Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16]F>O.C(O)C>[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]2[O:9][CH:15]=[CH:16][NH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: FCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1ccc(C2=NNC=CO2)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A solution of 2.9 g (0.07 mole) sodium hydroxide dissolved in 10 ml of water was added dropwise at room temperature to a mixture of 6.5 g (0.03 mole) 4-bromobenzoic hydrazide and 4.0 g (0.03 mole) 1-bromo-2-fluoroethane in 25 ml of ethanol. The resulting solution was refluxed for two and one-half hours. The mixture was cooled to room temperature, diluted with 150 ml of water and extracted several times with ether (100 ml). After separation and drying over anhydrous sodium sulfate, the solution was filtered and evaporated under reduced pressure leaving 4.6 grams of an oil (63.6% yield), which was purified by distillation. The product was characterized by IR and NMR spectroscopy.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([C:24]([O:26]C)=[O:25])=[CH:11][CH:10]=3)[CH3:2].C(O)C.[OH-].[K+]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([C:24]([OH:26])=[O:25])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(C(=O)OC)ccc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(C(=O)O)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 1-ethyl-6-methoxycarbonyl-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinoline-4-amine (1.4 g), ethanol (90 ml), KOH (2 g) and water (10 ml) is stirred at room temperature overnight. The reaction mixture is evaporated and the residue is partitioned between CH2Cl2 and water. The aqueous layer is separated, acidified with acetic acid and the solid that forms is collected by filtration and dried. The solid is recrystallized from hot acetic acid (50 ml) to afford 1.0 g of 1-ethyl-6-carboxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine. HOAc, m.p. 240° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH2:21]=[O:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][OH:22])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: C=O
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1
Product: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-fluoro-2-(imidazol-1-yl)benzophenone is heated in a bomb to 150° C. with 37% aqueous formaldehyde solution to give 5-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[CH3:16])[CH:6]=1>C(OCC)(=O)C.C(O)C>[CH3:16][C:8]1[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C)cn1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cn(-c2ccc(N)cc2C)cn1
Yield: 99.4 %

Procedure:
A mixture of 4-methyl-1-(2-methyl-4-nitro-phenyl)-1H-imidazole (1.26 g, 5.8 mmol) and of stannous chloride dehydrate (6.81 g, 30.2 mmol) in ethyl acetate (40 mL) and ethanol (20 mL) was stirred for 1 hour at 70° C. The reaction mixture was quenched by addition of water, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (1.08 g, 99%) as a yellowish gum. MS ISP (m/e): 188.4 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]([CH3:14])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1>>[CH2:1]([NH:3][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH3:14])[CH3:4])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCN
Product: CCNCc1ccc(N(C)C)cc1

Procedure:
prepared by reaction of ethylamine with 4-dimethylamino-benzaldehyde
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Cl)ccc4Cl)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 2,5-dichlorophenol, triphenylphosphine and di-tert-butyl azodicarboxylate.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:5]([C:6]2([CH3:11])[CH3:10])[CH:4]1[CH3:12])=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)=O>[N:13]1([CH2:1][CH:3]2[CH2:8][CH:7]3[CH2:9][CH:5]([C:6]3([CH3:11])[CH3:10])[CH:4]2[CH3:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: CC1C(C=O)CC2CC1C2(C)C
Solvent: O=CO
Product: CC1C(CN2CCCC2)CC2CC1C2(C)C
Yield: 73 %

Procedure:
33 g of (+)-3-formylpinane, 14 g of pyrrolidine and 70 g of formic acid are heated under reflux for 12 hours. Excess formic acid is then distilled off and the residue is boiled with 150 g of 25% strength aqueous potassium hydroxide solution. The amine separates out as the upper phase and is separated off and purified by fractional distillation. 31.8 g of (+)-3-pyrrolidinomethylpinane boiling at from 125° to 127° C/5 mm Hg are obtained.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=O)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=[CH:30][CH:31]=1
Reactant: Cc1ccc(C2c3c(C)c(NC(=O)c4ccc(F)cc4)c(C)c(C)c3OC2(C)C)cc1
Solvent: CO
Product: Cc1ccc(C2c3c(C)c(NCc4ccc(F)cc4)c(C)c(C)c3OC2(C)C)cc1
Yield: 39 %

