Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9].C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.O>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.27 g KOtBu was added to 109 mg 18-Krone-6 and 5 mL 4-fluoracetophenone in 150 mL THF. After 30 min at RT 10.7 g 4-fluoro-benzoic acid methyl ester was added and stirred for 3 h at RT. The reaction was decomposed with water and filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). The solvent was removed and 3.9 g of the desired compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:20].[OH-].[NH4+]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:20])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccnc3c(C#N)cnn23)c1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc(-c2ccnc3c(C(N)=O)cnn23)c1

Procedure:
A mixture of 7-(3-methylphenyl)pyrazolo[1,5-a]-pyrimidine-3-carbonitrile (prepared as described in Example 7 of U.S. Pat. No. 4,236,005) and concentrated sulfuric acid is stirred at room temperature for 16 hours. The solution is then carefully poured into ice with stirring and mixture is carefully made just basic with concentrated ammonium hydroxide. The solid is collected by filtration to give 7-(3-methylphenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=2[F:28])C(OCC)=O)=[CH:11][C:10]=1[CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[F:28][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=1[CH2:15][C:12]1[N:13]([CH3:14])[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:29])[CH:11]=1)[NH2:27]
Reactant: CCOC(=O)C(c1ccc(N)cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccccc1
Yield: 72.2 %

Procedure:
Ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(2-fluoro-4-aminophenyl)acetate (5.3 g, 13,4 mmol) [prepared as in Example 1, Step (c)] and 50% aqueous NaOH (5 ml) were dissolved in a 1:1 mixture of methanol/THF (100 ml), and the reaction mixture was refluxed for 30 min. After removing the solvents in vacuo, the residue was diluted with water and acidified with concentrated HCl. The product was extracted into ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was re-dissolved in DMF (200 ml) and refluxed for 30 min. The reaction mixture was cooled, poured into water/ice, and the product was extracted into ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. Evaporation of the solvent gave 3-fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (3.12 g, 69%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[C:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH2:18])[CH:14]=[C:13]([C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH2:28])[CH:12]=2)=[CH2:10])=[CH:5][CH:4]=1.C1COCC1.[H][H]>[Pd].CCO>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH:27]([C:13]2[CH:14]=[C:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH3:18])[CH:16]=[C:11]([CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:10])[CH:12]=2)[CH3:28])=[CH:34][CH:33]=1
Reactant: C=C(c1ccc(OC)cc1)c1cc(C(=C)c2ccc(OC)cc2)cc(C(=C)c2ccc(OC)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(C)c2cc(C(C)c3ccc(OC)cc3)cc(C(C)c3ccc(OC)cc3)c2)cc1

Procedure:
A mixture of 1,3,5-tris(1-(4-methoxyphenyl)vinyl)benzene (4) (19.61 g, 41 mmol), 5% Pd/C (500 mg), THF (50 mL) and EtOH (50 mL) was hydrogenated (50 torr) on a Parr® apparatus for 5 h. After this time the uptake of hydrogen ceased. The mixture was filtered through diatomaceous earth to remove the catalyst and rotary evaporated leaving the title compound as a colorless, viscous oil. Yield: 19.6 g (100%). 1H NMR (300 MHz, CDCl3, δ, ppm): 7.06 (d, J=8.7 Hz, 6H), 6.88-6.84 (m, 3H), 6.79 (d, J=8.9 Hz, 6H), 4.0 (q, J=7.5 Hz, 3H), 3.78 (s, 9H), 1.52 (d, J=7.3 Hz, 9H). 13C NMR (75 MHz, CDCl3, δ, ppm): 157.16, 145.83, 145.78, 145.74, 138.03, 137.99, 137.97, 127.55, 123.54, 123.46, 123.41, 113.36, 54.61, 42.94, 42.92, 21.29. Anal. calcd for C33H36O3: C, 82.46; H, 7.55. Found: C, 82.23; H, 7.40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Yield: 73.6 %

