Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6]C(C#N)=[CH:8][CH:9]=2)[CH2:4][NH:3]1.BrCC1C=C(C#N)C=CC=1C(OC)=O.N.CC[O:30][C:31]([CH3:33])=[O:32]>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:33]([C:31]([OH:30])=[O:32])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: N#Cc1ccc2c(c1)CNC2=O
Reactant: CCOC(C)=O
Agent: COC(=O)c1ccc(C#N)cc1CBr
Agent: N
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CNC2=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
1-oxoisoindoline-5-carbonitrile. To methyl 2-(bromomethyl)-4-cyanobenzoate (0.3 g, 1.18 mmol) in a sealed tube, was added 7N NH3 in MeOH (10 mL). The tube was then sealed and the reaction stirred at 40° C. for 18 h. The reaction progress was monitored by TLC (90% EtOAc in hexanes). The reaction was filtered to give the title compound as a white solid. 1H NMR (400MHz, DMSO-d6): δ 8.95 (s, 1H), 8.1 (s, 1H), 7.9 (d, J=8.0 Hz, 1H), 7.8 (d, J=8.0 Hz, 1H), 4.4 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1.C(OC([NH:46][CH2:47][CH2:48][C:49](O)=[O:50])=O)(C)(C)C.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC>>[NH2:46][CH2:47][CH2:48][C:49]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1)=[O:50]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)CCN)cc3)ncnc2n1
Yield: 23 %

Procedure:
The product of Example 13E was reacted with 3-tert-Butoxycarbonylamino-propionic acid using the procedure of Example 70 substituting 3-tert-Butoxycarbonylamino-propionic acid for Boc-Abu-OH to provide the crude title compound which was purified by HPLC with TFA then neutralized with an aqueous sodium carbonate solution to provide the title compound (15 mg, 23%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J=6.62 Hz, 6 H) 2.41 (t, J=6.25 Hz, 2 H) 2.83 (t, J=6.25 Hz, 2 H) 3.20 (m, 1 H) 6.97 (d, J=8.46 Hz, 1 H) 7.39 (d, J=8.46 Hz, 2 H) 7.54 (m, 3 H) 7.70 (m, 5 H) 7.95 (s, 1 H) 8.47 (s, 1 H) 8.79 (d, J=8.09 Hz, 1 H) 10.32 (s, 1 H); MS (ESI+) m/z 656/658 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 88.8 %

