Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([S:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[CH:9][C:8]=1[N+:18]([O-])=O)=[O:5]>O=[Pt]=O.C(O)C>[CH3:1][S:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([S:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[CH:9][C:8]=1[NH2:18])=[O:5]
Reactant: CSCC(=O)Nc1cc(SCC(C)C)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: CSCC(=O)Nc1cc(SCC(C)C)ccc1N

Procedure:
A mixture of 12.4 g of 2-(methylmercaptoacetylamino)-4-[(2-methylpropyl)thio]nitrobenzene, 1.3 g PtO2 and 200 ml of ethanol is reduced on the Parr hydrogenator at 50 psi until the required amount of H2 is absorbed. The mixture is filtered, the solvent removed and the residue used immediately in the next reaction.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([C:42]([O:44]CC3C=CC=CC=3)=[O:43])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)=[C:28]([CH:52]([CH3:54])[CH3:53])[NH:27][N:26]=1)(=[O:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])=[CH:35][CH:36]=2)=[C:28]([CH:52]([CH3:54])[CH3:53])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)OCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropy-1H-pyrazole (0.28 g) was dissolved in methanol (6 mL). To the solution was added 10% palladium-carbon powder (54 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.25 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH:27]2[CH2:29][CH2:28]2)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH3:31].N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH:27]2[CH2:28][CH2:29]2)[N:8]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:30][CH3:31])=[CH:34][CH:35]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C2CC2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(C2CC2)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 83.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-cyclopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-ethoxyphenyl)boronic acid (0.87 g), copper(II) acetate (0.95 g), pyridine (1.1 mL), triethylamine (1.8 mL), molecular sieves 4 A (2.0 g) and dichloromethane (20 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (1.1 g, 84%) as a pale-yellow liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[CH:10][C:11]1[C:16]([Br:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Br:19].BrC1C=C(C)C=C(Br)C=1C=O.Cl.C1(NN)C=CC=CC=1>>[C:3]1([NH:8][N:9]=[CH:10][C:11]2[C:12]([Br:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=2[Br:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Cc1cc(Br)c(C=NNc2ccccc2F)c(Br)c1
Agent: Cc1cc(Br)c(C=O)c(Br)c1
Agent: Cl
Solvent: NNc1ccccc1
Product: Cc1cc(Br)c(C=NNc2ccccc2)c(Br)c1

Procedure:
Similarly prepared to Intermediate 25 from 2,6-dibromo-4-methylbenzaldehyde and phenylhydrazine hydrochloride.
Reaction SMILES: C([O:9][CH2:10][CH:11]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)=[CH:17][C:16]=1[Cl:36])(=O)C1C=CC=CC=1.[OH-].[Na+].O>C(O)C>[CH2:29]([O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH:11]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:10][OH:9])=[C:16]([Cl:36])[CH:17]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCC(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)Nc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCC(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
The compound of Example 128-2 (560 mg) was dissolved in ethanol (10 mL). To this solution, a 1 mol/L aqueous solution of sodium hydroxide (5 mL) was added and the mixture was stirred at room temperature for 1 hour. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed with a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product as a colorless oil (290 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)(O)[O-].[Na+].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].O>C1COCC1>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCNc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-fluoronitrobenzene (2.0 g, 14 mmol) and sodium bicarbonate (5.9 g, 71 mmol) in 30 mL THF under nitrogen was added N1, N1-dimethylethane-1,2-diamine (1.7 mL, 16 mmol). The reaction was allowed to stir at ambient temperature for 3 h, and then a water-cooled reflux condenser was added and the mixture was heated to 70° C. for 16 h. The reaction was cooled to ambient temperature, filtered through paper, and concentrated in vacuo to give N-(2-(dimethylamino)ethyl)-2-nitrobenzenamine as a yellow oil. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>N1CCCCC1.CO>[C:13]([C:15](=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C(C#N)=Cc1ccc(OC)c(OC)c1

