Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH:22](=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)=O.O>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)[CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc2c(cc1Cl)CCNCC2c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: COc1cc2c(cc1Cl)CCN(C)CC2c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of benzazepine 3 (7.20 g, 19.6 mmol) in formic acid (2.3 g) was added 37% benzaldehyde (1.8 g). The mixture was heated to 90°-100° C. for four hours. After cooling the reaction mixture to room temperature, 4N hydrochloric acid solution (5.16 mL) was added. The mixture was condensed to dryness under reduced pressure. The residue was dissolved in water and then made basic with 25% sodium hydroxide solution. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a solid which was purified by column chromatography (silica gel; CH2Cl2 :MeOH:NH4OH;95:5:1) to give 4, 6.0 g (80%): mp 116°-118° C.; FT-IR (KBr)λ1500, 1380, 1270 and 1060 cm-1 ; 1H NMR (CDCl3)δd 7.65-7.35 and 7.21-6.90 (AA'BB',4H, ArH'), 7.13 (S, 1H, ArH #6), 6.38 (S, 1H, ArH #9), 4.40-4.10 (m, 1H, CH), 3.70 (S, 3H, OCH3), 3.10-2.45 (m, 6H, (CH2)3), 2.37 (S, 3H, NCH3). Anal. Calcd for C18H19BrCINO: C,H,N.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([O-:19])(=[O:18])=[O:17].[Na+:20]>[Cl-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([O-:19])(=[O:18])=[O:17].[Na+:20]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Reactant: COCCN
Agent: [Cl-]
Agent: [Na+]
Product: COCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Reaction time: 1 h
Yield: 87 %

Procedure:
To 30 ml of 2-methoxyethylamine, 27.5 g (0.1 mol) of sodium 2-chloro-5-nitrobenzenesulfonate was added. The reaction mixture was heated on a steam bath with stirring for 1 hour. After cooling, 100 ml of a saturated aqueous sodium chloride solution was added to the mixture. The crystals thus-precipitated were collected by filtration and washed with acetone to obtain about 30 g (yield: 87%) of sodium 2-(2-methoxyethylamino)-5-nitrobenzenesulfonate. This compound (30 g) was suspended in 100 ml of dimethylformamide. To the mixture anhydrous potassium carbonate (20 g) and methoxyethyl bromide (21g) were added, and heated on a steam bath with stirring for 1 hour. The reaction mixture was added to 100 ml of water and the insoluble materials were removed by filtration. To the filtrate an aqueous hydrochloric acid was added to render an acid condition. The crystals thus-precipitated were collected by filtration to obtain about 21 g (yield: 60%) of sodium 2-bis(2-methoxyethyl)amino-5-nitrobenzensulfonate. Melting Point: 202°-204° C.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][C:27]2[S:28][CH:29]=[CH:30][C:31]=2[CH3:32])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[CH3:32][C:31]1[CH:30]=[CH:29][S:28][C:27]=1[CH2:26][O:25][CH:23]1[CH2:22][NH:21][CH2:24]1
Reactant: Cc1ccsc1COC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccsc1COC1CNC1
Product: Cl
Reaction time: 3 h

Procedure:
1-Chloroethyl chloroformate (90 μL, 0.84 mmol) was added to a solution of 1-benzhydryl-3-((3-methylthiophen-2-yl)methoxy)azetidine (290 mg, 0.83 mmol) in dichloromethane (9 mL) at 0° C. The reaction mixture was stirred 3 hours, then 30 minutes at room temperature. Ethanol (9 mL) was added and the reaction mixture was stirred at 35° C. for an additional 3 hours. After concentration to dryness, the crude was triturated in pentane to give a yellow solid (200 mg, quantitative) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH:31]([O:34][C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:15])[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2cc(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 40.5 %

