Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:21][Mg+].[Br-].O>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:3]=1[C:4](=[O:5])[CH3:21]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc(-c2cccc(F)c2)ccc1F
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-N-methoxy-N-methyl-benzamide (1.8 g, 6.5 mmol, 1.0 eq) in THF (14 mL) at −20° C. was added MeMgBr (3.2 mL, 9.7 mmol, 1.5 eq). The mixture was stirred at 0° C. for 2 h then water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 20:1 to 10:1) to give the title compound as a white solid (1.3 g, 86%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10](Cl)[C:11]([CH3:13])=[CH2:12])(=[O:3])[CH3:2].[I-].[Na+].C[N+]1([O-])CC[O:22]CC1.CN(C)C=O>O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH:12]=[O:22])(=[O:3])[CH3:2]
Reactant: C=C(C)C(Cl)CCC(C)=CCOC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)CCC=C(C)C=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
1.15 g (3.99 mmols) of 6-chloro-3,7-dimethyl-2,7-octadienyl acetate (purity: 80%), 0.91 g (6 mmols) of sodium iodide and 1.36 g (10 mmols) of N-methylmorpholine N-oxide (monohydrate) were placed in a flask, to which was added 5 ml of N,N-dimethylformamide. The mixture was agitated at 50° C. for 4 hours. After completion of the reaction, 10 ml of water was added to the reaction mixture, followed by extraction twice each with 70 ml of diethyl ether. The resulting extract was washed with each 20 ml of 3% sulfuric acid, a saturated sodium hydrogen carbonate aqueous solution and a 10% sodium sulfite aqueous solution, and dried with magnesium sulfate. After drying, the solvent was removed by distillation from the solution and the resulting residue was purified by column chromatography using silica gel [eluent: ethyl acetate/hexane (volume by ratio)=1/9-1/3], thereby obtaining 0.627 g of 8-acetoxy-2,6-dimethyl-2,6-octadienal. Yield: 75%. The results of an instrumental analysis of the 8-acetoxy-2,6-dimethyl-2,6-octadienal are as follows.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[Li+].CC([N-]C(C)C)C.[N:25]1([C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:43][CH3:44])[C:37](N(OC)C)=[O:38])=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[N:26]1>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[N:25]1([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([O:43][CH3:44])[C:37]([C:12]3[S:13][CH:14]=[C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)[N:11]=3)=[O:38])=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cccn2)cc1
Reactant: COc1cc(-c2cscn2)cc(OC)c1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(-c2csc(C(=O)C(OC)c3ccc(-n4cccn4)cc3)n2)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a −20° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0.092 g, 0.305 mmol) in anhydrous THF (2 mL) under argon was added a solution of LDA (0.18 mL of a 2.0 M solution in THF/heptane/ethylbenzene, 0.37 mmol) dropwise. After stirring for 30 min, the reaction was cooled to −78° C. and a solution of 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.15 g, 0.55 mmol) in anhydrous THF (1.5 mL, 1.0 mL) was added dropwise. After stirring for 90 min, the mixture was quenched with brine and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by chromatography (0-35% EtOAc-hexanes) gave 2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxyethanone as a yellow solid (0.030 g, 20% yield). MS: m/z 514.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:4][CH:5]=[N:6][C:7]=1[CH2:8][S+:9]([O-:19])[C:10]1[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[N:18]=1.CCCCCC.C(N(CC)CC)C.CCCCCC.CC(O)C>CC(O)C>[CH3:1][C:2]1[C:7]([CH2:8][S@:9]([C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[O:19])=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][C:22]([F:25])([F:23])[F:24]
Reactant: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Yield: 27.2 %

