Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CN(C=O)C>C(OCC)(=O)C>[N:22]([CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:4]=1)=[N+:23]=[N-:24]
Reactant: O=c1c(CBr)cn(-c2ccccc2Cl)c2cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a 25 mL round-bottom flask containing the crude 3-bromomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (410 mg, 1.07 mmol) was added sodium azide (83.5 mg, 1.28 mmol) and DMF (9 mL). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude was purified by flash chromatography (silica gel, 24 g, 0-50% ethyl acetate in hexanes) to yield 3-azidomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (215 mg, 58%) as a light yellow solid. 1H NMR (DMSO-d6) δ ppm 8.17-8.36 (m, 2H) 7.83 (ddd, J=9.8, 7.9, 1.7 Hz, 2H) 7.68 (ddd, J=9.8, 7.8, 1.6 Hz, 2H) 7.48 (dd, J=8.7, 1.8 Hz, 1H) 6.70 (d, J=1.8 Hz, 1H) 4.09-4.44 (m, 2H). MS calcd. for C16H10Cl2N4O [(M+H)+] 346.0, obsd. 345.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].FC(F)(F)C(O)=O.[C:17]1([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(S)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
2-Chloro-4-fluoro-benzenethiol (250 g, 1.54 mol) was dissolved in dichloromethane (1.25 L) and trifluoroacetic acid (120 mL, 1.57 mol) followed by triphenylmethanol (400 g, 1.54 mol) were added at room temperature (ice bath cooling necessary during addition of triphenylmethanol). The mixture was stirred for 1.5 h at room temperature, concentrated and dried in vacuo to yield the title compound as a yellow solid (622 g, 99% purity by HPLC, 99%), that was used without further purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 6.55 (ddd, J=2.9 Hz, 8.0 Hz, 8.9 Hz, 1H), 6.91 (dd, J=6.2 Hz, 8.9 Hz, 1H), 6.97 (dd, J=2.9 Hz, 8.6 Hz, 1H), 7.20-7.27 (m, 9H), 7.34-7.39 (m, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].[I-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 34.0 g (0.2 mole) or p-phenylphenol (Eastman) and 10.8 g (0.2 mole) of sodium methoxide (MCB) in 500 ml of dry dimethylformamide is heated and stirred on a steam bath for 0.5 hour, after which 27.3 g (0.2 mole) of 6-chlorohexan-1-ol (MCB) and about 2 g of sodium iodide are added. The mixture is heated to reflux with stirring, and then allowed to cool to room temperature. The reaction mixture is partitioned between ether/acetone and water, and the organic phase is extracted with base, washed with water and brine, dried (Na2SO4), and the solvent evaporated. The resultant white solid product is recrystallized twice from methanol/acetone, to give the desired product, m.p. 103°-105° C.
Reaction SMILES: Cl.[CH:2]1[C:18]2[CH:17]=[C:16]3[C:8](=[C:9]4[C:14](=[N:15]3)[CH:13]=[CH:12][CH:11]=[CH:10]4)[NH2+:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:19]([O-:22])([OH:21])=[O:20].CCOC(C)=O.CCCCCC>C(O)(=O)C>[N+:19]([C:10]1[C:9]2[C:14]([CH:13]=[CH:12][CH:11]=1)=[N:15][C:16]1[C:8]=2[NH:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:18]=2[CH:17]=1)([O-:21])=[O:20].[N+:19]([C:12]1[CH:11]=[CH:10][C:9]2[C:14]([CH:13]=1)=[N:15][C:16]1[C:8]=2[NH:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:18]=2[CH:17]=1)([O-:22])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: C1=C2N=c3ccccc3=C2[NH2+]c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c3[nH]c4ccccc4cc-3nc2c1
Product: O=[N+]([O-])c1cccc2nc3cc4ccccc4[nH]c-3c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of quindolinium hydrochloride [(3.2 g, 1.25 mmol; obtained by acidification of quindoline (example 2) with HCl)], in glacial acetic acid (100 mL) was added dropwise at 0° C. HNO3 (d 1.54, 50 mL). The reaction mixture was stirred at room temperature for 24 hours and poured into ice. The resulting precipitate was collected and washed with a saturated solution of NaHSO4, water and dried to afford 2.4 g 72.5%) of an orange solid. TLC (silica gel, EtOAc-hexane, 1:1) showed two major spots with Rf 0.56 and Rf 0.30. Separation of 1 g of this mixture by LPLC, eluting with EtOAc-hexane (1:3), afforded 290 mg of 6-nitroquindoline (Rf 0.56) and 600 mg of 8-nitroquindoline. The structures of the two compounds were determined by COSY, HMQC, and HMBC 2D-NMR.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:7][CH:6]=1)(=O)C.[N+:23]([O-])([O-:25])=[O:24].[K+]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2CC(=O)O
Temperature: 0 °C
Yield: 69.3 %

