Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:36]1([Mg]Cl)[CH2:40][CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: Cl[Mg]C1CCCC1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2C2CCCC2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a −78° C. solution of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added cyclopentyl magnesium chloride (0.17 mL, 1.0 M in diethyl ether). The resulting solution was stirred under nitrogen less than 1 hour with warming to room temperature. The reaction was poured into water and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO2, 2:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.1328 g, 94%). mp 155-157° C. 1H NMR (300 MHz, DMSO d6) δ 1.50 (m, 2H), 1.66 (m, 2H), 1.79 (m, 2H), 2.09 (m, 2H), 2.90 (m, J=8 Hz, 1H), 3.26-3.37 (3H, obstructed by H2O), 7.49-7.63 (m, 3H), 7.71 (m, 3H), 7.97 (s, 1H), 8.10 (m, 2H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21ClN2O3S: C, 61.60; H, 4.93; N, 6.53. Found: C, 61.48; H, 4.81; N, 6.22.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[CH:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[N:34][N:33]=[CH:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cnnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cnnc3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M56) (280 mg, 0.526 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (121 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.CC([O-])(C)C.[K+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C[N:33](C=O)C>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH2:33])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2cnccc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cn(N)c2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 3-methyl-1H-pyrrolo[2,3-c]pyridine (1.21 g, 9.16 mmol), KOtBu (2.05 g, 18.3 mmol) in DMF (41 mL) is purged with N2 and stirred at rt for 2 h. Chloramine in ether (0.15 M, 92 mL) is added and the mixture is stirred for 20 min. The reaction is cooled to 00 C. and a solution of Na2S2O3 (5 g) in water (80 mL) is added. The mixture is stirred for 10 min, and then concentrated in vacuo. The residue is triturated in DCM and filtered. DCM is added, cooled to 0° C. and charged with BOC2O (541 mg, 2.48 mmol). The resulting mixture is separated by silica gel chromatography eluting with 10% MeOH in DCM to afford 3-methyl-pyrrolo[2,3-c]pyridin-1-yl amine (468 mg, 35%). MS: 148 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.27 (d, 1H), 7.46 (d, 1H), 7.09 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]CN(CC)CC.S(Cl)(Cl)(=O)=O>CO>[CH3:11][O:9][C:8]([C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)=[O:10]
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CCN(CC)CC
Solvent: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-2-pyrimidine carboxylic acid (6 g, 29.6 mmol) in MeOH (300 mL) was added Et3N (5.98 g, 59.2 mmol). The mixture was cooled to 0 degrees Celsius, and sulfonyl chloride (5.3 g, 44.4 mmol) was added dropwise to the solution. After addition, the mixture was stirred at rt for 12 hours. The solvent was removed and the residue was dissolved in ethyl acetate. The organic layer was washed with sodium bicarbonate, brine, and dried with sodium sulfate. The solvent was removed to give the pure product. MS: calc'd 217 (MH+), exp 217 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].O.[F:25][C:26]([F:31])([F:30])[C:27](O)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([C:26]([F:31])([F:30])[F:25])=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Yield: 55.5 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.20 g, 0.646 mmol) in trifluoroacetic acid (7 mL) was heated to reflux for 4.5 hours. The reaction mixture was cooled, water was added, and this was extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution and water, then dried over magnesium sulfate, and concentrate. The residue was purified by silica gel column chromatography to yield the title compound (139 mg, 55.5% yield) as white crystals.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:10]([O:12]CC)=[O:11])=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[S:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of ethyl 2-tert-butylthiazole-5-carboxylate (1.16 g, 5.44 mmol) in THF (10 mL) was added lithium hydroxide (0.45 g, 10.9 mmol) in water (5 mL) and the mixture was stirred for 16 h at RT. Solvents were removed under vacuum, and the thick liquid was diluted with water (5 mL) and acidified with 2M HCl solution to pH 4 to 5. The product precipitated, was filtered, washed with water (2×5 mL) and dried to provide 2-tert-butylthiazole-5-carboxylic acid as white solid (0.55 g, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H), 1.39 (s, 9H); MS (ESI) m/z: 186.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: N#Cc1cc(F)c(C(=O)Nc2ccnc(Cl)c2F)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)c(C(Cl)=Nc2ccnc(Cl)c2F)c(Cl)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 2-chloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-6-fluorobenzamide (0.805 g, 2.5 mmol) in thionyl chloride (7.5 mL) was heated under reflux for 65 h then cooled to ambient temperature. The reaction mixture was diluted with toluene and concentrated under reduced pressure to give the desired compound as a yellow solid (0.814 g, 96% yield). 1H NMR (300 MHz, CDCl3): δ 8.25 (d, J=5.1 Hz, 1H), 7.70-7.63 (m, 1H), 7.49 (dd, J=8.0, 1.0 Hz, 1H), 6.97 (t, J=5.0 Hz, 1H). LCMS (Method D): RT=4.09 min, m/z: 346 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(CO)COc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(CO)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 96.9 %

