Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH2:12]([O:19][C:20](=[O:40])[NH:21][CH:22]([C:25]1([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)[CH2:23][CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:19][C:20](=[O:40])[NH:21][CH:22]([C:25]1([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:26][CH2:27][CH:28]([NH:31][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:29][CH2:30]1)[CH2:23][CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(Nc2ccc3cnccc3c2)CC1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
In 1 mL of absolute toluene were dissolved 66.0 mg (0.32 mmol) of 6-bromo-isoquinoline, 151 mg (380 μmol) of {1-[4-amino-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamic acid benzyl ester (98), and 155 mg (476 μmol) of cesium carbonate. The solution was degassed twice, then 2.14 mg (9.5 μmol) of palladium acetate and 8.89 mg (14.3 μmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added and the reaction mixture was heated to 100° C. until complete conversion could be observed. The mixture was evaporated, then redissolved in 50 mL of dichloromethane and washed twice with 50 mL of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate, filtered, concentrated and purified by silica gel chromatography (dichloromethane:methanol) to give 48 mg of the pure desired product. Rt=1.38 min (Method 19). Detected mass: 524.4 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:16]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC1CCC(O)CC1
Solvent: c1ccncc1
Product: OC1CCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(Hydroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved in pyridine (15.0 mL) and the mixture was cooled to 0° C. To the reaction was added triphenylmethyl chloride (4.7 g, 0.017 mol) and the resulting mixture was stirred at 0° C. for 2 hours and at 25° C. for 16 hours. The reaction was then concentrated using a rotary evaporator, and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The reaction was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis isomer (0.74 g) 1H NMR (CDCl3): δ 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), 1.21-1.68 (m, 9H); and the trans isomer (2.72 g) 1H NMR (CDCl3): δ 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m, 1H), 2.88 (m, 2H), 1.98 (m, 2H), 1.88 (m, 2H), 1.60 (m, 1H), 0.99-1.37 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(=O)=O.[NH2:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[C:24]1([C:22]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:31][CH:30]=2)=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (35 ml,dry) was added to a mixture of 2,2-bis-trifluoromethyl 2-hydroxyacetic acid (1.08 g,5.1 mmol) and 1', 1'-carbonyldiimidazole (0.83 g, 5.1 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was refluxed for 0.5 hrs and cooled to 23° C. The reaction was treated with 4-aminobenzophenone (1.01 g, 5.1 mmol), stirred at 23° C. for 1.5 hrs, and then at reflux 18 hrs. The reaction was evaporated to a yellow oil-solid mixture. The mixture was dissolved in ethyl ether, treated with hydrogen chloride in ethyl ether, and filtered. The filtrate was evaporated to a yellow oil-solid mixture. Chromatography of this mixture on silica gel, eluting with 5% ethylether in methylenechloride provided the title compound as an off-white solid; mp=143°-146° C. 1H-NMR (250 MHz, d6 -DMSO): 7.67(m, 2H, ArH), 7.83(m, 5H, ArH),7.96(d, J=8.8, 2H, ArH), 9.82(s, 1H, OH), 10.82(s, 1H, NH). MS(CI,CH4): 392 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.Cl.[CH3:10][NH:11][O:12][CH3:13].C(N(CC)CC)C.CCCP(=O)=O>CN(C=O)C>[CH3:13][O:12][N:11]([CH3:10])[C:6]([CH:4]1[CH2:5][C:2](=[CH2:1])[CH2:3]1)=[O:8]
Reactant: C=C1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C1CC(C(=O)N(C)OC)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 3-methylenecyclobutanecarboxylic acid (525 mg, 4.68 mmol, Frontiers Scientific Services) in DMF (5 mL, aldrich) was added a solution of N,O-dimethyl hydroxylamine hydrochloride (0.55 g, 5.62 mmol, Aldrich) and triethylamine (0.78 mL, 5.62 mmol, Aldrich) in DMF (5 mL, Aldrich). The reaction was cooled to 0° C. and propylphosphonic anhydride solution (50 wt. % in DMF; 4.47 mL, 7.02 mmol, Alfa Aesar) was added. The reaction was stirred at RT for 16 h. The reaction was quenched with saturated NaHCO3 (10 mL) and stirred at RT for 5 min. The reaction was extracted with EtOAc (2×30 mL) and the combined organic extracts were washed with saturated ammonium chloride (2×40 mL), dried over MgSO4, and concentrated. The residue was dissolved in diethyl ether (5 mL) and the solution mixture was washed with H2O (2×10 mL), dried over MgSO4, concentrated, and dried in vacuo to give 398 mg of the title compound as a light yellow liquid. MS (ESI, positive ion) m/z: 156.1 (M+H).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A solution of methyl 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzoate (Part B) (2.232 g, 7.03 mmol) and 10.6 mL (10.6 mmol) of 1.0 N NaOH in 60 mL of 1:1 mixture of MeOH/THF was stirred at 80° C. for 20 h. The mixture was then cooled to room temperature, stirred for additional 7 h, and concentrated under reduced pressure. The residue was dissolved in 50 mL of 1.0 N HCl. This solution was extracted with 200 mL of EtOAc. The organic layer was washed with 200 mL of water. The combined aqueous layers were cooled to 0° C. and neutralized with 15 mL of 2.0 N NaOH. They were then concentrated under reduced pressure and the residue was taken up in 10% MeOH in CH2Cl2 and then filtered. The filtrate was concentrated and the residue was dried over P2O5 in a vacuum oven at 55° C.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[O:6]=[C:7]1[NH:12][CH2:11][CH2:10][N:9]2[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:8]12.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:1]1([CH2:4][N:12]2[CH2:11][CH2:10][N:9]3[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:8]3[C:7]2=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Temperature: 70 °C

