Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH2:9][O:10][C:11]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([F:27])[CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1([CH2:9][O:10][C:11]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:27])[CH:12]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)CCCCC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of tert-butyl 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoate (0.498 g, 1.33 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL). The solution was stirred at ambient temperature for 1 hour and the solvent was concentrated in vacuo to dryness. The residue was triturated with diethyl ether (10 mL) to afford the title compound as a colorless solid (0.32 g, 75%): 1H NMR (300 MHz, DMSO-d6) 12.88 (br s, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.93 (d, J=12.8 Hz, 1H), 4.14 (s, 2H), 2.02-1.95 (m, 3H), 1.72-1.65 (m, 3H), 1.51-1.43 (m, 4H), 1.24-1.18 (m, 1H), 0.91-0.85 (m, 2H), 0.61-0.56 (m, 2H); MS (ES−) m/z 316.2 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[C:20]([C:28]([O:30][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCCCCCCBr
Reactant: CCOc1ccc(-c2nc(-c3ccc(OCOC)c(C(=O)O)c3)cs2)cc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOC(=O)c1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1OCOC
Temperature: 25 °C
Reaction time: 14 h
Yield: 43.8 %

Procedure:
In 5 ml of dimethylformamide was dissolved 600 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-methoxymethoxyphenyl)thiazole. Thereto was added 56 mg of sodium hydride and 290 mg of 1-bromononane. The mixture was stirred at room temperature for 14 hours. The solvent was removed by distillation. To the residue were added 80 ml of dichloromethane and 30 ml of a 10% aqueous sodium hydroxide solution, and phase separation was conducted. The dichloromethane portion was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was subjected to silica gel column chromatography. There was obtained, from the dichloromethane layer, 340 mg of 2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazole as a colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH:14]1[C:15]2[CH:16]=[C:3]([CH2:2][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cc2ccccc2c2ccccc12
Product: CCOP(=O)(Cc1cc2ccccc2c2ccccc12)OCC
Temperature: 150 °C
Yield: 56.8 %

Procedure:
9-(Bromomethyl)phenanthrene (18 g, 66.4 mmol) and triethyl phosphite (10.7 g) were mixed and heated to 150° C. under N2 for 4 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to yield 12 g of product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:4][CH:3]=1.[CH3:29][N:30](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:28]=[C:9]1[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:5]1[S:6][C:2]([C:29]#[N:30])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C1N(Cc2ccc(Br)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)s1
Temperature: 25 °C
Yield: 44 %

Procedure:
A mixture of 1′-[(5-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.23 g, 0.49 mmol), zinc cyanide (0.07 g, 0.59 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.10 g, 0.11 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.06 g, 0.11 mmol), N,N-dimethylformamide (6.00 mL) and a catalytic amount of water (2 drops) was heated at 120° C. for 24 hours. After cooling down to ambient temperature, the organic solvent was evaporated in vacuo. The residue was extracted with ethyl acetate (5×15.0 mL) and the combined organic solution was passed through a bed of celite. The filtrate was successively washed with saturated aqueous ammonium chloride (25.0 mL), water (2×35.0 mL) and brine (40.0 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluted with 20-35% ethyl acetate in hexanes to afford solid which was further purified by preparative thin layer chromatography, eluted with 20% ethyl acetate in hexanes to afford the title compound (0.09 g, 44%): 1H NMR (300 MHz, CDCl3) δ 7.50 (d, 1H), 7.32-7.16 (m, 2H), 7.12-7.04 (m, 2H), 6.86 (d, 1H), 6.51 (s, 1H), 6.08 (s, 1H), 5.87 (d, 2H), 5.10 (ABq, 2H), 4.78 (ABq, 2H); MS (ES+) m/z 403.0 (M+1).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Br:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Br:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
t-Butyl amine (5.9 mL, 56 mmol, 1.0 eq) and DIPEA (9.7 mL, 56 mmol, 1.0 eq) were added to 350 ml DCM. The solution was cooled to 0° C. and a solution of 4-bromomethylbenzenesulfonyl chloride (15.1 g, 56 mmol, 1.0 eq) in 100 mL DCM was added drop-wise via an addition funnel. The mixture was then slowly warmed to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure and the residue was dissolved into 350 mL EtOAc. The organic was washed with 1N aq. HCl, saturated bicarbonate, water, saturated aqueous NaCl, dried over MgSO4, and filtered. The filtrate was concentrated to yield intermediate (2a) (13.6 g).
Reaction SMILES: Cl[CH:2]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.ClC1C=C(C2C=C(C(C3C=CC(F)=CC=3)O)[CH:35]=[N:36]C=2OC)C=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[CH:4]=[C:3]([CH:2]([NH:36][CH3:35])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:8]=[N:7][C:6]=2[O:9][CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ncc(C(Cl)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Reactant: COc1ncc(C(O)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(c1ccc(F)cc1)c1cnc(OC)c(-c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(Chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine. To a cooled solution, 0° C., of [5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol (Example 14, 1.43 g, 4.17 mmol), in DCM (10 mL), was added thionyl chloride (744 mg, 6.25 mmol) dropwise. The solution was allowed to warm up to room temperature, and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO2, 0-10% EtOAc/hexanes) afforded the title compound, which was used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=O)[C:5]([N:8]([CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:6][CH:7]=1.C[O-].[Na+].O>C(=O)(OC)OC.CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:20][C:4]=2[CH:3]=1
Reactant: CCCN(CCCCC(=O)OC)c1ncc(Br)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(=O)OC
Solvent: O
Product: CCCN1CCCC(C(=O)OC)=Cc2cc(Br)cnc21
Temperature: 65 °C
Yield: 99.9 %

