Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2([F:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:14][C:8]1([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:16]4[S:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Fc1nccnc1C1(F)CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: FC1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 80 °C

Procedure:
To a solution of 2-fluoro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazine (0.055 g, 0.275 mmol) and 4-(benzo[d]thiazol-2-ylamino)phenol (0.100 g, 0.412 mmol) in DMSO (0.9 mL) was added cesium carbonate (0.179 g, 0.549 mmol). The resulting mixture was heated to 80° C. overnight. The reaction mixture was partitioned between water, brine and DCM. The aqueous layer was back extracted with DCM and the combined organic layer was dried (Na2SO4) and concentrated. Purification by prep-plate TLC (5% MeOH/DCM) produced product. MS (ESI, pos. ion) m/z: 423.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][C:12]1[C:13]([N+:18]([O-:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=1)(=O)=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>CS(C)=O>[N:1]([CH2:10][CH2:11][C:12]1[C:13]([N+:18]([O-:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCCc1cccnc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCc1cccnc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
Sodium azide (1.16 g, 17.8 mmol) was added to a solution of 3-(2-methansulfonyloxyethyl)-2-nitropyridine (0.44 g, 1.78 mmol) in dimethyl sulfoxide (5 mL), then stirred overnight at 50° C. The reaction was cooled and worked up with saturated sodium bicarbonate and methylene chloride. The organic phase was dried over sodium sulfate. This material was chromatographed (silica gel, 0-50% ethyl acetate in hexane, gradient elution) to produce the title compound (0.190 g) as a yellow oil. MS 194 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13][OH:14])=[O:4].CC(C)([O-])C.[K+]>CC(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][O:14][CH2:13][C:7]=2[CH:8]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C1COCc2cc(Cl)ccc2N1
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
To a suspension of 2-bromo-N-(4-chloro-2-(hydroxymethyl)phenyl)acetamide (3.60 g, 12.9 mmol) in 2-propanol (129 ml) was added in small portions potassium tert-butoxide (3.77 g, 33.6 mmol) at 0-5° C. The reaction mixture was stirred for 90 minutes and subsequently poured on ice/water (500 ml). The precipitate was collected by filtration and washed with water. Residual water was removed by consecutive evaporation with two 50-ml portions of toluene to give the title compound (2.34 g, 92%) as light yellow solid. MS m/e: 196 ([M−H]−).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:18][O:19]C(OC)N(C)C>C1COCC1>[O:19]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=2)[C:9](=[O:10])[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:18]1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2)coc2ccccc12
Temperature: 120 °C
Yield: 16 %