Procedure:
1-[5-(3-Bromo-4-fluorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.139 mmol, 43.6 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.139 mmol, 29.4 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (51.8 mg, yield 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH2:15])=[S:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH:18]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=O.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[S:14][C:18]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Reactant: NC(=S)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2nc(CNC(=O)OCc3ccccc3)sc2-c2cccnc2)cc1
Reaction time: 2 h
Yield: 60.3 %

Procedure:
In 40 ml of acetonitrile was dissolved 1.12 g of benzyloxycarbonylaminothioacetamide. In the solution was suspended 2.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added while stirring 0.8 ml of triethylamine. The mixture was stirred for 2 hours under reflux. The resultant was left standing for cooling, then the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and, then, the solvent was evaporated off. The residue was recrystallized from ethyl acetate-isopropylether to give 1.3 g (yield 56%) of 2-(benzyloxycarbonylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(CC)=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCCCCCBr
Reactant: Clc1ccc(CC2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCN1CCCC1Cc1ccc(Cl)cc1

Procedure:
Boil 5 g of 2-(4-chlorobenzyl)pyrrolidine, 3.53 g of anhydrous potassium carbonate, 4.6 g of 1-bromohexane and 50 ml of ethyl methyl ketone under reflux for 18 hours. Work up according to the procedure o Example 67 to obtain 5.82 g (81% of theory) of the title compound as a colorless liquid of b.p. 110° to 112° at 0.005 mm of Hg.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)ccc1OCC=C(C)C
Yield: 70 %

Procedure:
In a manner identical to Example 15, 2,5-diprenyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.40 g (70%) of the aimed compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:40])[NH:11][C:12]2[C:13]([CH3:39])=[C:14]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:23][CH:22]=4)=[C:18]([C:36]#[N:37])[CH:17]=[N:16][N:15]3[CH:38]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[CH3:45]CO>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:40])[N:11]([C:12]2[C:13]([CH3:39])=[C:14]3[C:19]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:25][CH:26]=4)=[C:18]([C:36]#[N:37])[CH:17]=[N:16][N:15]3[CH:38]=2)[CH3:45])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCO
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)OCCN4CCOCC4)c(C)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(N(C)C(=O)OCCN4CCOCC4)c(C)c23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a mixture of 432A (27 mg, 0.050 mmol) and CH3I (3.1 μl, 0.05 mmol) in THF (1 ml) was added NaH (1.5 mg, 0.06 mmol). The resulting mixture was stirred at rt for 2 h under argon. A drop of EtOH was added to quench the reaction. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5/30/65 MeOH/EtOAc/CH2Cl2) gave 432 (17.1 mg, 62%) as a yellow oil. It has a retention time of 5.70 min (standard LC1 method, 8 min run). MS Found: (M+H)+=557.1
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[OH:29][C:6]1[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:10](=[O:22])[N:11]2[CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Temperature: 25 °C
Yield: 13.1 %

Procedure:
A mixture of 5-hydroxy-2-oxo-3-phenyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (50 mg, 0.13 mmol), β-alanine (678 mg, 7.6 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration. The solid isolated was purified twice by silica gel chromatography (0-15% MeOH/CH2Cl2, then 5-70% EtOAc/hexanes+1% AcOH) to give 7.7 mg of the title compound as a light yellow solid. MS: (+) m/z 452.32 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH:11](=[N:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cc(N=Cc2ccccc2)c(F)cc1Cl
Yield: 94.5 %