Procedure:
A mixture of 3,4-dimethoxybenzaldehyde 4.15 g, 0.025 mol), methyl cyanoacetate (2.48 g, 0.025 mol), methanol (100 mL) and piperidine (10 drops) is heated at reflux for 2 hours. The reaction mixture is then cooled and the product collected by filtration, washed with methanol and dried in air (yield--6.0 g, 97%). The following structure is supported by mass spectrometry: ##STR20## The compound has an absorption maximum at 361 nm in methylene chloride.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH:16]C(=O)OCC)=[S:15])[CH:11]=2)[NH:6][CH:5]=1)#[N:2]>[OH-].[Na+].C(O)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[S:15])[CH:11]=2)[NH:6][CH:5]=1)#[N:2]
Reactant: CCOC(=O)NC(=S)Nc1ccc2[nH]cc(CC#N)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCc1c[nH]c2ccc(NC(N)=S)cc12

Procedure:
A solution of ethyl [[[3-(cyanomethyl)-1H-indol-5-yl]amino]thiocarbonyl]carbamate (0.5 g) in 2N sodium hydroxide (3 ml) and ethanol (10 ml) was stirred at 40° C. for 2 h. The resulting precipitate was filtered off, triturated with water (40 ml), washed with ethanol (ca. 30 ml) and dried in vacuo to give the title compound as a white solid. (0.25 g) m.p. 212°-214°C.
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=[O:34].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:1]1([CH2:8][O:9][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH:33]=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(O)c1
Reactant: OCC1CCCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OCC2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold solution of cycloheptylmethanol (5.244 g, 40.9 mmol), triphenylphosphine (10.73 g, 40.9 mmol) and 3-hydroxybenzaldehyde (11) (5.0 g, 40.9 mmol) in THF (50 mL) was added diethyl azodicarboxylate (9.097 g, 44.99 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the residue was suspended in 20% diethyl ether-hexanes. Solids were removed by filtration then the mixture was concentrated under reduced pressure. Purification by flash chromatography (5% EtOAc-hexanes) gave 3-(cycloheptylmethoxy)benzaldehyde as a colorless oil. Yield (3.9 g, 41%): 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.46-7.51 (m, 2H), 7.39-7.40 (m, 1H), 7.25 (dt, J=6.8, 2.6 Hz, 1H), 3.81 (d, J=6.8 Hz, 2H), 1.88-1.93 (m, 1H), 1.76-1.82 (m, 2H), 1.22-1.68 (m, 10H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12]CNCC2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:21]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([O:34]CCI)=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]([CH3:38])[CH:24]=3)=[CH:22][C:15]=12>>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[C:21]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:12][CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]5[CH:4]5[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]5)=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]([CH3:38])[CH:24]=3)=[CH:22][C:15]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Reactant: C1CCN(C2CCNCC2)CC1
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCCCC1C1CCNCC1
Yield: 97.6 %

Procedure:
4-Chloro-2-[1-methyl-5-methoxy-6-(2-(4-piperidylpiperidin-1-yl)ethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 147b, but using 0.212 g of 4-piperidinopiperidine and 0.400 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. 0.415 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-(4-piperidylpiperidin-1-yl)ethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[C-:34]#[N:35].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CS(C)=O.CCOC(C)=O>[O:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:16]12[CH2:19][CH2:20][C:13]([CH2:12][C:34]#[N:35])([CH2:18][CH2:17]1)[CH2:14][O:15]2)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4Oc4ccccc4)(CC2)OC3)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCC12CCC(c3ccccc3Oc3ccccc3)(CC1)OC2
Temperature: 135 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
A mixture of (1-(2-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzene-sulfonate (230 mg, 0.495 mmol), Bu4NI (2 mg, 4.95 μmol), and NaCN (73 mg, 1.49 mmol) in DMSO (10 mL) was stirred at 135° C. under N2 for 20 h, then cooled to rt. The reaction was diluted with EtOAc (10 ml) and washed with water (20 ml×4). The organic layer was concentrated in vacuo to give a crude brown oil, which was purified by flash chromatography (SiO2) using a gradient from 0% to 30% EtOAc/hexane (20 min) to give the title compound (150 mg, 0.470 mmol, 95% yield) as a clear oil. LCMS [M+Na]+=342.1. 1H NMR (CDCl3) δ: 7.77-7.72 (dd, J=7.7, 1.9 Hz, 1H), 7.38-7.33 (m, 2H), 7.22-7.16 (m, 1H), 7.15-7.10 (m, 2H), 7.01-6.95 (m, 2H), 6.83-6.79 (dd, J=8.0, 1.3 Hz, 1H), 3.98 (s, 2H), 2.70-2.58 (m, 2H), 2.22 (s, 2H), 2.05-1.94 (m, 2H), 1.88-1.74 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[C:10]([N+:19]([O-])=O)[CH:9]=2)[C:3]1=[O:22].C(OCC)(=O)C.O.[OH-].[Na+]>Cl.[Zn]>[NH2:19][C:10]1[CH:9]=[C:8]([N:4]2[C:3](=[O:22])[C:2]([CH3:1])([CH3:23])[NH:6][C:5]2=[O:7])[CH:13]=[CH:12][C:11]=1[S:14][C:15]([F:18])([F:16])[F:17]
Reactant: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)c([N+](=O)[O-])c2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)c(N)c2)C1=O
Temperature: 50 °C
Yield: 25 %

