Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[C:13]1([CH3:21])[CH:18]=[CH:17][CH:16]=[C:15]([S:19]Cl)[CH:14]=1.C(Cl)(Cl)(Cl)[Cl:23]>>[C:13]1([CH3:21])[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH2:2][Cl:23])[CH:14]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cccc(SCl)c1
Product: Cc1ccc(S(=O)(=O)C(CCl)Sc2cccc(C)c2)cc1
Temperature: 44 °C
Yield: 27 %

Procedure:
p-Tolyl vinyl sulfone (27.3 g, 0.150 mole) was dissolved in 100 ml of reagent carbon tetrachloride to give a clear solution at 32° C. Addition of 27.3 g (0.172 mole) of m-toluenesulfenyl chloride gave a bright red solution. The exothermic reaction raised the temperature to 44° C. in ten minutes. The color faded to bright orange in 16 hours. Several weeks' standing at room temperature in a closed flask produced crystals. Filtration gave 19.5 g of crude product m.p. 80°-97°. Recrystallization from 50 ml of ethyl acetate-pentane (7:3) gave 13.8 g (27%) of pure product, m.p. 99.5°-100.5°.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[C:4]=2[CH:3]=1.[NH:24](C1C=CC=CC=1)C1C=CC=CC=1.C[C:38]1(C)[C:64]2[C:59](=[C:60](P(C3C=CC=CC=3)C3C=CC=CC=3)[CH:61]=[CH:62][CH:63]=2)O[C:40]2[C:41](P(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:42][CH:43]=[CH:44][C:39]1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[C:39]1([C:38](=[N:24][C:2]2[N:7]=[CH:6][C:5]3[N:8]=[CH:9][N:10]([CH:11]4[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]4)[C:4]=3[CH:3]=2)[C:64]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(n2cnc3cnc(Br)cc32)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCCC(n2cnc3cnc(N=C(c4ccccc4)c4ccccc4)cc32)C1
Temperature: 115 °C
Reaction time: 16 h
Yield: 519.1 %

Procedure:
To a solution of tert-butyl 3-(6-bromo-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.6 g, 1.58 mmol, 1.0 eq) in DMA (5 mL) were added Ph2NH (430 mg, 2.37 mmol, 1.5 eq), Pd3(dba)2 (87 mg, 0.095 mmol, 0.06 eq), Xantphos (91 mg, 0.16 mmol, 0.1 eq) and Cs2CO3 (0.8 g, 2.5 mmol, 1.6 eq) at rt under N2. The mixture was stirred at 115° C. for 16 h, cooled to rt and the solid was filtered off and washed with EtOAc (30 mL). The organic layer was washed with H2O (20 mL×2) and brine (10 mL), separated, dried (Na2SO4) and concentration in vacuo to afford a residue which was purified by silica gel column chromatography with EtOAc in PE (1/1 v/v) to give the title compound (0.4 g, 50%) as brown solid. 1H NMR (400 MHz, CDCl3) δ: 8.80 (s, 1H), 7.89 (s, 1H), 7.82 (d, 2H), 7.52-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.27-7.24 (m, 3H), 7.24-7.17 (m, 2H), 6.68 (s, 1H), 4.13-4.09 (m, 2H), 3.95-3.92 (m, 1H), 3.18-3.14 (m, 1H), 3.01-2.94 (m, 1H), 1.95-1.90 (m, 2H), 1.79-1.76 (m, 1H), 1.63-1.60 (m, 1H), 1.53 (s, 9H). ESI-MS (M+H+): 382.0.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([C@H:12]([OH:16])[CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH2:28].Cl>ClCCl>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH:28][C:9](=[O:11])[C@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C@H:12]([OH:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)O
Reactant: NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
(2R,3R)-2-Cyclohexylmethyl-3-hydroxyhexanoic acid (3.00 g, 13.1 mmol) is dissolved in 30 mL of anhydrous dichloromethane. EDC (2.77 g, 14.5 mmol) is added followed by 2-tetrahydropyranyloxyamine (3.08 g, 26.3 mmol). The reaction is stirred at 25° C. for 8 h and is then poured into 200 mL of 1 M hydrochloric acid. The mixture is extracted with two 250-mL portions of dichloromethane. The combined organics are then washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to afford (2R,3R)-2-cyclohexylmethyl-3-hydroxyhexanoic acid 2-tetrahydropyranyloxyamide as a foam (3.60 g, 84% yield).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[Cl:23][C:24]1[C:25]([CH3:33])=[N:26][NH:27][C:28]=1[C:29]([F:32])([F:31])[F:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:23][C:24]1[C:28]([C:29]([F:31])([F:30])[F:32])=[N:27][N:26]([CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:8]=[N:9][N:10]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[C:11]=3[CH:12]([CH3:14])[CH3:13])[C:3]2=[O:22])[C:25]=1[CH3:33]
Reactant: Cc1n[nH]c(C(F)(F)F)c1Cl
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C1CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 77.9 %