Procedure:
To an oven-dried microwave vial was added 4-methoxydeoxybenzoin (73 mg, 2.83 mmol), dimethyl formamide dimethyl acetal (0.188 mL, 1.41 mmol) and THF (0.100 mL). The reaction was heated to 120° C. for 2 min. The product was recrystallized from methanol and a few drops of water to afford 12 (50 mg, 66%) as a pink powder. Analytical data for isoflavone 12: 1H NMR (500 MHz, DMSO) δ 9.56 (s, 1H), 8.38 (s, 1H), 8.03 (d, J=9 Hz, 1H), 7.40 (d, J=9 Hz, 2H), 7.16 (s, 1H), 7.08 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 2H), 3.91 (s, 3H); 13C NMR (125 MHz, DMSO) δ 175.4, 164.3, 158.1, 157.9, 153.9, 130.8, 127.6, 124.4, 123.0, 118.3, 115.7, 115.4, 101.2, 56.8; LCMS: Mass calculated for C16H12O4, [M+H]+, 269. Found 269.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][S-:13].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:12][S:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
5-Chloro-2-nitroaniline (15 g, 87.2 mmol) was dissolved in 250 mL of DMF with stirring. Sodium thiomethoxide (9.8 g, 140 mmol) was added and the reaction stirred at 65° C. for 20 h. The reaction was cooled to rt and diluted with EtOAc. then washed with water (5×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 12.9 g (81%) of 5-(methylthio)-2-nitroaniline as a red-orange solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.97 Hz, 1H), 7.45 (br s, 2H), 6.78 (d, J=1.83 Hz, 1H), 6.47 (dd, J=1.83 and 9.16 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH3:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[C:15]([CH3:21])[N:14]=1>O1CCCC1>[CH3:12][C:13]1[C:18]([CH:19]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)[OH:20])=[CH:17][CH:16]=[C:15]([CH3:21])[N:14]=1
Reactant: Cc1ccc(C=O)c(C)n1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cnnn2C)c(C)n1
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 22.5 mL, 56.3 mmol) was added dropwise by syringe to a stirring solution of 1-methyl-1H-1,2,3-triazole (5.00 g, 60.2 mmol, prepared according to PCT Int. Appl., 2008098104) in dry tetrahydrofuran (400 mL) at −55° C. The resulting off-white slurry was stirred at −45° C. for 20 min, whereupon a solution of 2,6-dimethyl-pyridine-3-carbaldehyde (8.33 g, 61.7 mmol) in dry tetrahydrofuran (10 mL) was added dropwise by syringe. After 5 min, the cooling bath was removed and the reaction mixture was allowed to slowly warm. After 45 min, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (100 mL) were added. The whole was concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (300 mL). The organic solution was washed with saturated aqueous sodium chloride solution (100 mL, containing excess solid sodium chloride). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and the combined solution was concentrated. Ether (100 mL) was added to the residue and the mixture was sonicated for 20 min during which time a white solid crashed out. The solids were collected by filtration. Ether (100 mL) was added to the collected solids and the mixture sonicated a second time. After 20 min, the mixture was filtered and the solids were collected to provide the title compound as a fine powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[F:17])[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[C:11]([F:17])[CH:12]=1
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
5-(4-Bromo-2-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (3.0 g, 7.0 mmol) prepared in Step 3 and a solution of potassium hydroxide (790.9 mg, 14.1 mmol) in distilled water (47.0 mL) were added to methanol (47.0 mL). The reaction mixture was stirred at 70° C. for 2 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2.5 g of the titled compound as a white solid.
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].[CH3:7][N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[OH-].[Na+]>O.C1C=CC=CC=1>[CH3:7][N:8]1[C:12](=[O:13])[NH:6][CH:2]([CH2:3][CH3:4])[NH:5][C:9]1=[O:10]
Reactant: CN(C(=O)Cl)C(=O)Cl
Reactant: CCC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCC1NC(=O)N(C)C(=O)N1
Yield: 49.6 %

Procedure:
10.9 g (0.1 mol) of propionamidine hydrochloride were suspended in 125 ml of water and 200 ml of benzene. 15.6 g (0.1 mol) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 18 g (0.45 mol) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from 2 dropping funnels, with vigorous stirring. The reaction took place exothermically. The mixture was stirred for a further hour and the aqueous phase was separated off, acidified with glacial acetic acid and evaporated in vacuo. The residue was repeatedly extracted by boiling with ethyl acetate. The solution was concentrated in vacuo and cooled. The precipitate was filtered off. 7.8 g (50%) of 1-methyl-4-ethyl-tetrahydro-1,3,5-triazine-2,6-dione were obtained as colorless needles of melting point 202°-203°C.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[N:18][C:17]([C:20]([O:22]CC)=O)=[N:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14])[CH3:3].[OH-].[NH4+:26]>O1CCCC1.ClCCl>[OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[N:18][C:17]([C:20]([NH2:26])=[O:22])=[N:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14])[CH3:3]
Reactant: [NH4+]
Reactant: CCOC(=O)c1ncn([C@H](CCc2cccc(Cl)c2Cl)[C@H](C)O)n1
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](CCc1cccc(Cl)c1Cl)n1cnc(C(N)=O)n1
Temperature: 120 °C

Procedure:
A mixture of ethyl 1-[(2S,3R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxylate (11.6 mg) and ammonium hydroxide (28% in water; 0.5 ml) in tetrahydrofuran (3 ml) was heated in a steel sealed tube at 120° C. overnight. The mixture was taken up in dichloromethane, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a white powder of 1-[(2S,3R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxamide (4.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Yield: 77 %

Procedure:
A mixture of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (as the methyl hemiacetal) (1.09 g, 5.291 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (1.06 g, 5.291 mmol) in chloroform (50 ml) and MeOH (2.5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (3.37 g, 15.873 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the desired compound (1.591 g, 77%).
Reaction SMILES: [N:1]([C:4]1[C:5]([F:17])=[C:6]([CH:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3].[CH2:18]=[O:19].[OH-].[Na+]>CCO>[N:1]([C:4]1[C:5]([F:17])=[C:6]([CH:11]2[CH2:15][N:14]([CH2:18][OH:19])[C:13](=[O:16])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)ccc(C2CNC(=O)C2)c1F
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=Nc1c(F)ccc(C2CC(=O)N(CO)C2)c1F

