Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[N:11]=1)([CH3:5])[CH3:4].BrCC(C1C=CC([C:28]#[N:29])=CC=1)=O.C1N=CN(C(N2C=NC=C2)=N)C=1>O1CCCC1>[NH:29]=[C:28]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[N:11]=2)[C:3]([CH3:5])([CH3:4])[CH2:2][O:1]1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)cs1
Agent: N=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Yield: 19 %

Procedure:
A mixture of 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (2.00 g, 7.31 mmol), prepared in the same manner as described in step 3 of Example 52, and replacing 3-(2-bromoacetyl)benzonitrile with 4-(2-bromoacetyl)benzonitrile, and C-(di-imidazol-1-yl)-methyleneamine (1.30 g, 8.07 mmol) in 35 mL of tetrahydrofuran was refluxed under nitrogen for three days. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of hexane in methylene chloride as the eluent gave the title compound (417.2 mg, 19%) as an off-white solid, mp 158-161° C.; MS (ES) m/z 299.0 [M+H]+. Anal. Calcd for C15H14N4OS: C, 60.38; H, 4.73; N, 18.78. Found: C, 60.38; H, 4.82; N, 18.67.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[C:10]([NH2:16])(=[O:15])[CH2:11][C:12](N)=[O:13].S(=O)(=O)(O)O.N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:5][Si:4]([CH3:7])([CH3:6])[NH:16][C:10](=[O:15])[CH2:11][C:12]([NH:3][Si:4]([CH3:5])([CH3:6])[CH3:7])=[O:13]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NC(=O)CC(N)=O
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)NC(=O)CC(=O)N[Si](C)(C)C
Yield: 99004.2 %

Procedure:
7.5 ml (36 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 3.06 g (0.03 mmole) of malonamide, 18.3 mg (0.1 mmole) of saccharin, 50 ml of ethyl acetate and 5 ml of pyridine and by titrating with 1 N sulfuric acid the ammonia evolved, it was found that 30 mmoles were expelled after refluxing for one hour. Volatile material was vacuum evaporated and the residue, which crystallized upon standing, was dried in vacuo to obtain 7.32 g (99%) of N,N'-bis-(trimethylsilyl)-malonamide melting at 72°-76° C. NMR Spectrum (CDCl3): Δ0.24 (s, 18H); 3.20 (s, 2H); 6.5 (broad, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.CS(O[CH2:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[C:44]([Cl:48])[C:45]([Cl:47])=[CH:46][C:41]=2[NH:40][C:39]1=[O:49])(=O)=O>O>[Cl:47][C:45]1[C:44]([Cl:48])=[CH:43][C:42]2[N:38]([CH2:37][CH2:36][CH2:35][N:14]3[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[CH2:12][CH2:13]3)[C:39](=[O:49])[NH:40][C:41]=2[CH:46]=1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)c(Cl)cc21
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c3cc(Cl)c(Cl)cc32)CC1
Yield: 25 %

Procedure:
A mixture of 4.4 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 6 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 30 minutes with water-separator. After cooling, 6.2 parts of 3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1yl)propyl methanesulfonate are added and the whole is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in trichloromethane. The product is filtered off, stirred in methanol, filtered off again and dried, yielding 2 parts (25%) of 5,6-dichloro-1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 198°-202° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][NH:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([S:19][CH2:20][CH:21]([CH3:25])[C:22](O)=[O:23])(=[O:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]([C:22](=[O:23])[CH:21]([CH3:25])[CH2:20][S:19][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)CNCC1CCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)CC1CCCO1

Procedure:
To a solution of N-tetrahydrofurfurylglycine tert-butyl ester (6.6 g, 0.0307 mol) and 3-acetylthio-2-methylpropionic acid (5.3 g, 0.0307 mol) in dry methylene chloride (150 ml) chilled in an ice bath was added dicyclohexylcarbodiimide (6.7 g, 0.0325 mol). The resulting mixture was stirred with cooling for 30 minutes and then overnight at room temperature. Precipitated dicyclohexylurea was filtered and washed with a small amount of methylene chloride. Concentration of the filtrate afforded crude product as a thick yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:27]([CH3:26])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccc(Cl)cc1
Reactant: CNc1ccccc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccc(Cl)cc2)cc1)c1ccccc1
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 4-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide, and N-methyl-aniline, the title compound was isolated as a yellow solid in 76% yield (96% purity by HPLC).
Reaction SMILES: CC1C=CC=CC=1O[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:24][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1cc(C)cc(O)c1
Reactant: Cc1ccccc1OCCCCC(=O)O
Product: Cc1cc(C)cc(OCCCCC(=O)O)c1