Procedure:
A mixture of 3-bromo-1-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.035 g, 0.095 mmol), 4-chloro-3-methyl-5-(trifluoromethyl)-1H-pyrazole (0.050 g, 0.27 mmol) and K2CO3 (0.050 g, 0.36 mmol) in DMF (0.8 mL) was stirred at 60° C. for 40 min. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.036 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 5.05 (dd, J=9.2, 6.0 Hz, 1H), 4.04 (m, 1H), 3.81 (m, 1H), 2.99 (heptet, J=6.8 Hz, 1H), 2.87 (m, 1H), 2.76 (m, 1H), 2.42 (s, 3H), 1.22 (d, J=7.2 Hz, 3H), 1.12 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C21H20Cl2F3N5O [M+H]+486.1. found 486.1.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].CCOC(C)=O.CCCCCC>ClCCl>[C:13]([O:12][C:11](=[O:17])[NH:10][CH2:9][CH2:8][CH2:7][O:6][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
11.6 g (1.3 eq.) imidazole were added to a solution of 23 g (1 eq.) tert-butyl 3-hydroxypropylcarbamate in 230 ml dichloromethane. The reaction solution was stirred for 10 min at room temperature and then cooled to 0° C. 21.79 g (1.1 eq.) TBDMSCl were added to this solution at 0° C. and on completion of the addition the mixture was stirred for 1 h at room temperature. The reaction course was monitored by thin-layer chromatography (30% EtOAc/hexane). Once the conversion was complete, the reaction mixture was filtered over celite and the filtrate mixed with 200 ml water and extracted with dichloromethane. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 32 g (84%) of product were obtained in the form of an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=O)[CH:11]=[CH2:12])=[N:7][CH:8]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]=O)=[N:26][CH:27]=1.C([N:32](CC)CC)C>C(O)C.O1CCCC1.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[NH:32][C:10]([CH:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:26][CH:27]=1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc(Cl)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Cl)cn3)[nH]2)nc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution (3 mL) of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (89.0 mg) in ethanol-tetrahydrofuran (1:1) were added 5-chloropyridine-2-carbaldehyde (86.5 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (8.2 mg) and triethylamine (17 μL), and the mixture was stirred with heating under reflux for 2 h After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. To a solution of the obtained residue (MS: 433 (M)) in acetic acid (2 mL) was added ammonium acetate (376 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (117 mg, yield 92%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:20])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Yield: 99 %

Procedure:
0.33 g (0.0015 mol) of 1-benzylpiperidine-4-carboxylic acid was dissolved in 5 ml of oxalyl chloride for 2 hrs. The excess oxalyl chloride was distilled off. The residue was taken up twice in toluene and concentrated each time. 0.355 g (99%) of 1-benzyl-piperidine-4-carboxylic acid chloride was obtained as a pale beige solid. This was dissolved in 20 ml of toluene, treated with 0.3 ml (0.00224 mol) of triethylamine and 0.184 g (0.00195 mol) of phenol and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ether/hexane (1:2.5→1:2) as the eluent. 0.315 g (71%) of phenyl 1-benzyl-piperidin-4-carboxylate was obtained as a yellow oil. MS: me/e=296 (C9H22NO2+).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>C1C=CC=CC=1.CCCCC>[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26]
Reactant: Cc1ccc(N=C=S)c(Cl)c1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCC
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1ccc(C)cc1Cl

