Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:32][CH3:33])=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([NH2:45])=[CH:40][CH:41]=2)[CH2:36]1.Cl>CC(O)C>[CH3:33][O:32][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:39]4[CH:38]=[C:37]5[C:42]([CH2:43][CH2:44][N:35]([CH3:34])[CH2:36]5)=[CH:41][CH:40]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:22][C:21]=1[NH:23][C:24](=[O:31])[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reactant: CN1CCc2ccc(N)cc2C1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C)CC4)n2)cc1NC(=O)Cc1cccs1
Temperature: 180 °C
Yield: 53.5 %

Procedure:
To a solution of N-{5-[3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-methoxyphenyl}-2-(2-thienyl)acetamide (110 mg, 0.23 mmol) (see Example 48, step F) in anhydrous i-PrOH (3 mL) was added 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (39 mg, 0.24 mmol), followed by catalytic 12M HCl. After heating for 10 min in the microwave at 180° C., the reaction was quenched with saturated NaHCO3 (25 mL), the solvent removed by rotary evaporation, and the aqueous layer extracted with DCM (25 mL). The organic layer was concentrated and purified by column chromatography (1-10% MeOH in DCM) to provide the product (74 mg, 53%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.28 (s, 3H), 2.53-2.55 (m, 2H), 2.70-2.72 (m, 2H), 3.36 (s, 2H), 3.87 (s, 3H), 3.97 (s, 2H), 6.49 (d, 1H, J=5.1 Hz), 6.94-6.95 (m, 2H), 7.05-7.13 (m, 2H), 7.25-7.27 (d, 1H, J=8.1 Hz), 7.35-7.43 (m, 3H), 7.48 (s, 1H), 8.19 (d, 1H, J=5.3 Hz), 8.31 (s, 1H), 8.43 (d, 1H, J=8.6 Hz), 8.78 (d, 1H, J=6.8 Hz) 9.38 (s, 1H), 9.45 (s, 1H) ppm. ES-LC/MS m/z=602 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[C:8](=[O:9])[CH:7]([CH3:10])[CH2:6][N:5]([C:11]([O:13][CH3:14])=O)[CH2:4]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([OH:29])[CH2:27][OH:28].ClC(Cl)(Cl)C>O>[CH2:26]1[O:29][C:11]([N:5]2[CH2:6][CH:7]([CH3:10])[C:8](=[O:9])[CH:3]([C:1]#[N:2])[CH2:4]2)([O:13][CH3:14])[O:28][CH2:27]1
Reactant: COC(=O)N1CC(C)C(=O)C(C#N)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)(Cl)Cl
Product: COC1(N2CC(C)C(=O)C(C#N)C2)OCCO1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of crude 11 (200 g, 1.02 mol), 4-toluenesulfonic acid (35 g), 1,2-ethanediol (900 ml), and 1,1,1-trichlorethane (1 liter) was refluxed with a water separator overnight. The mixture was cooled, water (1 liter) was added and the phases separated. The aqueous phase was extracted 3 times with dichloromethane, and the combined organic phases were washed once with dilute sodium hydroxide solution and once with saturated sodium chloride solution. Drying over magnesium sulphate and evaporation in vacuo of the organic phase yielded 12 (195 g, 80%) as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][CH2:40][CH2:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH2:41][CH2:40][O:39][CH3:38])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 63.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (600 mg, 1.1 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (678 mg, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (77 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.4 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (400 mg, 63%) as a white solid: LC/MS m/e calcd for C29H29FN2O5S2 [M+H]+ 569.69, observed 569.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][N:21]=[C:22]2[N:27]=1
Reactant: Brc1cccc(-c2ccncc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccncc4)n3)cnc2n1
Yield: 46.7 %

Procedure:
6-Bromo-2,4′-bipyridine (0.34 g, 1.44 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-100%) and trituration with isohexane gave 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,4′-bipyridine (180 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.43 (1H, d, J 7), 7.77 (1H, d, J 8), 7.88-7.91 (3H, m), 7.98 (1H, dd, J 8 and 8), 8.59 (1H, s), 8.80-8.85 (1H, m), 10.51 (1H, d, J 7); m/z (ES+) 342 (M++M).
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH2:33])=[O:32].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:1]([S:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: NC(=O)CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCSCCCCCCCCCCC(N)=O
Temperature: 100 °C

