Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]=[C:6]1[O:12][CH:11]2[N:8]([C:9](=[O:13])[CH2:10]2)[CH:7]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH:5]=[C:6]1[O:12][CH:11]2[N:8]([C:9](=[O:13])[CH2:10]2)[CH:7]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:32])[CH3:2]
Reactant: CCSCC=C1OC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)CC=C1OC2CC(=O)N2C1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl 3-(2-ethylthioethylidene)-7-oxo-4-oxa-1-azabicyclo[3,2,0]heptane-2-carboxylate (704 mg) was dissolved in methylene chloride (40 ml) and treated with m-chloroperbenzoic acid (370 mg). The solution was stirred at 0° C. for 1.0 hour and washed with a dilute bicarbonate solution (×2). The extract was dried over MgSO4 and evaporated. Chromatography over silica gel yielded the title product as a mixture of R and S sulphoxides (295 mg);
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:32][CH2:31][O:30][CH2:29]4)=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:4]1[C:5]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:32][CH2:31][O:30][CH2:29]4)=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COC(OC)c1nc2c(cc1C1CCOC1)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(NC(=O)N2CCCc3cc(C4CCOC4)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Concentrated HCl (0.26 ml) was added to a solution of (racemic) N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 336, 157 mg, 0.314 mmol) in THF (1.2 ml) and H2O (0.4 ml) at room temperature. After stirring for 5 h at room temperature, sat. aq. NaHCO3 was added and the mixture extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]([CH3:17])[CH2:12][CH2:13][CH2:14][C:15]#[N:16].O.Cl>C(OCC)C>[OH:10][C:11]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:17])[CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: CC(=O)CCCC#N
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(O)(CCCC#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One hundred mL (0.1 mole) of a 1.0 molar solution of 4-chlorophenyl-magnesium bromide in diethyl ether is stirred, and a solution of 11.4 mL (0.1 mole) of 5-oxohexanenitrile in 125 mL of diethyl ether is added dropwise. The exothermic reaction causes the reaction mixture temperature to rise to about 31° C. The reaction mixture is then cooled in an ice-bath, and the dropwise addition of the nitrile solution is continued. The complete addition requires about 30 minutes. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for two hours. The reaction mixture is then poured into 500 mL of water and made acidic with aqueous 2N hydrochloric acid. The organic layer is separated, and the aqueous layer is extracted with one 250 mL portion of diethyl ether. The organic layers are combined and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residual oil. The oil is subjected to column chromatography on silica gel, using methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 15.0 grams of 5-hydroxy-5-(4-chlorophenyl)hexanenitrile. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[CH:12][CH:11]=2)[CH:4]=1.[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[NH:18]1[CH2:19][CH2:20][O:21][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:30])([F:1])[F:29])[N:8]=[CH:7][N:6]=3)=[CH:11][CH:12]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3cc(C(F)(F)F)ncn3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Nc2ccc([C@@H]3CNCCO3)cc2)ncn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(R)-tert-Butyl 2-(4-(6-trifluoromethylpyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (130 mg, 0.3 mmol) was dissolved in dioxane (1.2 ml) and a solution of HCl in dioxane (4 M, 1.15 ml, 4.59 mmol) was added. The reaction mixture was stirred at 60° C. for 2 hours. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (R)—N-(4-(morpholin-2-yl)phenyl)-6-(trifluoromethyl)pyrimidin-4-amine hydrochloride (96 mg, 87%) as a light yellow solid. MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Br.[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2)([O-:23])=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:28]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)c21
Yield: 43.1 %

Procedure:
147 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 97 mg of the target compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:22])[CH2:3]1.O[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26].S(Cl)(Cl)=O>O1CCOCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[O:9])[C:4](=[O:22])[CH2:3]1
Reactant: CCCCNC(=O)NO
Reactant: CC1CCN(C(=O)NCCc2ccc(S(=O)O)cc2)C(=O)C1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2CCC(C)CC2=O)cc1
Temperature: 60 °C

