Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1([N:22]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:8])(C)(C)C.C(O)C>ClC(Cl)C>[OH:5][NH:6][C:7]([C:9]1([N:22]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NOC(C)(C)C)CCN(Cc3ccccc3)CC2)cc1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[N-t-Butyloxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-piperidine is dissolved in dichloroethane (60 mL) and ethanol (1.0 mL) in a glass sealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 30 minutes at -10° C. The tube is sealed, gradually warmed to room temperature, and stirred overnight. At this point, hydrochloric acid gas is again bubbled through the reaction mixture as done previously and stirred at room temperature for an additional 24 hours. The reaction mixture is reduced to 1/3 volume in vacuo and triturated with diethyl ether. The solid is filtered off and dried in vacuo to provide 4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-piperidine, m.p. 135.5°-142° C.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([NH:19][CH2:20][CH:21]=[O:22])[CH:17]=[CH2:18]>C(O)C.O>[CH2:16]([N:19]([CH2:20][CH:21]=[O:22])[C:8]([NH:7][C:5]1[S:6][C:2]([F:1])=[CH:3][N:4]=1)=[O:9])[CH:17]=[CH2:18]
Reactant: O=C=Nc1ncc(F)s1
Reactant: C=CCNCC=O
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: C=CCN(CC=O)C(=O)Nc1ncc(F)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Fluorothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-allylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-fluorothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].[C:24]12([CH2:34][CH2:35]I)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.C(OCC)C>CN(C)C=O.O>[NH3:5].[C:24]12([CH2:34][CH2:35][N:5]3[CH2:6][CH:7]4[CH:3]([C:2]4([C:8]4[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=4)[CH3:1])[CH2:4]3)[CH2:25][CH:26]3[CH2:32][CH:30]([CH2:29][CH:28]([CH2:27]3)[CH2:33]1)[CH2:31]2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: ICCC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCC34CC5CC(CC(C5)C3)C4)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 57 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (630 mg, 7.52 mmol) and 1-adamantyl-2-iodoethane (Preparation 93, 58 mg, 0.2 mmol) and the reaction was heated at 50° C. for 20 h. After cooling diethyl ether (5 ml) and water (7 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×5 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (5 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (32 mg, 39%).
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([SH:12])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:5][C:6]1[N:11]=[C:10]([S:12][CH:2]([F:4])[F:1])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: COc1nc(N)nc(S)n1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(N)nc(SC(F)F)n1
Yield: 24.3 %

Procedure:
10.0 g of gaseous difluorochloromethane are passed into a suspension of 5.0 g of 2-amino-4-mercapto-6-methoxy-1,3,5-triazine and 4.8 g of potassium carbonate in 100 ml of dimethylformamide at a temperature of 70°-75° C. over a period of 90 minutes. The reaction mixture is evaporated, the residue is stirred with water and the solid precipitate is separated off to give 1.6 g of 2-amino-4-difluoromethylthio-6-methoxy-1,3,5-triazine of melting point 146°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:6])=[O:4]>[Pt]=O.C(O)C>[NH2:14][C:13]1[C:8]([O:7][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH3:6])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C(C)Oc1ncccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)C(C)Oc1ncccc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A mixture of 1.7 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine, 102 mg of platinum oxide and 7.5 ml of ethanol was stirred for 3.5 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 1.16 g of 3-amino-2-{1-(methoxycarbonyl)ethoxy}pyridine.