Procedure:
To a mixture of 220 mg of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 280 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 170 mg of DBU and 5 ml of DMF was added 65 mg of 55% sodium hydride while the former was stirred at room temperature. The resultant mixture was stirred for 2 hours at room temperature and then at 45° C. for 11 hours. The reaction mixture was concentrated to dryness under reduced pressure. Chloroform was added to the residue to dissolve the latter. The resultant solution was washed successively with a 10% aqueous solution of citric acid, a 5% aqueous solution of sodium hydrogencarbonate and saturated saline. The resulting chloroform layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol: 100/1), whereby 140 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.[CH3:43]O>[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[C:31]([CH3:43])[CH:32]=[C:33]([O:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: CO
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(OCCN(C)C)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Product: Cc1cc(OCCN(C)C)cc2c1CN(C(=O)c1cc(C(C)C)c(O)cc1O)C2
Yield: 35 %

Procedure:
(2,4-Bis-benzyloxy-5-isopropenyl-phenyl)-[5-(2-dimethylamino-ethoxy)-1,3-dihydro-isoindol-2-yl]-methanone (37 mg, 0.06 mmol) was hydrogenated in methanol at 50° C. over 10% palladium on charcoal using an H-cube hydrogenation apparatus, under free hydrogen conditions. The product was purified by preparative HPLC (basic method) to give the title compound as an off-white solid (9 mg, 35%). 1H NMR (MeOH-d4) 7.18 (1H, s), 6.77-6.65 (2H, br.m), 6.37 (1H, s), 4.85 (water obscuring CH2), 4.77 (2H, s), 4.08 (2H, t), 3.20 (1H, sept), 2.81 (2H, t), 2.39 (6H, s), 2.22 (3H, br.s), 1.21 (6H, d). MS: [M+H]+ 399.
Reaction SMILES: F[C:2]1C=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(C)[C@@H](CS([N:42]1CCN(C2N=CC(C3C=NC=CC=3)=CN=2)CC1)(=O)=O)C(O)=O>>[N:42]1[CH:2]=[CH:3][CH:4]=[C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:30])[CH3:31])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:18][CH2:19]3)=[N:10][CH:9]=2)[CH:6]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)NO
Yield: 88 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 3-methyl-2-(R)-[4-(5-pyridin-3-ylpyrimidin-2-yl)piperazine-1-sulfonylmethyl]butyric acid (0.137 g), to provide the title compound as a white solid (0.126 g, 88%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].Cl.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:23]([NH:25][NH2:26])=[O:24])[CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOCC>[CH2:18]([C:20]1[CH:21]=[C:22]([C:23]([NH:25][NH:26][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:5]=23)=[O:10])=[O:24])[CH:27]=[C:28]([CH3:30])[N:29]=1)[CH3:19]
Reactant: CCc1cc(C(=O)NN)cc(C)n1
Reactant: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NNC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (114 mg, 0.48 mmol), 2-ethyl-6-methyl-isonicotinic acid hydrazide hydrochloride (120.5 mg, 0.48 mmol) and DIPEA (0.49 mL) in DMF (8 mL) is added TBTU (190 mg, 0.59 mmol). The mixture is stirred at rt for 15 h. The mixture is diluted with Et2O (50 mL) and extracted with 1M aq. NaOH (2×20 mL). The aq. extracts are washed with EA (2×20 mL) and the combined organic phases are dried (MgSO4), filtered and evaporated to give crude 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazide; LC-MS: tR=0.83 min, [M+1]=400.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OC1CCNCC1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidin-4-ol (59.0 mg, 0.59 mmol). The title compound was obtained as a solid (45.0 mg, 19% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.06 (1H, m), 8.98 (2H, m), 8.51 (1H, s), 4.75 (1H, m), 4.07 (2H, m), 3.87 (1H, m), 3.66 (2H, m), 3.13 (1H, m), 2.98 (1H, m), 1.71 (2H, m), 1.23 (2H, m). MS m/z: 489.31, 491.26 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][C:19]1[C:24](=[O:25])[N:23]2[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]2=[N:21][C:20]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][C:19]3[C:24](=[O:25])[N:23]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]4=[N:21][C:20]=3[CH3:31])[CH2:6][CH:5]=2)=[CH:8]1
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCCl
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nc2c(C)cccn2c(=O)c1CCN1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
A solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)indole (25 g, 0.126 mol), 3-(2-chloroethyl)-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (33 g, 0.139 mol) and potassium carbonate (17.5 g, 0.127 mol) in acetonitrile (500 ml) and water (100 ml) was heated under reflux for 18 h. After cooling the precipitate was collected and washed with water, isopropyl alcohol and petroleum ether respectively. Yield 38 g (76%) of a pale yellow solid. M.p.: 210-212° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:18]Br>CCOCC>[Br:18][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CCCCCC(=O)c1ccccc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCC(Br)C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Anhydrous aluminum chloride (0.120 g.) is added to an ice-cooled solution of n-hexanophenone (21.1 g.) in anhydrous ether (20 ml.). The mixture is stirred and ice-cooled to a temperature below 10° C. during the dropwise addition of bromine (6.0 ml.) during 1 hour. The mixture is evaporated and the residual oil dissolved in ether (100 ml.). The solution obtained is washed first with a saturated aqueous solution of sodium thiosulphate (3× 30 ml.) and then with water. After drying (sodium sulphate) the ethereal solution is evaporated to give α-bromo-n-hexanophenone as an oil (28.0 g.) which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: NC1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(Cn2c(N3CCC(Nc4ncccn4)CC3)nc3ccccc32)cc1

