Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:4].[H-].[Na+].[CH:18](OC)=[O:19]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:18][OH:19])=[O:4]
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1C
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Reaction time: 8 h

Procedure:
2-Methoxycarbonylmethyl-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (5.7 g) in dry tetrahydrofuran (100 ml) was stirred at room temperature under argon. Sodium hydride (60% dispersion in mineral oil, 7.13 g) was added portionwise followed by methyl formate (2.5 ml) and the mixture was left to stir overnight. The reaction was cooled in ice and quenched by the addition of the minimum amount of methanol. The solution was again cooled and acidified to pH1 with aqueous 5N hydrochloric acid. The reaction was diluted with ethyl acetate and water, the aqueous separated and extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried (MgSO4) and filtered. The solvent was evaporated to yield an oil consisting of two layers. The top layer was discarded and the lower layer solidified on standing to give the crude title compound as a brown solid (8.62 g).
Reaction SMILES: [CH:1]1([C@H:7]([CH2:20][CH:21]=[CH2:22])[CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:23]#[N:24].[Na+].O>CS(C)=O>[CH:1]1([C@H:7]([CH2:20][CH:21]=[CH2:22])[CH2:8][C:23]#[N:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [C-]#N
Reactant: C=CC[C@H](COS(=O)(=O)c1ccc(C)cc1)C1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CC[C@H](CC#N)C1CCCCC1
Temperature: 90 °C

Procedure:
To the crude product, (S)-toluene-4-sulfonic acid 2-cyclohexyl-pent-4-enyl ester, in DMSO (40 mL) was added NaCN, and the resulting mixture was heated at 90° C. for 1.5 h. The reaction mixture was cooled to room temperature and treated with H2O (20 mL). The reaction mixture was then extracted with diethylether (3×25 mL), dried (MgSO4) and concentrated in vacuo to yield a residue which was purified by Kugelrohr distillation (0.19 mm Hg, 80-90° C.) to yield (R)-3-cyclohexyl-hex-5-enenitrile.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.O.N1(O)C2C=CC=CC=2N=N1.C(=NC1CCCCC1)=NC1CCCCC1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]([O:13][C@@H:24]2[CH:25]3[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]3)[CH2:23]2)=[O:12])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCc1cccc(NC(C(=O)O)c2ccc(OC)nc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-ethylphenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I73) (265 mg, 0.93 mmol), (R)-quinuclidin-3-ol (129 mg, 1.02 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (156 mg, 1.02 mmol), and N,N′-methanediylidenedicyclohexanamine (210 mg, 1.02 mmol) was dissolved in THF (10 ml) and stirred at room temperature overnight. The solvent was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain the title compound, which was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH:5]([CH2:8]O)[CH2:4]1)[CH3:2].[BrH:10].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:10][CH2:8][CH:5]1[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: Br
Reactant: CCN1CCC(CO)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCN1CCC(CBr)C1

Procedure:
A mixture of 5.0 g. (0.0388 mol.) of N-ethyl-3-hydroxymethylpyrrolidine and 50 ml. of 48% hydrogen bromide was refluxed for 17 hours. The reaction mixture was cooled, made basic by addition of solid sodium carbonate and extracted twice with methylene chloride. The combined extracts were dried (MgSO4) and evaporated to dryness to give 3-bromomethyl-N-ethylpyrrolidine.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](OC)(OC)(OC)C>>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: COC(C)(OC)OC
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1

