Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].Cl.Cl[CH2:22][C:23]1[S:24][C:25]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:28]=[C:27]([NH2:35])[C:26]=2[N:36]=1>CN(C)C=O>[NH2:35][C:27]1[C:26]2[N:36]=[C:23]([CH2:22][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[S:24][C:25]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: Nc1nc2ccccc2c2sc(CCl)nc12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2sc(CON3C(=O)c4ccccc4C3=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Triethylamine (7.3 mL, 52 mmol) was added to a solution of N-hydroxyphthalimide (3.42 g, 21.0 mmol) in N,N-dimethylformamide (DMF) (50 mL). 2-(Chloromethyl)[1,3]thiazolo[4,5-c]quinolin-4-amine hydrochloride (5.0 g, 18 mmol) was added to the resulting deep red solution, and the reaction was stirred overnight at ambient temperature. A precipitate formed and was isolated by filtration, washed with dichloromethane, and dried in a vacuum oven to provide 3.34 g of 2-[(4-amino[1,3]thiazolo[4,5-c]quinolin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a tan solid. The filtrate was concentrated under reduced pressure, and the residue was mixed with dichloromethane, filtered, washed with dichloromethane, and dried in a vacuum oven overnight to provide an additional 2.06 g of product.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1>C(O)C.[Pd]>[CH3:1][C@@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@H:4]([CH3:9])[O:3]1
Reactant: Cc1cc(=O)cc(C)o1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CC(=O)C[C@H](C)O1

Procedure:
A solution of 2,6-dimethyl-4H-pyran-4-one (2 g, 16.1 mmol) in 20 ml ethanol was stirred over 10% Pd/C (0.2 g) under hydrogen (15 psi) for 16 hours at ambient temperature. TLC showed two spots; one was desired product and second one was side product in a 1:1 ratio. GCMS M+ 128 for product, and M+ 130 for side product.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11](COCC[Si](C)(C)C)[CH:10]=2)=[O:8])[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C@@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1
Reaction time: 0.5 h

Procedure:
A solution of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide (70 mg, 0.134 mmol), 2 mL of dichloromethane and 2 mL of trifluoroacetic acid was stirred 1 h, then concentrated to a yellow solid. The solid was dissolved in 2 mL of dichloromethane and 1 mL of ethylenediamine, and the yellow solution was stirred 30 min. Water (20 mL) was added. The resultant precipitate was isolated by Buchner filtration, rinsing well with water then dichloromethane, and dried by air then in vacuo to afford 33 mg (56%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide as a pale yellow solid. MS: (M+Na)+=417; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.46 (d, J=8.69 Hz, 1H), 8.42 (s, 1H), 8.14 (d, J=7.93 Hz, 1H), 8.00 (d, J=1.51 Hz, 1H), 7.27 (dd, J=8.50, 1.70 Hz, 1H), 4.17 (s, 3H), 3.55-3.70 (m, 1H), 1.34 (d, J=6.80 Hz, 3H), 1.00-1.16 (m, 1H), 0.56 (td, J=8.31, 3.40 Hz, 1H), 0.42-0.50 (m, 1H), 0.26-0.41 (m, 2H).
Reaction SMILES: [CH:1]1[C:2]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:3]=2[NH:4][C:5](=[O:10])[C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:23]O>>[CH:1]1[C:2]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:3]=2[NH:4][C:5](=[O:10])[C:6]=1[C:7]([O:9][CH3:23])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc2c([nH]c1=O)OCc1ccccc1-2
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
Add 6.0 gm of 4,6-dihydro-3H[2]benzopyrano[3,4-b]pyridin-3-one-2-carboxylic acid to 100 ml of methanol. Dropwise, at 0° C., add 10 ml of thionyl chloride to the system. Heat the system at reflux for 6 hours. Remove the solvent by stripping. Isolate the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[NH:8][CH:9]=1.[OH-].[K+].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>CS(C)=O.C(OCC)(=O)C>[N:31]1([CH2:30][CH2:29][N:8]2[CH:9]=[C:5]([CH2:4][CH2:3][C:2]([F:23])([F:1])[F:24])[N:6]=[C:7]2[CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ClCCN1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCC(F)(F)F)c[nH]2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCC(F)(F)F)cn2CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 25.1 %