Procedure:
A mixture of 1.71 g (0.005 mole) of 1-{1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl}-4-piperidinamine, 0.57 g (0.005 mole) of 2-chloropyrimidine, 0.43 g (0.052 mole) of sodium bicarbonate and 19 ml of ethanol is brought to reflux temperature for 2 days and 2 nights. The mixture is evaporated to dryness, and water and 2N sodium hydroxide are added. The product is taken up with methylene chloride, decanted and washed with water. The product is chromatographed on a silica column (eluent: dichloromethane/methanol, 47:3).
Reaction SMILES: [C:1](C1C=CC2N(CC3N=CN(C(OC(C)(C)C)=O)C=3)C[C@@H](CC3C=CC=CC=3)N(S(C)(=O)=O)CC=2C=1)#N.O[C:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[C:41](C)[N:40]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[ClH:55].BrC1C=CC2N(CC3N=CNC=3)CCN(C(C3C4C(=CC=CC=4)C=CC=3)=O)CC=2C=1.ClC1C([N+]([O-])=O)=CC=C(C)N=1>C1(C)C=CC=CC=1>[Cl:55][C:41]1[CH:42]=[CH:43][C:44]([N+:45]([O-:47])=[O:46])=[C:39]([CH3:1])[N:40]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: Cc1ccc([N+](=O)[O-])c(O)n1
Reactant: Cl
Agent: Cc1ccc([N+](=O)[O-])c(Cl)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 92 °C

Procedure:
A mixture of Compound A, 2-hydroxy-3-nitro-6-methylpyridine (0.93 g, 6.05 mmol) and phosphorus pentachloride (48.9 g, 235 mmol) in toluene (10 mL) was heated at 92° C. for 16 hours and cooled to 0° C. Ice was added and the mixture was stirred and partitioned. The aqueous layer was washed with toluene and the combined organic phases were dried (magnesium sulfate), filtered and evaporated to afford 1.03 g of a 6:1 mixture of Compound B and 2-chloro-3-nitro-6-methylpyridine (100%) as a reddish brown crystalline semi-solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Methyl 5-chloropyrazine-2-carboxylate (CAS [33332-25-1], 1 g, 5.79 mmol) was dissolved in a mixture of THF (50 ml) and water (50 ml). Lithium hydroxide monohydrate (243 mg, 5.79 mmol) was added and the reaction mixture was stirred at RT overnight. The pH was adjusted to 1 with 1M HCl and the product was extracted with three portions of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 50 g, 0 to 20% MeOH in DCM) to yield the title compound as white solid (741 mg, 81%). MS (ISP): m/z=159.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[ClH:11]>C(O)C.CO.[Pd]>[ClH:11].[ClH:11].[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1
Reactant: Cc1cc(N)ncc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(N)ncc1CN