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of 4-(3-azido-2,4-difluoro-phenyl)-pyrrolidin-2-one a14 (1.84 g, 7.73 mmol), formaldehyde (35% w/w in water, 2.3 g) and NaOH (0.015 g) in EtOH (20 ml) is heated at 60° C. for 3 h. The reaction mixture is evaporated and dried azeotropically with toluene to give the crude alcohol which is purified by chromatography on silicagel (CH2Cl2/MeOH: 98/02 (v/v)) to give 4-(3-azido-2,4-difluoro-phenyl)-1-hydroxymethyl-pyrrolidin-2-one a15 (1.64 g, 79%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:16])(=O)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1ccc(O)cc1
Product: COc1ccc(C(C)(C)C)cc1

Procedure:
More specifically, the process for producing N-sec-butyl-4-tert-butyl-2,6-dinitroaniline comprises reacting 4-tert-butylphenol with dimethyl sulfate to produce 4-tert-butylanisole. The 4-tert-butylanisole is then reacted with nitrating agent to produce 2,6-dinitro-4-tert-butylanisole. The 2,6-dinitro-4-tert-butylanisole is then reacted with sec-butylamine to produce N-sec-butyl-4-tert-butyl-2,6-dinitroaniline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH3:19][OH:20].[H-].[Na+]>CS(C)=O>[CH3:19][O:20][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CO
Reactant: CCCC(Oc1ccc(Cl)nc1C)[C@H]1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(Oc1ccc(OC)nc1C)[C@H]1CCNC1
Temperature: 100 °C
Yield: 65.1 %

Procedure:
Add (3S)-3-(1-(6-chloro-2-methyl-3-pyridyloxy)-butyl)-pyrrolidine (S-2) (0.65 g, 2.44 mmol), DMSO (9.75 mL), methanol (0.493 mL, 12.18 mmol), and sodium hydride (0.390 g, 9.75 mmol) to a reaction vial. Evacuate the vial and purge with nitrogen. Heat the mixture at 100° C. over night. Pour the reaction mixture onto an SCX column and rinse with methanol. Attach the SCX column on top of a silica gel column and elute with 5-30% of NH3OH/ethanol (1:9) in chloroform to obtain 0.420 g (65%) of (3S)-3-(1-(6-methoxy-2-methyl-3-pyridyloxy)-butyl)-pyrrolidine
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:12])[C:8]([Cl:11])([Cl:10])[Cl:9].[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=[C:3]1[C:7](=[O:12])[C:8]([Cl:9])([Cl:10])[Cl:11]
Reactant: O=[N+]([O-])O
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2.12 g (9.34 mmol) of 1-methyl-2-trichloroacetyl-1H-pyrrole are dissolved in 9.5 ml of acetic anhydride and cooled to −20° C., and 0.43 ml (9.34 mmol) of nitric acid is added. The mixture is slowly warmed to RT and stirred at RT for 1 h. The reaction mixture is poured into 95 g of ice and stirred vigorously for 2.5 h (initially oily deposit then crystallization). The precipitate is filtered off with suction, triturated with 20 ml of methanol, filtered and dried under reduced pressure overnight. To remove the regioisomers, which are also formed, the product is triturated with 10 ml of acetic acid/water 1:1 for 2 h, and the solid is filtered off with suction and dried under reduced pressure. This gives a solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH3:15][O:16][CH2:17][CH2:18][NH:19][CH3:20]>>[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:20])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: CNCCOC
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: COCCN(C)CCCc1ccc2c(n1)COC2=O
Yield: 85.1 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and N-(2-methoxyethyl)methylamine (43 μL, 0.4 mmol) are reacted to provide the title compound as pale yellow oil (90 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23]O)[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].CCN(S(F)(F)[F:38])CC>ClCCl.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23][F:38])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1CO
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1CF
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate obtained by the method described in Example (27b) (0.14 g, 0.30 mmol) was dissolved in dichloromethane (5 mL). A solution of DAST (0.05 mL, 0.38 mmol) in dichloromethane (2 mL) was added dropwise at −40° C. The mixture was stirred at that temperature for 30 minutes. Brine was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 3/1, 1/1) to obtain 83 mg of the title compound as a colorless oily substance (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])=[CH:4][CH:3]=1.[CH2:19]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])[CH3:19])=[CH:17][CH:18]=1
Reactant: Cc1nccn1CCCNCc1ccc(Cl)cc1
Reactant: C=O
Solvent: O=CO
Product: Cc1nccn1CCCN(C)Cc1ccc(Cl)cc1

