Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[O:13]=[C:14](N1CCOC1=O)[CH2:15][CH2:16][CH:17]=O>>[CH3:1][C@H:2]1[C@@H:11]([N:12]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:13])[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3]1
Reactant: O=CCCC(=O)N1CCOC1=O
Reactant: C[C@@H]1CC2(CC[C@@H]1N)OCCO2
Product: C[C@@H]1CC2(CC[C@@H]1N1CCCC1=O)OCCO2
Yield: 77.6 %

Procedure:
Using the method in Example 167 and reagents cis-7-methyl-1,4-dioxa-spiro[4.5]dec-8-ylamine (Preparation 44) (2.3 g, 13.4 mmol) and 4-oxo-4-(2-oxo-oxazolidin-3-yl)-butyraldehyde (2.3 g, 13.43 mmol) yields 2.49 g (77%) of the title compound as a white solid. 1H NMR (CDCl3) δ 4.05-4.12 (m, 1H), 3.81-3.93 (m, 4H), 3.44 (t, 2H), 2.23-2.35 (m, 3H), 1.51-1.98 (m, 8H), 0.94 (d, 3H).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[K+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O.CN(C)C=O>[CH3:31][S:32]([C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2c(C(=O)CCN3CCN(c4ccccc4)CC3)ccc(O)c2N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)CCN2CCN(c3ccccc3)CC2)c2c1NC(=O)CC2

Procedure:
37.9 Grams of 8-hydroxy-5-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyril and 5.9 g of potassium hydroxide were dissolved in 400 ml of water and the solution was concentraed under a reduced pressure to obtain a residue. The residue was dissolved in 400 ml of dimethylformamide and the 12.0 g of methane-sulfonyl chloride was added dropwise to the solution under cooling condition. One hour after the addition either was added to the reaction mixture to obtain crystals. The crystals were collected by filtration and washed with acetone, then recrystallized from isopropanol to obtain 35.9 g of 8-methanesulfonyl-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril in light brown needle-like crystals. Melting point: 165°-167° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12]I>[OH-].[Na+]>[F:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2nc(S)sc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc2cccc(F)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a well-stirred solution of 7-fluoro-2-mercaptobenzothiazole (1.0 g, 5.4 mmol) in 10% aq. NaOH (10 mL) was added methyl iodide (2.14 g, 2.8 eq) dropwise, and the reaction mixture was stirred at rt for 30 min. A yellowish solid was collected by filtration, washed with cold water, and dissolved in ethyl acetate (50 mL). The EtOAc solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. 1H-NMR (CDCl3, 300 MHz): δ=7.66 (d, J=8.1 Hz, 1H), 7.40-7.33 (m, 1H), 7.04-6.97 (m, 1H), 2.80 (s, 3H).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:18][CH:17]=[CH:16]2)=[O:12].Cl>O.CS(C)=O>[C:24]([NH:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]([OH:6])=[O:12])=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc2c(NC(=O)c3ccccc3)nccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 230.9 %

Procedure:
To a stirred solution of 400 mg sodium chlorite and 80 mg sodium dihydrogen phosphate in 2.5 mL of water and 2.5 mL of dimethylsulfoxide in a cooling bath at room temperature was added dropwise a solution of 510 mg N-(6-formyl-1-isoquinolinyl)benzamide (1f) in 2.5 mL of dimethylsulfoxide. After 16 hours at room temperature a solution of 170 mg sodium chlorite in 0.5 mL of water and 1.0 mL of dimethylsulfoxide was added and stirred at room temperature for an additional 6 hours. Then 100 mL water was added, the pH adjusted to three using 2N hydrochloric acid and the resulting suspension was kept at 5° C. for 16 hours. The precipitate was collected to afford 450 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[CH:18][C:19]=1[NH2:20]>C1(C)C=CC=CC=1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[NH:20][C:19]2[CH:18]=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=2[N:13]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]c(-c3n[nH]c4ccc(Cl)cc34)nc2c1
Temperature: 100 °C

