Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.CCCCCC>[C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([O:14][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH2:11]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC1CC(O)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCC1CC(ON2C(=O)c3ccccc3C2=O)C1

Procedure:
Analogously to Example 1 b, but using ethyl acetate/hexane mixtures (1:3 and 1:1) in the flash chromatography, starting from 15.24 g (0.0757 mol) of 3-(N-BOC-aminomethyl)-cyclobutanol, 12.35 g (0.0757 mol) of N-hydroxyphthalimide, 19.85 g (0.0757 mol) of triphenylphosphine and 13.3 ml (0.0795 mol) of diethyl azodicarboxylate (93%), the title compound, which melts at 161°-162° C. after recrystallization from ethyl acetate, is obtained. Evaporation of the mother liquor and recrystallization of the residue from ethyl acetate/hexane gives a further batch of the title compound, m.p. 145°-150° C.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:24]1([CH2:30][CH2:31][CH2:32][C:33]#[CH:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.[Cu]I>[CH3:9][C:7]1[N:8]=[C:4]([N:1]2[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[N:2]2)[S:5][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C#CCCCc1ccccc1
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-n2cc(CCCc3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-azido-4-methylthiazole-5-carboxylate (5.31 g, 25.02 mmol) in tetrahydrofuran (50 mL) was added copper(I) iodide (4.76 g, 25.02 mmol), N,N-diisopropylethylamine (13.07 mL, 75.06 mmol) and 5-phenyl-1-pentyne (3.97 g, 27.52 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:4 ratio) to afford the title compound in 79% yield (7.04 g): 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.31-7.16 (m, 5H), 4.33 (q, J=6.0 Hz, 2H), 2.82 (t, J=9.0 Hz, 2H), 2.77-2.69 (m, 5H), 2.10-2.04 (m, 2H), 1.38 (t, J=6.0 Hz, 3H); MS (ES+) m/z 357.3 (M+1).
Reaction SMILES: BrC1OC(C2N=C3C=CC(C#N)=CN3C=2)=CC=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=O)[CH2:25]Br)=[CH:22][CH:21]=1)#[N:19].[NH2:30][C:31]1[C:36]([CH3:37])=[CH:35][C:34]([Br:38])=[CH:33][N:32]=1>>[Br:38][C:34]1[CH:35]=[C:36]([CH3:37])[C:31]2[N:32]([CH:25]=[C:24]([C:23]3[CH:28]=[CH:29][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:30]=2)[CH:33]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Cc1cc(Br)cnc1N
Agent: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1
Product: Cc1cc(Br)cn2cc(-c3ccc(C#N)cc3)nc12
Yield: 71 %

Procedure:
The same procedure described for 3a was used employing 4-Cyanophenacyl bromide and 2-Amino-5-bromo-3-methylpyridine. Yield 71%, mp 209-210° C. 1H NMR (DMSO-d6); δ 2.56 (s, 3H), 7.53 (s, 1H), 7.95 (d, J=8.1 Hz, 2H), 8.14 (d, J=8.1 Hz, 2H), 8.60 (s, 1H), 8.88 (s, 1H). 13C NMR; δ 143.3, 140.4, 133.3, 133.0, 128.1, 127.4, 127.0, 125.9, 119.2, 112.8, 111.2, 108.2, 16.7. MS (m/z, rel.int.); 312 (M+, 10), 230 (100), 217 (60), 205 (50).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH3:11])[C:5]=1[CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CO>[CH2:18]([O:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH3:11])[C:5]=1[CH:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of NaOH (1.77 g dissolved in 20 mL, 44.4 mmol) in de-ionized water was added dropwise to a suspension of 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (9.00 g, 40.3 mmol) in methanol (100 mL), and followed by benzyl bromide (5.28 mL, 44.4 mmol) at room temperature. The resulting suspension was refluxed for 3.5 h, and then stirred at RT for overnight. Methanol was removed under vacuum using the rotary evaporator, and the residue was diluted with water and extracted two times with CH2Cl2 (2×100 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of methanol and ethyl acetate (10/90, v/v) as eluant. Fractions rich in the product were pooled together and evaporated to dryness to give 4 g of 3-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:19].[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.O1CCCC1>[Br:19][C:11]1[NH:10][C:9]2[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:8]=2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Br
Reactant: COC(=O)c1cc2[nH]cc(C3CCCCC3)c2s1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Yield: 73 %

Procedure:
To a solution of methyl 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate obtained in Step 7 in chloroform (90 ml) and tetrahydrofuran (90 ml) was added pyridinium hydrobromide perbromide (21.7 g, 68 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 2 hr and concentrated under reduced pressure at room temperature. Ethyl acetate (300 ml) was added to the residue, and the mixture was washed successively with 1M aqueous sodium hydrogen sulfite solution (100 ml×3), water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml×2) and saturated brine (100 ml), and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent (100 ml) of n-hexane:ethyl acetate (25:1). The solid was collected by filtration, and dried under reduced pressure to give methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (17 g, yield 73%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:8]([CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1)=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1nc(-c2cccc(CSCc3ccccc3)n2)sc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2cccc(CS(=O)Cc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
2-[6-[(Benzylthio)methyl]-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.080 g, 0.22 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.037 g, 0.22 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.053 g, 64%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([NH2:18])[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:7]1[C:2]([NH:17][CH:14]2[CH2:15][CH2:16][CH:11]([NH2:18])[CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Yield: 54.8 %