Reaction SMILES: [CH3:1][NH:2][C:3]1CC(=O)[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1.[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=O.[C:24]([OH:27])(=O)[CH3:25]>O>[CH3:19][C:17]1[C:25]2[C:24](=[O:27])[N:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:4][C:3]=2[N:2]([CH3:1])[C:15](=[O:20])[CH:16]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)O
Reactant: CNC1=NN(c2ccccc2)C(=O)C1
Solvent: O
Product: Cc1cc(=O)n(C)c2[nH]n(-c3ccccc3)c(=O)c12
Reaction time: 6 h

Procedure:
3-Methylamino-1-phenyl-2-pyrazolin-5-one (1.9 g), ethyl acetoacetate (1.4 g) and acetic acid (8 ml) were refluxed while stirring for 6 hours. The reaction solution was diluted with water, and the resulting crystals were collected by filtration and washed with isopropyl alcohol to obtain 1.8 g of 4,7-dimethyl-2-phenylpyrazolo(3,4-b)pyridine-3,6-dione (melting point 179 - 181oC). In a solution of these crystals (1 g) in methanol (20 ml) and triethylamine (0.7 ml), 1,7-diphenyl-1,7-diaza-1,3,5-heptatriene hydrochloride (0.7 g) was dissolved, and then acetic anhydride (0.6 ml) was added, and the mixture was stirred at room temperature for one hour. The resulting precipitate was collected by filtration, washed with methanol and dried to obtain 5-[5-(N-acetylanilino)-2,3-pentadienylidene]-4,7-dimethyl-2-phenylpyrazolo(3,4-b)pyridine-3, 6-dione (0.2 g). To these crystals (0.15 g), N,N-dimethylformamide (5 ml) and 4,7-dimethyl-2-phenylpyrazolo-(3,4-b)pyridine-3,6-dione (0.08 g) were added, and stirred at 50° C. for 2 hours. After filtration of the reaction solution, the filtrate was diluted with water for crystallization. The resulting crystals were collected by filtration, washed with water and dried to obtain compound II-1 (0.2 g). Melting point 300° C. or more, λmaxMeOH 760 nm.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[C@H:9]1[C@@H:21](O)[C:22]([F:25])([F:24])[F:23])=[O:7])(C)(C)C.[N:27]([C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:38])[C:31]=1[F:39])=C=O>>[Cl:38][C:32]1[C:31]([F:39])=[C:30]([N:27]2[C@H:21]([C:22]([F:23])([F:24])[F:25])[C@@H:9]3[C@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[C:6]2=[O:7])[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Reactant: N#Cc1ccc(N=C=O)c(F)c1Cl
Product: N#Cc1ccc(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(F)(F)F)c(F)c1Cl

Procedure:
The title compound was prepared from (2R,3R)-3-(tert-butyl-dimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxyethyl)]pyrrolidine-1-carboxylic acid tert-butyl ester (66A) and 2-chloro-4-isocyanato-3-fluorobenzonitrile (73C) following procedures analogous to those found in Example 72. LCMS: m/z 364 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].Br[CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.[SH:33][C:34]1[S:35][CH2:36][CH2:37][N:38]=1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21](=[O:22])[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][S:33][CH:34]3[NH:38][CH2:37][CH2:36][S:35]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: SC1=NCCS1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(CSC5NCCS5)cc4)cc3)n(C)c(=O)c12
Yield: 19.3 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis (bromomethyl)benzophenone (1.75 g), 2-mercaptothiazoline (600 mg), and 1N-sodium hydroxide/water (11 ml) in DMF (20 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=3:1:1) and crystallized from methanol to provide the title compound as colorless solid (489 mg).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[O:17][C:16]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=3)[N:9]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:8]=2[C:7]([CH:30]=[CH2:31])=[CH:6][C:5]=1[F:32])([O-:3])=[O:2].[N+](=[CH2:35])=[N-]>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[O:17][C:16]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=3)[N:9]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:8]=2[C:7]([CH:30]2[CH2:35][CH2:31]2)=[CH:6][C:5]=1[F:32])([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc(F)c([N+](=O)[O-])c2nc(-c3ccc(P(=O)(OCC)OCC)o3)n(CC(C)C)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1ccc(-c2nc3c([N+](=O)[O-])c(F)cc(C4CC4)c3n2CC(C)C)o1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 1.0 mmol of 4-nitro-7-vinyl-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole and 0.1 mmol of Pd(OAc)2 in 8 mL of ether was added an ether solution of diazomethane (generated from 3.0 g of 1-methyl-3-nitro-1-nitrosoguanidine) at 0 ° C. After stirring at room temperature 20 h solvent was removed and the residue chromatographed to give 4-nitro-7-cyclopropyl-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C:34]5[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][NH:50][CH3:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C:34]5[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43][N:50]([CH3:51])[CH3:49])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5c(Cl)cccc5Cl)n4c3)c3ccccc32)n(CCOS(C)(=O)=O)n1