Procedure:
In a similar manner to Example 90, N-(4-chlorobenzyl)-3-(2-methylimidazol-1-yl)propylamine was treated with formaldehyde and formic acid to give N-(4-chlorobenzyl)-N-methyl-3-(2-methylimidazol-1-yl)propylamine, b.p. 160°-166° C. (0.2 mmHg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[CH:17]=[C:18]([C:21]#[N:22])[S:19][CH:20]=1>>[CH3:11][CH:9]1[O:8][C:7]([CH3:13])([CH3:12])[C:6]2[CH:14]=[C:2]([C:16]3[CH:17]=[C:18]([C:21]#[N:22])[S:19][CH:20]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1Nc2ccc(-c3csc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-thiophenecarbonitrile. An off-white solid: mp 175-176° C.; 1H-NMR (DMSO-d6) δ 8.39 (d, 1H, J=1.5 Hz), 8.13 (d, 1H, J=1.5 Hz), 7.47 (d, 1H, J=1.9 Hz), 7.36 (dd, 1H, J=8.4, 1.9 Hz), 6.59 (d, 1H, J=8.4 Hz), 6.41 (s, 1H), 4.78 (m, 1H), 1.51 (s, 3H), 1.47 (s, 3H), 1.28 (d, 3H, J=5.4 Hz); MS (ESI) m/z 285 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]=[C:14]([N:27]1[CH2:31][C:30]2=[CH:32][S:33][CH:34]=[C:29]2[CH2:28]1)[CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([OH:19])=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCCC1>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:17](=[O:19])[CH:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][C:14]([N:27]2[CH2:31][C:30]3=[CH:32][S:33][CH:34]=[C:29]3[CH2:28]2)=[O:13])[CH2:38][CH2:37]1
Reactant: O=C(O)C(CC(=O)N1Cc2cscc2C1)Cc1ccccc1
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(CC(=O)N2Cc3cscc3C2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
0.55 g (3.39 mmol) of carbonyldiimidazole is added to a solution of 1 g (3.17 mmol) of γ-oxo-α-(phenylmethyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-5-butanoic acid in 15 ml of dry tetrahydrofuran. The solution is stirred at room temperature for 1 h and then 0.42 ml (3.8 mmol) of 4-methylpiperazine is added and the solution is stirred at room temperature for 20 h. The mixture is then evaporated to dryness, the residue is dissolved in 50 ml of dichloromethane, and then the solution obtained is washed successively with twice 50 ml of a saturated sodium hydrogen carbonate solution and 20 ml of a saturated sodium chloride solution, dried over sodium sulphate and then evaporated to dryness. After recrystallization from ethanol, 1 g of a white solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:21]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15].S(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][Cl:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1Br
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Br
Reaction time: 2 h
Yield: 87 %

Procedure:
(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol (4.20 g) was added to thionyl chloride (5 mL) at 0° C., and the mixture was stirred for 2 hrs. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-{[2-bromo-4-(chloromethyl)phenoxy]methyl}-2-(2-furyl)-5-methyloxazole as pale-yellow crystals (3.82 g, yield 87%). Recrystallization from ethyl acetate-hexane gave pale-yellow needle crystals. melting point: 125-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][NH:15][C:14]2=[O:23])[CH2:9][CH2:8]1)=[O:6].I[CH3:31].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][N:15]([CH3:31])[C:14]2=[O:23])[CH2:11][CH2:12]1)=[O:6]
Reactant: CI
Reactant: COc1ccc(C(=O)N2CCC(N3C(=O)NCc4ccccc43)CC2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCC(N3C(=O)N(C)Cc4ccccc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2,4-dimethoxybenzoylpiperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (100 mg, 2.53 mmol) from Example 35 in DMF (50 mL) was added Nail (16 mg of a 60% suspension in mineral oil, 0.40 mmol) followed by iodomethane (0.031 mL, 0.50 mmol). The reaction was stirred for 18 h at ambient temperature. More NaH (10 mg, 0.25 mmol) and iodomethane (0.031 mL, 0.50 mmol) were added and the reaction was stirred at ambient temperature for 24 h. The reaction was quenched by the addition of HOAc (0.2 mL) and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 90:10 EtOAc:hexanes as eluant. The title compound was obtained as an oil (45% yield). TLC: Rf =0.42 (97:3 CHCl3 :MeOH) HPLC (method A): retention time 8.53 min FAB MS: m/z 410 (M+ +H)