Procedure:
2-Chloro-3-nitropyridine (10 g, 63.3 mmol), cyclohexane-1,4-diamine (7.2 g, 63.3 mmol), anhydrous dimethylformamide (100 mL) and anhydrous sodium carbonate (13.4 g, 126 mmol) were combined with stirring under nitrogen. The reaction mixture was stirred at room temperature for 14 hours. It was poured into water and the resulting orange solid was filtered off and found to be N1-(3-nitropyridin-2-yl)cyclohexane-1,4-diamine (8.2 g, 34.7 mmol, 54.9% yield) which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:39][NH2:40])=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[N:26][CH:27]=1)#[N:21]>C(O)CCC>[Si:1]([O:8][CH2:9][C:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:37]([C:34]3([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=5)=[CH:29][CH:30]=4)[CH2:36][CH2:35]3)=[N:39][N:40]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: N#Cc1ccc(-c2ccc(C3(C(=O)NN)CC3)cc2)nc1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (39.7 g, 124 mmol) and the compound (19.5 g, 70.1 mmol) obtained in Example 60-3) in 1-butanol (750 mL) was stirred at 140° C. for 13 h. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to obtain the title compound (33.1 g, 89%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25](OCC)=[O:26])[C:5]2[C:6](=O)[CH:7]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:6]3=[N:31][NH:32][C:25](=[O:26])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
To a solution of ethyl 7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (186 mg, 0.47 mmol) in methanol (1 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was stirred at 25° C. for 15 hr. Then the mixture was filtered to obtain a white solid (40 mg, yield 24%). LC-MS (ESI) m/z: 363 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.63 (s, 3H), 4.94-5.03 (m, 2H), 6.91-6.94 (dd, J1=11.6 Hz, J2=2.4 Hz, 1H), 7.05-7.08 (dd, J1=9.6 Hz, J2=2.4 Hz, 1H), 7.29-7.35 (m, 3H), 7.42-7.48 (m, 2H), 7.74 (s, 1H), 7.79 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:12]([C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([C:32](=[O:47])[NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:36]=2)=[CH:26][N:25]=1)[C:13](=[O:23])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].CCOCC>FC(F)(F)C(O)=O>[OH:30][C:28]1[C:27]([C:32](=[O:47])[NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:36]=2)=[CH:26][N:25]=[C:24]([NH:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:29]=1
Reactant: COc1ccc(CN(C(=O)CCC(=O)OC(C)(C)C)c2cc(OC)c(C(=O)NCc3cccc(-c4ccccc4)c3)cn2)c(OC)c1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)Nc1cc(O)c(C(=O)NCc2cccc(-c3ccccc3)c2)cn1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
A solution of the mixture (345 mg) containing tert-butyl 4-[(2,4-dimethoxyphenyl)methyl-{4-methoxy-5-[(3-phenylphenyl)methylcarbamoyl]-2-pyridyl}amino]-4-oxobutanoate in trifluoroacetic acid (4 mL) was left standing at room temperature for 17 hours. Ether (60 mL) was added to the reaction solution. The resulting suspension was filtered, and the product collected by filtration was washed with ether and dried under reduced pressure. To the obtained residue, a solution of boron tribromide in dichloromethane (1 M, 6 mL) was added at room temperature, and the mixture was stirred at 40° C. for 6 hours. The reaction mixture was cooled to room temperature, and water was then added thereto. The resulting suspension was filtered, and the product collected by filtration was washed with water and ether. The obtained residue was suspended in ethanol, and the suspension was shaken for 15 minutes in an ultrasonic bath and then filtered. The product collected by filtration was dried under reduced pressure to obtain the title compound (56.7 mg).
Reaction SMILES: I[C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([F:23])=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.[CH:26]#[C:27][CH:28]([OH:32])[CH2:29][CH2:30][CH3:31].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cu](I)I.CN(C=O)C.C(N(CC)CC)C>[OH:32][CH:28]([CH2:29][CH2:30][CH3:31])[C:27]#[C:26][C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([F:23])=[C:6]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(I)c(F)c(F)c3F)CC2)CC1
Reactant: C#CC(O)CCC
Agent: I[Cu]I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(O)C#Cc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 25 g of 5-iodo-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene was dissolved into 300 mL of DMF, to which 21 mL of triethylamine, 0.19 g of copper iodide (I), and 0.58 g of tetrakistriphenylphosphine palladium (0) were added, followed by heating to 55° C. Into this, the DMF (30 mL) solution containing 5.9 g of 1-hexine-3-ol was added dropwise for 20 minutes, and stirred for 3 hours. After the reaction mixture was poured into a sodium thiosulfate aqueous solution, and stirred for a while, an organic layer was separated and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water, 10% hydrochloric acid twice, water, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by sequentially carrying out column chromatography (silica gel, toluene) twice, activated carbon treatment (acetone), and column chromatography (silica gel, hexane/acetone), to obtain 20 g of 5-(3-hydroxy-1-hexynyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene.
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:10]1[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=1
Reactant: Fc1cccc(Oc2ccc(Br)cn2)c1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(F)c2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 52 %