Procedure:
Lansoprazole (racemate) (34.2 g) was dissolved in 2-propanol (1,710 ml) and hexane (1,140 ml) containing triethylamine (0.2%) and fractionated by HPLC (column: CHIRALCEL OD 50 mm dia.×500 mm, temperature: room temperature, mobile phase: hexane/2-propanol=85/15, flow rate: 60 ml/min, detection wavelength: 285 nm, single injection: about 300 mg) to isolate the individual optical isomers. Fractions of an optical isomer of shorter retention time were combined and concentrated; the individual lots were combined and dissolved in ethanol (250 ml); after triethylamine (3 ml) was added, the solution was filtered through a 0.45 μm filter. After the filtrate was concentrated, hexane was added, and the filtrate was again evaporated to dryness to yield R(+)-lansoprazole (9.31 g, optical purity 98.3% ee) as an amorphous substance.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[CH3:24])/[CH:21]=[CH:22]/[CH3:23])=[CH:15][CH:14]=1)[CH3:11].I([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[C:5]([O:4][C:3]([N:2]1[CH:22]([CH3:23])[CH:21]=[C:20]([CH3:24])[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:10][CH3:11])=[CH:18][CH:17]=2)[O:1]1)=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: C/C=C/C(C)=C/c1ccc(OCC)cc1
Reactant: CC(C)(C)OC(=O)NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CCOc1ccc(C2ON(C(=O)OC(C)(C)C)C(C)C=C2C)cc1
Temperature: 4 °C
Reaction time: 4 h

Procedure:
A solution of t-butyl N-hydroxycarbamate (11.14 g, 84 mmol) in dichloromethane (300 ml) was added dropwise over 25 mins to a stirred mixture of 1-(4-ethoxyphenyl)-2-methyl-pent-1E,3E-diene (8.46 g, 42 mmol) and tetrabutylammonium periodate (32.6 g, 75 mmol) in dichloromethane (300 ml) cooled to 4° C. under nitrogen atmosphere. After stirring for 4 h at 3-4° C. the reaction mixture was washed with 2M aqueous sodium carbonate containing sodium metabisulphite and then twice with water. The dichloromethane solution was dried over magnesium sulphate, filtered and evaporated to an oil (33.1 g). This was purified by chromatography twice on silica eluting with n-hexane: diethyl ether 4:1 to give 2-t-butoxycarbonyl-3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine as a yellow oil.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH2:27][CH2:28][CH2:29][C:30](=O)[CH3:31])[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]2[C:19]=1[CH:18]=[CH:17][C:16]([Cl:20])=[CH:15]2)=[O:10])[CH3:7].C([BH3-])#N.[Na+]>CO>[ClH:20].[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH2:27][CH2:28][CH2:29][CH:30]([NH:4][CH:1]([CH3:3])[CH3:2])[CH3:31])[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:14]2[C:19]=1[CH:18]=[CH:17][C:16]([Cl:20])=[CH:15]2)=[O:10])[CH3:7]
Reactant: CC(C)N
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)NC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5.2 ml. of isopropylamine in 25 ml. of methanol is treated with 4 ml. of 5-N methanolic hydrochloric acid. To this there are added successively under an atmosphere of argon at 20°-25° C. 3.85 g. of 5-chloro-2-(4-oxopentyl)-3-phenylisoindole-1-carboxylic acid ethyl ester and 0.4 g. of sodium cyanoborohydride and the mixture is then stirred for 48 hours at room temperature. While cooling, the mixture is made acidic with concentrated hydrochloric acid, stirred for an additional 1 hour at room temperature and subsequently evaporated to dryness under reduced pressure. The residue is made alkaline with 1-N sodium hydroxide with addition of ice and is extracted with ether. The extract is dried over sodium sulfate, concentrated, and the oily residue chromatographed on 200 g. of silica gel with a mixture of ethyl acetate/tetrahydrofuran/triethylamine (40:10:1). The homogeneous fractions are combined, concentrated, dissolved in ether and treated with an excess of ethereal hydrochloric acid. The precipitated hydrochloride is removed by filtration and washed with ether. After recrystallization from acetone, there is obtained 5-chloro-2-[4-(isopropylamino)pentyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 183°-185° C. (decomposition).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH:45]2[CH2:47][CH2:46]2)[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH:45]2[CH2:46][CH2:47]2)[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C2CC2)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C2CC2)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogen carbonate (1.6 g) and dimethyl sulfoxide (8 mL) was stirred at 50° C. for 30 min, 4′-[(4-butyl-2-cyclopropyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.80 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL), N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and recrystallized from dichloromethane and diisopropyl ether to give the title compound (0.62 g, 78%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C(N(CC)CC)C>[CH2:20]([NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of n-butylamine are added dropwise. After the addition is completed, the heating is continued for ten minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil is crystallized with 300 ml. of methanol to give 4-butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester, yield 110 g. (70%), m.p. 33°-35° (methanol).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:21]=[C:20]([CH3:22])[C:19]([CH:23]=O)=[CH:18][N:17]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:25]([O:28][CH2:29][CH3:30])([CH3:27])=[O:26].O>C1COCC1>[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:21]=[C:20]([CH3:22])[C:19](/[CH:23]=[CH:27]/[C:25]([O:28][CH2:29][CH3:30])=[O:26])=[CH:18][N:17]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccccc3)C2)nc1C
Temperature: 15 °C