Procedure:
0.6 g of 4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfinic acid (crude product m.p. 113°-115° C., prepared by reaction of 4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfochloride with sodium sulfite) and 0.3 g of N-hydroxy-N'-butyl urea are dissolved in 50 ml of dioxan. 0.4 g of thionyl chloride in 10 ml of dioxan is added dropwise to this solution, and the batch is heated for 2 hours at 60° C. Subsequently, the solvent is evaporated under reduced pressure, water is added dropwise to the residue, the oily substance is separated and reprecipitated from ammonia. The N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl urea obtained has a melting point of 155°-157° C., and, with the substance obtained according to Example 8, shows no depression.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 120 °C
Yield: 87 %

Procedure:
A stirred mixture of 1.0 g (0.0032 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-4-difluoromethyl -4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.66 g (0.0048 mole) of potassium carbonate, and 0.76 g (0.0048 mole) of 4-chloronitrobenzene in 20 ml of N,N-dimethylformamide was heated at 120° C. for approximately 18 hours. The reaction mixture was cooled and was poured into ice-water. This aqueous mixture was neutralized with hydrochloric acid and then was extracted with ethyl acetate. The organic phase was washed with water and then was dried over anhydrous magnesium sulfate. This mixture was filtered, and the filtrate was evaporated under reduced pressure leaving an orange oil. The orange oil was purified by column chromatography on silica gel, eluting with methylene chloride to yield 1.2 g of 1-[2,4-dichloro-5-(4-nitrophenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 99°-101° C., compound 92 of Table 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH:15]1([CH2:18][NH:19][C:20](=[O:36])[C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C.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:14][C:13]1[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([NH:19][CH2:18][CH:15]3[CH2:17][CH2:16]3)=[O:36])=[CH:22][CH:23]=2)=[CH:3][C:4]([C:5]([NH:7][CH:8]2[CH2:10][CH2:9]2)=[O:6])=[CH:11][CH:12]=1
Reactant: O=C(NC1CC1)c1ccc(Cl)c(Br)c1
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCC1CC1)c1ccc(-c2cc(C(=O)NC3CC3)ccc2Cl)cc1
Temperature: 85 °C

Procedure:
3-Bromo-4-chloro-N-cyclopropylbenzamide (Intermediate 18, 55 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (Intermediate 19, 60 mg), tetrakis(triphenylphosphine)palladium (5 mg) and aqueous sodium carbonate (2N, 0.5 ml) were mixed in DMF (1.2 ml) and heated at 85° C. under nitrogen for 18 hrs. Ethyl acetate was added to the cooled reaction, the reaction filtered and the filtrate reduced to dryness under vacuum. The residue was applied to a SPE cartridge (Si, 5 g) and eluted with an ethyl acetate/cylohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum to give 6-chloro-N3-cyclopropyl-N4′-(cyclopropylmethyl)-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[K+].C(O[C@@H:13]1[C@H:18]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C:15](=[O:34])[CH2:14]1)[C@:27]1([CH3:28])[C:22]([CH:23]=[C:24]([O:32][CH3:33])[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)(=O)C.O>CS(C)=O>[CH2:2]1[C@@H:14]2[C:15](=[O:34])[C@:16]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C:24]([O:32][CH3:33])=[CH:23]5)[C@@H:18]3[C@H:13]12)[CH3:17]
Reactant: C[S+](C)(C)=O
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 1 h

Procedure:
64.8 g of trimethylsulfoxonium iodide is dissolved in 900 ml of dimethyl sulfoxide under nitrogen atmosphere with stirring and to this solution 27.55 g of potassium hydroxide is added at 25-30° C. The reaction mixture is stirred for 1 hour, then 81.1 g of 15α-acetoxy-3-methoxy-androst-3,5-diene-17-one is added and stirring is continued at 25-30° C. until the reaction is finished (about additional 6 hours). The solution is slowly added to 4500 ml of water, the precipitate is compacted by stirring (30 minutes), filtered, washed with water until it is neutral and dried in vacuo to constant weight below 40° C. The title compound is crystallized from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N-:15]=[C:16]=[S:17].[K+].BrBr.O>C(O)(=O)C>[NH2:15][C:16]1[S:17][C:7]2[CH:6]=[C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Reactant: [N-]=C=S
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc2nc(N)sc2c1
Yield: 48.4 %