Procedure:
Following a procedure similar to that described in Example 1 and using 2.3 g. sodium in 250 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 16 g. 2-chloro-4-methylphenyl isothiocyanate (b.p. 80°-82° C./0.3 mm.; prepared from 2-chloro-4-methylaniline) in 100 ml. dry acetone there was obtained 1-(2-chloro-4-methylphenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 78°-80° C. (from benzene-n-pentane); hydrochloride (23 g.), m.p. 138°-140° C. (from isopropyl alcohol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH3:29].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:29][CH:23]1[CH2:24][CH2:25][CH2:26][CH:27]([CH3:28])[N:22]1[CH2:21][CH2:20][CH2:19][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: C[C@@H]1CCC[C@H](C)N1CCCCl
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC1CCCC(C)N1CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 33.8 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-2,6-cis-dimethyl-piperidine (410 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (280 mg, 33.9%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.85 (d, 2H), 3.93 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.95 (t, 2H), 2.51-2.36 (m, 2H), 2.40 (s, 2H), 2.14-2.04 (m, 2H), 1.96 (s, 6H), 1.93-1.82 (m, 4H), 1.74-1.51 (m, 3H), 1.41-1.21 (m, 3H), 1.13 (d, 6H).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]2)[O:6][N:5]=1)([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=3[F:36])[N:24]=[CH:25][C:18]=12.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[F:36][C:27]1[CH:28]=[C:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH:30]=[CH:31][C:26]=1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([NH:15][CH:12]3[CH2:13][CH2:14][N:10]([CH2:9][C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:11]3)=[C:18]2[CH:25]=[N:24]1
Reactant: CC(C)c1noc(CN2CCC(N)C2)n1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1noc(CN2CCC(Nc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)C2)n1
Yield: 91.4 %

Procedure:
A mixture of 1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-ylamine (354 mg, 1.68 mmol), 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.53 mmol), and potassium carbonate (3.18 g, 23 mmol) in THF (20 mL) was refluxed for 2 hours. Water was added to the reaction mixture and the product was extracted with ethylacetate. The ethylacetate layer was dried over MgSO4. The organic layer was concentrated in vacuo to afford compound A133 as a white solid (700 mg, 91%). Exact mass calculated for C22H25FN8O3S 500.18, found 501.1 (MH+).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:23]([S:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:23]([S:28]([CH2:29][C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)=[O:6])=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1SCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1S(=O)Cc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of m-chloroperoxybenzoic acid (65%, 160 mg, 0.60 mmol) in chloroform (2 mL) was added to a solution of N-(4-chlorophenyl)-2-(4-pyridylmethylthio)pyridine-3-carboxamide (300 mg, 0.84 mmol, Compound No. 1-1) in chloroform (18 mL) under ice-cooling, then the mixture was stirred at room temperature for 2 hours. The precipitated solid in the reaction mixture was filtered off, and dried under reduced pressure to give 220 mg of the target compound as a pale yellow solid. (Yield 69%)
Reaction SMILES: CCO.[C:4]([OH:11])(=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])[CH2:13]2>CCOC(C)=O>[CH:36]1[CH:37]=[CH:38][C:33]([C@@H:24]2[N:23]([C:21]([O:20][C@@H:14]3[CH:15]4[CH2:16][CH2:17][N:12]([CH2:19][CH2:18]4)[CH2:13]3)=[O:22])[CH2:32][CH2:31][C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[CH:34][CH:35]=1.[CH2:5]([C:4]([OH:11])=[O:10])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2C1c1ccccc1
Agent: O=C(O)CCC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 50 °C

Procedure:
A 6 ml portion of EtOH, 14 ml of EtOAc and 1.30 g of succinic acid were added to the thus obtained (1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester, dissolved by heating and cooled to 50° C., and then 0.003 g of seed crystal of solifenacin succinate produced in the same manner as in Example 1A was added thereto. This mixture was cooled to 30° C., and then again heated to 50° C. This was kept at 50° C. for 2 hours and then cooled to 0° C. spending 5 hours, and the precipitated crystals were collected by filtration, washed twice with 10 ml of EtOAc and then dried under a reduced pressure to obtain 2.855 g of solifenacin succinate as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]COS(C4C=CC(C)=CC=4)(=O)=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3]1.[C-]#[N:39].[K+].[I-].[K+].CCO[C:46]([CH3:48])=O>CS(C)=O>[CH3:37][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:48][C:46]#[N:39])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:35])([CH3:36])[NH:3]1
Reactant: CCOC(C)=O
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCCC#N)cc3)n2)CC(C)(C)N1