Solvent: C1CCOC1
Product: CN(C)CCn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A mixture of Intermediate 28a (110 mg, 0.15 mmol) and dimethylamine (2.0M in THF, 1.54 mL, 3.09 mmol) in anhydrous THF (2 mL) was stirred at 60° C. for 18 h in a sealed vial. The volatiles were concentrated in vacuo and the resultant residue was purified by MDAP (Method 7) to afford the title compound (44 mg, 43%). LCMS (Method 5): Rt 3.50 min, m/z 661 [MH+]. 1H NMR (400 MHz, DMSO): 1.19 (9H, s), 1.83-2.14 (4H, m), 2.18 (6H, s), 2.59 (2H, t, J=6.9 Hz), 3.96 (2H, t, J=6.9 Hz), 4.79-4.87 (1H, m), 5.53 (1H, t, J=4.0 Hz), 6.01 (1H, s), 6.92 (1H, d, J=8.7 Hz), 7.22-7.28 (1H, m), 7.30-7.38 (4H, m), 7.68-7.78 (3H, m), 7.90 (1H, dd, J=9.9, 0.8 Hz), 7.96 (1H, d, J=2.0 Hz), 8.15 (1H, s), 8.44 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([NH:18][C:19]([NH2:24])=[N:20][C:21](=[O:23])[CH3:22])=[S:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]Br>C(O)C.C(Cl)(Cl)Cl>[BrH:25].[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[S:17][N:24]=[C:19]([NH:20][C:21](=[O:23])[CH3:22])[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N=C(N)NC(=S)C1CCCN1C(=O)OCc1ccccc1
Reactant: BrBr
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Br
Product: CC(=O)Nc1nsc(C2CCCN2C(=O)OCc2ccccc2)n1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
2-(N′-Acetyl-guanidinocarbothioyl)-pyrrolidine-1-carboxylic acid benzyl ester (13.0 g, 37.4 mmol) was dissolved in ethanol (80 mL). The ethanol solution was cooled to 0° C. and a solution of bromine (6.50 g, 40.6 mmol) in chloroform (30 mL) was added dropwise over 5 minutes. The resulting solution was allowed to return to room temperature while stirring for 3 hours. The reaction mixture was concentrated under vacuo to afford 14.0 g (88%) of 2-(3-acetylamino-[1,2,4]thiadiazol-5-yl)-pyrrolidine-1-carboxylic acid benzyl ester hydrobromide.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:25][OH:26].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:26][NH:25][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(CCc3ccccc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(CCc3ccccc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15e (125 mg, 0.377 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (262 mg, 3.77 mmol) and a freshly prepared solution of sodium methoxide in methanol (130 mg, 5.655 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16e.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCNCC1
Reactant: O=C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCN(C2CCCCC2)CC1

Procedure:
Using procedures substantially equivalent to those described in example 27, N-(5-chloropyridin-2-yl)-2-[(1-cyclohexlpiperidin-4-ylcarbonyl)amino]benzamide (34 mg, 72%, 97% pure by HPLC analysis) was prepared from N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamide trifluoroacetate and cyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9](Cl)(Cl)Cl)=[N:8][C:4]=2[CH:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=[O:24].[Na+]>O1CCCC1.O>[CH2:15]([NH:22][C:9]([C:7]1[NH:6][C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])O
Reactant: NCc1ccccc1
Reactant: Clc1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 120.0 mg (0.45 mmol) 5-chloro-2-trichloromethyl-1H-benzoimidazole in 2 mL tetrahydrofuran (THF) was added slowly to a mixture of 53.5 μl (0.49 mmol) benzylamine and 373.8 mg (4.45 mmol, 10 equiv.) NaHCO3 in 8 mL THF and 4 mL water. The reaction mixture was stirred for 2 h at room temperature (20° C. to 25° C. in the following RT). The suspension was filtered and the filtrate was concentrated under reduced pressure. After purification by preparative RP-HPLC (CH3CN/H2O gradient and 0.05% formic acid) pure 5-Chloro-1H-benzoimidazole-2-carboxylic acid benzylamide was obtained as a white amorphous solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH:16]=1)=[O:14]>>[C:2]1([CH2:1][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[CH:16]=2)=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)Cc2ccccc2)c2cccnc21