Procedure:
6 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate, 150 ml of methanol, 30 ml of water and 2.2 g of potassium hydroxide are treated in the same manner as described in Example 8. 4.9 g of 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid are thereby obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].C(N(CC)C(C)C)(C)C.[CH3:59][CH:60]1[CH2:62][CH:61]1[C:63](O)=O>CN(C=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:63]([CH:61]5[CH2:62][CH:60]5[CH3:59])[N:48]([CH3:49])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:45][CH:44]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: CC1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CC1c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (235 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (200 mg), N,N-diisopropylethylamine (0.308 ml) and 2-methylcyclopropanecarboxylic acid (0.057 ml) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and concentrated in vacuo. The resulting solid was recrystallized from THF to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cccc(CO)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A solution of 43.00 g (0.18 mole) of 2-benzyloxy-3-methoxy-benzaldehyde of Example 1 in 300 mL of absolute ethanol is treated, with stirring, with 7.56 g (0.20 mole) of sodium borohydride. The temperature rises to 50° C. After one-half hour 10 mL of acetone is added, keeping the temperature at less than 60° C. with cooling. After 15 minutes the volatiles are stripped off at reduced pressure. Ice water (500 mL) is added and the product is extracted into 600 mL of ethyl acetate. The dried (NA2SO4) solution is concentrated. The remaining oil is dissolved in 100 mL of warm ether. Petroleum ether is added to turbidity to give 37.70 g (86% yield) of pure product; mp 58°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7](=[O:9])[CH3:8].[BH4-].[Na+]>CO.O.CC(O)=O>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH3:8]
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a mixture of 1-(2-methoxy-4-nitrophenoxy)propan-2-one (300 mg, 1.33 mmol) in 1.3 mL of MeOH and 1.3 mL of H2O at rt was added a solution of NaBH4 (53 mg, 1.40 mmol) in 0.5 mL of H2O dropwise over 5 min. The suspension was stirred at rt for 1 h and diluted with 0.2 mL of HOAc followed by 2 mL of H2O. The precipitate was filtered, washed with H2O and dried under vacuum to afford the title compound (270 mg) as a yellow solid. 1H NMR (CDCl3) δ 1.28 (d, J=6.05 Hz, 3H), 2.68, (s, 1H), 3.87-3.92 (m, 4H), 4.03-4.05 (m, 1H), 4.23-4.29 (m, 1H), 6.89 (d, J=9.35 Hz, 1H), 7.72 (d, J=2.20 Hz, 1H), 7.86 (dd, J=8.80 Hz, 2.75 Hz, 1H); 13C NMR (CDCl3) δ 18.66, 56.19, 65.90, 74.84, 106.73, 111.66, 117.60, 141.79, 149.21, 153.62; HPLC (Method # 1) 2.29 min retention time, (100%); LCMS (ES): m/z 228 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-bromophenyl)ethanol (3.48 mL, 24.87 mmol), p-toluenesulfonyl chloride (5.69 g, 29.8 mmol), and 4-(dimethylamino)pyridine (0.304 g, 2.487 mmol) in anhydrous dichloromethane (70 mL) was treated with triethylamine (6.93 mL, 49.7 mmol). The reaction stirred for 16 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10 to 20% ethyl acetate in hexanes, to give the title compound. MS ESI(+) m/z 356.9 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M111) (0.25 g, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (167 mg, 85%).
Reaction SMILES: CI.[C:3](=O)([O-])O.[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[C:21](=[O:25])[C:22]([OH:24])=[O:23]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[C:21](=[O:25])[C:22]([O:24][CH3:3])=[O:23]
Reactant: O=C([O-])O
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1cc(-n2cnnn2)ccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
Methyl iodide (1.87 ml, 4.26 g, 30 mmol) was added to a mixture of sodium hydrogen carbonate (2.52 g, 30 mmol), and 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoic acid (3.37 g, 13.6 mmol) in dimethylformamide (120 ml) and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added and mixture was extracted with ethyl acetate (4×100 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×100 ml), dried (MgSO4) and evaporated under reduced pressure to give methyl 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoate as an orange solid (3.36 g, 94%), 1H NMR (CDCl3) δ 9.02 (1H, s), 8.11 (1H, d, J=2.8 Hz), 8.03 (1H, dd, J=9.0, 2.8 Hz), 7.23 (1H, d, J=9.0 Hz), 3.99 (3H, s), and 3.96 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55](Cl)(=[O:57])=[O:56])=[C:50]([CH:59]([CH3:61])[CH3:60])[CH:49]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:56])=[O:57])=[C:50]([CH:59]([CH3:60])[CH3:61])[CH:49]=2)(=[O:40])=[O:41])=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)Cl)c(C(C)C)c2)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE 1.0 g, 2.71 mmol) and 2 mL of Et3N in 20 mL of CH2Cl2 was added 4-chlorosulfonyl-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester the (Intermediate 65, 1.6 g, 3.25 mmol, 1.2 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 2 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 68, 1.76 g, 79%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[CH:14]1(B(O)O)[CH2:16][CH2:15]1>ClCCl>[CH:14]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[C:7]([CH:12]=[O:13])=[CH:8]2)[CH2:16][CH2:15]1
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Reactant: OB(O)C1CC1
Solvent: ClCCl
Product: COc1ccc2c(C=O)cn(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
Dihydroxo-bis[N,N,N′,N′-tetramethylenediamine)copper (II) chloride (26 mg, 0.057 mmol) was added to a stirred room temperature mixture of 6-methoxy-1H-indole-3-carbaldehyde (100 mg, 0.568 mmol) and cyclopropylboronic acid (98 mg, 1.13 mmol) in dichloromethane (3 mL). Molecular sieves (4 A°, 100 mg) were added and the mixture was stirred under oxygen at room temperature for 48 hours. The reaction mixture was filtered over a pad of silica gel, washed with dichloromethane, partitioned between dichloromethane (10 mL) and 10% ammonium hydroxide (2×10 mL). The organic layer was washed with water (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 25 M), eluting with EtOAc/hexanes to give the title compound (50 mg) as a oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(Br)c1NC1CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-bromo-2-fluoro-3-nitrobenzene (4.1 g, 18.6 mmol) and cyclopropanamine (1.29 mL, 18.6 mmol) in THF (10 mL) was stirred under N2 at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water, filtered on a pad of Celite™, washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo. Purification of the residue by flash chromatography on a silica gel column using 30 to 50% gradient of DCM in hexane as eluent gave 2-bromo-N-cyclopropyl-6-nitroaniline: LC-MS (ESI) m/z 259.0 [M+H]+.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11]CC2CCC[N+]2(C(C2C=CON=2)C(=O)N)C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]C1.[Br-].OC[C@H]1CCC[N+]1(CC(=O)NC1C=CON=1)C.[Br-].[OH:54][CH:55]1[CH2:60][CH2:59][N+:58]([CH3:70])([CH2:61][CH2:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:57][CH2:56]1.C1(C(C2C=CC=CC=2)(O)C(O)=O)CCCC1>>[Br-:1].[CH:2]1([C@@:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:54][CH:55]2[CH2:56][CH2:57][N+:58]([CH3:70])([CH2:61][CH2:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH2:59][CH2:60]2)=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+]1(C(C(N)=O)c2ccon2)CCCC1COC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: C[N+]1(CCCc2ccccc2)CCC(O)CC1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Agent: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [Br-]
Product: C[N+]1(CCCc2ccccc2)CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,2R)-2-((R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-pyrrolidinium bromide (Example 1) by replacing (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate B) with 4-Hydroxy-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (Intermediate K) and by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:20])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1.C=O.[C:23](=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(#N)C.O.C(O)(=O)C>[CH3:2][O:3][C:4](=[O:20])[CH2:5][CH2:6][N:7]([CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1)[CH3:23]
Reactant: O=C([O-])O
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)CCN(C)CCC1COc2ccccc2C1