Procedure:
A 50-ml four-neck flask equipped with a dehydrating column was charged with 5-amino-2-chloro-4-fluorophenol (1 g), benzaldehyde (0.68 g), p-toluenesulfonic acid (10 mg) and toluene (50 g). The mixture was dehydrated under reflux under normal pressure for 5 hours, and then concentrated under reduced pressure. The precipitated crystals were filtered and washed with a small amount of hexane to give 1.46 g of 5-benzylidenamino-2-chloro-4-fluorophenol as pale brown needle crystals (yield, 94.5%), m.p., 157°-159° C.; MS (m/z) 249 (M+) 172; NMR (CDCl3, δ): 5.1-5.8 (broad, 1H), 6.83 (d, 1H, J=7.6 Hz), 7.15 (d, 1H, J=9.6 Hz), 7.4-7.6 (m, 3H), 7.8-8.0 (m, 2H), 8.47 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]=[N+:27]=[N-:28])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(N)C>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]=[N+:27]=[N-:28])(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(S(=O)(=O)N=[N+]=[N-])cc2)cc1
Agent: CCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(Oc2ccc(CCN)cc2)cc1
Yield: 271.6 %

Procedure:
Dissolve the mixture of {2-[4-(4-azidosulfonylphenoxy)phenyl]ethyl}carbamic acid tert-butyl ester (0.291 g, 0.695 mmol) in dichloromethane (12 mL). Add TFA (12 mL) and stir at room temperature for 5 hours. Concentrate the reaction mixture. Load the product onto an SCX column with methanol. Wash the column with methanol then elute with 50% (2.0 M NH3 in methanol) in methanol to give a mixture of 2-4-(4-fluorobenzenesulfonyl)oxyphenyl)ethylamine and the title compound (0.601 g, 98.5%): MS ES+ 336.9 (M+H+18(NH4))+; TLC [silica gel 60 F254, 30% ethyl acetate, 5% (2.0 M NH3 in methanol and 65% hexanes] Rf=0.034.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:21][O:20][C:5]1[C:6]2[N:7]=[C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])[S:9][C:10]=2[C:2]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(Br)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(-c2ccncc2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 6 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid (4-methoxy-7-pyridin-4-yl-benzothiazol-2-yl)-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-bromo-4-methoxy-benzothiazol-2-yl)-amide (192 mg, 0.50 mmol) and 4-pyridylboronic acid (92 mg, 0.75 mmol) using the general procedure A as a white solid in 6% yield. MS: m/e=381 (M+).
Reaction SMILES: NN.CC([N:7]([CH2:11][CH2:12][CH:13]([N:20]1C(=O)C2C(=CC=CC=2)C1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](=[O:10])[O-:9])(C)C>C1COCC1.CO>[NH2:20][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][CH2:11][NH:7][C:8](=[O:10])[O:9][C:14]([CH3:19])([CH3:15])[CH3:13]
Reactant: CC(C)(C)N(CCC(c1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 151.8 %

Procedure:
NH2NH2 (1.8 mL, 57.7 mmol) was added to a THF/MeOH (1:1, 30 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate (2.2 g, 5.79 mmol) and stirred at 50° C. in a sealed system. After 12 hours, the solids were filtered, washing with methanol. The filtrate was concentrated and purified by column chromatography using 5% MeOH in CHCl3 containing 1% NH4OH to give the title compound (1.1 g, 76%) as a white solid: LC-MS (ES) m/z=251 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCCCO
Product: O=C(NCCCO)c1cc2ccccc2[nH]1
Yield: 80 %

Procedure:
1H Indole-2-carboxylic acid (5.0 g, 31 mmol) and 3-amino-1-propanol (2.2 ml, 40.3 mmol) were coupled according to the procedure of Example 17 to 5.46 g (80% yield) of an off-white solid. MP 152-156° C.; 1H NMR (DMSO-d6): δ1.6-1.7 (m, CH2), 3.31-3.37 (q, CH2), 3.41-3.51 (q, CH2), 4.52 (t, NH), 7.0-7.19 (m, 3 Ar H), 7.40 (d, 1 Ar H), 7.58 (d, 1 Ar H), 8.46 (t, NH), 11.9 (s, NH) Electrospray Mass Spec: m/z 217.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH2:14][C:15]1[N:19]=[CH:18][O:17][N:16]=1.O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH2:14][C:15]1[N:19]=[CH:18][O:17][N:16]=1)(=[O:4])=[O:3]
Reactant: Nc1ccccc1SCc1ncon1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccccc1SCc1ncon1

