Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[C:29]([Cu])#[N:30].O>CN(C=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>[C:29]([C:2]1[C:3]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6])#[N:30]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc(Br)c1N1CCCCC1
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)cc(C(=O)Nc2ccc(Cl)c(Cl)c2)c1N1CCCCC1

Procedure:
To a solution of 3-bromo-N-(3,4-dichlorophenyl)-2-piperid-1-yl-5-trifluoromethylbenzamide, Example 3 (620 mg; 1 eq.) in DMF (10 ml, degassed for 1 hour with nitrogen), are added CuCN (200 mg; 1.8 eq.) and Pd(PPh3)4 (58 mg; 0.04 eq.). After refluxing for 3 hours under a nitrogen atmosphere, the reaction medium is cooled and poured into 20 ml of water. The product is extracted with ethyl acetate. After washing with water and then with saturated NaCl solution, the organic phase is dried over Na2SO4 and concentrated under vacuum. The oil obtained is purified by chromatography on silica (eluent: 9/1 heptane/EtOAc). 310 mg of 3-cyano-N-(3,4-dichlorophenyl)-2-piperid-1-yl-5-trifluoromethylbenzamide are obtained (white solid: m.p.=175° C.)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](C)([O-])[CH3:17].[K+].C(I)(C)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH:16]([CH3:17])[CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CC(C)C1CN(Cc2ccccc2)CCC1=O
Reaction time: 0.25 h

Procedure:
1-benzylpiperidin-4-one (10 g, 53.0 mmole) was added to the stirred suspension of potassium tert. butoxide (6.0 g, 54.0 mmole) in tetrahydrofuran (50 ml) at 10° C. The reaction mixture was stirred for 15 min, isopropyl iodide (10 g, 54.0 mmole) was added at 10° C. The resulting mixture allowed coming at room temperature and stirred for 16 hr, refluxed for 3 hr and concentrated to dryness. The residue was triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3-isopropylpiperid-4-one. Yield 3.3 g (28%), C15H21NO, m/z 232 (M+1).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH3:5][CH:6]([N:11]=[N:12][C:13](Br)([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:10])[CH3:9].O>CC(C)=O>[CH3:5][CH:6]([N:11]=[N:12][C:13]([N:3]=[C:2]=[O:1])([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: N#C[O-]
Reactant: CCC(C)(Br)N=NC(C)CC(C)C
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(C)(N=C=O)N=NC(C)CC(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of 3.25 grams (.04 moles) of potassium cyanate in 75 ml of 70% aqueous acetone in a 125 ml erlenmeyer flask was added 9.4 grams (.0377 moles) of 2-(1,3-dimethylbutylazo)2-bromobutane (from Example III) over 5 minutes while holding the reaction temperature at 15°-20° C with a cold water bath. After the addition was complete the reaction was stirred an additional hour at room temperature, poured into 200 ml of water and the product extracted with 100 ml of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 6.4 grams (80.5% crude yield). The infrared spectrum was in agreement with the structure of 2-(1,3-dimethylbutylazo)-2-isocyanatobutane (strong broad isocyanate band at 2125-2225 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:8]=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19]C(C)(C)C)=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)=C=O>Cl.O1CCOCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([NH:35][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=2)=[O:19])=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1oncc1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCC[C@@H]1c1oncc1Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4-chlorobenzyl)isoxazol-5-yl)pyrrolidine-1-carboxylate (32 mg, 0.9 mmol) was dissolved in 4M HCl in 1,4-dioxane (2 mL), stirred for 2 h and then concentrated in vacuo. The resulting reaction residue was suspended in dicloromethane (2 mL) and DIEA (31 μL, 0.18 mmol) before 1-isocyanato-4-(trifluoromethyl)benzene (25 mg, 0.13 mmol) was added. After 16 h of stirring, the reaction mixture was concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-2-(4-(4-chlorobenzyl)isoxazol-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamide (19 mg, 47%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1>O1CCOCC1>[Cl:3][CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(CCl)c(=O)[nH]1
Yield: 100 %

Procedure:
Thionyl chloride ((10 ml) was added to a suspension of 5-(hydroxymethyl)-2,4(1H,3H)-pyrimidinedione (0.60 g, 4.2 mmol)from step (11a) in dioxane (15 ml). The reaction was heated to reflux for 4 h, allowed to cool, and concentrated in vacuo to give the 5-(chloromethyl)-2,4(1H,3H)-pyrimidinedione (0.62 g, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([B:19]([OH:24])[OH:20])[CH:7]=[CH:6]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(B(O)O)ccc2c1
Reaction time: 1.5 h

