Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]#[C:28][C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: CCCC[Sn](C#Cc1ccc(Cl)cc1)(CCCC)CCCC
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc(C#Cc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A of Procedure 11 (30 mg, 0.092 mmol), tributyl((4-chlorophenyl)-ethynyl)stannane (79 mg, 0.185 mmol), copper (I) iodide (5.28 mg, 0.028 mmol), and palladiumtetrakis (16 mg, 0.014 mmol) in DMF (1 mL) was stirred under nitrogen at 55° C. for 3 hours. The reaction was cooled to RT, diluted with CH2Cl2, washed with water, sat. NaHCO3, dried (Na2SO4), and concentrated to afford the crude product. The residue was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient). The product was re-purified using HPLC (C18 column/10:90 to 90:10 MeOH—H2O) to afford the desired product 6-((4-chlorophenyl)ethynyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one J-2 (12.4 mg, 0.028 mmol, 30.0% yield) as a yellow solid. LC/MS 425 (M+H)+, tR 0.95 min (method 5); 1H NMR (400 MHz, CDCl3) δ 8.14-8.17 (1H, m), 7.55 (2H, d), 7.39 (2H, d), 7.01 (1H, d), 6.85-6.93 (2H, m), 6.75 (1H, s), 3.89 (3H, s), 3.88 (2H, s), 1.37 (6H, s).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC>O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[CH:9]1[OH:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cc1ccc2c(c1)C(=O)C(C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)Cc1ccc2c(c1)C(O)C(C(C)(C)O[SiH2]C(C)(C)C)CC2
Temperature: -12.5 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a −30° C. cooled solution of 2-(tert-Butyl-dimethyl-silanyloxymethyl)-7-(2,2-dimethyl-propyl)-3,4-dihydro-2H-naphthalen-1-one (2.20 g, 6.09 mmol) in tetrahydrofuran (20 mL) was added (S)-2-methyl-Cbs-oxazaborolidine (1 M in toluene, 0.61 mL, 0.61 mmol) and a solution of borane-methyl sulfide complex (2 M in tetrahydrofuran, 2.15 mL, 4.3 mmol) in tetrahydrofuran (5 mL). The reaction mixture was heated at −20 to −5° C. for 5 h. The reaction mixture was quenched with methanol (8.3 mL) at −5° C. and then allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure. Flash column chromatography (silica gel, 0-5% ethyl acetate/hexanes) recovered 790 mg of ketone and provided chiral 2-(tert-Butyl-dimethyl-silanyloxymethyl)-7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naphthalen-1-ol (980 mg, 70%): 1H NMR (300 MHz, CDCl3) δ 7.14 (s, 1H), 7.03-6.96 (m, 2H), 4.84 (d, J=2.5 Hz, 1H), 3.92-3.82 (m, 2H), 3.04 (d, J=3.7 Hz, 1H), 2.92-2.67 (m, 2H), 2.46 (s, 2H), 2.04-1.86 (m, 2H), 1.75-1.63 (m, 1H), 0.91 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[O:11][CH3:12].Cl[Sn]Cl.Cl>C1COCC1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: COc1c(N)cccc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-Bromo-2-methoxy-3-nitro-benzene (17.8 g, 0.0768 mol), SnCl2 (69.27 g, 0.3069 mol) and 4N HCl (80 mL) in THF (200 mL) is stirred at 80° C. for 16 h. After reaction, evaporated out THF and added NaHCO3 solution, filtered and the filtrate is extracted with ethyl acetate (3×800 mL). The combined organic phase is ished with water and brine, dried over Na2SO4, concentrated in vacuo to give the desired product. Yield: 14.8 g (96%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:31]4[CH:27]([CH3:26])[CH2:28][CH2:29][C:30]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4C(=O)CCC4C)cc3F)CC2)c(C)c1
Yield: 39 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and 5-methylpyrrolidin-2-one (48 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (81 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Br-].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][Zn+])=[CH:37][CH:36]=1.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:22]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Reactant: COc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2ccc3c(-c4ccc(C)c(C)c4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
A mixture of methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (34.0 mg, 0.070 mmol) and (4-methoxybenzyl)zinc(II) bromide (0.280 mL, 0.140 mmol) in N,N-Dimethylformamide (DMF) (1.2 mL) was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (8.08 mg, 6.99 μmol) was added and the mixture was irradiated in the microwave at 120° C. for 20 minutes. The mixture was diluted with ethyl acetate, washed with water, followed by brine, dried over sodium sulfate, filtered and then concentrated to give a dark residue. The crude residue was treated with 2M lithium hydroxide (0.140 mL, 0.280 mmol) in Tetrahydrofuran (THF) (0.8 mL) and Methanol (0.8 mL) and then stirred at 70° C. for 30 minutes. Additional 2 M lithium hydroxide (0.200 mL, 0.400 mmol) was added and the mixture was stirred at 70° C. for 2 additional hours. The mixture was concentrated and the residue was purified by reverse phase chromatography to afford the title compound as a white solid (11 mg, 31%). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.39-8.30 (m, 1 H), 7.41-7.29 (m, 2 H), 7.29-7.18 (m, 1 H), 7.17-7.09 (m, 2 H), 7.09-6.96 (m, 2 H), 6.81 (dd, J=2.0, 8.6 Hz, 2 H), 5.34 (s, 1 H), 4.04 (s, 2 H), 3.77 (s, 3 H), 3.68 (s, 3 H), 2.35 (m, 3 H), 2.30 (m, 3 H), 1.06 (m, 9 H); LC/MS (m/z) ES+=514 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=2[CH3:36])[C:5]([CH2:25][CH3:26])=[C:6]([N:8]([CH2:23][CH3:24])[CH:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:15][CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH2:23][CH3:24])[C:6]2[C:5]([CH2:25][CH3:26])=[C:4]([CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:27]([NH:28][CH2:29][C:30]2[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=2[CH3:36])=[O:39])[CH2:14][CH2:13]1
Reactant: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(CC)C1CCC(N)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 130.7 %

