19, 121.07, 118.95, 115.89, 113.14, 107.83, 107.40, 57.90, 55.63, 55.50, 48.77, 31.35; positive ESIMS m/z (rel intensity) 381 (MH+, 100). Anal. Calcd for C21H20N2O5: C, 66.31; H, 5.30; N, 7.36. Found: C, 66.03; H, 5.16; N, 7.26.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1)[C:12]1[N:16]([CH3:17])[N:15]=[N:14][N:13]=1
Reactant: NO
Reactant: COCc1cccc(C(=O)c2nnnn2C)c1
Agent: Cl
Solvent: c1ccncc1
Product: COCc1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a stirred solution of [3-(methoxymethyl)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (7.17 g, 31 mmol) in dry pyridine (50 mL) was added hydroxylamine hydrochloride (5.36 g, 77 mmol). The reaction mixture was stirred at 70° C. for 4 h, then concentrated in vacuo and diluted with ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, washed with water (100 mL) and dried (MgSO4). Evaporation of the solvent in vacuo afforded N-hydroxy-1-[3-(methoxymethyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine as a yellow oil [8.43 g, yield 99.5%; HPLC/MS:m/z=248 (M+H); log P(HCOOH)=1.54].
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH2:14][C:15]#[N:16])=[C:9]([F:17])[CH:8]=1.[OH-:18].[NH4+]>C(O)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([F:17])[C:10]([CH2:14][C:15]([NH2:16])=[O:18])=[C:11]([F:13])[CH:12]=1
Reactant: N#CCc1c(F)cc(Br)cc1F
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: NC(=O)Cc1c(F)cc(Br)cc1F
Temperature: 5 °C
Yield: 78 %

Procedure:
To a solution of sulfuric acid (0.96 mL, 18.1 mmol) in acetic acid (20 mL) was slowly added 2-(4-bromo-2,6-difluorophenyl)acetonitrile (0.84 g, 3.6 mmol) portion-wise while stirring, and the reaction mixture was then stirred for 1 h at 100° C. After cooling to 5° C., the mixture was carefully adjusted to pH 9 with 28-30% aq ammonium hydroxide and then was extracted with chloroform (3×40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% ethyl acetate/hexanes) provided the title product (0.71 g, 78%). MS(ES+) m/e 250 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 3.60 (s, 2 H) 5.54 (br. s., 2 H) 7.10-7.21 (m, 2 H).