Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4].C(N(CC)CC)C.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:32][C@@H:33]1[O:35][CH2:34]1)(=O)=O>CN(C=O)C>[CH2:19]([N:10]1[C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][CH2:32][C@H:33]3[CH2:34][O:35]3)=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:20]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCn1c2ccccc2c2cc(NC(=O)CN)ccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c2ccccc2c2cc(NC(=O)CNC[C@H]3CO3)ccc21

Procedure:
To a solution of 2-amino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide (6.1 g, 23 mmol) and triethylamine (6.3 mL, 45 mmol) in DMF (50 mL) was added a solution of (R)-(−)-glycidyl nosylate (5.9 g, 23 mmol) in DMF (20 mL). The resultant solution was stirred two days under nitrogen to form (S)-N-(9-Ethyl-9H-carbazol-3-yl)-2-(oxiranylmethyl-amino)-acetamide, which was then directly treated with diethyl amine (23 mL, 227 mmol) and methanol (100 mL). The mixture was stirred an additional two days, and then concentrated under reduced pressure to remove the methanol. The concentrated reaction was diluted with ethyl acetate (1 L) and washed with saturated aqueous Na2CO3 (1 L), water (2×500 mL), and then brine (250 mL). The organic solution was then dried (Na2SO4), concentrated under reduced pressure, and flash chromatographed (10:3:1 to 7:3:1 hexanes/diethylamine/acetonitrile) to give the title compound (4.4 g, 49%) as a brown oil which was converted to the dihydrochloride salt (methanol, ethereal HCl). The salt was then re-pulped from refluxing 2:1 ether/methanol to afford the dihydrochloride salt of the title compound as a colorless solid (3.5 g, 33%). MS m/z @ 397 (M+1).
Reaction SMILES: C[C:2]1[C:3]([CH3:16])=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:17](O)(=O)C1C=CC=CC=1>CC1C=CC(C)=CC=1>[CH3:16][C:3]1[CH:2]=[CH:15][C:14]([CH3:17])=[CH:13][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1C
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C)c(C(=O)c2ccccc2)c1

Procedure:
The dimethylbenzophenone fraction is contaminated with a small amount (0.05-0.1 lb/lb dimethylbenzophenones) of benzoic acid that co-distills with it. The benzoic acid is removed from the final product as described in Example 1. The washed dimethylbenzophenone product may or may not be given a final distillation in a 10 trays Oldershaw column to improve product color and purity as described in Example 1. Synthesis of dimethylbenzophenone from an isomeric mixture of xylenes will produce a mixture of six dimethylbenzo-phenone isomers. Synthesis from pure p-xylene will produce only 2,5-dimethylbenzophenone; pure m-xylene will produce 2,4-, 2,5-, and 2,6-dimethylbenzophenone; and pure o-xylene will produce 2,3- and 3,4-dimethylbenzophenone. Specific isomeric mixtures are produced by a provident choice of the composition of the initial xylene mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=[C:4]2[N:3]=1.[Cl:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:11]([Cl:18])=[C:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1cc(Cl)n2c(-c3ccccc3)ncc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Cl)n2c(-c3ccccc3)nc(Cl)c2n1

Procedure:
A mixture of 2,4-dichloro-6-phenylimidazo[1,5-a]pyrimidine (0.88 g), N-chlorosuccinimide (0.5 g) and benzoyl peroxide (0.04 g) in carbon tetrachloride (20 ml) was heated to reflux for 14 hours. The mixture was concentrated and purified by alumina column chromatography, eluting with benzene to give the objective product which was recrystallized from ethanol to yellow plates (0.32 g), mp 133°-134° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1)N.[H][H]>[Ni].C(O)C>[NH2:1][C:3]1[CH:8]=[C:7]([CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: NNc1cc(C2COCCO2)ccn1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C2COCCO2)ccn1
Reaction time: 4 h