Procedure:
5-(3,5-Dimethylphenoxy)pentanoic acid 26d was prepared in the same manner as 26b, except that 3,5-dimethylphenol was used as the starting material. 1H NMR (CDCl3, 400 MHz): 6.58 (s, 1H), 6.51 (s, 2H), 3.94 (t, 2H, J=5.6 Hz), 2.44 (t, 2H, J=7.2 Hz), 2.27 (s, 6H), 1.83 (m, 4H). MS (ESI): 245 [M+Na]+.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:18])=[N:13][C:12]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H].CCOCC>[Pd].CO.C(OCC)(=O)C>[ClH:18].[F:27][C:25]([F:26])([F:28])[C:22]1[N:21]=[CH:20][C:19]([C:12]2[N:13]=[CH:14][C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=2)=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)c3c(n2)CN(Cc2ccccc2)CC3)cn1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: Cl
Product: FC(F)(F)c1ccc(-c2ncc3c(n2)CNCC3)cn1
Yield: 69.7 %

Procedure:
A mixture of 220 mg of 7-benzyl-4-chloro-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine and 40–50 mg of 10% palladium on carbon in 8 mL of methanol and 5 mL of ethyl acetate was stirred under 1 atm of hydrogen for 3 h. The mixture was filtered and concentrated to give a yellow solid. Trituration with ether gave 120 mg of the title compound as an off-white powder. LC-MS 281.1 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1cccc(-c2ccccn2)c1F
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1c(-c2ccccn2)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid as described in Example 1 to give 3-[2-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 7.61-7.71 (3H, m), 7.87-7.91 (1H, m), 8.07-8.11 (2H, m), 8.20-8.24 (1H, m), 8.42 (1H, s), 8.87 (1H, dd, J 5 and 1), 9.42 (1H, dd, J 7 and 3); m/z (ES+) 359 (M++H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13]CCC1.C1(C2C=C(C)NC(=O)C=2C#N)CC1>>[NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13]1
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Agent: Cc1cc(C2CC2)c(C#N)c(=O)[nH]1
Product: Cc1cc(C2CC2)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone (Intermediate 3) using 4-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (5 g, 28.7 mmol). Obtained: 0.50 g (10%). LCMS E-S (M+H)=179.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76-11.78 (br s, 1H), 7.82-7.92 (br s, 3H), 5.61 (s, 1H), 3.94-3.99 (m, 2H), 2.11 (s, 3H), 1.98-2.05 (m, 1H), 0.95-1.01 (m, 2H), 0.74-0.79 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)N2CCNCC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][S:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.O1[CH2:38][CH2:37]OCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:38]2[CH2:37][CH2:24][N:28]([CH2:21][CH2:22][S:23][C:24]3[S:25][C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:27][CH2:26]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: ClCCSc1nc2ccccc2s1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)C2CCN(CCSc3nc4ccccc4s3)CC2)cc1
Yield: 35 %

Procedure:
To a mixture of 1.00 g (3.96 mmol) of 4-(diphenylmethyl)-piperazine and 1.28 g (5.57 mmol) of 2-(2-chloroethylthio)benzothiazole, were added 10 ml of dioxane, 2 ml of dimethylformamide and 0.85 g (6.15 mmol) of potassium carbonate, and the mixture was stirred under reflux for 3 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated. The residue was separated by silica gel column chromatography using a mixture of chloroform and methanol in the volume ratio 30:1 as the developing solvent, and the desired fraction was concentrated under reduced pressure to give 0.61 g (35%) of 2-[2-[4-(diphenylmethyl)-1-piperadinyl]-ethylthio]benzothiazole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:20]=[CH:21]/C(O)=O)=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].[K+].[C:29]([O:35][CH3:36])(=[O:34])[CH2:30][C:31]([O-])=[O:32]>C1COCC1>[CH3:36][O:35][C:29](=[O:34])[CH2:30][C:31](=[O:32])/[CH:21]=[CH:20]/[C:9]1[N:10]([CH:17]([CH3:18])[CH3:19])[C:11]2[C:16]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COC(=O)CC(=O)[O-]
Reactant: CC(C)n1c(/C=C/C(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 1 h