Yield: 92 %

Procedure:
This compound was prepared by the reaction of benzylmagnesium chloride (2.0 M solution in THF) with N-methoxy-N-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide as described in General Method 1. The desired compound was obtained in 92% yield as a light yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13]O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:42]([O:41][C:39]([C@@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([CH2:13][CH2:12][O:11][CH2:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:34]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: OCCOCC=C(c1ccccc1)c1cccc(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(Cl)c2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A mixture of 2-(3-(3-chlorophenyl)-3-phenyl-2-propen-1-yloxy)ethanol (52.2 g, 0.18 mol) and triethylamine (45.7 g, 0.45 mol) in dry toluene (200 ml) kept under a nitrogen atmosphere was cooled to 5° C. and a solution of methanesulphonyl chloride (41.4 g, 0.36 mol) in dry toluene (200 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1 h at 5° C. Water was added (250 ml) and the mixture was stirred at room temperature for 10 minutes. The phases were separated and the aqueous phase was extracted with a small portion of toluene. The combined organic extracts were washed with brine and dried over sodium sulphate. The mixture was filtered and the filtrate was reduced in vacuo to approximately 500 ml. Ethyl (R)-3-piperidinecarboxylate (56.8 g, 0.36 mol) and potassium carbonate (49.9 g, 0.36 mol) were added and the mixture was heated at reflux temperature for 7 days. The cooled reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with a sodium citrate buffer solution (pH 5) and then extracted with a 34% aqueous tartaric acid solution (3×100 ml). The combined acidic aqueous extracts were poured into a mixture of ice water (3 1) and ethyl acetate (400 ml). Sodium hydroxide pellets (27.2 g) was added until pH was measured at ca. 4 and the phases were separated. The organic phase was washed with a 5% sodium bicarbonate solution (3×150 ml) and dried over sodium sulphate. The solvent was evaporated in vacuo to give 57.5 g (74%) of (R)-N-(2-(3-(3-chlorophenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.45 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C.[Cl-].[Na+].O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(OCCCO)nc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
To a solution of t-butyldimethylsilyl chloride (0.93 g, 6.17 mmol) in CH2Cl2 (25 mL) was added 6-(3-hydroxypropoxy)nicotinonitrile (Example 66, 1 g, 5.61 mmol), Et3N (0.62 g, 6.17 mmol), and DMAP (0.014 g, 0.11 mmol). The mixture was stirred at rt for 18 h. The reaction mixture was diluted with brine and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (2:1 hexanes/EtOAc) to give the title compound (1.14 g, 69%). 1H NMR (400 MHz, CDCl3) δ 8.40 (dd, 1H), 7.69 (dd, 1H), 6.72 (dd, 1H), 4.40 (t, 2H), 3.73 (t, 2H), 1.90-1.98 (m, 2H), 0.82 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:12])[CH2:9][CH2:10][OH:11].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>[Cl-].[Na+].O>[Cl:13][C:14]1[N:19]=[C:18]([O:11][CH2:10][CH2:9][CH2:8][OH:12])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCOc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
To a round-bottom flask charged with NaH (336 mg, 8.29 mmol, 60% dispersion in mineral oil) and THF (100 mL), 1,3-propanediol (0.91 mL, 12.6 mmol) was added dropwise [H2 evolution] at rt. The reaction mixture was stirred for 30 min, then 2,4-dichloropyrimidine (5.0 g, 33.6 mmol) was added, and the reaction mixture was stirred for an additional 72 h. Brine was slowly added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to provide the product (350 mg, 22%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.01 (qt, 2H), 2.43-2.52 (b, 1H), 3.76 (t, 2H), 4.51 (t, 2H), 6.63 (d, 1H), 8.25 (d, 1H) LC-MS: RT=1.05 min, (M+H)+ 189.1.