Procedure:
13.2 Grams of octadecanethiol, 14.3 g of 11-bromoundecanamide, 1.7 g of potassium iodide, 20.7 g of potassium carbonate and 100 ml of N,N-dimethylacetamide were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with heating at 100° C. for 5 hours. The reaction mixture was cooled to room temperature and, then, introduced into ice water, and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 16.4 g of the desired product. m.p. 108° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N+](=[CH2:15])=[N-]>O1CCCC1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
Under ice-cooling, to a solution of 910 mg of 1H-5-indazolecarboxylic acid in 60 ml tetrahydrofuran was added an excess amount of a solution of diazomethane in diethyl ether, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, the residue was added with 50 ml of ethyl acetate, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 923 mg of the title compound as pale yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[NH:18]1[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[N:4]=[C:3]([CH2:2][N:18]3[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]3)[CH:8]=[N:7][C:6]=2[O:9][CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc[nH]n1
Reactant: COc1ncc(CBr)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine (Intermediate 3, 200.00 mg, 0.64 mmol), in acetone (3.19 mL), was added methyl 1H-1,2,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) and potassium carbonate (264.44 mg, 1.91 mmol). The reaction was stirred at room temperature for 2 h. The LCMS showed two peaks with [M+H] values consistent with the two major regioproducts. The mixture was diluted with DCM (5 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, SiO2, 20-100% EtOAc/hexanes) afforded the title compound (100 mg; 44%). 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.01 (td, J=1.1, 2.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.45-7.36 (m, 2H), 5.64 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H). [M+H]=360.24.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:34]([NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and phenyl isocyanate (0.013 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as an amorphous compound. 13C NMR (DMSO-d6) δ 195.1, 158.7 (dd), 155.7 (dd), 152.3, 148.9, 139.3, 139.1, 137.2, 133.4, 131.5, 129.6, 128.7, 127.0, 126.2 (dd), 124.2 (dd), 121.8, 120.3, 118.4, 118.2, 118.1, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 19.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[NH:11][N:10]=1.[OH-].[Na+].Cl[CH:18]([F:20])[F:19]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:18]([F:20])[F:19])[NH:11][N:10]=1
Reactant: FC(F)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reaction time: 6 h
Yield: 47.3 %

Procedure:
237 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazol from Example 3.1 were initially charged in 2160 ml of dioxane. A solution of 84 g of sodium hydroxide in 250 ml of water was added, and the mixture was heated at reflux. With stirring, 620 g (7.17 mol, 6.9 eq.) of gaseous chlorodifluoromethane were introduced, and, during the addition, the pH was monitored continuously and when it approached the neutral range (pH 9) increased to pH 12 by addition of additional NaOH solution. After 6 h, the mixture was allowed to cool, 1.7 l of water were added and the mixture was extracted three times with in each case 500 ml of MTBE. The combined organic phases were washed with in each case 1500 ml of water and saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was suspended in 500 ml of cyclohexane and heated to reflux, and undissolved particles were filtered off. The residue was once more extracted with 200 ml of boiling cyclohexane. The combined filtrates were concentrated to obtain the title compound. This gave 136.7 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1H-pyrazole as a solid. (Yield 47.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:9][CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(Br)cc2)CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 4-(4-bromophenyl)-4-methylpiperidine (285) (4.1 g, 16 mmol) in DCM (20 mL) was added (BOC)2O (5.7 g, 26 mmol). The resulting mixture was stirred at RT for 30 min before being diluted with water (10 mL). The mixture was extracted with DCM (10 mL×2). The combine organic layers were washed with brine, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 20% EtOAc in PE to give tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (286) (5 g, 88%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4](Cl)[N:3]=1.O.[NH2:18][NH2:19]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: Cn1c(=O)n(CCO)c2nc(N)nc(Cl)c21
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cn1c(=O)n(CCO)c2nc(N)nc(NN)c21
Temperature: 105 °C
Yield: 88.9 %

Procedure:
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one obtained in step 3 (8 g, 32.9 mmol), Hydrazine hydrate (16 ml, 32.9 mmol) and ethanol (300 ml) were heated at 100-110° C. for 16 hours. The reaction mixture was concentrated and solid obtained was filtered off and dried to obtain 2-amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyl-purin-8-one (7 g, 89%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([F:16])=[CH:14][NH:13][C:12](=[O:17])[CH:11]=2)[CH:3]=1.Br[CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([F:16])=[CH:14][N:13]([CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12](=[O:17])[CH:11]=2)[CH:3]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1F
Product: CC(C(=O)OC(C)(C)C)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
126 mg (0.51 mmol) of 4-chloro-2-(5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.05 eq. of tert-butyl 2-bromopropanoate (racemate) were reacted according to General Method 4B at 100° C. Yield: 48 mg (25% of theory)
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:28][C:29]([F:46])([F:45])[C@@H:30]([O:32][C:33](=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1)[CH3:31]>>[F:28][C:29]([F:46])([F:45])[C@H:30]([CH3:31])[O:32][C:33]([N:23]1[CH2:22][CH2:21][C:20]2([CH2:19][C:18]3([O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:27]3)[CH2:26]2)[CH2:25][CH2:24]1)=[O:34]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@H](OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2)C(F)(F)F

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and (S)-carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 12. LC (method 3): tR=0.95 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C@H:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][C@H:9]4[OH:35])[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 82.8 %

