Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(O)[C:5](=CC=1)[OH:6].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+].S(OC)([O:22][CH3:23])(=O)=O>O>[CH3:5][O:6][C:12]1[CH:11]=[C:10]([CH3:16])[CH:15]=[CH:14][C:13]=1[O:22][CH3:23]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(O)c(O)c1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C)cc1OC

Procedure:
In a 1 L, 3-necked flask was placed 500.0 g of 4-methylcatechol (4.03 mole, 1.0 eq.), 808 mL of toluene (5 mole/L) and 404 mL of water (10 mole/L). The flask was fitted with an overhead mechanical stirrer, thermocouple probe and a dropping funnel. The dropping funnel was charged with 357.1 g of sodium hydroxide (8.86 mole, 2.2 eq.) dissolved in 748 mL of water (11.8 mole/L). Dimethyl sulfate (838 mL, 8.87 mole, 1.1 eq.) was added to the flask. The contents of the flask were stirred well and the sodium hydroxide solution was added slowly to the flask. The temperature of the reaction rose to 35° C., at which point the addition of sodium hydroxide was slowed, such that the temperature did not exceed 35° C. External cooling by means of a chilled water bath applied. After the addition of sodium hydroxide was complete, the flask was removed from the chilled water bath and stirred until the temperature of the mixture returned to room temperature (~1.5 hours). Stirring was stopped. The phases were separated. The aqueous phase was extracted with fresh toluene (150 mL). The combined organic phases were dried over anhydrous potassium carbonate, filtered and concentrated by fraction distillation at atmospheric pressure. The crude product was purified by vacuum fractional distillation to provide a total of 559.6 g of the desired product.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N+:16]([O-])=[C:17](N)[N:18]=[N+:19]([O-])[C:14]=2[CH:13]=1)[CH:9]=[CH2:10]>CN(C=O)C>[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[CH:17][N:18]=[N:19][C:14]=2[CH:13]=1)[CH:9]=[CH2:10]
Reactant: C=CCOc1ccc2c(c1)[n+]([O-])nc(N)[n+]2[O-]
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2ncnnc2c1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) in DMF (15 ml) at 60°-65° C. was added 7-allyloxy-3-amino-1,2,4-benzotriazine-1,4-dioxide 23 (205 mg, 0.875 mmol) in small portions over 5 min. After 30 min additional t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) was added, and shortly thereafter the deep red solution effervesced and lightened appreciably in color over a period of a few minutes. After an additional 30 min the resultant orange solution was reduced under vacuum to a brown solid which was sequentially flash chromatographed (10% EtOAc/CH2CL2) and crystallized (CH2Cl2 /petroleum ether) to give 72 mg (38% yield) of the product 24 as light orange crystals, m.p 147°-148° C. NMR: δ (400 MHz, d6 -acetone) 4.89 (2H, ddd, H-1', J1 '2 '=5.5, J1 '.3 'cis =J1 '.3 'trans =1.5 Hz), 5.36(1 H, ddd, H-3', J3 '.2 'cis =10.5, J3 '.3 '=1.5 Hz), 5.52 (1 H, ddd, H-3', J3 '.2 'trans =17.5, J3 '.3 '=3, J3 '1 '=1.5 Hz), 6.14 (1 H, ddd, H-2', J2 ',3 'cis =10.5, J2 '.1 '-5.5 Hz), 7.70 (1 H, d, H-8, J8.6 =2.5 Hz), 7.74 (1 H, dd, H-6, J6.5 =9.5, J6.8 -2.5 Hz), 8.33 (1 H, d, H-5, J5.6 =9.5 Hz), 8.93 (1 H,s, H-3). UV: λmax 425, 410, 365, 355, 320, 245, 200. MS m/z (relative intensity) 220(4), 219(34 M+), 103(4), 77(4), 75(4), 63(13), 62(4), 42(3), 41(100), 39(16). Anal. Calc'd. for C10H9N3O3 : C, 54.79; H, 4.14; N, 19.17. Found: C, 54.73; H, 4.16; N, 9.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[CH:19]=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:19]([OH:20])[CH3:25])[CH:21]=[CH:22][CH:23]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
0.085 g (0.26 mmol) of 3-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde is dissolved in 8 ml of tetrahydrofuran under a stream of nitrogen. The medium is cooled to 5° C. before slow addition of 0.30 ml (0.90 mmol) of a methylmagnesium bromide solution (3M in ethyl ether). The medium is subsequently stirred at ambient temperature for 2 hours. Neutralization is carried out by adding, under cold conditions and dropwise, a saturated aqueous ammonium chloride solution and then dilution is carried out with ethyl acetate and water. The organic phase is separated and then the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified by chromatography on silica gel (by solid deposit), elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2). 0.048 g (53%) of the expected product is obtained in the form of a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:29][C:28]=5[CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.C(O)C>[Pt].[C].C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:29][C:28]=5[CH:27]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: O=C(c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Temperature: 25 °C