Procedure:
To a stirred solution of tert-butyl N-{4-[(5-chloro-3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-2-ethylphenyl)(ethyl)amino]cyclohexyl}carbamate (100 mg, 0.18 mmol) in CH2Cl2 (4.0 ml) at 0° C., was added trifluoroacetic acid (1.0 ml). The reaction mixture was stirred at 0° C. for 40 minutes and then stirred for 2 hours at room temperature. The reaction mixture was concentrated in-vacuo and the residue was basified with a saturated solution of NaHCO3 (aq) (10 ml) until the pH was 8. The aqueous residue was extracted with 20% MeOH/CH2Cl2 (4×15 ml). The combined organic layers were dried (MgSO4), filtered and concentrated in-vacuo to give the title compound (108 mg, 113%) as a yellow solid. LC-MS 48%, 2.88 min (7 minute LC-MS method), m/z=459.1 and 39%, 2.96 min (7 minute LC-MS method), m/z=459.1. 1H NMR shows a mixture of cis/trans isomers.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:17][C:18]([O:20]C)=O)[NH2:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]=[C:24]=[O:25].C[O-].[Na+]>>[CH3:22][N:23]1[C:18](=[O:20])[CH2:17][N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[NH:16][C:24]1=[O:25]
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Product: CN1C(=O)CN(c2ccc(OCc3ccccc3)cc2)NC1=O

Procedure:
Methyl [1-[4-(phenylmethoxy)phenyl]hydrazino]acetate (0.73 g) was treated with methyl isocyanate (0.5 ml) and then with sodium methoxide solution (3.5 ml). The product was recrystallised from tetrahydrofuran-hexane to give the title compound (0.56 g), m.p. 224°-227°, t.l.c. (ethyl acetate) Rf 0.55.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+:26]>>[Na+:26].[O:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]([O-:24])=[O:2])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 95.7 %