Procedure:
57.5 g (0.19 mol) of 7-acetamido-1-(ethoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 575 mi of concentrated sulfuric acid. The solution was cooled to 0° C., and 19.0 g (0.19 mol) of potassium nitrate were added a little at a time. The cooling was then removed and the mixture was stirred until the reaction was complete and was then poured into 2 1 of ice-water and heated on a water bath for 2 h. The pH was then adjusted with aqueous ammonia solution to about 4-5, and the precipitate was filtered off with suction. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (mobile phase: methanol/tetrahydrofuran/water=5:4:1+2.5% glacial acetic acid). The resulting product was combined with the first precipitate to yield 36.9 g (70%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].Cl.Cl[CH2:33][C:34]1[N:35]=[C:36]([CH3:39])[S:37][CH:38]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:33][C:34]3[N:35]=[C:36]([CH3:39])[S:37][CH:38]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(N3CCCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
Treat a solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.89 g, 2.77 mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride (0.15 g, 3.05 mmol, 49% dispersion in oil ) at room temperature. After 15 minutes, add slowly a solution of 4-chloromethyl-2-methylthiazole hydrochloride (0.56 g, 3.05 mmol, Lancaster Synthesis) and dimethylformamide (10 mL). After stirring 12 hours at room temperature, add water (10 mL) slowly and extract with dichloromethane.(150 mL). Wash the organic phase with water (3×10 mL), dry (Na2SO4) the organic layer, filter, concentrate the filtrate to remove the solvent and purify the residue by chromatography on silica gel eluting with 5% methanol in dichloromethane. Concentrate the desired fractions to afford 1.02 g of 4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:9]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)ncn1
Temperature: 125 °C
Yield: 39.2 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.32 g, 2.5 mmol), phenylboronic acid (0.38 g, 3.13 mmol), saturated aqueous sodium carbonate (0.80 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol) were suspended in a mixture of dimethoxyethane (15 mL)/ethanol (2 mL)/water (2 mL). The mixture was heated in the microwave at 125° C. for 20 min then concentrated in vacuo. The residue was purified by column chromatography (10-60% ethyl acetate/hexanes) to afford 6-phenylpyrimidin-4-amine (167 mg, 0.98 mmol, 39% yield) as an off-white solid. MS (LC/MS) R.T.=0.99; [M+H]+=172.23.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:5].[NH2:16][C:17]([NH2:19])=[S:18].C([O-])(=O)C.[Na+]>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[N:16]=1
Reactant: O=C(CCl)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(C(=O)c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 50 °C
Yield: 32.4 %

Procedure:
A mixture of chloromethyl-(4-nitrophenyl)diketone (2 g), thiourea (1.5 g) and sodium acetate (1.6 g) in ethanol (20 ml) was heated at 50° C. for 4 hours with stirring. The mixture was concentrated in vacuo and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-(4-nitrobenzoyl)thiazole (0.71 g, yield: 32.4%). mp: 194°-198° C. (dec.) IR (Nujol): 3300-3450, 1660, 1600, 1520, 1350 cm-1
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazole-4-yl]propionate (381 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for four hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (327 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 129–130° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](O)=[O:20])[C:3]=1[S:22][C:23]([F:26])([F:25])[F:24].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCOCC1.O>[CH:27]1([NH:30][C:19]([C:4]2[C:3]([S:22][C:23]([F:24])([F:26])[F:25])=[C:2]([NH2:1])[N:6]([C:7]3[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=3[Cl:18])[N:5]=2)=[O:20])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: Nc1c(SC(F)(F)F)c(C(=O)O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(SC(F)(F)F)c(C(=O)NC2CC2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthio-1H-pyrazole-3-carboxylic acid (0.85 g, 1.83 mmol) and 1,1-dicarbonylimidazole (0.36 g, 2.20 mmol) in dioxane was heated to. 55° C. for 2 hours. Cyclopropylamine (0.20 ml, 2.83 mmol) was then added and stirring continued at 55° C. for 6 hours. The cooled mixture was diluted with water, extracted with ethyl acetate, washed with aqueous potassium hydrogensulfate (5%), dried over magnesium sulfate and evaporated to give the title compound (0.762 g, yield 87%) as off-white crystals, mp 193° C., 1H NMR (CDCl3): 0.64 (m, 2H, cyclopropyl), 0.83 (m, 2H, cyclopropyl), 2,87 (m,1H, cyclopropyl), 4.31 (bs, 2H, NH2), 6.82 (bs,1 H, C(O)NH), and 7.80 (s, 2H, Ar—H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:13]=[C:6]2[C:7]([CH3:12])=[N:8][CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Cl-:1].[CH3:11][C:10]1[N:5]2[N:4]=[C:3]([CH2:2][P+:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:13]=[C:6]2[C:7]([CH3:12])=[N:8][CH:9]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ncc(C)n2nc(CCl)nc12
Solvent: CC#N
Product: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Product: [Cl-]
Yield: 110.8 %