Procedure:
To a solution of cyclopropylmethyl bromide (0.101 g, 0.75 mmol) and ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (31.4 mg, 0.150 mmol) in acetonitrile (2 mL) was added cesium carbonate (147 mg, 0.45 mmol). The reaction mixture was heated overnight at 70° C. Upon cooling to room temperature, the insolubles were removed by filtration and the solvent evaporated to dryness to afford crude Intermediate 33.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:14]2([CH2:17][C:16](=[O:18])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2([CH2:17][C:16]([OH:18])([CH3:21])[CH2:15]2)[CH2:19][CH2:20]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Yield: 55 %

Procedure:
To a stirred solution of 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (164 mg, 0.60 mmol) in dry THF (2 mL) was added dropwise a 1.4 M solution of methylmagnesium bromide in toluene/THF (0.56 mL, 0.78 mmol) under an atmosphere of nitrogen, at −78° C. After 1 h the solution was quenched with saturated NH4Cl(aq) and the resulting mixture partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated to give a residue, which was purified by column chromatography (Si—PCC, 0-70% EtOAc in cyclohexane) to give 2-Hydroxy-2-methyl-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (96 mg, 55%) as a colourless oil. LCMS (Method H): RT 4.13 min, [M+H]+ 290.4
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[N:7][N:6]2[CH:12]=1.[OH-].[NH4+:14]>>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([CH:12]=[C:3]([CH2:2][NH2:14])[N:4]=2)[N:7]=1
Reactant: Cc1ccc2nc(CCl)cn2n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1ccc2nc(CN)cn2n1
Temperature: 80 °C

Procedure:
A mixture of 2-(chloromethyl)-6-methylimidazo[1,2-b]pyridazine (0.6 g, 3.3 mmol) and ammonium hydroxide (25%, 30 ml) was heated to 80° C. in a sealed tube for lhr. The reaction mixture was concentrated under reduced pressure to give title compound as crude product. This material was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:25][CH2:26][O:27][C:28](/[C:30](/Cl)=[N:31]\O)=[O:29]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:17][N:31]=[C:30]([C:28]([O:27][CH2:26][CH3:25])=[O:29])[C:9]=2[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(I)c1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1noc(-c2cccc(I)c2)c1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.2 %

