Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][C:22]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])([OH:25])[CH2:21][CH2:20]2)[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([C:26]([C:22]3([OH:25])[CH2:21][CH2:20][N:19]([C:17]4[CH:16]=[CH:15][N:14]=[C:13]([CH3:12])[N:18]=4)[CH2:24][CH2:23]3)=[O:27])[CH2:29][CH2:30]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1nccc(N2CCC(O)(C(=O)N3CCNCC3)CC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCC(O)(C(=O)N3CCN(C(=O)c4ccc(Br)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromobenzoylchloride (0.53 g) in dichloromethane (3 ml) was added to a mixture of 1-(2-methylpyrimidin-4-yl)-4-(piperazin-1-ylcarbonyl)piperidine-4-ol hydrochloride (0.65 g) and triethylamine (1.7 ml) in dichloromethane (30 ml) at 5° C. The solution was stirred at ambient temperature for 18 hours. The resulting solution was evaporated to dryness. The residue was dissolved in dichloromethane and the solution was washed with water, dried (Na2SO4) and evaporated to dryness. The residue was purified by flash column chromatography on alumina (ICN alumina N32-63), using 0.1-0.4% methanol in dichloromethane as eluent. Recrystallisation from ethyl acetate/isohexane gave 1-(4-bromobenzoyl)-4-[1-(2-methylpyrimidin-4-yl)-4-hydroxy-4-piperidylcarbonyl]piperazine, as a colourless solid (0.53 g), mp114-117° C.
Reaction SMILES: C[Si](C)(C(C)(C)C(C)C)[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29]OS(C)(=O)=O)[CH2:11][O:10][C:9](=[O:35])[C:8]=2[C:7]([CH3:36])=[C:6]([O:37][CH3:38])[CH:5]=1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CO>[OH:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH2:11][O:10][C:9](=[O:35])[C:8]=2[C:7]([CH3:36])=[C:6]([O:37][CH3:38])[CH:5]=1
Reactant: C1COCCN1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](COS(C)(=O)=O)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Solvent: CO
Product: COc1cc(O)c2c(c1C)C(=O)OC[C@H](CN1CCOCC1)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A solution of 46 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethylpropyl)silanyloxy]-14-methoxy-13-methyl-4-(3-methyl[1,2,4]oxadiazol-5-yl)-9-(methylsulfonyloxymethyl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one in a mixture of 0.25 ml of morpholine and 0.25 ml of methanol was stirred at 20° C. for 18 h. The solution was evaporated in vacuo and the residue was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield 12 mg of (4R,9S)-16-hydroxy-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-9-(morpholin-4-ylmethyl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C1COCC1>O>[CH2:27]([O:26][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Yield: 100.6 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (112d) (2.28 g, 11.4 mmol), sodium bicarbonate (1.26 g, 15 mmol), benzyl chloroformate (2.69 g, 15 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 4.34 g of the title compound as a colorless solid (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: Brc1cccnc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1cncc(Nc2cccnc2)c1
Reaction time: 15 h
Yield: 84.4 %

Procedure:
To a solution of 3-bromopyridine (4.75 gm, 30 mmol) and 3-aminopyridine (1.88 gm, 20 mmol) in dry toluene (8 mL) was added sodium t-butoxide (2.3 gm, 24 mmol), tris(dibenylideneacetone) dipalladium(0) (63 mg, 0.069 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (183 mg, 0.317 mmol). The vessel was capped with a septum, degassed (3×), and heated at 100 C for ˜24 hours. The cooled reaction was diluted with methylene chloride, washed with NaHCO3 solution, water, and the organic layer dried over anhydrous sodium sulfate, filtered and the solvent concentrated to a small volume. Upon addition of diethyl ether and a few drops of methanol the product precipitated. After stirring this mixture for ˜15 hours the purified product was isolated by filtration to give 2.89 gm (84% yield) of the title compound.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][C@@H:26]([CH2:28][OH:29])[CH3:27]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][C@H:26]([CH3:27])[CH2:28][OH:29])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 41 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using D-alaninol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 41%) which was obtained as a white solid MS: m/e=372.