Procedure:
Methanesulphonyl chloride (1.39 g) was added dropwise to a cooled solution of 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (3.1 g) in pyridine (12 ml). The reaction mixture was then poured into water (75 ml) the so formed solid removed by filtration and crystallised from ethanol to give 3-(2-methylsulphonamidophenylthiomethyl)-1,2,4-oxadiazole, m.p. 106°.
Reaction SMILES: C1(=O)[O:6][C:4](=[O:5])C=C1.N[C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[CH:19]/[C:20]([NH2:22])=[O:21])/[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[C:4]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[CH:19]/[C:20]([NH2:22])=[O:21])/[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([OH:6])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: NC(=O)/C=C(\C(=O)O)c1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)/C=C(\C(=O)O)c1ccc(C(=O)O)cc1
Yield: 99 %

Procedure:
To a mixture of maleic anhydride (5.0 g. 50.9 mmol) in chloroform (100 ml) was added p-aminophenyl maleamic acid (6.99 g, 50.9 mmol). The resulting mixture was heated to reflux for 3 h. The solution was then cooled and a precipitate formed. The precipitate was filtered, washed with ethyl acetate and dried, to give 2N-(4-carboxyphenyl)maleamic acid (99%) as a solid.14 mp: 218-220° C. 1H NMR (DMSO-d6): δ 6.30 (d, J=12.0 Hz, 1H), 6.47 (d, J=1.20 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 10.59 (s, 1H), 12.83 (brs, 1H); HRMS (m/z): [M−H]− calcd for C11H8NO5, 234.0408; found, 234.0406.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>>[OH:15][CH2:14][C:13]([NH:12][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1cccnc1
Product: CC(C)(CO)NC(=O)c1cccnc1

Procedure:
100 g (0.66 mol) Ethyl nicotinate and 88g (0.99 mol) 2-amino-2-methyl-1-propanol were mixed and heated together under reflux for 2 hours. The excess amino alcohol was removed by distillation, bp 50°-60° (1 mm). The yellow residue was recrystallized from ether-acetone to give 87.3 g (0.45 mol), 68%, N-(1-hydroxy-2-methyl-2-propyl) nicotinamide, mp 91°-93°; ir (KBr) 3385, 3200, 1665, and 1590 cm-1 ; pmr (CDCl3) δ 8.8 - 7.3 (m, 4H), 6.7 (bs, 1H), 5.0 (s, 1H), 3.7 (s, 2H) and 1.4 (s, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:40]=[C:34]6[CH2:35][N:36]([CH3:39])[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+].O>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:40]=[C:34]6[CH2:35][N:36]([CH3:39])[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4CO)cn(C)c3=O)cc2C1
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a solution of 135b (280 g, 0.49 mmol) in MeOH (50 mL) was added NaBH4 (56 g, 1.47 mmol) at room temperature. After the reaction was stirred for 3 h, LCMS indicated the reaction was completed. Then the mixture was poured into H2O (50 mL) and extracted with DCM (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 135 (187 mg, 67%) as a white solid. MS: [M+H]+ 572. 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=5.5, 1H), 7.95 (d, J=2.0, 1H), 7.70 (d, J=2.0, 1H), 7.42 (s, 1H), 7.35 (d, J=5.5, 1H), 5.70 (s, 1H), 4.96 (t, J=7.0, 1H), 4.62 (s, 1H), 4.45 (s, 1H), 4.33 (s, 1H), 4.07-4.12 (m, 4H), 3.84 (s, 1H), 3.70 (s, 3H), 3.60 (s, 2H), 2.88 (t, J=5.5, 2H), 2.61 (s, 2H), 2.57 (s, 2H), 2.48 (s, 3H), 1.86-1.90 (m, 2H), 1.77 (s, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCOCC2)cc1
Yield: 47.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(morpholinomethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), morpholine (0.081 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.038 g (47%) of the title compound as a white solid.