Procedure:
To a solution of methyl 5-[(5-bromo-3-formylpyridin-2-yl)(propyl)amino]pentanoate (880 mg) in dimethyl carbonate (20 ml) was added a 28% sodium methoxide solution in methanol (951 mg), and the mixture was heated at 65° C. for 6 hours under a nitrogen atmosphere. The mixture was returned to room temperature, water was added thereto, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give methyl 3-bromo-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (835 mg) as a yellow oily material.
Reaction SMILES: [C:1]1([S:7][CH2:8][F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1C(=O)N(Br)C(=[O:15])C1>O>[C:1]1([S:7]([CH2:8][F:9])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FCSc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Product: O=S(CF)c1ccccc1
Yield: 89.5 %

Procedure:
Fluoromethyl phenyl sulphide (85 g, 351.63 mmol) was added to a mixture of methanol (250 ml) and water (50 mL) The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (75.10 g, 1.2 eq) was added in small portions maintaining the same temperature range. The reaction mixture was stirred until the reaction was complete, and then, was quenched with Na2SO3 solution (10%, 150 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8 with NaHCO3 saturated solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (200 mL, 300 mL). The combined organic layer was washed with water (2×300 mL) and concentrated to 1/3 of the volume. Heptane (50 mL) was added and the resulting mixture was concentrated again. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 49.8 g (89.6%) of the desired product as colourless oil at rt, which is a white solid at −20° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[CH2:11][NH:12]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[CH:5][C:4]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:2].N1CCCCC1>CN(C=O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[CH2:11][NH2:12])=[CH:5][C:4]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:2]
Reactant: Cc1cc(C)nc(Nc2cc(NC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)cnc2C#N)c1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cc(C)nc(Nc2cc(NC(=O)CN)cnc2C#N)c1
Reaction time: 1 h

Procedure:
To a suspension of 9H-fluoren-9-ylmethyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-2-oxoethyl]carbamate (120 mg, 0.23 mmol) in DMF (1.8 mL) was added piperidine (394 mg, 4.63 mmol). After 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (0-70% ethyl acetate/hexanes, linear gradient, followed by 0-12% methanol/dichloromethane, linear gradient) to afford N-{6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}glycinamide. MS ESI calc'd for C15H17N6O [M+H]+ 297. found 297. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.85 (d, J=2.1 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 6.64 (s, 1H), 6.61 (s, 1H), 3.31 (s, 2H), 2.29 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4].[Li+].[CH3:15][CH:16]([N-]C(C)C)C.ICC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCC(C(C)C)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(C(=O)OC)CCC(C(C)C)CC1
Yield: 78.5 %