Procedure:
We have also found an alternative, more efficient and simple method for esterification using trimethyl orthoacetate. The method involves dissolving 4-iodo-3-nitrobenzoic acid in trimethyl orthoacetate and refluxing the solution for 15 hours. Removal of the solvent under reduced pressure, gives 4-iodo-3-nitro benzoic methyl ester as a solid in almost quantitative yield (98%, 97% HPLC). It contains about 1.5% starting acid. Since the residual starting acid does not interfere in the next step, the material can be taken directly for the next stage. However, if required, the material can be further purified by crystallization from methanol and water with little loss of yield (95% Y, 98.3% HPLC).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[N:23]1([NH:22][C:19]([C:16]2[CH:17]=[N:18][C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:14][CH:15]=2)=[O:21])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: NN1CCc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCc2ccccc21)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
Oxalyl chloride in DCM (2 M, 1.5 mL) is added to a solution of 2-phenyl-pyrimidine-5-carboxylic acid (200 mg, 2 mmol) in DCM (20 mL) and stirred at rt for 2 h. The reaction solution is concentrated in vacuo. The residue is dissolved in DCM (20 mL). N-amino-indoline (268 mg, 2 mmol) and triethylamine (404 mg, 4 mmol) are added and stirred at rt overnight. The mixture is concentrated in vacuo and the residue is purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid (2,3-dihydro-indol-1-yl)-amide (195 mg, 31%) as a solid. MS: 317 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.07 (t, 2H), 3.77 (t, 2H), 6.76 (m, H), 6.82-6.95 (m, H) 7.09-7.24 (m, 2H), 7.54-7.63 (m, 3H), 8.52 (d, 2H), 9.28 (s, 2H) and 2-phenyl-pyrimidine-5-carboxylic acid (indol-1-yl)-amide (10 mg, 2%). MS: 315 (M+H). IC50=2 nM.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:11]([CH2:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCOCC.O>[O:20]=[C:19]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCNC(=O)COc1ccccc1
Yield: 53 %

Procedure:
To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4 g) and phenoxyacetyl chloride (2.76 ml) in 50 ml of Et2O and 50 ml of water was added one portion of NaHCO3 (4.2 g). After 2 hr the layers were separated and the organic phase was washed (1N HCl, brine), dried (MgSO4), and filtered. Evaporation of the solvent under vacuum gave 3.1 g (53%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCOCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (500.0 mg, 1.4 mmol, 1.0 equiv) and morpholine (1.5 mL, 16.8 mmol, 12 equiv) in methylpyrrolidone (15.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (20.0 mL), and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-morpholinoisonicotinamide (358.6 mg, 0.90 mmol) as yellow solids in 63% yield: 1H NMR (DMSO-d6, 500 MHz) δ 8.30 (d, J=5.1 Hz, 2H), 7.50 (s, 1H), 7.22 (d, J=5.1 Hz, 2H), 7.10 (s, 1H), 6.92 (s, 2H), 3.70-3.73 (m, 4H), 3.53-3.55 (m, 4H), 2.26 (s, 3H), 2.05 (s, 6H); ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:31])[CH:8]([O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C.Cl>O.O1CCCC1>[CH3:27][N:25]([CH3:26])[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH:8]([O:28][CH2:29][CH3:30])[C:7]([OH:31])=[O:6])=[CH:11][CH:12]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(N(C)C)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(N(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Lithium hydroxide hydrate (38 mg; 0.90 mmole) dissolved in water (2 ml) was added to a solution of 3-{4-[2-(4-dimethylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (described in Example 99) (232 mg; 0.60 mmole) in tetrahydrofuran (6 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 5. Tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the mixture was extracted with ethyl acetate (10+5 ml), dried (sodium sulfate) and the solvent was evaporated in vacuo. Purification by filtration on silica gel gave 180 mg (yield 84%) of 3-{4-[2-(4-dimethylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:12]>>[OH:12][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc2cn[nH]c2c1
Product: Oc1ccc2cn[nH]c2c1
Reaction time: 1 h
Yield: 51 %

Procedure:
6-aminoindazole (2.66 g, 20 mmol) is added to 20% of dilute sulfuric acid and the reaction is performed under microwave radiation at 170° C. for 1 hour using microwave powder of 600 watt, and then terminated. The reaction solution is cooled, adjusted to pH=7 with 5% NaOH and stirred for 10 minutes to precipitated a deposit, which is recrystallized in water to obtain 1.5 g of 6-hydroxyindazole, with a yield of 51%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9].Cl[CH:19]([F:21])[F:20]>O1CCCC1>[CH3:17][O:16][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:14]=1[O:15][CH:19]([F:21])[F:20])[C:8]([O:10][CH3:11])=[O:9]
Reactant: FC(F)Cl
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(OC(F)F)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.144 g, 6 mmol) was added portionwise to a solution of methyl 3,5-dimethoxy-4-hydroxy-benzoate (0.21 g, 1 mmol) in tetrahydrofuran (20 mL) cooled to 0° C. After 2 hours, chlorodifluoromethane (gas) was introduced by sparge for 10 minutes every 2 hours (5 times). After 18 hours, an additional portion of sodium hydride (0.048 g, 2 mmol) was added followed by chlorodifluoromethane (gas) sparge for 10 minutes. The reaction mixture was sealed and stirred for 3 weeks. The reaction mixture was cooled to -78° C. and methanol (5 mL) was added. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][CH2:33]O)(=[O:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:28]([O:31][CH2:32][CH2:33][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:10]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCCO
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)OCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(F)cc3)[nH]2)cc1