Procedure:
Combine tert-butyl 4-(4-(3,3,3-trifluoropropyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.27 g, 6.53 mmol), potassium hydroxide (1.20 g, 3.3 eq) (freshly powdered), and 1-(2-chloroethyl)pyrrolidine hydrochloride (1.34 g, 1.2 eq) in dimethyl sulfoxide (100 mL). Heat the reaction mixture at 50° C. overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 4:1 dichloromethane:isopropyl alcohol, to give tert-butyl 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(3,3,3-trifluoropropyl)-1H-imidazol-2-yl)piperidine-1-carboxylate as a thick yellow oil (0.73 g, 25%). MS (ES) m/z=445 [M]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:13])=O>>[CH3:1][N:2]=[C:3]([Cl:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1ccccc1
Product: CN=C(Cl)c1ccccc1
Yield: 91 %

Procedure:
N-Methyl benzamide (55.97 g., 418 mmole) and thionyl chloride (114.7 g, 0.96 mole) were treated as in Example I. Yield 58.4 g (91%) of the title compound, b.p. 80°-90° C. (~0.1 mm Hg).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]([OH:14])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][C:21](CBr)=[CH:20][C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].[CH3:34]COCC>>[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:34][O:14][CH:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Reactant: CCOCC
Reactant: CCCCC(O)CCC1CCCCC1
Product: CCCCC(CCC1CCCCC1)OCc1cccc(C(=O)OC)c1-c1ccccc1C

Procedure:
The ether was prepared using the method described in Example 1205B starting with the compound from Example 1192A and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1132A-D. m/e (ESI) 437 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 5-amino-2-chloropyridine as a white solid as described in Example 1. 1H NMR (CDCl3): 8.89-8.84 (m, 1H), 8.52 (d, J=2.1, 1H), 8.27-8.23 (m, 1H), 8.21-8.17 (m, 1H), 7.83 (s, 1H), 7.53-7.50 (m, 1H), 7.39 (d, J=8.7, 1H).
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][N:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]>C1C=CC=CC=1.[Al].CCOCC.CO>[CH3:13][NH:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: CN=C(C)c1ccccc1
Agent: [Al]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: CO
Solvent: c1ccccc1
Solvent: CCOCC
Product: CNC(C)c1ccccc1
Reaction time: 20 h
Yield: 50.6 %

Procedure:
(R,R)-Ethylene-1,2-bis(η5 -4,5,6,7-tetrahydroindenyl) titanium (R)-1,1'-binaphth-2,2'-diolate (53 mg, 0.089 mmol) was dissolved in 4 mL of dry benzene in a Schlenk tube under a nitrogen atmosphere. The tube was wrapped in aluminum foil. A solution of n-butyllithium (72 μL, 0.12 mmol, 1.6M in hexane) was added and the mixture was shaken until it turned a dark red brown color. After 5 min. phenylsilane, (164 μL, 1.33 mmol) was added and the reaction mixture turned blue, then brown, in color. After 10 minutes acetophenone N-methyl imine (119 mg, 0.89 mmol) was added. The tube was shaken and left for about 20 hours at room temperature. The resulting solution was diluted with 15 mL of ether and 3 mL of methanol and allowed to stir for 2 hours. The reaction mixture was then washed with 10 mL of water and extracted with 1M HCl (2×10 mL). The aqueous layer was separated, basified with 5M NaOH (until strongly basic to pH paper), and extracted with ether (3×20 mL). The ether solution was dried over anhydrous sodium sulfate and concentrated to yield 60 mg (0.45 mmol, 50% yield) of N-methyl-1-phenylethylamine as a yellow oil. The yield for repeated experiments ranged from 50 to 80%.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20](C(O)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl>ClCCl.O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)O)c4ccccc43)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCN(c2ccc(N3CCNc4ccccc43)cc2)CC1
Reaction time: 16 h

Procedure:
31.5 g of the tert-butyl ester of 4-[4-(4-(methanesulphonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid are placed in 400 ml of dichloromethane and then 333 ml of 4N hydrochloric acid in dioxane are added. After stirring for 16 h under an inert atmosphere, the solvents are evaporated under reduced pressure. Water, a saturated aqueous sodium hydrogencarbonate solution and dichloromethane are added. The aqueous sodium phase is extracted twice with dichloromethane. The organic phases are combined, washed with water and dried over magnesium sulphate and then the solvent is evaporated under reduced pressure. 23.2 g of 1-[4-(4-(methanesulphonyl)piperazin-1-yl)phenyl]-1,2,3,4-tetrahydroquinoxaline are obtained. The product is subsequently used as is without other purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:30](=[S:32])=S.CI.[NH2:35][C@H:36]([C:40](O)=[O:41])[CH:37]([CH3:39])[CH3:38]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[C:40](=[O:41])[CH:36]([CH:37]([CH3:39])[CH3:38])[NH:35][C:30]2=[S:32])[CH2:17][CH2:16]1
Reactant: S=C=S
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COc1cc2ncnc(N3CCC(CN)CC3)c2cc1OC
Solvent: CI
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(CN4C(=O)C(C(C)C)NC4=S)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
A mixture of 6,7-dimethoxy-4-[4-(aminomethyl)-piperidino] quinazoline (302 mg; 1 mmol), triethylamine (0.14 ml; 1 mmol), carbon disulfide (66 mcl; 1 mmol) and ethanol (3 ml) was stirred at room temperature for 2 hours. After addition of methyl iodide (62 mcl; 1 mmol), the mixture was further stirred for 1 hour. After addition of L-valine (351 mg; 3 mmol) and triethylamine (0.42 ml, 3 mmol), the reaction solution was refluxed for 10 hours. The resultant reaction solution was left at room temperature for 12 hours to precipitate crystals which were then recovered by filtration. The crystals were successively washed with an aqueous solution of 10% NaHCO3, water and ethanol and dried. The dried material was recrystallized by using a mixture of chloroform and ethanol to yield the desired product (188.6 mg; 41.1%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.O>[CH3:25][S:26]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:3]1)(=[O:28])=[O:27]
Reactant: COc1ccc(CCCN2CC[C@H](O)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCCN2CC[C@H](OS(C)(=O)=O)C2)cc1