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2cc(Cl)cc(S(=O)(=O)Cl)c2n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1ccc2cc(Cl)cc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-6-chloroquinoline-8-sulfonyl chloride (500 mg, 1.8 mmol), 4-aminobenzoic acid (300 mg, 2.2 mmol) and pyridine (1 mL) in 10 mL of THF was stirred at 30° C. overnight, when LCMS indicated that the reaction was complete. The resulting mixture was concentrated, and the residue was purified by a standard method to yield the title compound. LCMS (m/z): 378.8 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of 2,4-dichloropyrimidine (32.4 g) in methanol (200 ml) was added dropwise a solution of sodium methoxide (11.7 g) in methanol (120 ml) over 40 min and the mixture was stirred for 30 min. The reaction mixture was poured into water (500 ml) and extracted with chloroform (300 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from hexane to give the title compound (21.5 g) as white crystals, m.p.=50-52° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]=1[C:20]1[O:21][CH:22]=[CH:23][N:24]=1.[N:25]1([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]3[C:12](=[O:13])[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[N:5]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:4]=3[C:20]3[O:21][CH:22]=[CH:23][N:24]=3)=[O:36])=[CH:33][N:32]=2)[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
6-Morpholin-4-yl-N-(2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridin-3-yl-methyl)-nicotinamide was prepared starting from intermediate B and 6-morpholin-4-yl-nicotinic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.65-8.67 (m, 2H) 8.48 (d, J=2.90 Hz, 1H) 8.05-8.15 (m, 1H) 7.98 (d, J=0.75 Hz, 1H) 7.85 (dd, J=8.70, 2.90 Hz, 1H) 7.55 (dd, J=8.20, 4.40 Hz, 1H) 7.23-7.45 (m, 5H) 7.18 (d, J=0.75 Hz, 1H) 6.79 (d, J=8.30 Hz, 1H) 4.25 (d, J=4.20 Hz, 2H) 3.62-3.73 (m, 4H) 3.47-3.57 (m, 4H).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:10]1[CH2:11][CH2:12][CH:8]([C:7]2[C:2]([O:29][C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:14]4[S:13][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[N:15]=4)=[CH:28][CH:27]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Fc1ncccc1C1CCOC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCOC2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydrofuran-3-yl)pyridine (1.00 g, 5.98 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (1.56 g, 6.44 mmol) and cesium carbonate (4.88 g, 14.98 mmol) in DMSO (10 mL). The reaction mixture was sealed under argon and was heated thermally at 100° C. for 24 h. The reaction was cooled to rt and diluted with water. The product turned into a gum and the aqueous solution was decanted. The gum was stirred over MeOH for 1 h resulting in a precipitate that was filtered, washed with MeOH and dried in vacuo to give the title compound as a white crystalline solid. MS (ESI, pos. ion) m/z: 389.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[O:7][CH:8]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:5]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(-c2nc(CCN)co2)cc1
Product: N#Cc1ccc(-c2nc(CCNC(=O)c3cncc(-c4noc(C(F)(F)F)n4)c3)co2)cc1
Yield: 23 %

Procedure:
This compound was synthesized from 4-(4-(2-aminoethyl)oxazol-2-yl)benzonitrile and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (30 mg, yield 23%) as an off white solid. 1H NMR (400 MHz, CDCl3) δ 9.69 (m, 1H), 9.47 (m, 1H), 9.18 (m, 1H), 8.18-8.16 (d, J=8.3 Hz, 2H), 7.78-7.76 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 3.92-3.91 (m, 2H), 3.05-3.02 (t, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C21H13F3N6O3: 454.10. found: 453.2 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:21]1([CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](Cl)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:31])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccccc1Cc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