Procedure:
5-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine and diethylazodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-acetoxyethyloxy)phenyl)-5-(4-fluorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16]([I:17])[C:11]=3[O:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:23]4[N:22]([CH3:21])[C:30]5[C:25]([CH:24]=4)=[CH:26][CH:27]=[CH:28][CH:29]=5)=[O:32])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][O:10][C:11]=2[C:16]([I:17])=[CH:15][N:14]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-7-iodofuro[3,2-c]pyridin-4-amine (2.53 g, 6.65 mmol) in pyridine (30 mL) was cooled to 0° C. and 1-methyl-1H-2-indolecarbonyl chloride (2.57 g, 13.3 mmol) was added. The mixture was stirred for 15 minutes at 0° C. and then allowed to rise to ambient temperature over an 18 hour time period. The solvent was removed in vacuo and the residue was dissolved in water (50 mL) and brought to pH 12 with 0.1 N aqueous sodium hydroxide, at which point a precipitate formed. The suspension was extracted with dichloromethane (4×25 mL) and the combined organic layers were washed with brine (25 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (3.21 g, 89%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 8.04 (t, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.30-7.37 (m, 2H), 7.25 (d, 1H), 7.11-7.18 (m, 2H), 5.75-5.83 (bs, 2H), 4.04 (s, 3H), 3.93 (s, 3H); RP-HPLC (Conditions d) Rt 8.73 min.; MS: MH+ 539.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CNCC2CCNCC2)cc1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CNCC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
Under ice-cooling, to 200 ml of a tetrahydrofuran (THF) solution containing 5.0 g of N-(4-piperidylmethyl)-N-benzylamine was added dropwise 50 ml of a THF solution containing 2.9 ml of benzyl bromide. After stirring the mixture at the same temperature for one hour, THF was removed from the reaction mixture under reduced pressure and a saturated sodium hydrogen carbonate aqueous solution was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. Precipitated crystals were recrystallized from an ethanol solution to give 3.6 g of N-(1-benzylpiperidin-4-ylmethyl)-N-benzylamine (yield: 50%, melting point: 240° C. or higher).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.CO.[OH-].[Na+]>C1COCC1.Cl>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of methyl 4-(4-biphenylylcarbonylamino)benzoate (1.998 g) in THF (60 ml)/methanol (20 ml) was added 1N aqueous sodium hydroxide (8 ml) and stirring was continued at room temperature for 18 hr. The reaction mixture was diluted with 1 N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The resulting crude crystals were washed with diethyl ether to obtain the titled compound (1.760 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1SC)[CH3:2].[NH2:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13](O)=[O:14]>CC(N(C)C)=O>[CH2:1]([N:3]1[C:4]2=[N:10][C:11]3[C:12]([C:13](=[O:14])[N:5]2[CH2:6][CH2:7]1)=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[CH3:2]
Reactant: CCN1CCN=C1SC
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)O
Solvent: CC(=O)N(C)C
Product: CCN1CCn2c1nc1ccc(C(F)(F)F)cc1c2=O