Procedure:
tert-Butyl 3-(3-iodophenyl)-3-oxopropanoate (1.91 g, 5.52 mmol) was dissolved in ethanol (6 mL), cooled to 0° C., and Et3N (558 mg, 5.52 mmol) was added. After stirring 20 minutes, ethyl chlorooximidoacetate (836 mg, 5.52 mmol) in EtOH (3 mL) was added to the reaction mixture over 30 min. The reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was concentrated in vacuo and purified by column chromatography (0–13% ethyl acetate in hexanes) to provide the titled compound (860 mg, 35%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=2[N:9]=[CH:8]1.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:42][O:43][NH:44][CH3:45]>C(Cl)Cl.O>[CH3:42][O:43][N:44]([CH3:45])[C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid (170 mg, 0.69 mmol) in DCM (5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (190 mg, 1 mmol), HOBt (160 mg, 1 mmol), TEA (0.3 mL) and N-methoxy-methanamine hydrochloride (100 mg, 1 mmol). The mixture was stirred at RT overnight. The mixture was poured into water and extracted with EtOAc. The organics were washed sequentially with water and brine, then dried (Na2SO4). Removal of solvent followed by SiO2 chromatography afforded N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxamide (140 mg, 85% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:57])[CH3:54])=[O:51])[N:5]=1.C1(C)C=CC=CC=1.CO>O>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
A mixture of trityl candesartan cilexetil (20 g, 23.45 mmol), toluene (60 ml), methanol (60 ml), and water (1 ml) was gently refluxed for about 12 h. The reaction was monitored by HPLC. The solution volume was reduced by evaporation under reduced pressure (30 mbar) at a temperature of about 55° C. 60° C. to obtain viscous oil of candesartan cilexetil as a residue (36.5 g).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH3:26][C@H:27]1[CH2:32][C:31](=O)[CH2:30][CH2:29][C@H:28]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>C1COCC1>[CH3:2][O:3][CH:4]=[C:31]1[CH2:30][CH2:29][C@@H:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C@@H:27]([CH3:26])[CH2:32]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCC(=O)C[C@@H]1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC(=COC)C[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (1.7 g, 5.0 mmol) in THF (10 mL) was added sodium hydride (108 mg, 4.5 mmol, 60 wt %) in several portions at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. Then ethyl rel-(1R,2S)-2-methyl-4-oxocyclohexanecarboxylate (500 mg, 2.7 mmol) in THF (5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. Water was then added dropwise at 0° C. and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give ethyl rel-(1R,2S)-4-(methoxymethylidene)-2-methylcyclohexanecarboxylate, which was dissolved in THF and aqueous hydrochloric acid (6 M) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then diluted with water. The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl rel-(1R,2S)-4-formyl-2-methylcyclohexanecarboxylate. MS ESI calc'd for C11H19O3 [M+H]+ 199. found 199. 1H NMR: (400 MHz, CDCl3) δ 9.67-9.57 (m, 1H), 4.22-4.05 (m, 2H), 2.65-1.52 (m, 9H), 1.25 (t, J=7.2 Hz, 3H), 1.03-0.88 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:22](=O)[CH:21]2[CH:16]([NH:17][CH2:18][CH2:19][CH2:20]2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.N>C1COCC1>[CH2:7]([N:14]1[CH2:22][CH:21]2[CH:16]([NH:17][CH2:18][CH2:19][CH2:20]2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCCNC3C2)cc1
Yield: 93.7 %

Procedure:
In 50 ml of anhydrous THF was suspended 4.9 g of lithium aluminum hydride, and a solution of 3 g of 6-benzyl -5,7-dioxo-octahydropyrrolo[3.4-b]pyridine in 50 ml of anhydrous THF was added thereto dropwise with stirring while cooling with ice. After the addition, the reaction mixture was heated under reflux for 6 hours. After completion of the reaction, 4.9 ml of water, 4.9 ml of aqueous ammonia, and 15 ml of water were added to the reaction mixture in this order while cooling with ice, followed by stirring for 30 minutes. The reaction mixture was filtered through Celite®, and the filter cake was washed with THF (100 ml×4). The combined filtrate and washings were dried over anhydrous sodium sulfate and concentrated to yield 2.49 g of the titled compound as an oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][C:16]([CH3:22])([CH3:21])[CH2:15][C:14]=3[NH:13][C:12]3[NH:23][N:24]=[CH:25][C:11]2=3)=[N:6][CH:7]=1.[CH2:26]1[CH:28]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:27]1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[F:40].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[F:33][C:34]1[CH:35]=[C:36]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH:10]3[C:19]4[C:18](=[O:20])[CH2:17][C:16]([CH3:22])([CH3:21])[CH2:15][C:14]=4[NH:13][C:12]4[NH:23][N:24]=[CH:25][C:11]3=4)=[N:6][CH:7]=2)[CH:37]=[CH:38][C:39]=1[F:40].[CH2:27]1[CH:28]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:26]1
Reactant: CC1(C)CC(=O)C2=C(C1)Nc1[nH]ncc1C2/C=C/c1ccc(Br)cn1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: NC(=O)CC1CC1
Product: CC1(C)CC(=O)C2=C(C1)Nc1[nH]ncc1C2/C=C/c1ccc(-c2ccc(F)c(F)c2)cn1

