Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([Sn](CCCC)(CCCC)CCCC)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].Br[C:27]1[N:28]=[C:29]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]=[O:44])[CH2:39][CH2:38]2)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH:43]([N:40]1[CH2:39][CH2:38][N:37]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:36]=[C:27]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])=[CH:12][CH:11]=3)[N:28]=2)[CH2:42][CH2:41]1)=[O:44]
Reactant: O=CN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCCS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Yield: 61.8 %

Procedure:
Propyl-(4-tributylstannylphenyl)sulfone (1.59 g) and 3-bromo-1-(4-formylpiperazin-1-yl)isoquinoline (0.93 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.13 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 5N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-formylpiperazin-1-yl)-3-[4-(propylsulfonyl)phenyl]isoquinoline (0.76 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[H-].[Na+].[N+:20]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])[CH:26]=[CH:27][C:28]=1[NH2:29])([O-:22])=[O:21]>C(Cl)Cl.CN(C=O)C.C1COCC1>[N+:20]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:37])([F:38])[F:39])[CH:26]=[CH:27][C:28]=1[NH:29][C:9](=[O:11])/[CH:8]=[CH:7]/[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)([O-:22])=[O:21]
Reactant: O=C(O)/C=C/C1CCOCC1
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(/C=C/C1CCOCC1)Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-3-(tetrahydro-pyran-4-yl)-acrylic acid (prepared as described in PCT Publication WO 2005/101989 (A2,A3), 0.200 g, 1.28 mmol) in dry CH2Cl2 (5 mL) was treated with oxalyl chloride (0.110 mL, 0.00128 mol) and DMF (1 drop) at room temperature for 1 h. The volatiles were evaporated in vacuo (water bath temperature <30° C.). At the same time, a suspension of NaH (78.8 mg, 1.97 mmol, 60% dispersion in oil) in dry THF (3 mL) was treated portionwise with 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (278 mg, 0.985 mmol, prepared as in STEP A above) and stirred at room temperature for 30 min. The residue was taken up in dry THF (2 mL) and slowly added to the NaH mixture. The resulting mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g Sepra Si 50 SPE column (Isco system: flow rate=20 mL/min; eluting with EtOAc/hexane, 5:95, v/v over 5 min and 5:95 to 40:60, v/v over 25 min) to yield (E)-N-(3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-3-(tetrahydro-pyran-4-yl)-acrylamide as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1)=[CH2:2]>CCO.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(NC(=O)C(C)(C)C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 8 h
Yield: 97 %