Procedure:
A solution of 2-amino-5-cyano-4-methylpyridine (200 mg, 1.50 mmol) in a mixture of ethanol (17 mL) and methanol (7 mL) was hydrogenated for 48 h at atmospheric pressure in the presence of 1N hydrochloric acid (3 mL) and 10% palladium-on-charcoal (50 mg). The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. Crystallization from chloroform-methanol afforded pure title compound; yield 98 mg (31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[CH2:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11].[CH3:16][Mg]Br.CCOCC>C1(C)C=CC=CC=1.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]([NH:15][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH3:16])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CCS(N)(=O)=O
Reactant: C[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCS(=O)(=O)NC(C)c1cncc(Br)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a vial is added 5-bromonicotinaldehyde (300 mg, 1.61 mmol) and ethanesulfonamide (220 mg, 2.02 mmol) in 6 ml of toluene, followed by the addition of titanium(IV) isopropoxide (1 ml, 3.23 mmol). The reaction mixture is stirred at 120° C. for 6 hours. The reaction mixture is concentrated. The residue is dissolved in 5 ml of THF and is cooled to −40° C., methylmagnesium bromide, 3M in ether (1.6 ml, 4.84 mmol) is added dropwise. The reaction mixture is warm up and stirred at room temperature for 18 hours. The reaction mixture is diluted with EtOAc, washed with saturated NH4Cl, (aq.) brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 130 mg of ethanesulfonic acid [1-(5-bromo-pyridin-3-yl)-ethyl]-amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=3)[NH2:17])[N:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([NH:17][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26])[CH:18]=3)[N:11]=2)[N:8]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)cn2n1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)cn2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
To a stirred solution of 5-(6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.050 g, 0.206 mmol) in acetonitrile (5 mL) containing pyridine (0.618 mmol) is added trimethylacetylchloride (0.206 mmol). The mixture is stirred at room temperature for 4 hours, concentrated to dryness, then purified via chromatography (hexanes to EtOAc) to afford the title compound (0.060 g, 86%) as a white solid: Rf 0.57 (EtOAc); LCMS (m/z)=339.4 [M+H]+, tR=6.37 min. (10 min run)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4OC)CC3)c(OC)nc2c1
Yield: 84 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 3.13-3.16 (m, 4H), 3.66-3.78 (m, 4H), 3.88 (s, 3H), 3.90 (s, 3H), 4.12 (s, 3H), 6.87-7.14 (m, 7H), 7.76 (d, J=5.1 Hz, 1H).
Reaction SMILES: ClC1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([NH:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[N:3]=1.C([N:31](C(C)C)C(C)C)C.C(O[CH2:42][CH3:43])(=O)C>[C-]#N.[Zn+2].[C-]#N>[C:19]1([CH2:18][NH:17][C:4]2[N:3]=[C:43]([C:42]#[N:31])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nc(NCc2cccc3ccccc23)c2ncn(C3CCCCO3)c2n1
Reactant: CCOC(C)=O
Reactant: CCN(C(C)C)C(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1nc(NCc2cccc3ccccc23)c2nc[nH]c2n1
Temperature: 100 °C

Procedure:
Tetrakistriphenylphosphine palladium (1.1 g, 0.95 mmol) was added to a solution of 2-chloro-N-(1-naphthylmethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (7.5 g, 19 mmol) (Preparation 9), zinc cyanide (1.4 g, 11.9 mmol) and N-ethyl-N-isopropyl-2-propanamine (4 ml, 23 mmol) in N′N′-dimethylformamide (80 ml). The reaction mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and ethyl acetate (250 ml) was added. The resulting mixture was extracted with aqueous sodium hydroxide solution (2M, 100 ml). The sodium hydroxide layer was extracted with more ethyl acetate (50 ml). The ethyl acetate layers were combined and washed with water (50 ml) and then dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (100 ml) and the solvent was removed under reduced pressure again. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:2 by volume) increasing in polarity to dichloromethane:methanol (90:10 by volume). The solvent was removed under reduced pressure to give the title compound (1.8 g) as a foam. The major product of this reaction was actually 6-[(1-naphthylmethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (2.7 g).
Reaction SMILES: [CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])CCC(OC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:36]O>C(O)(C)C>[CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[OH:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OO
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)CCC(=O)OC
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCC
Yield: 43.5 %

Procedure:
Using the general procedure of Example 2, 57.5 grams (0.116 mol) of the product of Example 7 in 450 ml of isopropanol is oxidized using 5.6 ml (0.15 Mol) of 70% aqueous hydrogen peroxide solution to give 21.5 grams (44% yield) of the above-named product as a white solid melting at 94°-96° C.