To 3.03 g of methyl 4-aminobenzoate and 3.12 g of N,N-diisopropylethylamine in 75 ml of methylene chloride is added 5.54 g of 2-(phenylmethyl)benzoyl chloride and the reactants stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried (Na2SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 5.04 g of the desired product as a crystalline solid, m.p. 138°-139° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH2:26])[CH:18]=[CH:19][C:20]=1[C:21]1[N:22]=[CH:23][S:24][CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:17]2[CH:18]=[CH:19][C:20]([C:21]3[N:22]=[CH:23][S:24][CH:25]=3)=[C:15]([F:14])[CH:16]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cscn2)c(F)c1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (165 mg, 0.746 mmol) and 3-fluoro-4-(thiazol-4-yl)benzenamine (145 mg, 0.747 mmol) in CH3CN (5 mL) at room temperature, DIEA (0.260 mL, 1.49 mmol) was added. The mixture was stirred at room temperature overnight, during which time solids precipitated out. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(3-fluoro-4-(thiazol-4-yl)phenylamino)pyrimidine-5-carboxylate as a solid (186 mg). MS 379.3 and 381.3 (M+H, Cl pattern)
Reaction SMILES: CS[S:3][CH3:4].C(P(CCCC)CCCC)CCC.[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH2:38]O)=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1.C(OCC)(=O)C>[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH2:38][S:3][CH3:4])=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Oc1ccc(CCCCn2ccnc2CO)cc1
Reactant: CSSC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CSCc1nccn1CCCCc1ccc(OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dimethyl disulfide (8.94 ml) and tributylphosphine (24.7 ml) were added to a solution of [1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]methanol (10.0 g) in pyridine (13.4 ml) at room temperature, and the mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted with ethyl acetate, successively washed with 1N aqueous sodium hydroxide solution (3 times) and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-2-[(methylthio)methyl]-1H-imidazole. 4N Hydrochloric acid (33 ml) was added to the product, and the mixture was stirred at 50° C. for 2 hr. After cooling, the reaction mixture was combined with water and ethyl acetate and separated. The water layer was adjusted to pH 6 by adding 30% aqueous sodium hydroxide solution to salt out and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether to give the titled compound (7.31 g) as a colorless crystal powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[I:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1.[F:22][CH:23]([F:26])[CH2:24]I>CN(C=O)C>[F:22][CH:23]([F:26])[CH2:24][N:19]1[CH:20]=[CH:21][C:17]([I:16])=[N:18]1
Reactant: Ic1cc[nH]n1
Reactant: FC(F)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)Cn1ccc(I)n1
Reaction time: 1.25 h
Yield: 50.5 %

Procedure:
A stirred solution of NaHMDS in THF (1.0 M, 3.1 mL, 3.1 mmol) was cooled in an ice water bath under Ar. 3-iodo-1H-pyrazole (500 mg, 2.6 mmol) was added as a solution in DMF (1 mL), washing with additional DMF (2×1 mL). 1,1-difluoro-2-iodoethane (0.47 mL, 5.2 mmol) was added in one portion and the mixture was removed from the cold bath. After 1.25 h, the reaction mixture was diluted with water and EtOAc. The phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel (0-15% EtOAc in hexanes) to provide 1-(2,2-difluoroethyl)-3-iodo-1H-pyrazole 7.02 (339 mg). Regiochemistry was assigned by NOE studies. LCMS-ESI+ (m/z): [M+H]+ calcd for C5H6F2IN2: 259.0; found: 258.2. 1H NMR (400 MHz, Chloroform-d) δ 7.29 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.06 (tt, J=55.4, 4.3 Hz, 1H), 4.45 (td, J=13.4, 4.3 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH2:7])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 5 h
Yield: 78.9 %

Procedure:
{2-[4-(3-Trifluoromethyl-phenoxy)-phenyl]ethyl}-carbamic acid tert-butyl ester (354 mg, 0.928 mmol, 1 eq) was dissolved in dry DCM (3 ml) under argon atmosphere and TFA (355 μl, 5 eq) was added. Reaction mixture was stirred for 5 h. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a product 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (206 mg, yield=64.7%, purity=65%). [M+H]+=282.28 1H NMR (300 MHz; CDCl3) δ/ppm 2.76-2.80 (m, 2H), 2.93-3.04 (m, 2H), 6.92-6.98 (m, 2H), 7.02-7.35 (m, 5H), 7.37-7.45 (m, 1H)