Procedure:
4-Isopropyl-cyclohexanecarboxylic acid methyl ester (1.1 g, 6 mmol) was alkylated using a method analogous to General Procedure F using LDA (9 mmol) and iodoethane (1.4 g, 9 mmol) in THF (20 mL) at −78° C. to RT to produce 1-ethyl-4-isopropyl-cyclohexanecarboxylic acid methyl ester (1.0 g, 78% yield) as a mixture of isomers. Hydrolysis of this ester using KOH (12.5 mmol) in aqueous EtOH (1:1; 5 mL) at 150° C. for 2 hr in a pressurized vessel following a microwave method analogous to General Procedure G2 gave 1-ethyl-4-isopropyl-cyclohexanecarboxylic acid (800 mg, 86% yield) as a mixture of isomers after workup by evaporation of the solvent, treatment with aq 2 N HCl, extractive workup, and evaporation of the solvent.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[CH:11]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)O)[CH3:2].[OH-].[Na+]>Cl.[Zn]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[CH2:11][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1C(O)c1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cccc(CC)c1Cc1ncc[nH]1
Temperature: 25 °C

Procedure:
To a solution of 90 mg (0.39 mmol) (2,6-diethyl-phenyl)-(1H-imidazol-2-yl)-methanol (Example 96) in 2 ml concentrated aqueous HCl solution were added 500 mg zinc foil and heated to reflux for 20 hours. Then the mixture was cooled to ambient temperature, aqueous sodium hydroxide solution added, the turbid solution filtered and the filtrate extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. 2-(2,6-Diethyl-benzyl)-1H-imidazole was obtained as off-white solid: MS (EI): 214.3 (M+.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][N:26]=[N+]=[N-])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN=[N+]=[N-])cc3c21)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Yield: 91.7 %

Procedure:
A solution of the product from Step A (1.28 g, 3.17 mmol) in THF (25 mL) was stirred with polymer supported triphenylphosphine (4 eq, 3 mmol/g, 12.7 mmol, 4.23 g) at 50° C. for 2 hours. Water (2.5 mL) was added and the mixture was stirred for another hour; more water (5 mL) was added and the reaction mixture was filtered. The solids were washed well with THF and the filtrate was evaporated to a residue which was dried under a vacuum to give a foam (1.10 g, 92%): LC/MS m/z 379 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:33]([Br:34])=[CH:32][C:31]([C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[Br:38]>C(#N)C>[Br:34][C:33]1[CH:32]=[C:31]([C:35](=[O:37])[CH3:36])[CH:30]=[C:29]([Br:38])[C:28]=1[O:27][CH2:26][CH2:25][CH2:24][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Br)c1
Yield: 58.7 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2- benzisoxazole (2.0 g, 9.0 mmol), K2CO3 (1.3 g), and 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone (2.65 g, 9.0 mmol) and acetonitrile (50 ml) was heated at reflux for 3 hours. At the end of the reaction, the solvent was evaporated and the residue was extracted into dichloromethane (150 ml). The insolubles were filtered off. The dichloromethane solution was concentrated down to an oil. The purification was done by flash chromatography on a silica gel column (SiO2, 47 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 600 ml). The material thus purified as a colorless oil, solidified on standing. Recrystallization from ethanol gave 1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]ethanone as white crystals (2.93 g, 57%), m.p.=102°-103° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:17])[CH2:10][C:11](=[O:16])[CH2:12][CH2:13][O:14][CH3:15].[Cl-].[Mg+2].[Cl-].[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[CH3:7][O:8][C:9](=[O:17])[CH:10]([C:21](=[O:23])[CH3:22])[C:11](=[O:16])[CH2:12][CH2:13][O:14][CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCC(=O)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Yield: 88 %

