Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC(Br)[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[Cl-].[Li+].C(OCC)C.[CH2:33]([Cl:35])[Cl:34]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][CH:33]([Cl:35])[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)Br)c3c2)c1=O
Reactant: ClCCl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Cl)Cl)c3c2)c1=O

Procedure:
A solution of 3-[3-(dibromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.750 g, 0.00150 mol) and lithium chloride (0.950 g, 0.0225 mol) in N,N-dimethylformamide is stirred at room temperature for 48 hours and diluted with ethyl acetate. The resultant mixture is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a foam. Column chromatography of the foam using silica gel, methylene chloride, and a 1% diethyl ether in methylene chloride solution gives the title product as a white foam (0.530 g, mp 148-149° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-:16].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH3:25]>C(#N)C>[CH2:22]([N:12]1[CH2:13][CH2:14][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])([OH:16])[CH2:10][CH2:11]1)[CH2:23][CH2:24][CH3:25]
Reactant: O=C([O-])[O-]
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Reactant: CCCCBr
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidine (0.02 g, 0.081 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), bromobutane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 303 (M+, 2), 302 (M+, 4), 260 (65), 258 (bp), 242 (18), 240 (27).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[O:33][C:34]=1[CH3:35].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl]-1H-pyrazol-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 58.0 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 4-Chloromethyl-5-methyl-2-(2-thienyl)oxazole (310 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-methoxy-4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (500 mg, yield: 66%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:31])[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CCCCCC.C(OCC)(=O)C.[OH-].[K+]>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH:20]=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:31])[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)C[C@H]1[C@H](C=C(C(=O)O)C(C)C)OC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
199 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoate was dissolved in 1.16 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide, and the mixture was stirred overnight at room temperature. The mixture was cooled to 0° C. and adjusted to pH 2 with 1N hydrochloric acid, and then 12 ml of water was added thereto. The mixture was extracted 3 times with 10 ml of ethyl acetate. The organic solvent layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoic acid as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: CC(C)c1cccc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reaction time: 18 h
Yield: 67 %

Procedure:
To 3-bromo-4-nitro-1H-indazole (4.91 g, 20.3 mmol) in DMF (50 mL) was added 2-(chloromethyl)-6-isopropylpyridine hydrochloride (4.18 g, 20.3 mmol) and K2CO3 (8.41 g, 60.8 mmol). The reaction mixture was stirred for 18 hours. Solvent was removed under reduced pressure. The residue was diluted with EtOAc (100 mL). The resulting suspension was washed with water and brine. The combined organic extracts were dried (Na2SO4), filtered and purified by silica gel flash chromatography (1:2 EtOAc/hexanes) to give the desired product (67%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][P:5]1(=[O:10])[O:9]C[CH2:7][O:6]1.[CH3:11][N:12]([CH3:14])[CH3:13].[C:15](#N)C>>[OH-:4].[NH2:1][CH2:2][CH2:3][O:4][P:5]([OH:10])([O:6][CH2:7][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])=[O:9]
Reactant: CN(C)C
Reactant: CC#N
Reactant: NCCOP1(=O)OCCO1
Product: C[N+](C)(C)CCOP(=O)(O)OCCN
Product: [OH-]
Temperature: 25 °C

Procedure:
2-(2-aminoethoxy)-2-oxo-1,3,2-dioxaphospholane was dissolved in acetonitrile (20 ml) and added to trimethylamine (14.3 ml) in a glass pressure bottle stored in liquid nitrogen. The pressure bottle was closed, allowed to warm to ambient temperature over 0.5 hour and was then warmed to 60° C. for 16 hours. A pale yellow gum was deposited during this time. Excess trimethylamine was bubbled off and the supernatant decanted. The gum was dissolved in methanol, preabsorbed onto silica gel and purified by chromatography on silica gel eluting with methanol and methanol/25% aqueous ammonia mixtures. 2-[(2-Aminoethoxyhydroxyphosphinyl)oxy]-N,N,N-trimethylethanaminium hydroxide, inner salt was obtained as a pale yellow foam.
Reaction SMILES: [O:1]=[C:2]([NH:17][CH:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[CH2:29](N1CCCC(N)C1)C1C=CC=CC=1.C(N1CC[C@@H](N)C1)C1C=CC=CC=1>>[O:1]=[C:2]([NH:17][CH:18]1[CH2:22][CH2:21][CH2:29][N:20]([CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CCN(C2CCOCC2)C1
Reactant: NC1CCCN(Cc2ccccc2)C1
Agent: N[C@@H]1CCN(Cc2ccccc2)C1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CCCN(C2CCOCC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-(2-oxo-2-{[1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide whereby 1-benzylpiperidin-3-amine was substituted for (3R)-1-benzylpyrrolidin-3-amine as was isolated as a white solid.
Reaction SMILES: C([Li])CCC.CN(C)[CH2:8][CH2:9][N:10](C)[CH2:11][CH2:12]N(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C(C1C=CN=CC=1)#N.C1C[O:37][CH2:36][CH2:35]1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:36]([C:35]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:37]
Reactant: Fc1ccc(F)cc1
Reactant: CN(C)CCN(C)CCN(C)C
Reactant: C1CCOC1
Agent: N#Cc1ccncc1
Agent: [Li]CCCC
Product: O=C(c1ccncc1)c1cc(F)ccc1F
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 51.5 %