Procedure:
A mixture of 9.56 g. (49 mmoles) of 1-(2-hydrazino-4-pyridyl)-1-ethylenedioxyethane and 35 g. of Raney nickel in 150 ml. of absolute ethanol was shaken in a hydrogen atmosphere at an initial pressure of 3 atms. at room temperature for 4 hours. The catalyst was filtered and the filtrate concentrated to give 1-(2-amino-4-pyridyl)-1-ethylenedioxyethane as a white solid, m.p. 123°-126° C. The residual material was dissolved in 60 ml. of 2 N hydrochloric acid and heated at 75° C. for 3 hours. The mixture was cooled, neutralized with sodium bicarbonate and extracted with chloroform (30 ml.×6). The combined extracts were dried and concentrated to give a pale yellow solid, which on recrystallization from toluene gave 5.0 g. (75%) of 1-(2-amino-4-pyridyl)-1-ethanone, m.p. 133°-133.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cncc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.5 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 3-pyridinecarboxaldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (95.0 mg, 49.5% yield) as white crystals.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:16]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24])(=[O:19])(=[O:18])[NH2:17]>COCCOC>[C:1]1([NH:7][NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([S:16](=[O:18])(=[O:19])[NH2:17])[CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: NNc1ccccc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Reaction time: 144 h
Yield: 44.8 %

Procedure:
In a 1 liter round bottom flask were placed phenyl hydrazine (54.1 g, 0.5 mol), triethylamine (50.5 g, 0.5 mol), and 150 ml of 1,2 dimethoxyethane. Then the mixture was cooled to ice-bath temperature and with good stirring and over 10 minutes a solution of 3-sulfamoyl-4-chlorobenzoyl chloride 97.1% (61 g, 0.24 mol) in 150 ml 1,2 dimethoxyethane was added dropwise. The reaction was permitted to reach ambient temperature. After standing for 6 days the solvent was evaporated under vacuum and the residue taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 2N H2SO4, with water and finally with 1 molar sodium bicarbonate solution. The ethyl acetate phase was separated and dried with magnesium sulfate, clarified and concentrated to crystallization. 35 g of product mp 189°-190° C. were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[C:23](OCC)(=O)[CH3:24]>>[ClH:20].[CH2:23]([C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[CH:18]=1)[CH3:24]
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCc1cc(C)cnc1N1CCNCC1

Procedure:
By reaction and treatment in the same manner as in Example 53 and using 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g), which is the intermediate described in Preparation Example 48, a compound was obtained, which was treated with 4N hydrogen chloride/ethyl acetate (2 mL) to give the title compound (1.1 g).
Reaction SMILES: [CH2:1]([N:9]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][CH2:17][NH:18][C@@H:11]2[CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.O>[CH2:25]([O:32][C:33]([N:18]1[C@@H:11]2[CH2:10][N:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][CH2:17]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CCN2CCC[C@@H]3CCN[C@@H]3C2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@H]2CCCN(CCc3ccccc3)C[C@H]21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of (3aR,8aS)-7-Phenethyl-decahydro-pyrrolo[2,3-c]azepine (4.0 g, 16.37 mmol) (Reference: PCT Int. Appl., 2005097791, 20 Oct. 2005) in ethyl acetate (100 mL) was added a solution of potassium carbonate (6.79 g, 49.1 mmol, 3.0 eq) in water (100 mL). The biphasic solution was cooled to 0° C. then benzylchloroformate (2.80 mL, 19.64 mmol, 1.2 eq) added dropwise. The resulting mixture was stirred for 3 hr at 23° C. The mixture was partitioned and the aqueous layer extracted with Ethyl Acetate. The combined organic layers were washed with water followed by brine and the organic layer dried (Na2SO4), filtered, and the filtrate concentrated to yield an orange oil. The crude was purified using silica gel chromatography (1:2 Ethyl Acetate/Heptane to 100% Ethyl Acetate followed by 12:1 CH2Cl2/Methanol) giving (3aR,8aS)-7-Phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.[I-:28].[Na+].O>CC(CC)=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]2=[O:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:28]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
5.0 g of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 80 ml of ethyl methyl ketone, mixed with 5.7 g of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 6.8 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one is obtained as crude product, which is used without further purification in the next stage.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: NCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (150 mg, 0.50 mmol, 1.00 equiv), 2-(2-bromophenyl)ethanamine (300.5 mg, 1.51 mmol, 3.00 equiv), potassium carbonate (347.3 mg, 2.52 mmol, 5.00 equiv), toluene/DMSO (5/1 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum and applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 110 mg (47%) of methyl 3-(2-bromophenethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: CC1C=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N1C2C(=CC=CC=2)C(=O)C1=O.CC(C)=O.[F:30][C:31]([F:36])([F:35])[C:32]([CH3:34])=O>[OH-].[K+]>[F:30][C:31]([F:36])([F:35])[C:32]1[CH:34]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)C(F)(F)F
Reactant: Cc1cc(C(=O)O)c2ccccc2n1
Agent: O=C1Nc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(C(F)(F)F)nc2ccccc12