Procedure:
A solution of 6-methoxy-2-bromonaphthalene (25 g) in tetrahydrofuran (300 ml) was cooled at −78° C. under a nitrogen atmosphere. n-Butyllithium (2.66 M solution in hexane) (42 ml) was added dropwise thereto over 1.5 hours, and the solution was stirred for 30 minutes. Triisopropyl borate (26.5 ml) was added dropwise thereto for 30 minutes, then the solution was stirred for 40 minutes while warming from −78° C. to 0° C. 1N hydrochloric acid (200 ml) and ethyl acetate (200 ml) were sequentially added thereto, the solution was stirred, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (18 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([CH2:85][CH3:86])[CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][N:82]([CH2:85][CH3:86])[CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:32])([F:33])[F:34])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0299 g (0.233 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0459 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-trifluoromethyl-benzamide (I-206) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=N[NH:9][C:8]=12.IC1C=CC=CC=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:11]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=1[NH2:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1nccc2c(-c3ccccc3)n[nH]c12
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: Ic1ccccc1
Solvent: CS(C)=O
Product: COc1nccc(Cc2ccccc2)c1N
Yield: 69.8 %

Procedure:
A solution of 7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridine (113 mg), iodobenzene (1.02 g), L-proline (23.0 mg), potassium carbonate (346 mg) and copper(I) iodide (19.1 mg) in DMSO (10 mL) was stirred under nitrogen atmosphere at 180° C. for 1 hr. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (75 mg).
Reaction SMILES: C(O[C:6](=[O:23])[NH:7][C:8]1[CH:9]=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][N:38]2[N:41]=[CH:42][C:43](C(Cl)=O)=[C:37]2[N:36]=1>O1CCOCC1.ClCCl>[F:22][C:19]([F:20])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[O:11][N:10]=[CH:9][C:8]=1[NH:7][C:6]([C:43]1[CH:42]=[N:41][N:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[N:36][C:37]=12)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1cnoc1-c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1cnoc1-c1ccccc1C(F)(F)F)c1cnn2ccc(Cl)nc12
Temperature: 40 °C
Yield: 85.7 %

Procedure:
A mixture of [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (345 mg, 1.05 mmol, 1.0 equiv), 4M HCl in dioxane (2 mL) in 1,4-dioxane (3 mL) was heated to 40° C. for 20 hours. The mixture was concentrated under vacuum affording a residue which was dissolved in dichloromethane (12 mL) and treated with diisopropylethylamine (271 mg, 2.10 mmol, 2.0 equiv). The mixture was cooled with an ice-bath, and a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (1.05 mmol, 1.0 equiv) in dichloromethane (6 mL) was added dropwise. The resultant mixture was stirred at ambient temperature for 18 hours. The solution was washed sequentially with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution and water. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated (methanol), and the isolated solid was washed with methanol and diethyl ether before drying under vacuum to give 367 mg (86%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide. LCMS (ESI) m+H=408.0 (mono Cl); 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.35 (d, 1H), 9.22 (s, 1H), 8.71 (s, 1H), 8.03 (d, 1H), 7.97-7.82 (m, 3H), 7.38 (d, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([CH:11]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:12]([OH:14])=O)[CH2:8][CH:9]=[CH2:10].Cl.[O:30]=[C:31]1[CH2:36][CH2:35][C:34]([NH2:43])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32]1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[CH2:7]([CH:11]([C:15]1[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[C:12]([NH:43][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32][C:31](=[O:30])[CH2:36][CH2:35]1)=[O:14])[CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CCCC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
Oxalyl chloride (4.22 mL, 48.4 mmol) was added to a solution of (RS)-α-(3-butenyl)-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 8, 24.2 mmol) and dimethylformamide (0.1 mL) in dichloromethane (80 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and toluene was added and evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and added to a stirred, cooled (0° C.) solution of 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 3, 4.58 g, 24.2 mmol) in dichloromethane (150 mL). Pyridine (4.1 mL, 50.8 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was washed with hydrochloric acid (1M, 2×200 mL), saturated aqueous sodium hydrogen carbonate (2×200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with isohexane/diethylether (7:1) and the solid was collected and dried in vacuo. The solid was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (2:1), to give the title compound (6.22 g, 52%). 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.73 (2H, s), 7.31-7.25 (5H, m), 5.80-5.70 (2H, m), 5.05-4.97 (2H, m), 3.52-3.47 (1H, m), 2.86-2.80 (1H, m), 2.65-2.57 (1H, m), 2.50-2.31 (6H, m), 2.27-2.18 (1H, m), 2.09-1.95 (2H, m), and 1.81-1.72 (1H, m).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.F[C:46](F)(F)[C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:48].P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[C:49]1([C@H:47]([OH:48])[CH3:46])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of acetophenone, Compound 2, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (R)-1-Phenylethanol, Compound 2a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: Nc1ccccn1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccccn2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-aminopyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H46Cl2N7O3 [(M+H)+] 742.3034, observed 742.3032.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([N:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[N:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:36]([C:34]1[N:33]=[N:32][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:35]=1)=[O:37])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=C(O)c1cn(Cc2ccccc2)nn1
Product: CCOC(=O)C(C(=O)c1cn(Cc2ccccc2)nn1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (0.6 g, 27%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 1-benzyl-1H-[1,2,3]triazole-4-carboxylic acid. MS: 517.1 (MH+).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH:23](O)[CH:24]1[CH2:26][CH:25]1[C:27]#[N:28].[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=1)[NH:36][CH:35]=[CH:34]2>ClCCCl>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:23]([C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:13]=1[F:12])[CH:24]1[CH2:26][CH:25]1[C:27]#[N:28]
Reactant: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1F
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(C(F)(F)F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
1.63 g (7.35 mmol) of indium(III) chloride and 0.85 ml (11.0 mmol) of trifluoroacetic acid were added to 1.59 g (6.13 mmol) of the compound from Example 164A and 1.90 g (7.35 mmol) of the compound from Example 87A in 100 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 763 mg (27% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([C:17]([CH:19]([CH3:21])[CH3:20])=[CH2:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:36][S:37]([O-:39])=[O:38].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([CH:17]([CH2:18][S:37]([CH3:36])(=[O:39])=[O:38])[CH:19]([CH3:20])[CH3:21])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)[O-]
Reactant: C=C(c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1)C(C)C
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C(CS(C)(=O)=O)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 60 °C