Procedure:
Butyl lithium (70 ml of 2.22M solution, 155 mmole) was added to a solution of pentamethyldiethylenetriamine (23.3 ml, 155 mmole) in THF (250 ml) at -70° C. The solution was stirred for 5 min and 1,4-difluorobenzene (17.7 g, 155 mmole) in THF was added at -70° C. The solution was stirred for 2 hr during which time it was cooled to -75° C. and 4-cyanopyridine (15.6 g, 150 mmole) in THF was added at -75° C. The mixture was allowed to warm to 25° C. slowly and then quenched with ammonium chloride solution. The mixture was diluted with ether and the organic layer was separated. The organic layer was washed with water and 3N hydrochloric acid. The acid washes were stirred for 2 hr and basified with sodium hydroxide. The basic mixture was extracted with ether and the ether solution concentrated in vacuo. The crude product was purified by chromatography on silica eluting with ethyl acetate-hexane (20:1) to give 4-(2,5-difluorobenzoyl)pyridine (16.9 g, 51.5%).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=1)[CH3:5]>Cl>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:17])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Agent: Cl
Product: CC(Oc1ccc(N)cc1)C(=O)O
Temperature: 10 °C
Yield: 98.1 %

Procedure:
To a mixture 2-(4-acetylamino-phenoxy)-propionic acid methyl ester 62 (320 grams, 1.35 mol) in concentrated hydrochloric acid (8 liters) was refluxed for 48 hours. Excess concentrated hydrochloric acid was distilled in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried to give pure 63 (240 grams, 81.7%) as a brown powder. The melting point was found to be 175-180° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(OCC)(=O)C>[CH3:34][O:33][C:31]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:32]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) and sodium bicarbonate (75 mg) in dry tetrahydrofuran (6 mL) at 0° C. under N2 is treated with methyl chloroformate (38 μL), and the resulting mixture is stirred at 0° C. for one hour. The reaction is then diluted with ethyl acetate (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 165-166° C.
Reaction SMILES: Br[C:2]1[C:3](C#N)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:11](=[O:14])([O-])[O-:12].[Na+].[Na+].[C:17](B1OC(C)(C)C(C)(C)O1)([CH3:19])=[CH2:18]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:17]([CH3:19])=[CH2:18])[C:3]([C:11]([OH:12])=[O:14])=[N:4][CH:5]=1
Reactant: N#Cc1ncc(Cl)cc1Br
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: C=C(C)c1cc(Cl)cnc1C(=O)O
Temperature: 90 °C
Yield: 82.1 %

Procedure:
A microwave glass vessel was charged with 3-bromo-5-chloropicolinonitrile (0.5 g, 2.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) and sodium carbonate (0.731 g, 6.90 mmol). The vial was evacuated and back-filled with nitrogen. Dioxane (10 mL) and water (3 mL) were added. The reaction mixture was degassed and isopropenylboronic acid pinacol ester (0.474 ml, 2.53 mmol) was added. The reaction mixture was heated to 90° C. for 2 hs. The reaction mixture was partitioned between water and EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in EtOH (7 mL) and NaOH (5M, 3 mL). The solution was heated to 115° C. for 1.5 hrs. The reaction mixture was partitioned between water and EtOAc. The organic phase was discarded and the aq. phase was acidified with aq. 2 M HCl and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure to obtain the title compound as a light-yellow solid (0.373 g, 82%). MS m/z=198.1 [M+H]+. Calculated for C9H8ClNO2: 197.024
Reaction SMILES: [ClH:1].[CH:2]1([C:8]2([CH2:23][S:24][CH3:25])[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>O1CCOCC1>[Cl-:1].[CH:2]1([C:8]2([CH2:23][S:24][CH3:25])[CH2:14][CH:13]3[NH2+:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CSCC1(C2CCCCC2)CC2CCC(C1)N2C(=O)OC(C)(C)C
Reactant: Cl
Solvent: C1COCCO1
Product: CSCC1(C2CCCCC2)CC2CCC(C1)[NH2+]2
Product: [Cl-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.0 N HCl in dioxane (20.0 mL) was added tert-butyl 3-cyclohexyl-3-[(methylthio)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (3-5) (0.870 g, 2.46 mmol). The mixture was stirred at room temperature for three hours and the volatiles were removed under vacuum to give (3-6) as a pale solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:20])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[OH:30]>>[OH:30][C:24]1[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:17]([C:15]1[O:14][N:13]=[C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:20])[CH:16]=1)=[O:19]
Reactant: Nc1ccc(O)cc1O
Reactant: C[C@@H](COc1cc(C(=O)O)on1)NC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H](COc1cc(C(=O)Nc2ccc(O)cc2O)on1)NC(=O)OC(C)(C)C