Procedure:
2-Methylcinchoninic acid has been prepared, as disclosed in Bull. Soc. Chem., France, 1956, 1294, by the reaction of isatin and acetone in 30 percent aqueous potassium hydroxide solution. However, it has been found that when isatin is reacted with 1,1,1-trifluoroacetone in an attempt to produce 2-trifluoromethyl cinchoninic acid in an analogous manner, the desired product cannot be obtained.
Reaction SMILES: [N+](=C)=[N-].[CH3:4]N(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+].[O:20]=[C:21]1[C:34]2[C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=[CH:30][C:29]=2[O:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2>CO>[CH3:4][O:36][C:35]([C:33]1[C:34]2[C:21](=[O:20])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1)=[O:37]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C(O)c1cccc2oc3ccccc3c(=O)c12
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc2oc3ccccc3c(=O)c12
Yield: 100 %

Procedure:
Esterification of acid can be achieved by several conventional methods by those skilled in the art. These procedures include utilizing diazomethane or methyl alcohol catalyzed by mineral acids. For example, ethereal diazomethane solution can be prepared from N-methyl-N-nitrosotoluene-p-sulphonamide and potassium hydroxide from a water bath. 9-Oxoxanthene-1-carboxylic acid (1.29 g, 5 mmol) in absolute methanol is added to this ethereal diazomethane solution at 0° C. until a pale yellow color formed. Removal of the solvent provides the desired ester solid in 100% yield. Thus the final products, Examples 5-9, can be prepared by condensation hydrazine with the ketonester 11 as described in General procedure C.
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[CH2:2].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7]>>[Cl:3][C:1]([Cl:4])=[CH:2][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(=O)Cl
Reactant: C=C(Cl)Cl
Product: CC(C)C(=O)C=C(Cl)Cl

Procedure:
condensing vinylidene chloride with isobutyryl chloride in the presence of a Lewis acid to produce 1,1-dichloro-4-methyl-1-penten-3-one,
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([Cl:20])=[N:7][C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[N:9][C:10]=1[Cl:11].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](O)=[O:33].CCOC(C)=O>C1COCC1>[Cl:20][C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])=[C:10]([Cl:11])[N:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])=[CH:15][CH:14]=2)[N:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 669.2 %

Procedure:
A mixture of methyl[2-(4-aminobenzyl)-4,6-dichloropyrimidin-5-yl]acetate (0.073 g, 0.23 mmol), 2-naphthoic acid (0.048 g, 0.028 mmol), and WSCI (0.049 g, 0.026 mmol) in anhydrous THF (3 mL) was stirred at room temperature under Ar atmosphere for 10 hours. EtOAc (80 mL) was then introduced and the organic phase was washed sequentially with saturated NaHCO3, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained as a light orange oil was triturated with diisopropyl ether and the separated solids was collected by suction to give methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.090 g, 78% yield) as a white powder.
Reaction SMILES: FC(F)(F)C1C=CC(NS([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=O)=O)=CC=1.[CH3:25][OH:26]>[Pd]>[CH3:25][O:26][C:13]1[CH:21]=[C:20]([C:21]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:22])[NH:18]3)=[CH:14][CH:13]=2)[CH:19]=[CH:15][CH:14]=1
Reactant: CO
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)ccc2N1
Agent: [Pd]
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Yield: 75 %