Procedure:
5-Chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-benzaldehyde (2.4 g, 10 mmol) and 6-chloro-1,3-dihydro-indol-2-one (1.7 g, 10 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (0.8 g, 11.2 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. Then the precipitate was collected by filtration to give title compound as yellow solid (Yield: 3.8 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 1.7 g. (0.02 mole) of piperidine and 5.8 g. (0.02 mole) of 2,4-dichloro-5-chlorosulfonylbenzoic acid (Sturm, et al., Ber., 99, 328 (1966) in 70 ml. of water and cooled to 15° C. is treated dropwise with 50 ml. of 1 N sodium hydroxide. When the addition is complete, the mixture is allowed to warm to room temperature and remain for 1 hr. The hazy suspension is filtered and the clear filtrate acidified with 12 N hydrochloric acid. The precipitated solids are filtered and dried, 7.7 g., m.p. 200°-205° C. A sample is recrystallized from acetonitrile, m.p. 205°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[N:10]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:16][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:14]=[C:13]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[N:12]=1
Reactant: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2nc(Cl)nc(Nc3ccc(Cl)cc3)n2)cc1
Yield: 62 %

Procedure:
The reaction of (4-chloro-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine with p-anisidine, according to method 2, gave 6-chloro-N-(4-chlorophenyl)-N′-(4-methoxyphenyl)-[1,3,5]triazine-2,4-diamine (51 mg, 62%): 1H NMR (CDCl3) 7.21–7.50 (6 H, m), 6.91 (2 H, d, J=11 Hz), 3.85 (3 H, s).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O[Li].O>O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1
Reaction time: 10 h

Procedure:
A solution of the methyl 4-[[4-(2,2,3,3,4,4,4-heptafluorobut-1-oxy)anilino]-1-piperidinyl]methyl]benzoate (0.59 g, 1.13 mmol) in a 3 to 1 mixture of THF and water (40 mL) was added LiOH.H2O (8 eq, 385 mg). The reaction mixture was heated at reflux with stirring for 10 h. The reaction was allowed to cool, concentrated, diluted with water (3 mL), and acidified to a pH of 6 with an aqueous solution of 2N HCl. The solid was collected by filtration, dried, and recrystallized from water (5 mL) to give 0.32 g of 4-[[4-(2,2,3,3,4,4,4-heptafluorobut-1-oxy)phenylamino]-1-piperidinyl]methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, 2H), 7.38 (d, 2H), 6.668 (d, 2H), 6.50 (d, 2H), 4.60 (t, 2H), 3.50 (s, 2H), 3.30 (br., 1H), 3.10 (m, 1H), 2.75 (m, 2H), 2.05 (m, 2H), 1.85 (m, 2H), 1.30 (m, 2H) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[F:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[N:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH2:27][C:24]3[CH:25]=[N:26][C:21]([O:20][C:19]4[CH:29]=[CH:30][C:16]([F:15])=[CH:17][CH:18]=4)=[CH:22][CH:23]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: NCc1ccc(Oc2ccc(F)cc2)nc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(Oc2ccc(F)cc2)nc1
Yield: 54 %