Procedure:
The title compound is prepared according to procedure C from 125 mg of 4-[(E)-2-(5-bromopyridin-2-yl)vinyl]-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinoline-3-cyclopropylmethylcarboxamide, 60 mg of 3,4-difluorophenylboronic acid, 134 mg of K3PO4 and 37 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride.
Reaction SMILES: [C:1]([O:4]C1C=CC=CC=1)(=[O:3])[CH3:2].C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[F:25][C:26]([F:62])([F:61])[C:27]1[CH:28]=[C:29]([S:37]([NH:40][C:41]2[CH:56]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:54]=[CH:53][C:42]=2[O:43][C:44]2[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=2C([O-])=O)(=[O:39])=[O:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:35][C:33]([F:36])([F:34])[C:31]1[CH:30]=[C:29]([S:37]([NH:40][C:41]2[CH:56]=[C:55]([C:57]([F:59])([F:60])[F:58])[CH:54]=[CH:53][C:42]=2[O:43][C:44]2[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=2[CH2:2][C:1]([OH:4])=[O:3])(=[O:38])=[O:39])[CH:28]=[C:27]([C:26]([F:61])([F:62])[F:25])[CH:32]=1
Reactant: O=C([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Oc1ccccc1
Agent: OC(c1ccccc1)c1ccccc1
Product: O=C(O)Cc1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Following the procedure of Example 1(f) except substituting benzhydrol 2-[3,5-bis (trifluoromethyl)phenylsulfonamido]-4-trifluoromethylphenoxy]phenyl acetate for benzhydrol 2-[2-[3,5-bis(trifluoromethyl)phenylsulfonamido]-4-trifluoromethylphenoxy]benzoate, the title compound was obtained; mp 165°-166° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([S:45]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][N:6]3[C:2](=[O:1])[C:3]([CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)([CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[NH:4][C:5]3=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)=[O:16])[CH2:9][CH2:10]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
According to the procedure of Example 13, the title compound of 40B (50 mg, 0.099 mmol) and benzenesulfonyl chloride (0.025 ml, 0.198 mmol) were reacted to generate the title compound as a white solid (25 mg, 0.037 mmol, 37% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:9]=2[CH2:10]Cl)=[CH:4][C:3]=1[CH3:18].C([O:21][P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>>[C:23]1([P:22]([CH2:10][C:9]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:18])[CH:4]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(C)c(CCl)c(-c2ccc(F)c(C)c2)c1
Reactant: CCOP(c1ccccc1)c1ccccc1
Product: Cc1cc(C)c(CP(=O)(c2ccccc2)c2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: 150 °C

Procedure:
2.90 grams (12 mmol) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzaldehyde (prepared according to Stokker, Journ. Med. Chem., Vol. 29 p.170, 1986) was reduced with 0.454 grams (12 mmol) of sodium borohydride in ethanol (20 mL) at 0° C. The reaction was stirred 1 hr, quenched with aqueous ammonium chloride and the mixture extracted with ether. The organic portion was dried (MgSO4) and concentrated to give 2.90 grams of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl alcohol as an oil which solidified on standing. The crude solid was treated with 1.31 mL of thionyl chloride and heated on a steam bath for 1 hour. After cooling to room temperature, the crude mixture was taken up in water and extracted with ether. The ether was washed with water and dried(MgSO4), and concentrated to give an oily residue which was purified by silica gel chromatography (25% methylene chloride/75% hexane) to give 2.70 grams (85.6%) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl chloride as a solid. 2.06 grams (7.84 mmol) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl chloride was treated with ethyldiphenylphosphinite (2.08 grams, 9.01 mmol) and heated to 150° C. for 3 hrs. After cooling to room temperature, the crude mixture was purified by silicagel chromatography (10% acetone/90% methylene chloride) and the appropriate fractions concentrated and recrystallized from ether/hexane to provide the above-titled compound. MP 109-111° C.