Procedure:
A flask was charged with 5-chloro-1H-indazole-3-carbaldehyde (1.0 equivalent) and 3,4-diaminotoluene (1.0 equivalent) in toluene and EtOH. The reaction mixture was heated to 100° C. for 18 hours. The solvent was then evaporated, and the residue was purified by reverse phase HPLC yielding a white solid. LC/MS (m/z) 283.1 (MH+), Rt 2.5 minutes.
Reaction SMILES: [N+:1]([C:4]1[C:9](F)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].Cl.[C:12]([N:22]1[CH2:27][CH2:26][NH:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>CS(C)=O>[N+:1]([C:4]1[C:9]([N:25]2[CH2:26][CH2:27][N:22]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:23][CH:24]2[C:28]([OH:30])=[O:29])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1cccnc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A mixture of 2.8 g. of 2-nitro-3-fluoropyridine, 5.0 g. of 4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, 25 ml. of triethylamine, and 90 ml. of dimethyl sulfoxide is heated at 55° with stirring for 11/2 hours, then allowed to stand at room temperature overnight. A similar workup to that described in Example 1 gives 4.5 g. of the title product as a viscous orange glass. Thin layer chromatographic analysis of this material shows one single spot.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.CCN(CC)CC.[Cl:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([C:30](Cl)=[O:31])[CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([C:30]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:31])[CH:25]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Yield: 59.8 %

Procedure:
To a stirred and cooled (0° C.) solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (7.15 g, 34.7 mmol) and Et3N (14.0 g, 138.8 mmol) in DCM (100 mL) was added 6-chloropyrimidine-4-carbonyl chloride (5.5 g, 34.7 mmol). After addition, the resulting mixture was stirred at 25° C. for 16 h, at which time LCMS showed the completion of the reaction. The solvent was evaporated and the residue purified by flash chromatography to give the (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (7.2 g, yield: 60%). LCMS (m/z): 347.0 [M+H]+
Reaction SMILES: F[C:2]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH:14][CH2:15][CH2:16][NH:17][NH2:18]>CO>[OH:14][CH2:15][CH2:16][N:17]1[C:2]2[C:11](=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[N:18]1
Reactant: NNCCO
Reactant: COC(=O)c1cccc(C=O)c1F
Solvent: CO
Product: COC(=O)c1cccc2cnn(CCO)c12
Yield: 64.6 %

Procedure:
A mixture of methyl 2-fluoro-3-formylbenzoate (3.6 g, 19.9 mmol) from Step C above and hydroxy ethyl hydrazine (1.5 g, 19.9 mmol) in MeOH (16 mL) was irradiated with microwaves at 150° C. for 1.5 h. The reaction mixture was cooled and partitioned between H2O and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate and then the combined organic extracts were dried (Na2SO4) filtered, concentrated and purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 1-(2-hydroxyethyl)-1H-indazole-7-carboxylate as a yellow solid (2.83 g, 65%): 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.5 Hz, 1H), 4.84 (t, J=5.0 Hz, 2H), 4.13-4.07 (m, 2H), 3.99 (s, 3H), 3.20-3.10 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9].[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([C:30](O)=[O:31])=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:2][NH:1][C:30]([C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:19])=[O:20])[CH:22]=1)=[O:31]
Reactant: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
A mixture of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (100 mg, 0.65 mmol), 1-(phenylsulfonyl)-1H-indole-3-carboxylic acid (196 mg, 0.65 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (319 mg, 0.84 mmol) and triethylamine (98 mg, 0.97 mmol) in anhydrous dichloromethane (10 mL) was stirred at room temperature for 15 hours. Then the mixture was filtered and the solid was washed with water (10 mL), methanol (10 mL) and dichloromethane (10 mL) in turns to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(phenylsulfonyl)-1H-indole-3-carboxamide as a white solid (78 mg, 28%). LRMS (M+H+) m/z: calcd 435.13. found 435.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[F:8][C:9]1[CH:34]=[CH:33][C:12]([O:13][CH2:14][C@@H:15]2[O:20][C@@H:19]([O:21][CH:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:23][CH2:24]Cl)[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:22]([O:21][C@H:19]2[CH2:18][CH2:17][CH2:16][C@H:15]([CH2:14][O:13][C:12]3[CH:33]=[CH:34][C:9]([F:8])=[CH:10][CH:11]=3)[O:20]2)[CH2:23][CH2:24][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:31][CH:30]=1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(OC[C@H]2CCC[C@H](OC(CCCl)c3ccc(F)cc3)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OC[C@H]2CCC[C@H](OC(CCn3ccnc3)c3ccc(F)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
A mixture of 56 mg of imidazole and 36 mg of 55% sodium hydride was stirred in 2 ml of dimethylformamide at 60°-70° C. for 30 minutes. The mixture was left to cool at room temperature, and then a solution of 218 mg of trans-6-(4-fluorophenoxymethyl)-2-[3-chloro-1-(4-fluorophenyl)propoxy]tetrahydropyran in 1 ml of dimethylformamide was added, and the mixture was heated, with stirring, at 80°-90° C. for 6 hours. At the end of this time, the mixture was treated and the product purified essentially as described in Example 34(b)(i), to give 110 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:18]([CH3:19])[CH2:17][NH:16][CH:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:18]([CH3:19])[CH2:17][N:16]([C:32](=[O:33])[CH2:31][O:30][C:28]4[S:29][C:25]([Cl:24])=[CH:26][CH:27]=4)[C@@H:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCC1NCC(C)N(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C(O)COc1ccc(Cl)s1
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)C(C)CN1C(=O)COc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 123 using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-6-methyl-piperazine-2-one, EXAMPLE 87, and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24. 1H NMR (CD3OD300 MHz) δ8.68 (s, 1H), 8.27 (d, 1H), 7.62 (m, 2H), 6.54 (d, 1H), 6.18 (m, 1H), 7.39 (d, 1H), 4.94 (m, 4H), 4.15 (m, 2H), 3.76 (m, 2H), 3.44 (s, 3H), 3.10 (m, 2H), 1.28 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([C:20]1[N:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:23]=[C:22]([CH:29]=O)[CH:21]=1)[CH2:18][CH3:19]>>[C:25]([N:24]1[C:20]([CH2:17][CH2:18][CH3:19])=[CH:21][C:22]([CH2:29][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)=[N:23]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Product: CCCc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1C(C)(C)C
Yield: 76.5 %