Procedure:
To a suspension of 1.75 g of 5,5-dimethyl-3-{3-nitro-4-[(trifluoromethyl)thio]phenyl}imidazolidine-2,4-dione obtained in stage b) below in 60 mL of concentrated hydrochloric acid are added, portionwise, 7.5 g of zinc powder. The reaction mixture is heated at 50° C. for 8 hours and then cooled to room temperature and poured into a mixture of 100 mL of ethyl acetate and 20 mL of water. 5N sodium hydroxide solution is then added to pH 8 and the solid formed is then filtered off through Celite and washed with ethyl acetate. The phases are separated, the aqueous phase is washed with ethyl acetate and the combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 400 mg of 3-{3-amino-4-[(trifluoromethyl)thio]phenyl}-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: O.[OH-].[Na+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH:22]3[CH2:24][CH2:23]3)=[CH:17][N:16]=2)[C:13]=1[CH3:14])=[O:8])C.Cl>C(O)C>[Cl:21][C:20]1[C:15]([N:12]2[C:13]([CH3:14])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]2)=[N:16][CH:17]=[C:18]([CH:22]2[CH2:23][CH2:24]2)[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(C3CC3)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ncc(C2CC2)cc1Cl
Temperature: 90 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Water (2 ml) and 4N aqueous solution of sodium hydroxide (2 ml) were added to a solution of 1-(3-chloro-5-cyclopropylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (240 mg) in ethanol (4 ml) at room temperature, and stirred at 90° C. for six hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution (9 ml) was added. The precipitated solid was collected by filtration to give the titled compound (157 mg) as a light brown solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]4[C:18]([CH3:20])([CH3:19])[C:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:3]=1)(=[O:25])[CH3:24]
Reactant: Cn1c2c(c(=O)n1-c1cccc(I)c1)C1CCC2(C)C1(C)C
Reactant: CC(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)c1ccccc1-c1cccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1

Procedure:
A mixture of 2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 23; 80 mg, 0.2 mmol), 2-acetyl-phenyl-boronic acid (49 mg, 0.29 mmol), potassium carbonate (66 mg, 0.47 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol) in dimethoxyethane (4 mL) was sealed under argon and heated at 80 degrees overnight and then at 90 degrees over the weekend. The reaction mixture was diluted with dichloromethane, filtered through a cotton plug and frit, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-80% ethyl acetate/hexanes to give (4S,7R)-2-(2′-acetyl-biphenyl-3-yl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one and unreacted starting material (40 mg, 50%). The product was further purified by preparative HPLC (Gilson 215 collector, Shimadzu prep HPLC system, Leap autoinjector. Solvent (A) 0.05% TFA/H2O (B) 0.035% TFA/ACN, using a linear gradient of 20-80% solvent B in 10 minutes, with a C-18 column, 2.0×10 cm eluting at 20 ml/min and UV-directed collection) followed by lyophilization to give (4S,7R)-2-(2′-acetyl-biphenyl-3-yl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (9 mg, 11%) as a white solid. ES(+)-MS (M+H) 401.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1.CS(O[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)(=O)=O>CC#N>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH2:10]2)[CH2:6]1
Reactant: CC(C)(C)C(=O)CN1CC2CNCC(C1)O2
Reactant: CS(=O)(=O)OCCc1ccc(C#N)cc1
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1CC2CN(CCc3ccc(C#N)cc3)CC(C1)O2
Temperature: 50 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 3,3-dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone (from step (ii) above; 56 mg, 0.25 mmol), TEA (0.35 mL, 2.5 mmol) and MeCN (2 mL) was treated with 4-cyanophenethyl methanesulfonate (see step (iii) above; 84 mg, 0.37 mmol). The resulting mixture was stirred at 50° C. for 24 h. The solvents were removed by evaporation, the crude product was dissolved in DCM and then the solution was added to an ion-exchange solid-phase extraction plug (2 g, CBA (carboxylic acid on silica support)). After 1 h, the plug was washed with DCM (15 mL), after which the product was finally eluted with DCM:MeOH:TEA (90:5:5), to give 84 mg (95%) of the title compound.
Reaction SMILES: C([CH2:4][SiH:5](Cl)[Cl:6])C=C.[CH2:8]([Mg]Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CCCCCC>O1CCCC1>[CH3:4][SiH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[Cl:6]
Reactant: C=CCC[SiH](Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC[SiH](C)Cl