Procedure:
A solution of diethylphosphonoacetcacid ethyl ester (1.79 g) in THF (5 ml) was added dropwise to a mixture of 60% sodium hydride in oil (341 mg) in THF (60 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarbaldehyde (1.58 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate (1.7 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)=[O:6]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 5 °C
Yield: 73 %

Procedure:
To a 22 L open-mouth round bottom flask fitted with a three-necked flange head, a mechanical stirrer, a nitrogen inlet and an outlet connected to an HCl scrubbing tower was added 2,5-dichlorobenzoylchloride (4500 g, 21.5 mol) and phenyl ether (5489 g, 32.3 mol). The solution was cooled in ice to 5° C. under stirring and aluminum chloride (3700 g, 27.8 mol) was added slowly. After about 300 g aluminum chloride was added, the solution started to foam violently. The rest was added carefully over about 10 min. On several occasions, the stirring had to be stopped to control the foaming. The temperature of the reaction mixture was about 35° C. after the addition. The mixture was then stirred for about 30 min. and poured into about 20 gallons of ice water. The large reddish mass was dissolved by adding about 12 L of methylene chloride and stirring. The organic layer was separated and the aqueous layer was extracted with some methylene chloride. After methylene chloride was removed from the combined organic layer by distillation, the residue was recrystallized twice from cyclohexane (2×10 L), washed with cooled hexane, air dried and then vacuum dried to afford 5387 g monomer (73%). The mother liquor was kept for later recovery of remaining product.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH:8]1([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1>CO.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH:8]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: C1CN(C2CC2)CCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
4.0M HCl in dioxane (42.7 mL, 170.78 mmol) was added to a stirred solution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (7.73 g, 34.16 mmol) in a mixture of methanol (50.0 mL) and ethyl acetate (200 mL). The resulting suspension was stirred at room temperature for 24 h under nitrogen. The white solid filtered off to give 1-cyclopropylpiperazine dihydrochloride (6.30 g, 93%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])#[N:2].CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([N:14]([CH2:13][CH:8]1[C:9]2[C:4](=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:35]
Reactant: CC(C)(C)OC(=O)NCCNCC1CCCc2c(C#N)cccc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1CCCc2c(C#N)cccc21)C(=O)CCl
Reaction time: 8 h

Procedure:
A solution of tert-Butyl (2-{[(5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (0.20 g, 0.61 mmol) in DCM (5 mL) was added Et3N (74 mg, 7.2 mmol), followed by chloro-acetyl chloride (81 mg, 7.2 mmol). The reaction mixture was stirred overnight. The product was purified by prep-TLC (Pet Ether:EtOAc=1:1) to give the title product. MS m/z: 406 [M+1]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Br[C:8]1[CH:13]=[CH:12][N:11]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=[C:10]2[N:9]=1.C(N(CC)CC)C>O>[N:9]1[C:10]2[N:11]([C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:12]=[CH:13][C:8]=1[N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1
Reactant: OC1CNC1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: OC1CN(c2ccn3c(n2)nc2ccccc23)C1
Temperature: 25 °C
Yield: 99 %