Procedure:
The said starting material was also prepared by dissolving 154.6 g of ethyl 2-(p-aminophenyl)propionate [Arzneim. Forsch, Vol. 23, p. 1090 (1973)] in 95% acetic acid and 261 g of potassium isothiocyanate were added with stirring. A solution of 149.4 g of Br2 in 750 ml of 95% acetic acid was then added dropwise at 18°-25° C. over 2 hours and the mixture was stirred for an extra half hour, then poured into 8 liters of water. The mixture was filtered through celite and then neutralized to pH 5-6 using 6+ liters of 20% Na2CO3 solution. The product was then extracted with CH2Cl2 and the organic layer was separated, washed with water, dried over MgSO4 and finally filtered and evaporated to dryness. The crude product was dissolved in 300 ml of hot ethyl acetate and an equal volume of petroleum ether (40°-60° C.) was added. On cooling, cream colored crystals were formed which were filtered off, washed with ethyl acetate/petroleum ether and dried to obtain 97 g (48.5% yield) of the ethyl 2-amino-α-methylbenzothiazole-6-acetate melting at 146° C. A second crop of 29 g was obtained from the mother liquors for a total yield 63%.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])=O)(C)(C)C.[ClH:20]>C(OCC)(=O)C>[ClH:20].[C:14]1([S:11]([CH2:10][CH2:9][NH2:8])(=[O:12])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCS(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
The sulfone from Step F (1.20 g, 4.21 mmol) was dissolved in ethyl acetate (10 mL). The solution was saturated with hydrogen chloride gas and stirred for 1 hour, then concentrated in vacuo. The residue was partitioned between methylene chloride (10 mL) and water (10 mL). The layers were separated and the aqueous layer was washed with methylene chloride (3×10 mL) and concentrated in vacuo to provide the title compound as a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])(=[O:3])[CH3:2].[Se](=O)=[O:15]>O1CCOCC1.O>[CH3:9][C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5][C:4]=1[C:1](=[O:3])[CH:2]=[O:15]
Reactant: CC(=O)c1sc2ccccc2c1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)C=O)sc2ccccc12

Procedure:
A 52.9 g portion of 2-acetyl-3-methylbenzothiophene was added to a solution of 36.9 g of selenium dioxide in 95 ml of dioxane and 13 ml of water at 55°-60° C. The mixture was refluxed overnight, filtered, washed with dioxane and evaporated. The residue was purified by flash column chromatography, eluting with hexane:ethyl acetate (8:2), giving 5.1 g of 3-methyl-a-oxobenzo[b]thiophene-2-acetaldehyde.
Reaction SMILES: C([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH2:28])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[C:13](=[O:29])[CH:12]1[CH2:30][O:31][CH3:32])=O)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:64][C:65]1[CH:66]=[CH:67][C:68]2[N:72]=[C:71](C(O)=O)[NH:70][C:69]=2[CH:76]=1>CN(C=O)C>[NH2:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:71]4[NH:70][C:69]5[CH:76]=[C:65]([Cl:64])[CH:66]=[CH:67][C:68]=5[N:72]=4)=[O:8])[C@@H:12]([CH2:30][O:31][CH3:32])[C:13]3=[O:29])=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: COCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Reactant: O=C(O)c1nc2ccc(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, EXAMPLE 75, (20 mg, 0.066 mmol) in 1.5 mL of DMF is added TBTU (923.4 mg, 0.073 mmol), diisopropylethylamine (0.013 ml, 0.073 mmol) and 6-chloro-1H-benzoimidazole-2-carboxylic acid (prepared from literature in Eur.J.med.Chem. 1993, 28, 71) (14.3 mg, 0.073 mmol). The resulting mixture is left to stir at room temperature overnight. The crude mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (30.1 mg, 55%) is isolated as a white powder. C23H22ClN7O3 MS m/z: 480, 481. Anal. cald. for C23H22ClN7O3. 2C2HF3O2: C, 45.81; H, 3.42; N, 13.85. Found C, 45.19; H, 3.59; N, 13.76.
Reaction SMILES: Cl.C(OC([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](OC3CCNC3)[CH:19]=2)[NH:14][C:13]=1C)=O)C1C=CC=CC=1.CC(C)=O.C([BH3-])#[N:33].[Na+]>CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:13]1[NH2:33]
Reactant: Cc1[nH]c2ccc(OC3CCNC3)cc2c1C(=O)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Nc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 189.2 %