Procedure:
was prepared as follows. Allylmethyldichlorosilane (0.69 moles, available from the Aldrich Chemical Co., Milwaukee, Wis., USA) was put into a reaction flask with 250 milliliters of tetrahydrofuran (THF). One molar octadecylmagnesium chloride (0.65 moles) in THF was added portionwise to the flask while the mixture was stirred and cooling to a temperature range of about -10° to +5°. The temperature of this mixture was allowed to increase to 24°. Hexane was added to the mixture, and the solid filtered off. The filtrate was evaporated on a rotary evaporator to leave an oil. The oil was vacuum-distilled, providing 134.7 g (55.8% relative to the theoretical yield) of ally methyl octadecyl-chlorosilane (compound A) as a clear, colorless oil. The boiling point of compound A was 188°/0.1-191°/0.2 mm, and gas chromatography/mass spectrometry (GC/MS) showed 100% compound A.
Reaction SMILES: [Br-].Br[CH2:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[Cl-].[NH4+]>C1COCC1.O>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[CH:3])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: BrCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve 276.5 g (0.634 mole) of bromoethyltriphenylphosphonium bromide in 1800 ml THF and cool to -78° C. Add 67.6 g (0.062 mole) potassium tert.-butoxide and stir at -78° C. for 2 hours. Add 89.12 g p-chlorobenzaldehyde in 200 ml THF to cold reaction mixture and stir for 30 minutes. Add 142.3 g potassium tert.-butoxide and then allow to warm to room temperature. After 18 hours, add 500 ml saturated aqueous ammonium chloride solution and 500 ml H2O and extract with 500 ml diethyl ether. Wash organic layer with 2×400 ml saturated aqueous sodium chloride solution, dry over magnesium sulfate, filter and evaporate solvent to dryness. Wash residue with 200 ml hexane and filter off precipitate. Evaporate hexane and dissolve material in 150 ml hexane:methylene chloride (66:33) solution and elute through column containing 300 g silica gel (Merck 60-230 mesh) with hexane:methylene chloride (66.33) solution. Monitor column chromatography using thin-layer chromatography on silica gel (hexane:methylene chloride, 66:33). Collect desired fraction and evaporate solvent. Distill residue in vacuo and collect fraction boiling at 65° C. (8.5 mmHg) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)CCC.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=[C:2]([NH2:1])[CH:7]=2)[CH:19]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: Nc1cc(-c2cccnc2)cc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
A stirred solution of 3-amino-5-bromo-benzotrifluoride (Apollo, England; 1.12 g, 5 mmol) and 3-(tri-n-butylstannyl)pyridine (Maybridge Chemical Co. Ltd., England; 2.0 g, 5.4 mmol) in xylene (30 mL) was purged with argon for 10 minutes at 20° C. Tetrakis(triphenylphosphine)-palladium (0) (1.16 g, 1.0 mmol) is then added and the resulting mixture is heated at 140° C. for 36 hours under an argon atmosphere. The mixture is then cooled, treated with an aqueous solution of sodium hydroxide (100 mL of 0.1 M) and purged with air for 2 hours. The resulting mixture is then diluted with ethylacetate (200 mL) and filtered. The organic phase is then sequentially washed with water (2×80 mL) and saturated aqueous sodium chloride (1×80 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent ethyl acetate) to afford the title compound as a brown oil. 1H-NMR (400 MHz, DMSO-d6, δ): 5.73 (br s, 2H), 6.83 (dd, 1H), 6.99 (d, 1H), 7.04 (d, 1H), 7.39 (dd, 1H), 7.64 (d, 1H), 8.42 (m, 1H) and 8.53 (dd, 1H).