Reaction SMILES: [N:1](=[C:3]([C:9]([CH3:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])O.[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C(#N)C>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[C:19]([C:18]2[CH:21]=[CH:22][C:15]([O:14][C:13]([F:12])([F:23])[F:24])=[CH:16][CH:17]=2)[NH:20][C:9]=1[CH3:11])=[O:5])[CH3:8]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)[nH]c1C
Temperature: 0 °C
Yield: 71.8 %

Procedure:
To a solution of 7.9 g of ethyl 2-oximinoacetoacetate in acetonitrile (100 ml) was added 10.5 g of 4-(trifluoromethoxy)benzylamine (as R4—CH2—NH2). The reaction mixture was then refluxed for 17 hours under argon atmosphere. After such time the reaction mixture was cooled down to 0° C., the solid was filtered off, washed with acetonitrile, and dried in vacuo to yield 11.2 g of a light yellow powder, MS (ISP) 315 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:17]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:5]=[O:6]
Reactant: SC1CCCC1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(SC2CCCC2)c(Br)c1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
A solution of 3-bromo-4-fluorobenzaldehyde (517.4 mg) in DMSO (8 ml) was added with potassium carbonate (514.9 mg) and cyclopentanethiol (250 μl, TCI), and stirred at 90° C. for 17 hours. The reaction mixture was extracted with ethyl acetate (50 ml), and the organic layer was washed successively with water and saturated brine, and dried. Then, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=8:1) to obtain the title compound (Intermediate S-23, 644.7 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:17].Cl>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1CCCCN1Cc1ccccc1
Reactant: BrP(Br)Br
Agent: Cl
Solvent: c1ccccc1
Product: BrC[C@H]1CCCCN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
Charge (R)-(1-benzylpiperidin-2-yl)methanol (30.0 g, 0.146 mol, ˜1.0 eq., crude) in 350 mL benzene and add a solution of phosphorus tribromide (20.6 mL, 0.219 mol, 1.5 eq) in benzene at 0° C. under nitrogen atmosphere. Heat the reaction mass at 70° C. for 16 h. After completion of reaction, quench the reaction with saturated solution of sodium carbonate (100 mL) and extract the compound in EA (3×100 mL). Wash the organic layer with brine and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and dissolve the solid residue in diethyl ether. Filter the dissolved portion and add slowly HCl (1.2 eq, 2 N in diethyl ether) and stir for 30 minutes at RT. Filter the precipitated salt and wash with EA followed by hexane. Dry under high vacuum to get 13.2 g of (R)-1-benzyl-2-(bromomethyl)piperidine as hydrochloride salt. MS(ES): m/z=268, 270 (M+H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9])(=[O:4])=[O:3].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([Cl:18])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3-chlorosulfonyl-4-fluoro benzoic acid (2.5 g, 10 mmol) in methylene chloride at 0° C. is added oxalyl chloride (1.33 g, 11 mmol), followed by the addition of 1 drop of N,N,-dimethylformamide. The reaction mixture is warmed up to room temperature and stirred for an additional 4 h. The solvent is removed, and the residue is dried under vacuum for 1 hr to obtain the title compound as an oil, which is used for the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][N:10]=1)=[O:5])C.[CH3:20][NH2:21]>C1COCC1>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:8]1[O:7][C:6]([C:4](=[O:5])[NH:21][CH3:20])=[N:10][N:9]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CN
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Solvent: C1CCOC1
Product: CNC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1

Procedure:
Prepared in an analogous fashion to Description 35 from 5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (prepared as described in JOC (1995), 60(10), 3112-20) (0.150 g) using 2.0M methylamine in THF.