Procedure:
Compound 75 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B(O)O.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The title compound was prepared as described in Example 159 substituting 4-bromoaniline and (2-chloro-4-(trifluoromethyl)phenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[O:16][C:15]([NH:14][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]4)=[N:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(OC)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: COc1ccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)cc1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 10B for the product of Example 1H.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].[N+](=CC)=[N-]>ClCCl>[CH3:7][CH2:8][O:5][C:1]([CH:2]([OH:3])[CH3:4])=[O:6].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: CC(O)C(=O)O
Agent: CC=[N+]=[N-]
Agent: O=C(O)CO
Solvent: ClCCl
Product: CCOC(=O)C(C)O
Reaction time: 8 h
Yield: 172.4 %

Procedure:
130 g of a lactic acid/glycolic acid copolymer having a weight-average molecular weight of about 5,000 (lactic acid/glycolic acid=50/50 (mol %)) was dissolved in 1,900 ml of dichloromethane; this solution was stirred and cooled. While the solution was ice cooled, the above-described diazoethane solution was added dropwise, followed by stirring at room temperature for 2 hours. After the solution was kept standing overnight, the solvent was distilled off under reduced pressure; the residue was vacuum dried at room temperature to yield 131 g of the ethyl ester of lactic acid/glycolic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([CH:21]=1)[C:9]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)=[O:10])([O-])=O.O.NN>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([CH:21]=1)[C:9]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)=[O:10]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1cc([N+](=O)[O-])ccc1O
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Yield: 74.1 %