Procedure:
(S)-3-Hydroxy-1-[3-(4-methoxyphenyl)propyl]pyrrolidine (310 mg, 1.32 mmol) was dissolved in dichloromethane (10 ml). Triethylamine (173 mg, 1.71 mmol) and methanesulfonyl chloride (196 mg, 1.71 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture (50:1) of dichloromethane and methanol. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-[3-(4-methoxyphenyl)propyl] pyrrolidine in the form of a light yellow oil (336 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:9]=2)[CH:7]=1.[C:27]1(=O)[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[N:11]=[C:12]([N:14]3[C:30](=[O:31])[CH2:29][CH2:28][C:27]3=[O:32])[N:13]=2)[CH:7]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N2C(=O)CCC2=O)n1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of the title compound of Example 29 (0.19 g, 0.50 mmol) and succinic anhydride (0.30 g, 3.0 mmol) in toluene (18 ml) was heated under reflux for 6 hours. After cooled to room temperature, the mixture was filtered. The filtrate was washed with saturated aqueous sodium bicarbonate solution (3×10 ml), dried over magnesium sulfate, and concentrated under reduced pressure to provide 1-[4-(5-chloro-2-methyl-phenyl)-6-(4-trifluoromethyl-phenylamino)-pyrimidin-2-yl]-pyrrolidine-2,5-dione as a white solid (96% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[N:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C@@H:12]([O:18][C:19]([C:21]1([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11]2>C(#N)C>[Br-:1].[C:28]1([C:21]2([C:19]([O:18][C@@H:12]3[CH:13]4[CH2:16][CH2:17][N+:10]([CH2:2][CH2:3][C:4]5[CH:9]=[N:8][CH:7]=[CH:6][N:5]=5)([CH2:15][CH2:14]4)[CH2:11]3)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: BrCCc1cnccn1
Solvent: CC#N
Product: O=C(O[C@H]1C[N+]2(CCc3cnccn3)CCC1CC2)C1(c2ccccc2)CCCCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 68 h
Yield: 38.2 %

Procedure:
2-(2-Bromo-ethyl)-pyrazine (Example 32a) (43 mg) was added to a solution of 1-phenyl -cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in acetonitrile (1 mL). The reaction mixture was allowed to stir at room temperature for 68 h. The volatiles were evaporated and the product was purified by silica gel chromatography eluting with 0-20% MeOH/dichloromethane. The relevant fractions were combined and concentrated, dissolved up in dichloromethane, filtered and evaporated to give the title compound (30 mg) as a yellow gummy glass.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(O)C1[O:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C>[C:5]([O:4][CH2:1][C:2]1[O:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccco1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccco1
Yield: 99.5 %

Procedure:
Procedure was as in example 2, but acetic anhydride was added to the mixture of furfuryl alcohol and triethyl amine. The crude yield was 1149 g and the concentration was 58.7%, i.e., the yield was 99.5%. The crude product was washed 4 times with 200 ml water, whereby 641.3 g furfuryl acetate was obtained, its concentration was 96.2%, i.e., the yield was 91.0%.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-isohexyl-6-methylpiperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 70 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-isohexenyl-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 164.2-167.0° C.; 1H NMR (250 MHz) δ9.44 (s, 2H), 5.71 (s, 2H), 4.18 (s, 1H), 3.56 (s, 1H), 2.0-1.5 (m, 12H), 0.94 (dd, 6H); 13C NMR (62.7 MHz) δ135.7 (s), 123.6 (s), 4.84 (s), 47.9 (s), 36.9 (s), 28.9 (s), 28.4 (s), 28.2 (s), 22.5 (s), 22.1 (s), 17.6 (s), 17.2 (s) ppm. FT-IR (neat): 3429, 3165, 2940, 1620, 1550, 1478, 1400, 1354, 1097, 890. Elemental Analysis for C12H24NCl: C, 66.17%; H, 11.13%; N, 6.43%. Found: C, 66.25%; H, 11.05%; N, 6.50%.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(O)C.O>[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:11]2[CH2:10][CH2:9][CH:8]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 4 h