Procedure:
The title compound is prepared in 54% yield (130 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (180 mg, 0.64 mmol, Step-1 of Intermediate-1) and (6-(4-fluorophenoxy)pyridin-3-yl)methanamine (140 mg, 0.64 mmol, Amine-18) in a similar manner to Intermediate-2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[CH3:8].[CH2:27](I)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:7]([O:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)[CH3:8]
Reactant: CCCCCCCCI
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCNc1ccc(Oc2ccc(CC(=O)OCC)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A slurry of 3.45 g of anhydrous potassium carbonate in 50 ml of hexamethylphosphoramide (HMPA) containing 6.8 g of ethyl[p-(p-aminophenoxy)phenyl]acetate is heated to 50° C. A solution of 6 g of n-octyliodide in 10 ml of HMPA is added over 2 hours. The heating is continued for 24 hours. The mixture is diluted with 100 ml of H2O and extracted with two 100 ml portions of ether. The combined extracts are washed with two 100 ml portions of H2O, 100 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a brown liquid, which yields, after silica gel chromatography (benzene, then CHCl3) and bulb-to-bulb distillation of the CHCl3 elutate, a pale yellow oil, b.p. 194° at 0.05 mm.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24]>>[CH3:28][S:25]([CH2:23][CH2:24][O:21][C:19]([CH3:22])([CH3:20])[CH2:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])(=[O:27])=[O:26]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Yield: 64.4 %

Procedure:
Using the general method of Example 8 Part D, 1-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (2.0 g, 6.7 mmol) was reacted with methyl vinyl sulfone (1.42 g, 13.4 mmol). The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude product as an oil. This material was purified by column chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 1.75 g of 1-{2-[2-(methylsulfonyl)ethoxy]-2-methylpropyl}-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a colorless foam.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (1.20 g, 3.38 mmol) in DCM (5 mL) was added TFA (5 mL) and the resulting mixture was stirred at RT for 1.5 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording (S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a yellow oil (861 mg, quantitative). LCMS: RT 1.97 and 2.19 min [M+H]+ 256.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9].ClC1C=C[C:18]([S:21]([CH2:24]C#N)(=[O:23])=[O:22])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11](=[C:24]([S:8]([CH3:3])(=[O:10])=[O:9])[S:21]([CH3:18])(=[O:23])=[O:22])[C:12]#[N:13])(=[O:10])=[O:9]
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CCS(=O)(=O)c1ccccc1Cl
Product: CS(=O)(=O)C(=C(C#N)S(=O)(=O)c1ccccc1Cl)S(C)(=O)=O

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(2-chlorobenzenesulfonyl) acetonitrile is utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methylaniline (41 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (15 mg, 21%). 1H NMR (CDCl3): 9.62-9.61 (m, 1H), 8.73-8.69 (m, 2H), 7.89 (s, 1H), 7.44-7.40 (m, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.00 (dd, J=0.9, 8.4 Hz, 1H), 6.88 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4][C:3]1=2.[Br:19]Br>>[Br:19][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:18])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]=1[OH:14]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Reactant: BrBr
Product: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br