Procedure:
Using 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)isoxazole-5-carboxylic acid and 4-aminobenzene-1,3-diol hydrochloride, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:28]1[CH2:27][C:26]2[C:30](=[CH:31][C:23]([C:21]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=4)=[O:11])=[CH:34][CH:33]=3)=[O:22])=[CH:24][CH:25]=2)[NH:29]1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)s1
Temperature: 79 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A dry 100 mL flask was charged with 5-Acetyl-thiophene-2-carboxylic acid (0.9339 g, 5.49 mmol) and thionyl chloride (6 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (80 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the 5-Acetyl-thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.16 g, 3.94 mmol, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Mg].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)#N.Cl.C([O:21]CC)C>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1)=[O:21]
Reactant: CCOCC
Reactant: N#Cc1ccccn1
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Product: O=C(c1ccc(Br)cc1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1,4-dibromobenzene (70 g) in diethyl ether (200 mL) was added magnesium turnings (8.66 g) at ambient temperature under an N2 atmosphere. After 15 minutes the mixture began to reflux. The reaction mixture was stirred for 5 hours. Stirring was then ceased and after some solids settled to the bottom, the solution was transferred via a cannula into a stirred mixture of 2-cyanopyridine (34.32 g) in diethyl ether (100 mL) at 0° C. The mixture was stired overnight. The mixture was then cooled to 0° C. and 200 mL aqueous 4N HCl was added. The layers were separated. The ether layer was extracted 2×150 mL 4N HCl . The acidic layers were combined and basified with sodium carbonate. The resultant mixture was extracted with 3×300 mL ether. The ether layers were combined, dried over MgSO04, filtered and concentrated by evaporation to afford 44 g of crude material. This was stored at -15° C. overnight and was then distilled at 50 millitorr at 130° C., and redistilled to yield 24.74 g of 4-[2-pyridylcarbonyl]bromobenzene as a white solid. (300 MHz, DMSO): 7.67-7.72 (m,1, aromatic), 7.75-7.79 (d,2, aromatic), 7.91-7.96 (d,2, aromatic), 8.01-8.12 (m,2, aromatic), 8.72-8.74 (d,1, aromatic); MS: (CI) 264 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:17]>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=2[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[O:17])=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(N(C)C)cc2)cc1
Yield: 91 %

Procedure:
Using the procedure described in Example 55, Part B, 4-dimethylaminobenzoic acid and 2-amino-N-(4-methoxyphenyl)benzamide (1.25 mmol), yielded 444 mg (91%) of the title compound as a white solid.
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CS(O[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)=[CH:20][C:18]=2[CH:19]=1)(=O)=O>>[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)=[CH:20][C:18]=2[CH:19]=1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Agent: Br
Product: C[C@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 1C can be processed as described in Example 1D to provide the title compound.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].O>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[C:16]=2[N+:21]([O-:23])=[O:22])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc2cc(O)ccc2c1)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=C(Oc1ccc2c([N+](=O)[O-])c(O)ccc2c1)c1ccccc1

Procedure:
The thus obtained 6-hydroxy-2-naphthyl benzoate was dispersed in acetic acid, nitric acid was added dropwise to the dispersion while keeping it at 15° C., and water was further added thereto, followed by stirring. The thus obtained deposit was recrystallized from ethanol/acetic acid to obtain 6-hydroxy-5-nitro-2-naphthyl benzoate.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5].CCN(CC)CC.C[O:25][C:26](=O)[C:27]1[C:32]([NH:33][C:34]([CH:36]2[CH2:38][CH2:37]2)=[O:35])=[CH:31][CH:30]=[C:29]([Cl:39])[C:28]=1[CH2:40]Br>CN(C=O)C>[Cl:39][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:34]([CH:36]2[CH2:37][CH2:38]2)=[O:35])=[C:27]2[C:28]=1[CH2:40][N:1]([CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5])[C:26]2=[O:25]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CC#N)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 75.5 %

Procedure:
To the DMF solution (20 ml) of 3-Amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (1.55 g, 7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (2.42 g, 7 mmol). The mixture was heated at 90° C. for 12 hrs then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {7-chloro-2-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (2.4 g, 80%): mp 200-202° C.; 1H NMR (CDCl3) δ 0.90-0.94 (m, 2H, c-CH2), 1.09-1.14 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.64-1.70 (m, 1H, c-CH), 3.12-3.32 (m, 2H, CH2CN), 3.89 (s, 3H), 3.99-4.12 (m, 3H, OCH2CH3+CHHN), 4.37 (d, J=18 Hz, 1H. CHHN), 5.62-5.68 (m, 1H, NCH), 6.87-6.98 (m, 3H, Ar), 7.40 (d, J=9 Hz, 1H, Ar), 8.47 (t, J=9 Hz, 1H, Ar), 10.34 (s, 1H, NH); 13C NMR (CDCl3) δ 8.5, 14.7, 16.2, 21.2, 46.4, 51.8, 56.0, 64.7, 111.7, 112.2, 116.9, 118.4, 119.1, 119.8, 121.9, 127.9, 133.3, 136.9, 138.9, 149.9, 150.0, 169.0, 172.7; Anal Calcd for C24H24ClN3O4: C, 63.50; H, 5.33; N, 9.26. Found: C, 63.43; H, 5.31; N, 9.01