Procedure:
Pyridine (5.3 ml, 65.92 mmol) was dropped within 3 min to an ice cooled solution of 5-methoxy-3-oxo-pentanoic acid methyl ester (5.28 g, 32.96 mmol) and anhydrous magnesium chloride (3.14 g, 32.96 mmol) in dichloromethane (50 ml). Acetic anhydride (3.27 ml, 34.6 mmol) was added within 3 min. The reaction mixture was stirred over night at RT and after partial removal of the solvent under reduced pressure it was partitioned between ether and 1 N HCl/water. The ether solution was concentrated under reduced pressure to give 5.87 g (29 mmol, 88%) 2-acetyl-5-methoxy-3-oxo-pentanoic acid methyl ester.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@@H:30]([NH2:32])[CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:30]([NH:32][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc2ccccc12

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (S)-1-(1-naphthyl)ethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 366.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.40 (d, J=4.6 Hz, 1H); 8.34 (br s, 1H); 8.23 (d, J=8.2 Hz, 1H); 7.97 (d, J=7.6 Hz, 1H); 7.82 (d, J=8.2 Hz, 1H); 7.67 (d, J=6.9 Hz, 1H); 7.47 (t, J=7.7 Hz, 1H); 6.77 (s, 1H); 6.03 (br s, 2H); 1.80 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH2:9].C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH:9][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cc(Br)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cc(Br)ccc1F

Procedure:
Dissolve 5-bromo-2-fluorobenzylamine hydrochloride (500 mg, 2.08 mmol) in dichloromethane (8 mL) and diisopropylethylamine (0.90 mL, 5.20 mmol) and treat with methanesulfonyl chloride (0.19 mL, 2.49 mmol). After 4.5 h dilute with ethyl acetate and wash with 0.5 N hydrochloric acid, an aqueous saturated solution of sodium bicarbonate, and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate to give the title compound as a pale orange oil, which crystallizes upon standing (573 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][N:36]([CH3:43])[CH3:35])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCC(=O)O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 150 mg, 0.33 mmol) and 4-dimethylamino-butyric acid (107 mg, 0.64 mmol) using a similar method to that employed for Example 14 (38 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH3:14])[C:12]=1[OH:13])[C:8]#[N:9].Cl>CO>[OH:13][C:12]1[C:11]([CH3:14])=[CH:10][C:7]([C:8]([NH:2][OH:3])=[NH:9])=[CH:6][C:5]=1[CH3:4]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)c1O
Yield: 30.7 %

Procedure:
To dry methanol (190 mL) is carefully added K-tert.-butylate (18.68 g, 166 mmol) followed by hydroxylamine hydrochloride (9.92 g, 143 mmol). The suspension is stirred for 30 min before 3,5-dimethyl-4-hydroxybenzonitrile (7.00 g, 147 mmol) is added. The mixture is refluxed for 32 h, then the suspension is diluted by adding 2 N aq. HCl. The solution is extracted twice with DCM (100 mL). The aq. layer is basified (pH 9) by adding solid NaHCO3 and extracted five times with DCM followed by four times with EA. The combined organic layers are dried over Na2SO4 and evaporated to dryness to give 4,N-dihydroxy-3,5-dimethyl-benzamidine (7.9 g) as a colourless solid; LC-MS: tR=0.62 min, [M+1]+=181.14.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[CH2:34][CH2:33][CH2:32]1.C1COCC1>>[N:31]1([C:22]2[N:21]=[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:28])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:30])([F:29])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])[C:25]([Br:26])=[CH:24][CH:23]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: C1CNC1
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCC2)ccc1Br
Temperature: 150 °C

Procedure:
To a microwave tube containing (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (330 mg, 0.637 mmol) was added a 2M solution of azetidine in THF (4 mL, 8 mmol). The tube was sealed and the reaction was heated at 150° C. for 30 minutes in the microwave. The reaction was cooled and concentrated. The residue was purified via flash chromatography on silica gel (0 to 75% ethyl acetate/hexanes) to afford (4S,5R)-3-[(6-azetidin-1-yl-3-bromopyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=537.9 and 539.8 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.78 (s, 2H), 7.51 (d, J=8.6 Hz, 1H), 6.10 (d, J=8.7 Hz, 1H), 5.77 (d, J=8.6 Hz, 1H), 4.86 (d, J=17.0 Hz, 1H), 4.35 (m, 1H), 4.20 (d, J=16.9 Hz, 1H), 4.01 (m, 4H), 2.40 (m, 2H), 0.78 (d, J=6.7 Hz, 3H).