Procedure:
[4-(5-nitropyridin-2-yloxy)phenyl](4-piperonylpiperazin-1-yl)methanone (0.36 g, 0.78 mmol) was dissolved in a mixed solvent consisting of ethanol (5 mL) and THF (5 mL). To the resulting solution was added 5% platinum-carbon (0.06 g), and stirred at room temperature under a hydrogen atmosphere. Two hours later, the 5% platinum-carbon was removed by filtration, and the solvent was evaporated under reduced pressure, to thereby yield 0.32 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][CH:25]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:27]3[CH2:28][CH2:29][C:30](=[O:31])[CH:25]([CH3:24])[CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC1CNCCC1=O
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CC1CN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CCC1=O
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3-methylpiperidin-4-one (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-55% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (34 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.57 Hz, 3H) 1.46 (s, 6H) 2.74-2.97 (m, 2H) 3.30 (t, J=11.87 Hz, 1H) 3.57-3.69 (m, 1H) 4.56-4.70 (m, 2H) 6.38 (d, J=2.27 Hz, 1H) 7.48 (s, 1H) 7.60 (d, J=8.59 Hz, 2H) 8.00 (d, J=8.59 Hz, 2H) 8.13 (d, J=2.27 Hz, 1H) 10.93 (s, 1H). ESI-MS: m/z 408.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][C:29]([OH:34])([C:32]#[CH:33])[CH2:30][OH:31].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:33]#[C:32][C:29]([OH:34])([CH3:28])[CH2:30][OH:31])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#CC(C)(O)CO
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1)CO
Yield: 47.1 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-10-(3,4-dihydroxy-3-methyl-but-1-ynyl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 30 mg of the titled compound (47.1% yield). M+1=453.0.
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.COCC(O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.S(=O)(=O)(O)O.OC=CC1C=CC=CC=1>C(OCC)(=O)C>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OC=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C=Cc1ccccc1
Solvent: COCC(C)O
Product: C=Cc1ccc(O)cc1

Procedure:
A solution was prepared by dissolving 100 parts by weight, as the total amount, of p-t-butoxystyrene and styrene (molar ratio was p-t-butoxystyrene:styrene=80:20) in 150 parts by weight of propylene glycol monomethyl ether. This solution was kept under a nitrogen atmosphere at 70° C. for 10 hr with 4 parts by weight of azobisisobutyronitrile supplied to proceed polymerization. Then, sulfuric acid was added to the reaction solution, and the resultant solution was kept at 90° C. for 10 hr to covert the p-t-butoxystyrene unit into a hydroxystyrene unit through deprotection. Ethyl acetate was added to the obtained copolymer, the resultant solution was washed with water 5 times, the ethyl acetate phase was collected, and the solvent was removed to obtain p-hydroxystyrene/styrene copolymer (hereinafter, referred as “alkali soluble resin (A-1)”).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Li])CCC.CI>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C(C)C(=O)O)ccc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Specifically, a solution of 2-(4-benzyloxy-3-methoxyphenyl) acetic acid 15.0 g, 55.1 mmoles) in dry THF (350 mL) was cooled to -78° C. under argon and treated dropwise with n-butyllithium (42 mL, 2.6M in hexanes). The yellow suspension was then allowed to warm to -10° C. and stirred for 60 minutes. A solution of methyl iodide (3.9 mL, 62.6 mmoles) in THF (15 mL total solution) was then added dropwise via syringe over 30 min resulting in a now homogeneous and clear solution. After 2 hours the THF was rotary evaporated and the residue was dissolved in ethyl acetate (500 mL), extracted with 10% phosphoric acid (3×100 mL), extracted with brine (1×100 mL) and dried over magnesium sulfate. Rotary evaporation afforded a yellow oil which solidified on standing. The solid was triturated with n-pentane and filtered to give 2-(4-benzyloxy-3-methoxyphenyl)propionic acid (14.0 g, 89%) as a yellow powder.