Procedure:
To a stirred solution of 3-{4-(5-chloropyridin-3-yl)-2-(3-methylbut-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (synthesized in a manner similar to Example 9.1; 20 mg, 0.046 mmol) in dry ethanol (0.7 mL) was added sodium methanesulfinate (47 mg, 0.46 mmol) followed by acetic acid (27 μL, 0.046 mmol). The reaction mixture was heated to 60° C. for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by reverse phase prep-HPLC (Kromasil C18, water/MeOH+0.1% TFA) to give 3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-methyl-1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one (TFA salt, racemate). 1H NMR (400 MHz, DMSO-d6): δ 12.90 (br s, 1H), 8.86 (s, 1H), 8.85 (s, 1H), δ 8.43 (s, 1H), 8.24 (s, 1H), 4.07-3.96 (m, 2H), 3.84-3.79 (m, 1H), 3.67-3.64 (m, 2H), 3.02 (s, 3H), 2.21-2.16 (m, 1H), 1.39 (d, J=11.6 Hz, 2H), 1.22-1.15 (m, 2H), 1.04 (d, J=6.7 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.70 (d, J=6.5 Hz, 3H), 0.78-0.41 (m, 6H). MS ES/APCl calc'd. for C27H33ClN6O4S [M+H]+ 573. found 573.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[N:2]=1.S(Cl)(Cl)=O.[CH:13]1([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[CH:19]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-]>C(Cl)Cl.CS(C)=O>[CH:13]1([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([NH:25][C:26](=[O:34])[C:27]3[CH:28]=[CH:29][C:30]([O:8][CH2:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:31][CH:32]=3)[CH:19]=2)[CH2:15][CH2:14]1
Reactant: OCc1cccnn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O=S(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.9 %

Procedure:
To a solution of 3-pyridazinylmethanol (140 mg, 1.27 mmol) in DCM (5 mL) was added thionyl chloride (103 μl, 1.42 mmol) and the resulting mixture stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure and then to the residue in DMSO (4 mL) was added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg, 0.636 mmol), cesium carbonate (621 mg, 1.91 mmol) and tetrabutylanunonium iodide (235 mg, 0.636 mmol) and the resulting mixture stirred at 60° C. for 16 h. The reaction mixture was added to a 20 g SCX column and product eluted with methanol. Concentration under reduced pressure gave impure product which was further purified on silica column chromatography eluting with 0-20% methanol/ 1% anmmonium hydroxide SG 0.88 in ethyl acetate. Evaporation and trituration with DCM and diethyl ether and filtration gave the title compound as a solid (15 mg, 5.9%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.86 (m, 1H), 5.54 (s, 2H), 7.21 (d, 2H), 7.34 (d, 1H), 7.64 (m, 1H), 7.79 (m, 2H), 7.86 (m, 1H), 7.99 (m, 2H), 8.37 (m, 1H), 9.24 (m, 1H), 9.86 (s, 1H); Mass Spectrum: M−H− 401.