Procedure:
A suspension of 6 g of 5-nitro-2-hydroxy-N-(1H-indol-4-yl)-benzamide of Example 50, 600 ml of methanol and 15 ml of 64% hydrazine hydrate and 6 g of Raney nickel was refluxed for two hours and filtered. The filtrate was evaporated to dryness under pressure at 50° C. and the residue was taken up in a 1-1 mixture of chloroform and methanol. The mixture was filtered and the crystalline product was dried to obtain 4 g of 5-amino-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at >260° C.
Reaction SMILES: CO[C:3]([O:8][CH3:9])(OC)OC.C(O)(=O)C.[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:14]1([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]3[N:31]=[C:3]([O:8][CH3:9])[N:32]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)[C:27]=3[CH:26]=2)=[O:46])(=[O:22])=[O:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Tetramethoxymethane (0.250 g) is added to an acetic acid solution (3 ml) of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide (0.400 g), and the solution is stirred for two hours at 80° C. Methanol is added to the reaction solution, and precipitated crystals are collected. The crystals are washed in a mixture solvent of acetone (1 ml) and methanol (8 ml), separated through filtration, dried and thus, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole (0.280 g) is obtained. 1H-NMR (DMSO-d6, δ): 4.17 (3H, s), 5.33 (2H, s), 7.30 (2H, d, J=8.2 Hz), 7.35 (1H, t, J=7.4 Hz), 7.44 (2H, t, J=7.5 Hz), 7.50 (1H, d, J=8.4 Hz), 7.60-7.65 (6H, m), 7.68-7.72 (2H, m), 7.98-8.01 (2H, m), 8.05 (1H, d, J=1.5 Hz), 8.18 (1H, s), 12.50 (1H, s).
Reaction SMILES: NC(N)=O.[CH3:5][O:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=1[OH:21])(=[O:12])=[O:11].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([S:10]([NH:9][CH2:8][CH2:7][O:6][CH3:5])(=[O:12])=[O:11])[C:14]=1[OH:21])=[O:31]
Reactant: O=C=Nc1ccccc1Br
Reactant: COCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: COCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 72.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-(2-methoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (140 mg, 0.50 mmol) and 2-bromophenylisocyanate (119 mg, 0.60 mmol) were coupled to form the desired urea (174 mg, 72%). EI-MS (m/z) 476.0, 478.0, 479.9 (M−).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CCCCCC.CN(C=O)C>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:7]3[CH2:16][CH2:17][N:4]([CH3:3])[CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: CC1(c2ccncn2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (275 mg, 11.45 mmol) was washed with hexane and dried under vacuum. DMF (4 mL) was added, resulting in a suspension. 2,3,4,5-Tetrahydro-2-methyl-8-chloro-1H-pyrido[4,3-b]indole (500 mg, 2.27 mmol) dissolved in DMF (2 mL) was added dropwise and the reaction mixture stirred for 30 min. at RT. 4-(2-Methyl-oxiranyl)-pyrimidine (620 mg, 4.55 mmol) dissolved in DMF (2 mL) was added dropwise and the reaction mixture was stirred overnight at RT. The progress of reaction was monitored by TLC. The mixture was quenched with ice-cold water and the mixture extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (4×20 mL) followed by brine (1×20 mL), dried over sodium sulfate and the solvent evaporated under vacuum. The residue was washed with hexane and crystallized from ether:DCM and hexane. 1H NMR (CD3OD, oxalate salt) δ (ppm): 9.10 (s, 1H), 8.50 (d, 1H), 7.50 (d, 1H), 7.36 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 4.40 (m, 4H), 3.60 (m, 2H), 3.40 (m, 1H), 3.20 (m, 1H), 3.05 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:37])[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH:31]1([O:30][C:29]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), were added triethylamine (188 μl, 1.35 mmol) and cyclohexyl carbonochloridate (78 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(cyclohexyloxycarbonylamino)-2-phenylacetate (105 mg; 60% yield).
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.O1CCOCC1>[OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].[CH:23]1([NH:22][C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The N-hydroxy-5-norbornene-2,3-dicarboximide active ester of N-benzyloxycarbonyl DL-2-benzyloxycarbonyl DL-2-hydroxy-4-aminoburyric acid was prepared according to the procedure of M. Fujino, et al [Chem. Pharm. Bull. Japan, 22, 1857 (1974)]. To an ice cold solution of 0.40 g. of N-benzyloxycarbonyl-DL-2-hydroxy-4-aminoburyric acid and 0.32 g. of N-hydroxy-5-norbornene-2,3-dicarboximide in 3 ml. of tetrahydrofuran-dioxane (1:1 v/v), there was added, with stirring, 0.36 g. of N,N'-dicyclohexylcarbodiimide and 1 ml. of the above solvent mixture. The solution was stirred in the cold for 30 minutes and then at room temperature for 2 hours. The N,N'-dicyclohexylurea which formed in the above reaction was collected on a filter and washed with three 1-ml. portions of tetrahydrofuran-dioxane (1:1 v/v).