Procedure:
The procedure of Example 23 was repeated except that 4.9 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α, 2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 3.7 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol (yield: 83%).
Reaction SMILES: [N:1]1([C:6]2[C:7]([C:21]([F:24])([F:23])[F:22])=[CH:8][C:9]([N+:18]([O-])=O)=[C:10]([CH:17]=2)[NH:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:5]=[CH:4][N:3]=[CH:2]1.NC1C=C(C(F)(F)F)C(N2C=CN=C2)=CC=1NCCCCO.[C:47]([OH:52])(=O)[C:48](O)=[O:49].[BrH:53]>C(O)C.[C].[Pd]>[BrH:53].[Br:53][CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:10]2[C:9](=[CH:8][C:7]([C:21]([F:24])([F:23])[F:22])=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:17]=2)[NH:18][C:48](=[O:49])[C:47]1=[O:52]
Reactant: O=C(O)C(=O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(-n2ccnc2)cc1NCCCCO
Agent: [Pd]
Agent: Br
Agent: Nc1cc(C(F)(F)F)c(-n2ccnc2)cc1NCCCCO
Solvent: CCO
Product: O=c1[nH]c2cc(C(F)(F)F)c(-n3ccnc3)cc2n(CCCCBr)c1=O

Procedure:
At room temperature, 4-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylanilino)butanol (5.79 g) synthesized in Reference Example 6 was subjected to reduction in ethanol at ordinary temperature using 10% palladium-carbon as the catalyst, thereby converting it into 4-[2-amino-5-(1H-imidazol-1-yl)-4-trifluoromethylanilino)butanol which was subsequently dissolved in 48% hydrobromic acid aqueous solution (50 ml). Then, oxalic acid (2.27 g) was added, followed by heating overnight under reflux. The reaction solution was concentrated under a reduced pressure, and addition of water to the resulting residue followed by concentration was repeated several times. When the residue became a water-insoluble solid, this was collected by filtration, washed with water and then dried under a reduced pressure, and the resulting crude product was recrystallized from DMF-water to give 1-(4-bromobutyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione hydrobromide (2.46 g). The resulting bromobutylquinoxalinedione (2.46 g) and tetra-n-butylammonium bromide (0.15 g) were dissolved in a two layer system solution of chloroform (50 ml), water (50 ml) and DMF (25 ml), and the solution was adjusted to pH 7 by adding 1 N sodium hydroxide. Then, sodium azide (3.12 g) was added, followed by heating overnight under reflux. The organic layer was separated from the reaction solution, washed with water, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. As the remaining solid substance, 1-(4-azidobutyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (1.61 g) was obtained. Next, in an atmosphere of hydrogen, the resulting azidobutylquinoxalinedione (1.30 g) was subjected to reduction under normal pressure in DMF (65 ml) using palladium-carbon as the catalyst. The reaction solution was filtered to collect insoluble matter including the catalyst. This was dissolved in heated DMF, filtered during hot condition and then recrystallized to give 1-(4-aminobutyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (0.82 g).
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:6]1[C:2]2([NH:1][C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[O:8][CH2:7]2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCCC1
Reactant: NC1(CO)CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CCC2(CC1)NC1(CCCC1)CO2
Temperature: 20 °C
Reaction time: 72 h
Yield: 97.2 %

Procedure:
To a solution of 1-amino-1-(hydroxymethyl)cyclopentane (Method B1c; 1.44 g, 12.54 mmol) in CH2Cl2 (10 mL) at 4° C. was added TFA (0.097 mL, 1.25 mmol), cyclohexanone (1.30 mL, 12.54 mmol) and sodium sulfate (2 g) and the reaction was warmed to 20° C. The reaction was stirred for 72 h and was sequentially washed with water (10 mL) and a saturated NaHCO3 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure to give 14-aza-7-oxadispiro[4.2.5.1]tetradecane (2.38 g, 97%): GC-MS m/z 195 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:19])[CH:9]([NH2:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl.[CH2:21]([O:23][C:24]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:25]=1[C:26](=N)OCC)[CH3:22].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:19][C:26]([C:25]3[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:24]=3[O:23][CH2:21][CH3:22])=[N:18][CH:9]2[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: NC(CCC1CCCCC1)C(N)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CCC2CCCCC2)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-4-(2-cyclohexyl-ethyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-4-cyclohexyl-butane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 441.2309, calculated for C26H34N2O2Cl [(M+H)+]441.2304.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[CH3:9])(O)=O.S(Cl)(Cl)=O.S(N)([NH2:29])(=O)=O>S1(CCCC1)(=O)=O>[C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[CH3:9])#[N:29]
Reactant: NS(N)(=O)=O
Reactant: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Cc1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 97.8 %

Procedure:
By the method of Example 5, Step C, 117.0 g (0.3451 mole) of 4-carboxy-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole was reacted with 205.3 g (1.73 moles) of thionyl chloride and 45.1 g (0.47 mole) of sulfamide in 390 mL of sulfolane, yielding 108 g of 4-cyano-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole. The nmr spectrum was consistent with the proposed structure.