Procedure:
A solution of toluene-4-sulfonic acid 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester (80 mg, 0.15 mmol), (Step A of Example 190), KCN (20 mg, 0.31 mmol) and a catalytic amount of potassium iodide in 2 ml DMSO was stirred for 2 hours at 100° C. The reaction mixture was diluted with EtOAc and washed with water. The crude product was purified using preparative TLC. Yield: 9 mg (16%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21]S(C1C=CC(C)=CC=1)(=O)=O.[CH3:32][O:33][C:34](=[O:53])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][C:38]=1[CH2:44][CH2:45][NH:46][C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:32][O:33][C:34](=[O:53])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:21][CH2:20][CH2:19][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:39][C:38]=1[CH2:44][CH2:45][NH:46][C:47]([O:49][CH:50]([CH3:51])[CH3:52])=[O:48]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1
Reactant: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1CCNC(=O)OC(C)C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[5-methyl-2-(4-morpholin-4-yl-phenyl)-oxazol-4-yl]-ethyl ester (44 mg, 0.10 mmol; Preparation 5) and 3-[4-hydroxy-2-(2-isopropoxycarbonylamino-ethyl)-phenyl]-propionic acid methyl ester (31 mg, 0.10 mmol) in DMF (1.0 mL) was treated with K2CO3 (30 mg). The resulting suspension was stirred at 65° C. for 16 h and diluted with water (10 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified using silica gel chromatography (50% EtOAc/hexanes to yield 3-(2-(2-isopropoxycarbonylamino-ethyl)-4-{2-[5-methyl-2-(4-morpholin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester.
Reaction SMILES: [C:1]1([CH3:46])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:13][CH:12]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([O:42]CC)=[O:41])[CH:35]=3)=[O:32])[C:11]2=[O:45])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:46])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[O:23])[CH2:13][CH:12]([NH:30][C:31](=[O:32])[NH:33][C:34]3[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=3)[C:40]([OH:42])=[O:41])[C:11]2=[O:45])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C3CCCCC3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)C1CCCCC1
Yield: 50.3 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (168 mg) solution (12 ml) and tetrahydrofuran (12 ml) were added, and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride (50ml). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and isoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 240 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 3-methoxypropan-1-ol (15.9 mL, 166 mmol) in CH2Cl2 (75 mL) and pyridine (50 mL) was added 4-(dimethylamino)pyridine (1.0 g, 8.3 mmol) followed by p-toluenesulfonyl chloride (31.7 g, 166 mmol). The mixture was allowed to stir at ambient temperature for 72 hours then was quenched with 5% aqueous HCl (20 mL), extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (31 g, 127 mmol, 76% yield). MS (DCI/NH3) m/z 262 (M+NH4)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.[NH2:32][C:33]1[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:34]=1[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:32][C:33]1[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:34]=1[C:35]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)=[O:36]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)c2cc(I)ccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a stirred solution of 15 g (74.4 mmol) of methyl 4-(aminomethyl)benzoate hydrochloride, 300 ml of dimethylformamide and 10.3 ml (7.53 g, 74.4 mmol) of triethylamine were added, at room temperature, followed by 10.06 g (74.4 mmol) of 1-hydroxybenzotriazole hydrate, 19.6 g (74.4 mmol) of 2-amino-5-iodobenzoic acid and 14.3 g (74.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride. After stirring at room temperature overnight, the mixture was concentrated and the residue was dissolved in 300 ml of dichloromethane. The organic phase was washed with 150 ml H2O, 150 ml HCl 1N, and 150 ml H2O, dried over sodium sulfate and concentrated. The residue was recrystallized from 170 ml acetonitrile to afford after filtration 19.6 g of the desired product (yield: 70%).