Procedure:
A solution of 3.6 g. of 1-ethyl-2-methylthioimidazoline, 5.0 g. of 2-amino-5-trifluoromethylbenzoic acid and 50 ml. of dimethylacetamide is refluxed for 24 hours and then the reaction mixture concentrated in vacuo. The residue is dissolved in methylene chloride, washed first with 2 N sodium hydroxide solution and then with water, dried over magnesium sulfate, filtered and chromatographed on silica gel while eluding with methylene chloride to obtain 1-ethyl-7-trifluoromethyl-2,3-dihydro-imidazo[2.1-b]quinazolin-5(1H)-one.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C@:22]12[C@:21]3([CH3:26])[CH2:20][CH2:19][C@H:18]4[C:17]([CH3:27])([CH3:28])[C@@H:16]([OH:29])[CH2:15][CH2:14][C@:13]4([CH3:30])[C@H:12]3[CH2:11][CH2:10][C@@H:9]1[C@@H:8]1[C@@:7]3([CH2:31][O:32][C@H:4]1[C:2]([CH3:1])([CH3:3])[CH2:5][CH2:6]3)[CH2:24][CH2:23]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC[C@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](O)C(C)(C)[C@@H]6CC[C@]54C)[C@H]2[C@H]1OC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
In 100-ml flask stir 2 g of Betulin in 50 ml of CH2Cl2 at 0° C. Add 5 ml of 99% CF3COOH and stir for 30 minutes. Pour reaction mixture in 100 ml of cracked ice and separate the organic part. Extract with CH2Cl2 (3×10 ml) and wash combined organic extracts with conc. NaHCO3 (2×20 ml) and water (2×20 ml), and dry the extract over Na2SO4 (anh.). Evaporation of solvent gives 1.98 g of Allobetulin, which was recrystallized from hexane-dichloromethane to yield white needles mp. 268-269° C. [lit. 265-268], IR (KBr) 3448.5, 2941.5, 2866.6, 1780.7, 1456.6, 1384.4, 1168.9, 1035.0, cm−1; 1H NMR (CDCl3) d 3.75 (D, J=10.3 Hz, 1H, 28-H), 3.51 (S, 1-H, 19-H), 3.41 (D, J=10.3 Hz, 1H, 28-H), 3.18 (DD, 1H, 3-H), 0.74, 0.76, 0.81, 0.88, 0.89, 0.94, 0.94 (all S, 7×3H, 27-, 23-, 24-, 25-, 26-, 29-, 30-Me), 1.01-1.74 (complex CH—, CH2, 25H,); 13C NMR (CDCl3) d 88.41, 79.38, 71.49, 55.77, 51.35, 47.07, 41.78, 40.99, 40.88, 40.87, 39.16, 37.52, 36.95, 36.51, 34.40, 34.18, 32.96, 29.08, 28.27, 27.57, 26.72, 26.72, 26.50, 24.82, 21.26, 18.54, 16.79, 15.96, 15.72, 13.82; MS (EI) 442, 424, 411, 371, 355, 303, 273, 257, 245, 231, 220, 207, 203, 189, 177, 162, 149, 135, 121, 107.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CS[C:11](=N)[N:12](C1C=CC=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH:12]([C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSC(=N)N(c1ccccc1)c1ccccc1
Reactant: Nc1ccccc1N
Product: c1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
Then, 101.2 g (0.973 mol) of o-phenylenediamine and 235.5 g (0.973 mol) of S-methyl-N,N-diphenylisothiourea were changed into a four-necked flask of 1l capacity, and reacted at 140° C. for 10 hours. The reaction product was cooled and filtered, and the filter cake was washed with xylene to obtain the aimed 2-anilinobenzimidazole having a melting point of 193.2°-194.5° C. in an yield of 149.2 9 (73.2%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:1]([NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: C=CCNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
In a round bottom flask with a stir bar, a solution of allyl amine (10 mL, 133.6 mmol) in dichloromethane (350 mL) was cooled to 0° C. A solution of benzoyl chloride (17.05 mL, 147.0 mmol) in dichloromethane (20 mL) was added dropwise via addition funnel. Once the addition was complete, the solution was stirred at 0° C. for 2 h. The solution was concentrated and the residue was purified on silica gel chromatography (Combiflash. Rf system, 330 g RediSep cartridge) using EtOAc/hexanes as a mobile phase. The desired fractions were collected and concentrated to afford N-allylbenzamide (19.6 g, 91%) as a yellow oil. N-allylbenzamide (1.0 g, 6.21 mmol) was dissolved in dichloromethane (60 mL) and cooled to −78° C. A Tygon tube connected to an ozone generator was fitted with a gas dispersion tube and a stream of ozone was bubbled through the solution at −78° C. Once a pale blue color persisted in the solution, the ozone stream was removed and the solution was treated with dimethyl sulfide (13 mL, 186 mmol) and allowed to warm to ambient temperature over 30 min. The solution was concentrated to give a yellow residue that was subjected to high vacuum for 2 h. The resulting N-(2-oxoethyl)benzamide was used without further purification.