Procedure:
A catalytic amount of Pd/C was added to a solution of N-(5-vinylpyridin-2-yl)pivalamide (23 g, 0.11 mol) in EtOH (200 mL). The reaction mixture was stirred under hydrogen atmosphere overnight. The catalyst was filtrated off and the solution was concentrated in vacuo to afford N-(5-ethylpyridin-2-yl)pivalamide (22 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 8.15 (d, J=8.4, 1H), 8.09 (d, J=2.4, 1H), 7.96 (br s, 1H), 7.54 (dd, J=8.4 and 2.4, 1H), 2.61 (q, J=7.5, 2H), 1.30 (s, 9H), 1.23 (t, J=7.5, 3H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11][C:10]=1[F:25])[O:6][CH2:7][CH3:8])C.CO.O[Li].O.Cl>C1COCC1.O.CC(OC)(C)C>[F:15][C:14]1[CH:13]=[C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:11]=[C:10]([F:25])[C:9]=1[CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(Oc2ccc(OC)cc2)cc1F
Agent: Cl
Agent: [Li]O
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C(=O)O)c1c(F)cc(Oc2ccc(OC)cc2)cc1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
(RS)-[2,6-Difluoro-4-(4-methoxy-phenoxy)-phenyl]-ethoxy-acetic acid ethyl ester (455 mg) was dissolved in THF (2.4 ml), MeOH (2.4 ml) and H2O (1.0 ml) and LiOH.H2O (104 mg) was added. The reaction mixture was stirred 1 h at 60° C. The solution was diluted with cold H2O (15 ml) and TBME (15 ml) and acidified with 1 N HCl. The aqueous layer was extracted with two more portions of TBME (15 ml). The combined organic layers were dried (MgSO4) and the solvent was evaporated to obtain 398 mg (95%) of (RS)-[2,6-difluoro-4-(4-methoxy-phenoxy)-phenyl]-ethoxy-acetic acid. White waxy solid. MS 336.9 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].[C:7]1([S:13][C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[C:3]([C:2]([NH:1][C:14](=[O:15])[S:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH3:5])#[N:4]
Reactant: O=C(Cl)Sc1ccccc1
Reactant: CC(C)(N)C#N
Solvent: C1COCCO1
Product: CC(C)(C#N)NC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
3.4 g. (0.04 mole) of 2-amino-2-methylpropanonitrile are dissolved in 10 ml. of dioxane and a solution of 3.2 ml. (0.2 mole) of (phenylthio)carbonyl chloride in 10 ml. of dioxane is added. After stirring for one hour at room temperature, the reaction mixture is filtered, the filtrate is concentrated, and the solid residue is recrystallized from a small amount of toluene to yield 2.7 g of (1-cyano1-methylethyl)carbamothioic acid, S-phenyl ester; m.p. 152°-155°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoate (2.88 g, 5.83 mmol) in a mixture of ethanol (90 mL) and tetrahydrofuran (90 mL) was added 2 M aqueous sodium hydroxide solution (30 mL), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (2.70 g, yield 99%) as a pale-yellow oil.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[Br:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31](=[O:33])[CH3:32].N(CCO)CCO>O1CCCC1>[Br:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]([OH:33])[CH3:32]
Reactant: CC(=O)c1cccc(C)c1Br
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: Cc1cccc([C@@H](C)O)c1Br
Temperature: -20 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
(+)-B-chlorodiisopinocampheylborane (8.46 g, 26.4 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to −20° C., slowly added dropwise with a solution of 1-(2-bromo-3-methylphenyl)ethanone (4.30 g, 20.3 mmol) described in US 2007/167506 in tetrahydrofuran (50 mL), and stirred for 18 hours. The reaction solution was added with diethanolamine (6.38 g, 60.8 mmol), cooled to room temperature, and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and added with n-hexane (100 mL). The precipitated solids were filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a white solid (4.30 g, yield 99%, 95.6% ee).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.FC1C=C(CN[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC2)C=CN=1.[F:88][C:89]([F:99])([F:98])[C:90]1[C:91]([CH:96]=O)=[N:92][CH:93]=[CH:94][CH:95]=1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][CH2:96][C:91]1[C:90]([C:89]([F:98])([F:88])[F:99])=[CH:95][CH:94]=[CH:93][N:92]=1)[CH2:19][CH2:18]2
Reactant: O=Cc1ncccc1C(F)(F)F
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ncccc3C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 3-trifluoromethylpyridine-2-carbaldehyde was used instead of 2-fluoropyridine-4-carboxaldehyde in Step 1. LCMS: m/e 689.6 (M+H)+, 4.12 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.83 (d, J=4.3 Hz, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.72 (dd, J=5.0, 7.8 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.31 (dd, J=1.5, 6.1 Hz, 1H), 4.85 (s, 1H), 4.76 (s, 1H), 4.44 (d, J=16.2 Hz, 1H), 2.80 (dt, J=5.5, 11.0 Hz, 1H), 2.25-2.10 (m, 5H), 2.02 (dt, J=3.5, 12.1 Hz, 1H), 1.92-1.79 (m, 2H), 1.78 (s, 3H), 1.76-1.68 (m, 3H), 1.64-1.54 (m, 4H), 1.52-1.43 (m, 3H), 1.40 (br. s., 1H), 1.36 (s, 3H), 1.32-1.22 (m, 2H), 1.16-1.13 (m, 3H), 1.08 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:42][CH2:43][C:44]2[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=2[CH3:50])=[O:14])=[CH:15][CH:16]=1)[CH3:7]
Reactant: CC(Oc1cccc(F)c1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccc(F)c3)cc2)c(O)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A mixture of 4-(1-(3-fluorophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 2 mmol), N-hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.3 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(3-fluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (Compound I-42) (135 mg, 34%). LRMS (M+H+) m/z: calcd. 394.17. found 394. HPLC purity (214 nm): 91%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.30 (t, J=4.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.20 (q, J=8.1 Hz, 1H), 6.77-6.64 (m, 3H), 5.83 (s, 1H), 5.57 (q, J=6.3 Hz, 1H), 4.27 (d, J=4.8 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.53 (d, J=6.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15]>O>[CH2:14]([NH:16][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH3:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCN
Solvent: O
Product: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
2-nitrobenzenesulfonyl chloride (10 g) is added portion-wise to 70% ethylamine in water at 0-5° C., maintaining the temperature. It is stirred for 15 minutes until completing the transformation. Water (80 mL) is added, maintaining the temperature. It is stirred for 30 minutes. It is filtered, washed and dried, obtaining 8.97 g of N-ethyl-2-nitrobenzenesulfonamide.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:24]=[CH:23][C:22]2[NH:21][CH:20]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH:19]3[C:18]=2[CH:17]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:24]=[CH:23][C:22]2[NH:21][CH:20]3[CH2:25][CH2:26][NH:27][CH2:28][CH:19]3[C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Nc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-c2ccc3c(c2)C2CNCCC2N3)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
In a 50 ml flask, tert-butyl 8-(2,4-dichlorophenyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (215 mg) was dissolved in 5 mL dichloromethane and cooled to 0° C. with an ice bath. After the addition of 5 mL trifluoroacetic acid, the reaction stirred at room temperature for 45 minutes. The reaction was concentrated in vacuo then diluted with 5M sodium hydroxide. After three ethyl acetate extractions, the combined organics were washed with brine then dried over magnesium sulfate and concentrated to give crude material which was purified by column chromatography (0.5/5/93.5 ammonium hydroxide/methanol/dichloromethane) to give 101 mg (62%) of the title compound as an off-white solid. MS (ESI+) for C17H16N2Cl2 m/z 319.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.C1C(=O)N([Cl:35])C(=O)C1>CC#N>[Cl:35][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([NH:11][C:12]([C:14]2[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=2)=[O:13])[CH:6]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(Cl)c2cc(F)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (300 mg, 0.824 mmol) in MeCN (20 mL) is treated with NCS (185 mg, 1.42 mmol) and the mixture is stirred at 60° C. in a sealed flask for 2 h. The mixture is then concentrated, diluted with 10% aqueous Na2S2O8 (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-20% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylicacid(3 chloro-5-fluoro-indol-1-yl)-amide (160 mg, 49%). MS: 399 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 8.04 (d, 1H), 7.92 (d, 1H), 7.18 (m, 1H), 7.04 (s, 1H), 7.00 (m, 3), 6.76 (m, 1), 2.52 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15]>CN1CCCC1=O>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[CH2:2][NH:17][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCN
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: CN1CCCC1=O
Product: CC(C)CCNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 5.0 9 (30.0 mmole) of 2-(chloromethyl)benzimidazole in 25 mL of anhydrous 1-methyl-2-pyrrolidinone is treated at 0° C. with 17.4 mL (150 mmole) of isoamylamine. The reaction mixture is allowed to warm to room temperature and stir for 16 hr. The reaction mixture is poured into 800 mL of ice/water, and the tan solid filtered and dried to afford 6.08 g (93%) of (benzimidazol-2-ylmethyl)(3-methylbutyl)amine.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH2:12][CH2:4][CH:3]=[CH2:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1ccccc1
Product: C=CCCc1ccccc1
Yield: 94 %