Procedure:
3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound L, 155 mg, 0.62 mmol) was dissolved in 1 ml of HOAC. To this solution was added Br2 (0.033 ml, 0.62 mmol). The reaction mixture was left at room temperature for over night. A stream of air was passed through the reaction mixture to remove the unreacted Br2. The remaining solid was dissolved in small amount of THF and purified by column chromatography (ethyl acetate/hexane 1/1) to yield the desired product as a cream colored solid.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[C:9](#[N:12])[CH:10]=[CH2:11]>C(O)C>[C:9]([CH2:10][CH2:11][NH:7][CH:4]1[CH2:5][CH2:6][CH:1]([NH:8][CH2:2][CH2:3][C:4]#[N:7])[CH2:2][CH2:3]1)#[N:12]
Reactant: C=CC#N
Reactant: NC1CCC(N)CC1
Solvent: CCO
Product: N#CCCNC1CCC(NCCC#N)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
In a 5-liter reactor, 531.5 g of 1,4-cyclohexanediamine were placed and warmed at 80° C. until total fusion of the product. Then 675 mL of acrylonitrile were added and the mixture was warmed at 80° C. for 1 h, and at 100° C. for 2 h. Then 960 mL of ethanol were added and it was cooled down to room temperature, occurring the precipitation of a solid. After filtering, washing with ethanol and drying, 952.2 g (92.8%) of the title compound were obtained as a brown solid. Elemental analysis (%): theory, C 65.49, H 9.09, N 25.45; found, C 65.80, H 9.20, N 26.16.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=3[O:40]C)[CH:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=3[OH:40])[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(O)cc1F
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A solution of 4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4-methyl-1,3-oxazolidin-2-one (54) [prepared by methods described in WO2007/005572] (1.4 g) in DCM (5 mL) was treated with BBr3 (0.9 mL) at 15-16° C. and the reaction mixture stirred for 1 hr. The mixture was quenched with ice and diluted with EtOAc (150 mL) The mixture was washed with water, sat'd NaHCO3 solution, and brine, dried (Na2SO4), filtered and the solvent concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to give 1.01 g (60%) of 55. 1H NMR (CDCl3) δ: 7.85 (s, 1H), 7.75-7.62 (m, 4H), 7.42 (m, 1H), 6.96 (dd, 1H), 7.69 (dd, 1H), 5.64 (d, 0.5H), 5.39 (d, 0.5H), 4.92-4.80 (m, 1H), 4.18 (d, 0.5H), 3.99 (d, 0.5H), 3.85 (m, 0.5H), 3.75 (m, 0.5H), 3.19 (m, 1H), 1.17-1.25 (m, 6H), 0.57 (d, 1.5H), 0.45 (d, 1.5H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([CH3:11])([C:7]([F:10])([F:9])[F:8])[C:4](Cl)=[O:5].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:4](=[O:5])[C:3]([CH3:11])([C:7]([F:10])([F:9])[F:8])[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C(=O)Cl)(C(F)(F)F)C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CC(C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)(C(F)(F)F)C(F)(F)F

Procedure:
Following the procedure of Example 3, making variations only as required to use (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropionyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (35% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.96, 6.80, 3.91-3.75, 3.58, 1.58-1.48, 0.78-0.63, 0.48-0.43, 0.11-0.04. MS (ES+) m/z 468.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[OH:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>CC(OC)(C)C>[Br:12][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:15](=[O:16])[C:14]([F:21])([F:20])[F:13])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCC(O)c1cccc(Br)c1
Solvent: COC(C)(C)C
Product: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a cooled (0° C.) solution of 3-amino-1-(3-bromophenyl)propan-1-ol (24) (40 g, 173.8 mmol) in MTBE (250 mL) was added ethyl trifluoroacetate (28 mL, 234.7 mmol) over 7 min and the reaction mixture was stirred at room temperature for 50 min. Concentration under reduced pressure gave trifluoroacetamide 25 as a colorless oil. Yield (55.35 g, 98%): 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.51 (t, J=2.0 Hz, 1H), 7.41 (dt, J=7.6, 2.0 Hz, 1H), 7.25-7.32 (m, 2H), 5.46 (d, J=6.4 Hz, 1H), 4.55-4.60 (m, 1H), 3.20-3.23 (m, 2H), 1.75-1.82 (m, 2H).