Procedure:
Crude 2-methyl-5-(pyrrolidin-3-yloxy)-1H-indole-3-carboxylic acid benzyl ester, hydrochloride (0.040 g, 0.100 mmol, 1 eq, Example 47, Step A) was suspended in methanol (5 mL). Acetone (0.100 mL) was added followed by the addition of sodium cyanoborohydride (0.013 g, 0.2 mmol, 2.0 eq). The reaction mixture was kept at pH 6 and stirred at room temperature. After 24 hours, the reaction was quenched with aqueous sodium bicarbonate, extracted several times with CH2Cl2. The combined organic layers were dried over sodium sulfate, loaded on silica gel and chromatographed (ethyl acetate/methanol/triethylamine 87/10/3. 0.025 g (64% yield) of the indole-amine was obtained as a brown semisolid, and converted to the corresponding HCl salt: LC/MS (ESI+) 393 (M+1), Anal. (C24H28N2O3.HCl) C, H, N.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][C:11](=[O:17])[CH2:12][C:13](=[O:16])[CH2:14][CH3:15]>>[CH3:6][N:4](/[CH:3]=[C:12](/[C:13](=[O:16])[CH2:14][CH3:15])\[C:11]([O:10][CH3:9])=[O:17])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC(=O)OC
Product: CCC(=O)/C(=C/N(C)C)C(=O)OC
Temperature: 110 °C

Procedure:
To N,N-dimethylformamide dimethyl acetal (0.384 ml, 2.88 mmol) was added methyl-3-oxo-pentanoate (250 mg, 1.92 mmol) and the mixture was heated to 110° C. in a sealed vessel. After 30 minutes the reaction mixture was cooled and concentrated to afford methyl (2Z)-2-[(dimethylamino)methylene]-3-oxopentanoate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccc3)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) in dichloro methane (5 mL) was added benzoyl chloride (0.04 mL, 0.35 mmol) with ice cooling. Upon completion of addition, the resultant solution was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 70 mg of methyl 2-(4-benzamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 53%. MS (ESI+APCI) M+1=415.20.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=O>>[CH2:44]([N:43]([CH2:46][CH3:47])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:37][CH:38]=1)[CH3:45]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: CCN(CC)CCOc1ccc(CCCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 76.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-diethylacetamide (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (23 mg) was obtained.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[N:4]1>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:3][N:4]=1
Reactant: BrBr
Reactant: c1cnc2[nH]ncc2c1
Solvent: ClC(Cl)Cl
Product: Brc1n[nH]c2ncccc12
Reaction time: 8 h
Yield: 85.7 %

Procedure:
Bromine (1.91 mL, 37.1 mmol) was added dropwise to a solution of 1H-pyrazolo[3,4-b]pyridine (2.6 g, 21.8 mmol) in CHCl3 (100 mL), and the reaction mixture was left at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was taken up in ethyl acetate (200 mL) and saturated NaHCO3 (50 mL) The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried, filtered and concentrated to give 3-bromo-1H-pyrazolo[3,4-b]pyridine (3.7 g, 86%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:28]1(S(Cl)(=O)=O)[CH2:32]C[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH:26]5[CH2:30][CH2:29][CH2:28][CH2:32]5)(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: O=S(=O)(Cl)C1CCCC1
Product: O=S(=O)(C1CCCC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 20 %

Procedure:
According to the procedure for compound 398 using cyclopentanesulfonyl chloride (97 mg, 0.57 mmol) afforded 9.7 mg (20% yield) of 403, as a solid.