Procedure:
Example 1 was repeated except that 1.0 L of tetrahydrofuran was used as a solvent in place of the mixed solvent of 250 ml of tetrahydrofuran and 750 ml of toluene, and 127.0 g (yield 94%) of 4-phenyl-1-butene was obtained. The analysis of the product by gas chromatography indicated the purity of 98.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1I.[C-:17]#[N:18].[Na+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18]
Reactant: [C-]#N
Reactant: FC(F)(F)Cc1cnc2c(I)c(Cl)ccn12
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Reaction time: 2 h

Procedure:
A 2.0-5.0 mL microwave vial was charged with 7-chloro-8-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (50 mg, 0.139 mmol) and dissolved in DMF (1387 μl). To that stirring solution was added sodium cyanide (7.14 mg, 0.146 mmol) followed by copper(I) iodide (39.6 mg, 0.208 mmol). The vial was sealed and degassed using ultra pure argon and sonication for 2 min. The vial was then placed in a reaction block preheated to 120° C. After 2 hours, LCMS showed ˜7.5:1 (product:starting material). The mixture was diluted with EtOAc and sat'd sodium bicarbonate and the contents of the flask were transferred into a separatory funnel where the aqueous was extracted twice with EtOAc and discarded. The combined organics were washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The crude was taken on into a coupling reaction without any further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, J=7.3 Hz, 1H), 7.78 (s, 1H), 7.43 (d, J=7.5 Hz, 1H), 4.30 (q, J=11.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:56]=[CH:55][C:5]([CH2:6][C:7]2([C:51]([O:53][CH3:54])=[O:52])[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:19]4[C:44]3[CH:49]=[CH:48][N:47]=[C:46]([CH3:50])[CH:45]=3)=[O:15])[CH2:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[F:1][C:2]1[CH:56]=[CH:55][C:5]([CH2:6][C:7]2([C:51]([O:53][CH3:54])=[O:52])[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:44]3[CH:49]=[CH:48][N:47]=[C:46]([CH3:50])[CH:45]=3)=[O:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1
Reaction time: 0.25 h

Procedure:
In a flask, methyl 1-(4-fluorobenzyl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamido)cyclohexanecarboxylate (230 mg, 0.31 mmol) was reacted with trifluoroacetic acid (3 mL) for 1 hour. After reaction completion triethylsilane (0.1 mL) was added, and the reaction was stirred for an additional 15 minutes. The reaction was concentrated and rinsed with diethyl ether. The crude product was progressed to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11](C(OCC)C)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:31])([F:30])[C:27]([CH3:29])=[O:28]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([C:27]([CH3:29])([C:26]([F:31])([F:30])[F:25])[OH:28])[NH:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CCOC(C)n1cnc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: CC(=O)C(F)(F)F
Product: CC(O)(c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)F

Procedure:
By the procedure described in the second paragraph of Example 1, 4,5-bis(4-fluorophenyl)-1-(α-ethoxyethyl)imidazole was reacted with 1,1,1-trifluoroacetone to give 4,5-bis(4-fluorophenyl)-α-methyl-α-trifluoromethyl-1H-imidazole-2-methanol, m.p. 191°-192°. The infrared and NMR spectra were consistent with the assigned structure.