Procedure:
The title compound (96 mg, 95%) was prepared from the compound from step 1 (100 mg, 0.30 mmol) and 1N NaOH (0.3 mL, 0.3 mmol) by the procedure described in Example 2: MS (ESI) m/z 313 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 2.57 (t, J=4.8 Hz, 4H), 2.67 (s, 2H), 3.07 (t, J=4.8 Hz, 4H), 6.89-6.96 (m, 6H), 7.04 (m, 1H), 7.32 (m, 2H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:11]3([OH:27])[CH2:12][CH2:13][C@@H:14]2[CH2:15][C:16]#[N:17])[CH2:6]1)(=O)C.P([O-])(O)(O)=O.[Na+]>CO.O1CCCC1.[OH-].[Na+]>[OH:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:11]3([OH:27])[CH2:12][CH2:13][C@@H:14]2[CH2:15][C:16]#[N:17])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](CC#N)CC[C@]32O)C1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC#N)CC[C@]12O
Yield: 86.2 %

Procedure:
A solution of 11.18 g of 3β-acetoxy-14β-hydroxy-5β-pregnane-21-nitrile in 260 ml of methanol, 260 ml of tetrahydrofuran and 143 ml of 1N NaOH was stirred at room temperature for 20 hrs. The mixture was then neutralized with sodium dihydrogenphosphate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to dryness under reduced pressure to give 8.55 g of 3β,14β-dihydroxy-5β-pregnane-21-nitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(C(O)=O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc(C2CCC3(CC2)OCCO3)nc1
Yield: 95.5 %

Procedure:
A solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid (776 mg) in dimethylsulfoxide (3 ml) was stirred at 150° C. for 1.5 hours. After completion of the reaction, the reaction solution was left stand to room temperature, water was added and extracted with ethyl acetate. The organic solution was washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-bromo-2-(1,4-dioxaspiro[4,5]decane-8-yl)pyridine (646 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethoxy-benzenesulfonamide was synthesized (83%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in a similar manner as described in Examples 70-91.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.[CH3:40][S:41]([OH:44])(=[O:43])=[O:42]>C(Cl)(Cl)Cl.C(OCC)(=O)C.O.CN(C=O)C>[CH3:40][S:41]([OH:44])(=[O:43])=[O:42].[O:20]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:18]1[C:16]1[CH:15]=[CH:14][C:6]2[N:7]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[C:3]([CH3:2])=[N:4][C:5]=2[CH:17]=1
Reactant: Nc1ccccc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (51.2 g, 0.19 mol), 2-aminophenol (24.0 g, 0.21 mol), anhydrous DMF (500 mL) and WSC (45.0 g, 0.23 mol) was stirred for 3 hours under an argon atmosphere. Water (2 L) was added, the solid obtained was filtered off, washed with water, After drying at reduced pressure at 50° C., an obtained solid (45.2 gm 0.13 mol) was dissolved in dioxane (500 mL). Methanesulfonic acid (62.5 g, 0.65 mol) was added thereto and this was stirred at 90° C. for 8 hours. The solvent was concentrated at reduced pressure, water (1 L) was added, and the pH was adjusted to 4 with 1N NaOH. Chloroform (2 L) was added for extraction, and then the aqueous layer was extracted with chloroform (1 L), these were combined and the organic layer was washed with brine (1 L). After MgSO4 drying and filtration, the solvent was concentrated under reduced pressure. The residue obtained was dissolved in chloroform (100 mL) and ethyl acetate (150 mL) and methanesulfonic acid (25.0 g) was added. After stirring awhile in the cold, the precipitated solid was filtered off and this was dried under reduced pressure at 50° C. to yield the title compound (23.7 g, 28.1% yield) as a light purple solid.
Reaction SMILES: S[C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([CH3:11])=[CH:9][NH:8][C:6]=2[N:7]=1.C[O-].[Na+].CO>CO.[Ni]>[CH3:11][C:10]1[C:5]2[C:4](=[O:12])[NH:3][CH:2]=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c[nH]c2nc[nH]c(=O)c12
Temperature: 50 °C
Yield: 65.3 %