Procedure:
0.8 g (2.46 mmol) of (E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-acrylic acid in 4 ml of THF are introduced into a 50 ml three-necked round-bottomed flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen delivery line. 0.5 g (2.96 mmol) of 1,1-carbonyldiimidazole is then added in portions in the course of 5 min. and stirring is carried out at room temperature for 1 hour. 0.24 g (2.46 mmol) of magnesium chloride and 0.39 g (2.46 mmol) of monomethyl malonate potassium salt are then added and the suspension is stirred for 24 hours at 35° C. The reaction mixture is cooled and filtered and the residue is washed twice with 25 ml of THF. The filtrate is concentrated by evaporation, taken up in 30 ml of ethyl acetate, washed with 15 ml of 1N hydrochloric acid, three times with 20 ml of saturated sodium hydrogen carbonate solution and three times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The residue is purified by means of flash chromatography (hexane/ethyl acetate=8:1). An orange resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[C:11]([Cl:17])[C:10]=1[N+:18]([O-:20])=O)([C:3](OCC)=[O:4])=[O:2]>C(O)C.[Pt]>[OH:20][N:18]1[C:10]2[C:9](=[CH:14][C:13]([Cl:15])=[C:12]([Cl:16])[C:11]=2[Cl:17])[NH:8][C:1](=[O:2])[C:3]1=[O:4]
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)c(Cl)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(Cl)c(Cl)c2n(O)c1=O
Yield: 10.8 %

Procedure:
A solution of 2.0 g (5.9 mmol) N-ethoxalyl-2-nitro-3,4,5-trichloroaniline in 50 ml ethanol was hydrogenated at atm. pressure by using 70 mg Pt-C (5%) as a catalyst. The precipitate was filtered off and the filter cake was washed with 10 ml 1N aqueous potassium hydroxide. The filtrate was acidified with concentrated hydrochloric acid and the precipitate was filtered off, washed with water, ethanol and ether to give 0.18 g (11%) of 1-hydroxy-6,7,8-trichloroquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 7.4 (1H, s) MS m/z: 280 (M+, trace, 3Cl), 265 (35%), 237 (100%), 173 (55%).
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6](O)=O)C)=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11].C(OC(=O)C)(=O)C>>[CH3:1][N:3]1[CH:5]=[CH:6][C:10]([C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:11]1
Reactant: CN(C=O)CC(=O)O
Reactant: C#CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(C)c1
Yield: 71.3 %