Procedure:
To a diethyl ether (100 mL) solution of 5-bromo-2-(3-fluoro-phenoxy)-pyridine (5.81 g, 21.7 mmol) described in Manufacturing Example 71-1-1 was added n-butyl lithium (13.8 mL, 1.57 M n-hexane solution, 21.7 mmol) under nitrogen atmosphere at −78° C., which was stirred for 40 minutes at −78° C. N,N-Dimethylformamide (2.02 mL, 26.0 mmol) was then added to the mixture at −78° C., and stirred for 25 minutes as the temperature was gradually raised to 0° C. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with 1 N aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (2.47 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH2:10][OH:11])[CH2:8][OH:9])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[OH:9][CH2:8][C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)([CH3:12])[CH2:10][OH:11]
Reactant: CC(CO)(CO)c1cc(N)no1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CO)(CO)c1cc(NC(=O)Oc2ccccc2)no1

Procedure:
To a stirred mixture of 2-(3-aminoisoxazol-5-yl)-2-methylpropane-1,3-diol (1 equivalent) and potassium carbonate (2-5 equivalents) in anhydrous THF at rt is added dropwise phenyl chloroformate (1-2 equivalents) and stirring is continued at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined organic extracts are washed with water or brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford phenyl 5-(1,3-dihydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH3:22])=[CH:20][N:19]=[CH:18]2)=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH2:25]=[O:26]>C1(C)C(C)=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]2[CH2:25][OH:26])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: C=O
Reactant: Cc1cncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 1, 5-(trifluoromethyl)-2-(5-methylimidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 5-(trifluoromethyl)-2-[2-(hydroxymethyl)-5-methylimidazol-1-yl]benzophenone.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12](=[O:21])[CH2:11]2)[CH2:6][CH2:5]1>C(O)C.O>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([CH:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:12]([OH:21])[CH2:11]2)[CH2:8][CH2:9]1
Reactant: CN1CCN(C2CCc3ccccc3C(=O)C2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCN(C2CCc3ccccc3C(O)C2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
8.8 g of sodium borohydride were added over 20 minutes at 22°-26° C to a solution of 8.8 g of the product of Step A in 8.8 ml of ethanol and 8.8 ml of water and the mixture was stirred for 1 hour at 20° C. The ethanol was evaporated and the mixture was poured into water and was extracted with methylene chloride. The organic extracts were washed with water, dried and evaporated to dryness to obtain 9 g of a mixture of the isomers of raw 7-(4-methylpiperazin-1-yl)-5-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5]NN=1.CO[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[H-].[Na+].C(#N)CC>>[CH3:5][CH:6]([C:9](=[O:20])[C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)[C:2]#[N:1]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCC#N
Product: CC(C#N)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 96 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 4-trifluoromethyl-benzoic acid methyl ester (3.0 g, 14.7 mmol, 1.0 eq), NaH (1.2 g, 29.4 mmol, 2.0 eq) and propionitrile (4.9 mL, 69.4 mmol, 4.7 eq). The crude product was extracted with DCM and used in the following step without further purification (3.2 g, yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH:19]=[C:20]([CH3:22])[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:19]=[C:20]([CH3:22])[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC(C)=CBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)=CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (565 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from 1-bromo-2-methyl-propene (0.51 mL), a small iodine flake, and magnesium powder (146 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].C(Cl)(=O)C([Cl:21])=O.C(=O)=O>C(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:21])=[O:14]
Reactant: O=C(O)CCCCCCCCCCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCCCC(F)(F)F

Procedure:
Dissolve 12,12,12-trifluorododecanoic acid (244 mg, 0.96 mmol) in methylene chloride (5 mL) and add dimethylformamide (3 drops). Add oxalyl chloride (85 μL, 0.96 mmol) and stir until evolution of carbon dioxide is complete to give 12,12,12-trifluorododecanoyl chloride.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11]2=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:16]=[C:10]2[C:9]1=O)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:9]1[C:10]2=[N:16][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[C:11]2[CH:12]=[CH:13][N:8]=1
Reactant: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccccc2Cl)cc1
Yield: 77 %

Procedure:
A stirred suspension of 6-benzyl-2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7(6H)-one (1A-3, 925 mg, 2.07 mmol) in POCl3 (20 ml) was heated at reflux for 5 days. After the reaction was cooled and concentrated, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous NaHCO3 and then brine. The solution was dried (Na2SO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 40S column using 0–40% ethyl acetate in hexanes to afford I-9A-1a as an off-white solid (600 mg, 77%): +ESI MS (M+1) 374.3; 1H NMR (400 MHz, CD2Cl2) δ 8.00 (d, J=6.2 Hz, 1H), 7.60–7.45 (m, 5H) 7.38 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H).