Procedure:
3.0 g (0.01 mol) of 3-{N-[2-(chroman-3-yl)ethyl]amino}propionic acid methyl ester hydrochloride are suspended with stirring in 30 ml of acetonitrile, and 4.0 ml (0.05 mol) of 37% formaldehyde in water are added thereto. 0.84 g (0.01 mol) of sodium hydrogen carbonate is then added and stirring is continued, yielding a clear solution. 1.0 g of sodium cyanoborohydride is added in portions to the solution and the pH of the suspension is then adjusted to 7 by the dropwise addition of glacial acetic acid. The reaction mixture is then stirred for 1 hour at room temperature, the solvent is distilled off under reduced pressure and the oily residue is partitioned between 50 ml of diethyl ether and 15 ml of N sodium hydrogen carbonate solution. The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation. Purification by chromatography on a silica gel column (diameter 2 cm, length 30 cm, Kieselgel® Merck 60) with toluene/ethanol (9:1 parts by volume) yields 3-{N-[2-(chroman-3-yl)ethyl]-N-methylamino}-propionic acid methyl ester in the form of an oil. 3-{N-[2-(chroman-3-yl)ethyl]-N-methylamino}-propionic acid hydrochloride having a melting point of 169°-170° is obtained from the latter in a manner analogous to that described in Example 1 by heating with 20 ml of 4N hydrochloric acid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Br.[OH-].[Na+]>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[N:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccnc(N3CCN(C)CC3)c2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2nccc3ccc(O)cc23)CC1
Yield: 89.5 %

Procedure:
A mixture of 795 mg of 7-methoxy-(4-methylpiperazin-1-yl)-isoquinoline and 8 ml of 47% aqueous hydrobromic acid solution was heated under reflux for 2.5 hours. After cooling, the solution was neutralized with 20% aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (saturated ammonia water:methanol:chloroform=1:10:90) to provide 673 mg (80%) of 7-hydroxy-1-(4-methylpiperazin-1-yl)isoquinoline.
Reaction SMILES: COC(=O)C.C[O:7][C:8](=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH3:19].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=1>CN(C=O)C>[CH3:50][S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[C:10]([CH2:9][C:8]([OH:7])=[O:20])=[C:11]2[CH3:19])=[CH:42][C:43]=1[C:51]([F:52])([F:54])[F:53])(=[O:49])=[O:48]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: COC(C)=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methanesulfonyl-3-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (200 ml) under an inert atmosphere of Argon is added dropwise, BEMP (19.9 ml, 69.1 mmol) over five minutes. After stirring at room temperature for 1 hour, the resulting solution is added dropwise to a stirred solution of 1-bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene (23.9 g, 75.4 mmol) and stirred for 18 hours. The reaction is concentrated in vacuo with toluene and the resulting oil is purified by chromatography on silica eluting with iso-hexane/acetone (15:1). The crude is further purified by dissolving in hot ethyl acetate and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the solvent is removed in vacuo. The resulting solid is re-crystallized from ethyl acetate/iso-hexane to yield the titled product as a white solid. (MH+441).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH2:6])=[S:5].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=O>C(O)C>[Cl:7][CH2:8][C:9]1[N:6]=[C:4]([CH2:3][O:2][CH3:1])[S:5][CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: COCC(N)=S
Solvent: CCO
Product: COCc1nc(CCl)cs1

Procedure:
A solution of 9 g of 2-methoxy-thioacetamide and 10.87 g 1,3-dichloroacetone in 90 ml ethanol was refluxed for 2 h. The solvent was evaporated and the residue neutralized with saturated sodium bicarbonate solution. After extraction with ether the organic phase was washed twice with water and dried over sodium sulfate. Evaporation of the solvent left 13.0 g crude product.