Procedure:
Azetidin-3-ol hydrochloride (0.022 g, 0.202 mmol), 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.05 g, 0.202 mmol) and Triethylamine (0.028 ml, 0.202 mmol) were heated to 100° C. for 10 minutes in a microwave. Let the reaction cool to room temperature. Diluted with water and vacuum filtered ppt. Washed with water to afford 1-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)azetidin-3-ol (0.048 g, 0.200 mmol, 99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>[H-].[Na+].CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3ncc(Br)cc32)cc1

Procedure:
Scheme B shows a general method for preparing substituted 4-azaindoles (compounds A1 and A3) depicted in Scheme A. The method begins with the installation of an amine protecting group (G) on starting material B1, in which for example, 6-bromo-1H-pyrrolo[3,2-b]pyridine is reacted with TsCl in sodium hydride and DMF to give 6-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine. Treatment of the resulting protected intermediate B2 with an oxidizing agent (e.g., mCPBA) gives an N-oxide intermediate B3, which undergoes cyanation via, for example, reaction with trimethylsilyl cyanide in the presence of base (e.g., tertiary amine such as Et3N) and DMF. The resulting intermediate B4 is deprotected (e.g., Ts is removed via contact with aq NaOH) and is optionally N-alkylated through reaction with an alkyl halide B6 (e.g., X2 is I) under basic conditions (e.g., NaH in DMF). As in Scheme A, reaction of the resulting bromide B7 with a boronic acid or boronate, stannane, or amine (A4) under Suzuki, Stille, or Buchwald conditions, respectively, gives an R1-substituted 4-azaindole intermediate B8. Treatment of bromide B7 or intermediate B8 with a reducing agent (e.g., borane-THF) or reaction with an alkyl-Grignard or alkyl-lithium reagent followed by reduction with sodium borohydride gives, respectively, an amine intermediate B9 or desired compound A1. As in Scheme A, reaction of the amine intermediate B9 with a 6-halopyrimidine derivative A2 gives desired compound A3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(OC)c(OC)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate (28 mg, 0.091 mmol) and 1-(3-methoxy phenyl) piperazine (27 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (27 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:2) mixture and concentration gave 26 mg of the titled compound (yield, 64%). 1H NMR (300 MHz, CDCl3) δ 3.27-3.29 (m, 4H), 3.78-3.81 (m, 7H), 3.94 (s, 3H), 3.97-3.98 (m, 1H), 4.00 (s, 3H), 4.15 (s, 3H), 6.47-6.49 (m, 2H), 6.56-6.58 (m, 1H), 7.11 (s, 1H), 7.14-7.27 (m, 3H).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[NH2:15][C:16]1[CH:17]=[C:18]([C:23]([F:26])=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20]>ClCCl.C(OCC)C>[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:25]1[CH:24]=[C:23]([F:26])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[NH2:15]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)c1cc(N)ncc1F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cc(N)[n+](N)cc1F
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To an ice-cooled white suspension of O-(mesitylsulfonyl)hydroxylamine (1.18 g, 5.48 mmol) in dichloromethane (8.44 ml) is added dropwise a solution of methyl 2-amino-5-fluoroisonicotinate (932 mg, 5.48 mmol) in dichloromethane (2.53 ml). The resulting light brown suspension is stirred for 2 hours at room temperature. The suspension is cooled to −5-0° C., diluted with diethylether (15 ml) and stirred for 30 minutes. The solid is collected by filtration, washed with diethyl ether and dried affording 1,2-diamino-5-fluoro-4-(methoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate (1.72 g, 81.4%) as a light brown solid. MS: m/z=186.0 (M+).