Procedure:
By using 4-fluoro-N-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 39%. Melting point: 92-94° C. (Methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8][C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Cc1ccc(Sc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Sc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 86.9 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-methylthiophenoxy)phenyl]-N-methylcarbamate (1.93 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (3.01 g), diethyl cyanophosphonate (1.75 g), triethylamine (1.08 g) and anhydrous tetrahydrofuran (80 ml) and the reaction mixture was purified to give the desired product (2.96 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:19][C:20]1[C:29]2[CH:28]=[N:27][C:26]([S:30][CH3:31])=[N:25][C:24]=2[N:23]([C@H:32]2[CH2:36][CH2:35][C@H:34]([O:37][Si](C(C)(C)C)(C)C)[CH2:33]2)[C:22](=[O:45])[CH:21]=1>C1COCC1>[NH2:19][C:20]1[C:29]2[CH:28]=[N:27][C:26]([S:30][CH3:31])=[N:25][C:24]=2[N:23]([C@H:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]2)[C:22](=[O:45])[CH:21]=1
Reactant: CSc1ncc2c(N)cc(=O)n([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ncc2c(N)cc(=O)n([C@H]3CC[C@H](O)C3)c2n1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1 M in THF, 0.576 mL) was added dropwise, at RT, under argon atmosphere, to a mixture of 5-amino-8-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.443 mmol) in anhydrous THF (5 mL) and the resulting mixture was stirred overnight. A second aliquot of solution of tetrabutylammonium fluoride (1 M in THF, 0.6 mL) was then added and the reaction mixture was stirred for 2 h. A third aliquot of solution of tetrabutylammonium fluoride (1 M in THF, 1.8 mL) was then added and the reaction mixture was stirred for 2 h. A fourth aliquot of solution of tetrabutylammonium fluoride (1 M in THF, 1.3 mL) was then added and the reaction mixture was stirred overnight. The reaction was quenched with water (20 mL) followed by NH4Cl (sat'd aq). The resulting mixture was extracted with EtOAc (10×20 mL) and the combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by preparative TLC (DCM/MeOH, 90/10) to give 106 mg (82% yield) of 5-amino-8-(trans-3-hydroxy-cyclopentyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[C:18]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][C:20]([OH:27])=[C:21]([CH2:23][C:24](O)=[O:25])[CH:22]=1>C(Cl)Cl>[Cl:16][C:17]1[C:18]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][C:20]2[O:27][C:24](=[O:25])[CH2:23][C:21]=2[CH:22]=1
Reactant: O=C(O)Cc1cc(Cl)c(N2CCCCC2)cc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.5 g (31.5 mmoles) of dicyclohexylcarbodiimide in 40 ml of absolute methylene chloride is added at room temperature in the course of approximately 3 minutes to a solution of 8.1 g (30 mmoles) of crude 5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenylacetic acid in 50 ml of absolute methylene chloride. The reaction mixture is stirred at room temperature for 30 minutes. The precipitated dicyclohexylurea is filtered off with suction and washed with methylene chloride. The filtrate is concentrated by evaporation in a vacuum rotary evaporator and the residue is chromatographed over silica gel with the eluant methylene chloride/hexane (1:1). Recrystallisation from hexane yields 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one having a melting point of 129°-131° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[CH2:13][C:14]#[N:15])=[CH:6][CH:5]=1.[CH3:20][N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl.Cl>CS(C)=O>[C:14]([C:13]1([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:26][CH2:25][N:21]([CH3:20])[CH2:22][CH2:23]1)#[N:15]
Reactant: N#CCc1ccccc1Sc1ccc(F)cc1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2.3 g of 99% sodium hydride are slowly added to a mixture, under nitrogen, of 4.3 g of 2-(4-fluorophenylthio)benzyl cyanide in 30 mls of dimethylsulfoxide. After total addition, the mixture is stirred for an additional five minutes and then a mixture of 3.9 g of 95% mechlorethamine hydrochloride in 20 ml of dimethylsulfoxide is added portionwise over a 40 minute span. After this addition, the reaction is stirred for one hour in a hot water bath at 70° C. and then permitted to stand at ambient temperature for 16 hours. The cooled reaction mixture is poured onto 150 ml of crushed ice and the diluted mixture is extracted thrice with 60 ml portions of ether. The combined ether extracts are successively washed with one 25 ml portion of a saturated sodium chloride solution and dried, providing 4-cyano-4-[2-(4-fluorophenylthio)phenyl]-1-methylpiperidine.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])=[O:4].O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)N(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Methyl 3-(N,N-dimethylcarbamoyl)benzoate (2.30 g, 11.1 mmol) obtained in Step 1 was dissolved in a mixed solvent (1:1) (50 mL) of methanol and water, and lithium hydroxide monohydrate (932 mg, 22.2 mmol) was added thereto, followed by stirring at room temperature for 1 hour. 3 mol/L hydrochloric acid was added to the reaction mixture to adjust the pH to 3, and the precipitated solid was collected by filtration to afford 3-(N,N-dimethylcarbamoyl)benzoic acid (2.12 g, 99%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[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.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:23]1([NH:27][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: NC1CCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCC3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.32 mmol) in DMSO (1 mL) in was added cyclobutanamine (100 mg, 1.41 mmol) and DIEA (110 mg, 0.85 mmol). The resulting solution was stirred for 2 hours at 70° C., and then quenched by the addition of water (50 mL) and extracted with dichloromethane (4×20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2%-10% ethyl acetate in petroleum ether) to afford methyl 3-(cyclobutylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (67 mg, 58%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30]>C(OCCO)C>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(C(=O)O)c3C)c2cc1OC
Yield: 24.7 %