Procedure:
To a solution of 126 parts of 4-(diphenylmethyl)piperidine in 1200 parts of 95% ethanol is added a solution of 69 parts of sodium carbonate in 1500 parts of water. The resultant mixture is heated at the boiling point under reflux with vigorous stirring while a solution of 112 parts of 4-nitrobenzyl chloride in 800 parts of 95% ethanol is rapidly stirred in, and for 4 hours thereafter. Solvent is then removed by vacuum distillation, and the residue is partitioned between dichloromethane and water. The organic layer is separated, dried over anhydrous potassium carbonate, and stripped of solvent by vacuum distillation. The residue, recrystallized from anhydrous ethanol, affords 1-[(4-nitrophenyl)methyl]-4-(diphenylmethyl)piperidine melting at approximately 130°-131°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[CH3:21][CH:22]([CH3:28])[C:23](=O)[CH2:24][C:25]#[N:26]>>[CH:22]([C:23]1[CH:24]=[C:25]([NH2:26])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH:10]=2)[N:12]=1)([CH3:28])[CH3:21]
Reactant: Cn1cnc2cc(N)ccc21
Reactant: O=N[O-]
Reactant: CC(C)C(=O)CC#N
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)c1cc(N)n(-c2ccc3c(c2)ncn3C)n1
Yield: 72.6 %

Procedure:
Using a procedure analogous to Example B22, 1-methyl-1H-benzo[d]imidazol-5-amine (0.50 g, 3.4 mmol), NaNO2 (0.28 g, 4.1 mmol), SnCl2.2H2O (2.8 g, 14 mmol) and 4-methyl-3-oxopentanenitrile (0.45 g, 4.1 mmol) were combined to afford crude 3-isopropyl-1-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-5-amine (0.63 g, 73% yield) as a foam which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 7.72 (dd, J=0.40 and 1.2 Hz, 1H), 7.60 (dd, J=0.40 and 8.4 Hz, 1H), 7.42 (dd, J=2.0 and 8.4 Hz, 1H), 5.32 (s, 1H), 5.08 (brs, 2H), 3.85 (s, 3H), 2.75 (septet, J=6.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 250.0 (M+H+).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (2.5 g, 14.56 mmol) and anhydrous potassium carbonate (7 g, 50.64 mmol) in dry DMF (25 mL) was stirred for 30 min at room temperature. Benzyl bromide (2 mL, 16.82 mmol) was added dropwise into the reaction mixture and heated at 65° C. for 14 h. The reaction mixture was cooled to room temperature, filtered and quenched with ice water (25 mL). The resulting mixture was extracted in ethyl acetate (2×20 mL) and the combined organic layers were washed with water (2×15 mL) followed by brine (20 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated. The crude product obtained was purified by crystallisation using 2% methanol in chloroform to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:36])[CH2:31][C:32](=[O:34])[OH:33])=[O:28])=[O:24])OCC[O:18]2)=[CH:13][CH:12]=1)(=[NH:10])[NH2:9]>FC(F)(F)C(O)=O.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:36])[CH2:31][C:32](=[O:33])[OH:34])=[O:28])=[O:24])=[O:18])=[CH:13][CH:12]=1)(=[NH:9])[NH2:10]
Reactant: N=C(N)c1ccc(C2(CC(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc3ccccc3)C(=O)O)OCCO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N=C(N)c1ccc(C(=O)CC(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A solution of 100 mg of N-[N-[N-[[2-(p-amidinophenyl)-1,3-dioxolan-2-yl]acetyl]glycyl]-L-α-aspartyl]-3-phenyl-L-alanine trifluoroacetate in 10 ml of trifluoroacetic acid/water 9:1 is left to stand at room temperature overnight. After removal of the solvent, chromatography of the residue (RP-18; elution with water-water/acetonitrile 1:1) and recrystallization there are obtained 33 mg of N-[N-[N-[(p-amidinobenzoyl)acetyl]glycyl]-L-aspartyl]-3-phenyl-L-alanine trifluoroacetate (1:1), m.p. 225°-230° C. (decomposition).