Procedure:
A mixture of 117.1 g (1 mole) of N-formylsarcosine prepared in the Reference Example 1, 98.10 g (1 mole) of ethyl propiolate, and 638 ml of acetic anhydride was stirred using a magnetic stirrer over an oil bath at 130° C. for 22 hours. The reaction mixture was concentrated under vacuum. 100 ml of toluene was added to the residue and the mixture was evaporated under reduced pressure. This procedure was repeated to obtain a brown oily substance. This oily substance was distilled under vacuum to obtain 109.19 g (yield 71.3%) of a colorless or light-yellow oil of the title compound as fractions with a boiling point of 103°-104° C. at 4 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O.C(#N)C>C(OCC)(=O)C>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[CH:6][C:5]=2[I:15])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(-n2nccc2C2CC2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Ic1cnn(-c2ccccc2)c1C1CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
5-cyclopropyl-1-phenyl-1H-pyrazole (200 mg, 1.09 mmol) and N-iodosuccinimide (366 mg, 1.63 mmol) were added to acetonitrile (5 ml). The reaction mixture was heated to 70° C. After 6 hours, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and brine, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford 5-cyclopropyl-4-iodo-1-phenyl-1H-pyrazole.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([OH:23])[CH:22]=1)=[O:16].C([O-])([O-])=O.[K+].[K+].[CH3:30][N:31](C=O)[CH3:32].CNC>>[C:15]([C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:23][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:31]([CH3:32])[CH3:30])[N:5]=[CH:4][N:3]=1)(=[O:16])[CH3:14]
Reactant: CC(=O)c1cccc(O)c1
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1c(Oc2cccc(C(C)=O)c2)ncnc1N(C)C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 4,6-dichloropyrimidin-5-yl-acetate (221 g, 1 mol), 3-hydroxyacetophenone (136 g, 1 mol) and K2CO3 (207 g, 1.5 mol) in DMF (150 mol) is stirred at 100° C. for 90 minutes. The dark mixture is cooled to 0° C. and dimethylamine (450 ml of a 40% aqeous solution) is added. Stirring is continued at room temperature for 16 hours. Dilution with water and extraction with ether gives methyl 4-(3-acetylphenoxy)-6-dimethylamino-pyrimidin-5-yl-acetate as a brownish oil (purity>95%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]3)=[N:6][CH:5]=2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 52 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), was converted, using cyclopropylamine instead of cyclopropanemethylamine, to the title compound (50 mg, 52%) which was obtained as a white solid. MS: m/e=440.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1ccccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccccc1-c1nc(-c2cccnc2)no1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.38-7.49 (m, 2 H), 7.64 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.70-7.79 (m, 1 H), 8.28 (td, J=7.5, 1.9 Hz, 1 H), 8.57 (dt, J=8.1, 1.9 Hz, 1 H), 8.74 (dd, J=4.7, 1.7 Hz, 1 H), 9.31 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9][C:10]([C:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]=2)=[CH:11][CH:12]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)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.CN(C)C=O>[CH2:19]([C:8]1[C:7]([C:29]#[C:28][C:30]2([OH:38])[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[CH:12][CH:11]=[C:10]([C:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]=2)[N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: O=S(=O)(Oc1ccc(C2=CCOCC2)nc1Cc1ccccc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ccc(C3=CCOCC3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
A mixture of 60.7 g of 2-benzyl-6-(5,6-dihydro-2H-pyran-4-yl)-3-pyridyl trifluoromethane sulfonate, 23.0 mg of 3-ethynyl-3-quinuclidinol, 17.6 mg of tetrakis(triphenylphosphine)palladium(0), 2.9 mg of cuprous iodide, 63.6 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 60° C. for 1.5 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 40.7 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH:24]=[C:23]([C@:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:26][CH3:27])[N:22]=[N:21]4)=[CH:16][CH:17]=3)[N:12]=[C:11]([C:33]#[N:34])[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=[O:36].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH:24]=[C:23]([C@:25]([OH:32])([C:28]([F:31])([F:29])[F:30])[CH2:26][CH3:27])[N:22]=[N:21]4)=[CH:16][CH:17]=3)[N:12]=[C:11]([C:33]([NH2:34])=[O:36])[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-4-(3,5-dichlorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carbonitrile (30 mg, 0.059 mmol) in acetone (1.5 mL) and water (1 mL) was added sodium percarbonate (28 mg, 0.18 mmol). After 1.5 h at 50° C., the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 524 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([SiH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH3:13]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Si:21]([CH3:22])([CH3:23])[CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: C=CCc1ccc(F)c(Cl)c1
Reactant: CCOc1ccc([SiH](C)C)cc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Cl)c2)cc1
Temperature: 130 °C
Yield: 81.5 %

Procedure:
Three drops of a 30% strength solution of hexachloroplatinic acid in isopropanol were added with the aid of a pipette to a mixture of 234 g (1.37 mol) of 3-(3-chloro-4-fluorophenyl)propene and 261 g (1.45 mol) of (4-ethoxyphenyl)dimethylsilane. After a short time, an exothermic reaction took place and the mixture warmed to about 130° C. After cooling, the product was distilled in vacuo. 392 g (82%) of (4-ethoxyphenyl)-(dimethyl)-(3-(3-chloro-4-fluorophenyl)propyl)silane were obtained as a colorless oil of b.p.0.1 =165°-170° C., the purity of which was determined to be 97.4% by gas chromatography.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:14][CH:13]=[C:12]([F:16])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(F)cccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Fuming nitric acid (11 g, 174 mmol) was added to a solution of methyl 2,6-difluorobenzoate (25 g, 145 mmol) in concentrated sulfuric acid (50 mL) at 0° C., and the reaction was stirred for 30 min at 0° C. The reaction mixture was poured over ice-water. The precipitate was filtered off by suction to give the desired product of Step B (25.1 g, 80.6%). 1H NMR (400 MHz, CDCl3) δ ppm 8.13-8.20 (m, 1H), 7.02-7.10 (m, 1H), 3.93 (s, 3H).