Reaction SMILES: O.[NH2:2][NH2:3].CS[C:6]([S:33][CH3:34])=[CH:7][C:8]([C:10]1[N:26](C2CCCCO2)[C:13]2=[CH:14][C:15]3[C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=3[CH:20]=[C:12]2[N:11]=1)=O>C(#N)C>[CH2:21]([N:18]1[C:19]2[CH:20]=[C:12]3[N:11]=[C:10]([C:8]4[CH:7]=[C:6]([S:33][CH3:34])[NH:3][N:2]=4)[NH:26][C:13]3=[CH:14][C:15]=2[C:16]([CH3:24])([CH3:25])[C:17]1=[O:23])[CH3:22]
Reactant: CCN1C(=O)C(C)(C)c2cc3c(cc21)nc(C(=O)C=C(SC)SC)n3C1CCCCO1
Reactant: NN
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4cc(SC)[nH]n4)nc3cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
Hydrazine monohydrate (0.92 g, 1.8 mmol) was added to a suspension of 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-1-(tetrahydro-pyran-2-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (0.68 g, 1.81 mmol) in acetonitrile (15 mL) and stirred for 24 h. After cooling to room temperature the precipitate was collected, washed with acetonitrile and ether to yield 0.5 g (81%) of a pale white powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:14])[CH2:7][C:8](=[S:13])[O:9][CH:10]([CH3:12])[CH3:11].[C:15](=O)([O-])[O-].[K+].[K+].CC(C)=O.CI>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:14])/[CH:7]=[C:8](/[O:9][CH:10]([CH3:11])[CH3:12])\[S:13][CH3:15]
Reactant: CC(C)OC(=S)CC(=O)c1ccco1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CS/C(=C\C(=O)c1ccco1)OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of isopropyl 3-(2-furyl)-3-oxopropanethioate (3.7 g, 17.5 mmol), potassium carbonate (7.3 g, 52.4 mmol) and acetone (15 mL) was heated under reflux for 1 hour. After cooling the mixture to 0° C., methyl iodide (2.17 mL, 34.9 mmol) was added thereto, followed by stirring at room temperature for 2 hours. After diluting the reaction solution with ethyl acetate, the insoluble matters were filtered off. The filtrate was concentrated, and then the residue was purified by silica gel column chromatography (elution solvent; ethyl acetate/hexane=1:1), to give the title compound (3.2 g, 81%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][O:13][C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17].[CH3:21][O:22][C:23](=[O:33])[C:24]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])[C:24](=[O:25])[C:26]1[CH:27]=[CH:28][C:29]([O:1][CH2:2][C:3]#[C:4][C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:12][O:13][C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[CH:30][CH:31]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCOc1ccc(C(=O)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A stirred solution of 2,2-dimethylbutanoic acid [2-(3-hydroxy-1-propynyl)-3-methylphenyl]methyl ester (1.05 g), 4-hydroxyphenylglyoxylic acid methyl ester (0.693 g) and triphenylphosphine (1.26 g) in tetrahydrofuran (30 mL) was cooled to 0° C., and a solution of diethyl azodicarboxylate (0.76 mL) in tetrahydrofuran (5 mL) was added over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour then at room temperature overnight. The solvent was evaporated and the residue triturated with diethyl ether to remove most of the triphenylphosphine oxide. The filtrate was concentrated in vacuo and the resulting oil was chromatographed over silica gel (10 g; diethyl ether-hexane; 1:19) to furnish 1.4 g of 4-[3-[2-[(2,2-dimethyl-1-oxobutoxy) methyl]-6-methylphenyl]-2-propynyloxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][CH2:41][O:40][CH3:39])[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCCN1CCNCC1
Product: COCCCN1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OC(C)C)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methoxy-propyl)-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51N4O3Cl2 [(M+H)+] 693.3333, observed 693.3334.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[C:11]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:22]2)=[C:10]1[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]=O>C(O)=O>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][CH3:35])=[CH:15][CH:16]=2)[C:11]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:22]2)=[C:10]1[CH3:34])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CCN2CCCC(CC3CCCCC3)C2)c2cc(N)ccc2n1C(=O)c1ccccc1
Reactant: C=O
Solvent: O=CO
Product: CNc1ccc2c(c1)c(CCN1CCCC(CC3CCCCC3)C1)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of the 1-benzoyl-3-[2-(3 -cyclohexylmethylpiperidino)ethyl]-5-amino-2-methylindole described above in Example 95 with formaldehyde and formic acid affords 1-benzoyl-3-[2-(3-cyclohexylmethylpiperidino)ethyl]-5-methylamino-2-methylindole.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: Nc1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc2ccccc12)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.8 g (0.02 mol) of 1-naphthylamine and 2.0 g (0.02 mol) of triethylamine in 50 ml tetrahydrofuran is added dropwise at 15-20° C. a solution of 4.4 g (0.02 mol) of 4-chloro-3-nitro-benzoic acid chloride in 20 ml tetrahydrofuran. The solution is stirred for 30 minutes at ambient temperature. Then the solvent is evaporated off and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are concentrated by evaporation, triturated with ether, suction filtered and dried.