Procedure:
Using an analogous procedure to that described in EXAMPLE 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 196.5 mg (1.3 mmol) of 3-amino-2-methylbenzoicacid to give 89.6 mg (24.7%) of the product as a gray solid, m.p. 242-245° C., mass (electrospray, m/e): M+H 364.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: COC(=O)CBr
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure A: Reaction of (5-Aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol, methylbromoacetate and DIPEA in CH2Cl2 gave (4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid methyl ester as a white foamy solid. 1H NMR (CDCl3) δ 1.60 (m, 1H), 1.80 (br s, 1H), 1.98 (m, 1H), 2.19 (m, 2H), 2.22 (s 3H), 2.25 (s, 3H), 2.64 (m, 1H), 2.79 (m, 1H), 3.40 (s, 2H), 3.63-3.77 (m, 8H), 3.91 (t, 1H, J=7.5 Hz), 4.15 (m, 2H), 4.36 (d, 1H, J=12.0 Hz), 7.01 (dd, 1H, J=7.5, 3.0 Hz), 7.16 (d, 1H, J=7.5 Hz), 7.21-7.31 (m, 4H), 8.16 (s, 1H), 8.37 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.3, 18.6, 21.1, 22.1, 29.8, 50.4, 52.1, 53.3, 54.4, 54.6, 57.9, 63.0, 121.9, 127.4, 131.4, 131.8, 132.2, 133.8, 134.9, 136.3, 136.9, 139.3, 139.7, 142.6, 146.5, 146.9, 153.7, 157.3, 173.2. HPLC: 98%. ES-MS m/z 489 [M+H]+, 511 [M+Na]+. Anal. Calcd. for C29H36N4O3.0.1 CH2Cl2: C, 70.31; H, 7.34; N, 11.27. Found: C, 70.54; H, 7.48; N, 11.17.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)c1c(C)cccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of methyl 2-hydroxy-6-methylbenzoate (prepared according to Doehner et al, WO 01/05739, 10.0 g), tert-butyldimethylsilyl chloride (11.0 g), N,N-di-isopropylethylamine (32 mL) and DMAP (0.75 g) in DCM (400 mL) was stirred at room temperature overnight. The mixture was washed with water and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give methyl 2-(tert-butyldimethylsilyloxy)-6-methylbenzoate (11.9 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+]>CN(C)C=O.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CCCN1Cc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC1CCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
Into a 3,000 ml 3-necked roundbottom flask, was placed a solution of 1-benzyl-2-(chloromethyl)pyrrolidine (150. g, 714 mmol) in N,N-dimethylformamide (1,500 ml). This was followed by the addition of a solution of NaCN (54.2 g, 834 mmol) in water (300 ml). The resulting solution was heated to reflux for 2 hours. After cooling to ambient temperature, the solution was dissolved in 6,000 ml of water. The resulting solution was extracted with ethyl acetate (3×3,000 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford 2-(1-benzylpyrrolidin-2-yl)acetonitrile.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[CH3:15])[CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:2]([N:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6]/[C:5]/1=[CH:15]\[C:16](=[O:18])[CH3:17])[CH3:3]
Reactant: CC[n+]1c(C)sc2ccc(OC)cc21
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1/C(=C/C(C)=O)Sc2ccc(OC)cc21
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A series of benzothiazole compounds including TG003 were synthesized according to the procedures reported by Gupta et al. (27). In the case of TG003, a mixture of commercially available 5-methoxy-2-methylbenzothiazole (202 mg, 1.12 mmol) and ethyl iodide (2.70 ml, 33.7 mmol) was refluxed for 24.5 h. The precipitate was filtrated, washed with ethyl acetate (20 ml) on a funnel, and dried under reduced pressure to afford 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (270 mg, 0.805 mmol, 71.9%) as a pale green solid. To a suspension of 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (502 mg, 1.49 mmol) in acetonitrile (2.0 ml), acetic anhydride (330 μl, 3.49 mmol) and triethylamine (490 μl, 3.51 mmol) were successively added at room temperature. After refluxing for 2 h, the mixture was cooled to room temperature and concentrated under reduced pressure. Water (50 ml) was added to the residue, and the mixture was extracted with ethyl acetate (three times with 15 ml). The combined organic extracts were washed with brine (30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (18 g, CH2Cl2/ethyl acetate, 4:1) to afford (Z)-1-(3-ethyl-5-methoxy-2,3-dihydrobenzothiazol-2-ylidene) propan-2-one (TG003) (201 mg, 0.806 mmol, 54.1%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1c2n(c3c(-c4ccnc(Cl)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (50 mg, 59%), MS (ISP) m/z=335.4 [(M+H)+], mp 281° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OCCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(OCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
4-Phenethyloxybenzoic acid methyl ester 10 (7.66 g, 29.89 mmol) was dissolved in diethyl ether and chilled to 0° C. LiAlH4 was slowly added and allowed to stir at 0° C. for 3 hours. The mixture was quenched with H2O. After addition of 3N NaOH the mixture was allowed to stir for 30 min. The mixture was then acidified with 4.5N HCl, extracted, dried, and concentrated in vacuo to give about 6.7g of a crystalline (4-phenethyloxyphenyl)methanol 11.