Procedure:
3′-Methoxy-3-nitrobiphenyl-4-acetic acid (5:2 g) was dissolved in methanol and hydrogenated over 0.8 g 10% palladium on carbon for 3 hours at room temperature. The catalyst was removed by filtration, washed with methanol and the filtrates combined and concentrated to give a brown solid. The solid was chromatographed on silica gel in ethyl acetate:hexane:acetic acid 33:66:1 to give 3.0 g (75% yield based on 4-fluoro-3′-methoxy-3-nitrobiphenyl) of 6-(3-methoxypheny)-2-oxindole as a pink solid.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[CH:15]=[N:14][NH:13][C:10]2=[CH:11][N:12]=1.CN([CH:19]=[O:20])C>C1COCC1>[NH:13]1[C:10]2=[CH:11][N:12]=[C:7]([CH:19]=[O:20])[CH:8]=[C:9]2[CH:15]=[N:14]1
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2cn[nH]c2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
t-BuLi (27 mL, 1.7 M in pentane) was added to 100 mL of THF at −78° C. 5-bromo-1H-pyrazolo[3,4-c]pyridine (3.0 g, 15 mmol) was added dropwise to the solution in 50 ml of THF via addition funnel. The resulting mixture was stirred for 1 h, at which point DMF (6.0 mL, 76 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred 2 h. The reaction was then carefully quenched with aq. NH4Cl and diluted with EtOAc. The resulting biphasic mixture was partitioned in a separatory funnel. The aqueous portion was extracted three tines with EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (100% CH2Cl2 to 7.5% MeOH/CH2Cl2), afforded the desired 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (1.1 g, 50% yield) as a white solid. H1 NMR (MeOD, 400 MHz) keto tautomer: 10.17 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H); enol tautomer: 9.00 (s, 1H), 8.25 (s, 1H), 8.05 (s, 2H), 5.73 (s, 1H). MS (API-ES) m/z (%): 147 (100%, M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4].[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[NH2:18])=[O:30])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: Nc1c(C(=O)O)ccc2ccccc12
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2N)CN1CC1CCCCC1

Procedure:
(2S,4S)-4-[(1-Amino-naphthalene-2-carbonyl)-amino]-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester and 1-amino-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C24H32N3O3[(M+H)+] 410, obsd. 410.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([O-])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([N:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[CH2:22][CH2:23]3)=[CH:28][CH:29]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[CH2:26][CH2:25]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCN(CCCO)CC2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCN(CCCO)CC4)cc3)cc2)cc1)c1ccc(N2CCN(CCCO)CC2)cc1

Procedure:
Compound 318 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(4-(3-hydroxypropyl)piperazino)benzoate. [M+H]+ calcd for C41H48N6O5: 705.37; found: 705.19.
Reaction SMILES: F[C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:16]C1C(I)=C(C=CC=1)C(O)=O.FC1C(I)=C(C=CC=1)C(O)=O>>[CH3:16][C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: O=C(O)c1cccc(F)c1-n1cccn1
Agent: O=C(O)c1cccc(F)c1I
Product: Cc1cccc(C(=O)O)c1-n1cccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 93 substituting 3-methyl-2-iodobenzoic acid for 3-fluoro-2-iodobenzoic acid. 1H NMR (500 MHz, CDCl3): 7.79 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.5 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 6.53 (s, 1H), 2.07 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([CH:36]=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.CC(=CC)C.[O-:44]Cl=O.[Na+]>C(O)(C)(C)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([C:36]([OH:44])=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(C(=O)O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
5-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate F4, 19 mg, 0.036 mmol) was dissolved in 2-methyl-2-butene (300 μl, 2.83 mmol) and t-Butanol (0.5 ml), then a solution of NaClO2 (32.6 mg, 0.360 mmol) and K2H2PO4 (49.0 mg, 0.360 mmol) in 0.5 mL of water added and the mixture stirred at rt for 2 hrs. The reaction was quenched by the addition of 2M HClaqueous (1 ml) and the crude purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (8 mg, 40.9%) as white solid.