Reaction SMILES: [O-]CC.[Na+].[C:5](=[O:18])([O:9][C@@H:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)OCC.[C:19]1([C@H:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH:22]1[CH:21]=[CH:20][C:19]([C@@H:25]2[N:26]([C:5]([O:9][C@@H:10]3[CH:15]4[CH2:14][CH2:13][N:12]([CH2:17][CH2:16]4)[CH2:11]3)=[O:18])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]2=3)=[CH:24][CH:23]=1
Reactant: CCOC(=O)O[C@H]1CN2CCC1CC2
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Yield: 12.1 %

Procedure:
In a mixture of 10 ml of toluene and 0.5 ml of DMF and in the presence of 0.21 g of sodium ethoxide, 1.00 g of ethyl (R)-quinuclidin-3-yl carbonate and 1.05 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline were stirred for 7 hours while evaporating the solvent, 20 ml of toluene and 20 ml of water were added thereto, and the thus obtained organic layer was washed with 20 ml of water and then mixed with 15 ml of 1 M hydrochloric acid aqueous solution. A 30 ml portion of EtOAc and 1 M sodium hydroxide aqueous solution were added to the obtained water layer. The thus obtained organic layer was dried with sodium sulfate, concentrated under a reduced pressure and then dried, and the thus obtained solid was purified by a silica gel column chromatography to obtain 0.22 g of solifenacin.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=[O:4].[H-].[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:10]1[C:9]2[CH:16]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[O:13][CH:12]([CH3:14])[C:11]1=[O:15])[CH3:20]
Reactant: CCI
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)C(C)Oc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 6-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.2 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.5 g) and ethyl iodide (1.8 g) and the mixture was stirred at room temperature for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:1 (v/v)] to give 4-ethyl-6-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.0 g).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]3[O:17][C@@:18]45[CH2:28][CH:27]=[CH:26][C:25]([CH3:30])([CH3:29])[C@@H:24]4[CH2:23][CH2:22][C@H:21]([CH3:31])[C@@:19]5([CH3:32])[CH2:20][C:13]=3[C:12]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:11][C:10]=2[C:9]1=[O:41])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Si:34]([O:33][C:12]1[C:13]2[CH2:20][C@:19]3([CH3:32])[C@@H:21]([CH3:31])[CH2:22][CH2:23][C@H:24]4[C:25]([CH3:30])([CH3:29])[CH:26]=[CH:27][CH2:28][C@@:18]34[O:17][C:14]=2[C:15]2[CH2:16][NH:8][C:9](=[O:41])[C:10]=2[CH:11]=1)([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]
Reactant: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a solution of Compound (40b) (115 mg, 0.20 mmol) in 10 ml of dry dichloromethane were added 50 μl (0.46 mmol) of anisole and 32 μl (0.42 mmol) of trifluoroacetic acid under ice-cooling, and the mixture stirred for 4 hours at room temperature and allowed to stand over night. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; n-hexane:ethyl acetate=3:2) to give 94 mg (98%) of Compound (41b).