Procedure:
In methanol (714 ml) was suspended 2-mercapto-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (15.06 g) followed by addition of 28% sodium methoxide/methanol (18.4 ml). While this solution was stirred at 50° C., Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the filtrate was neutralized with 1N-HCl (90 ml). The solvent was distilled off under reduced pressure and the resulting precipitate was collected by filtration, rinsed serially with water, methanol and ether, and dried to provide the title compound (8.1 g). 1H-NMR (DMSO-d6) δ: 6.44(1H,d,J=3.OHz), 7.03(1H,d,J=3.0 Hz), 7.83(1H,s), 11.80(1H,brs).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH:10]([OH:24])[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[C:14]1([O:13][C@@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[OH:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OC1CN(Cc2ccccc2)CC1Oc1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CNC[C@H]1Oc1cccc2ccccc12

Procedure:
Eighteen grams of 1-benzyl-4-(1-naphthoxy)-3-pyrrolidinol in 200 ml. of ethanol was treated with ca. 2 g. of 10% palladium-on-charcoal under hydrogen at 60° C. for 20 hr. The mixture was cooled, filtered and ethanol removed. The residue was crystallized from benzene and had a melting point of 112°-115° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[N:15]=2)[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[F:25][C:22]([F:23])([F:24])[C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)[NH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylcarboxylic acid methyl ester (13.4 mmol) in 50 ml of THF was added LiOH (80.3 mmol) in 30 ml of H2O. The mixture was stirred at 60° C. for 2 hours, then concentrated, diluted with H2O and washed with ether. The aqueous layer was acidified to pH 5-6, extracted with EtOAc, dried over Na2SO4, and concentrated to give trans-4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexyl-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[F:21])[CH:7]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1

Procedure:
The phenyl bromide (78)(106 mg, 0.28 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.Cl>CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]([OH:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: O=C(CCC1CCNCC1)c1ccnc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCC1CCNCC1)c1ccnc2ccccc12
Reaction time: 2 h
Yield: 53.4 %

Procedure:
2 g of sodium borohydride were added in 20 minutes, at the ambient temperature, to 13 g of 1-(4-quinolyl)-3-(4-piperidyl)-1-propanone in 200 ml of methanol. After reacting for 2 hours at the ambient temperature, the reaction medium was acidified by addition of an aqueous solution of hydrochloric acid, the methanol removed by distillation under reduced pressure and the aqueous phase washed with ethyl acetate. The aqueous phase was made alkaline by addition of an aqueous solution of sodium hydroxide, then extracted with chloroform. The chloroformic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. 13 g of crude product were thus obtained, which were fixed on a column of silica gel. It was then eluted with a mixture of 90 parts by volume of chloroform and 10 parts by volume of diethylamine. 7 g of the desired product were thus isolated in the form of the base, which was converted into dihydrochloride by the action of hydrochloric acid in ethanol. 3.2 g of 1 -(4-quinolyl)-3-(4-piperidyl)-1-propanol dihydrochloride (racemic) which melted at 195° C. were thus obtained.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[CH3:15][O:16]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH:15]=[O:16])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CC=O)CC1

Procedure:
In a manner analogous to that described in Example 2, paragraphs (a) and (b), trans-4-pentylcyclohexanecarboxaldehyde was reacted in a Wittig reaction with methoxymethyl-triphenylphosphonium chloride and potassium t-butylate and the resulting enol ether was subsequently hydrolyzed in tetrahydrofuran/2N hydrochloric acid to give (trans-4-pentylcyclohexyl)acetaldehyde.