Procedure:
A mixture of 2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (prepared as described in WO2009152825) (500 mg, 2.54 mmol, Eq: 1.00) and triphenylphosphine (667 mg, 2.54 mmol, Eq: 1.00) in acetonitrile (24.9 ml) was refluxed for 18 hours under argon atmosphere. The solvent was evaporated the light pink solid was triturated with ether, the solid was filtered off, washed with ether and dried in vacuo affording (5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium chloride (1.292 g, 72.5%) as a light pink solid. MS-Cl: m/e=423 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc(C)c(C(=O)O)n1
Product: Cc1ccc(C)c(C(=O)Nc2nnn[nH]2)n1
Yield: 62 %

Procedure:
0.76 g of 3,6-dimethyl-2-pyridinecarboxylic acid, 0.82 g of N,N'-carbonyldiimidazole and 0.51 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.68 g of N-(5-tetrazolyl)-3,6-dimethyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.[C:33]1([CH3:61])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:60])[CH2:46][CH2:47][C:48]2[CH:53]=[C:52]([S:54](Cl)(=[O:56])=[O:55])[CH:51]=[CH:50][C:49]=2[O:58][CH3:59])(=[O:41])=[O:40])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]1([CH3:61])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:60])[CH2:46][CH2:47][C:48]2[CH:53]=[C:52]([S:54]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:56])=[O:55])[CH:51]=[CH:50][C:49]=2[O:58][CH3:59])(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE, 800 mg, 2.17 mmol) and 3 mL of Et3N in 20 mL of CH2Cl2 was added the chlorosulfonyl ester (Intermediate 60, 1.2 g, 2.60 mmol, 1.2 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature 1 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give Intermediate 63 (1.2 g, 70%) as an off-white foam.
Reaction SMILES: [F:1][C:2]1[C:3](=[NH:20])[NH:4][C:5](=[O:19])[N:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:4]1[C:3](=[NH:20])[C:2]([F:1])=[CH:7][N:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[C:5]1=[O:19])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(=N)[nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 20 mL microwave vial, 5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one (111 mg, 0.37 mmol) was stirred at room temperature in dimethyl formamide (3 mL) together with anhydrous potassium carbonate (210 mg, 0.55 mmol). Benzylbromide (89 μL, 0.75 mmol) was added. The reaction was capped and placed on a Biotage Initiator microwave reactor for 20 min at 130° C., with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc; 250 mL), and washed with water (H2O; 3×100 mL). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and the solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2, EtOAc/Hexanes gradient) afforded 3-benzyl-5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one as a pale yellow oil (15 mg; 11%): 1H NMR (400 MHz, CDCl3) δ 8.09-8.02 (m, 3H), 7.38-7.27 (m, 6H), 7.00-6.96 (m, 2H), 4.65 (d, J=5.7 Hz, 2H), 3.87 (s, 3H). ESIMS m/z 391 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COC(CN)OC
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NCC(OC)OC)n1
Temperature: 40 °C

Procedure:
A mixture of 2-chloro-6-(methyloxy)-3-nitropyridine (10 g, 53 mmol), aminoacetaldehyde dimethylacetal (5.6 g, 6.2 ml, 53 mmol) and potassium carbonate (7.4 g, 53 mmol) in acetonitrile (100 mL) and DMF (10 mL) was heated at 40° C. for 30 minutes. The mixture was filtered and extracted with DCM and brine. The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a yellow solid (12.4 g, 90%).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]=2[C:12](OCC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].O>CO.C1COCC1>[OH:24][NH:23][C:12]([C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1-c1ccccc1
Reactant: NO
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1cc(-c2ccccc2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a stirring solution of ethyl 2,5-diphenylthiophene-3-carboxylate 70 (0.440 g, 1.427 mmol) in methanol (7 mL) and THF (7 mL) was added 50% hydroxylamine in water (1.4 mL, 23.31 mmol) and the resulting mixture was stirred at room temperature for 45 minutes then concentrated to one third volume. The solution was neutralized with 3N HCl to pH 7 and the desired product was filtered then purified by Gilson (55 to 95% MeOH in H2O) to afford the title compound 71 (87 mg, 21% yield) as a white solid. 1H NMR: (DMSO-d6) d(ppm) 1H, 10.96 (s, 1H), 9.14 (s, 1H), 7.71-7.69 (m, 2H), 7.57-7.55 (m, 3H), 7.48-7.34 (m, 6H) LRMS (ESI): (calc) 295.36 (found) 296.22 (MH)+
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N:31](CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25][C:28]#[N:31])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Oc2cccc(CO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Oc2cccc(CC#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-yloxy)-phenyl]-methanol (0.092 g, 0.243 mmol) and N,N-diisopropylethylamine (3 μL, 0.486 mmol) were dissolved in DCM at 0° C. Methanesulfonyl chloride (28 μL, 0.365 mmol) was added and the reaction stirred for 5 minutes then sodium cyanide (0.024 g, 0.486 mmol) and DMF (2 mL) were added. The reaction was then concentrated under vacuum and DMF (2 mL) was added. The reaction was heated to 60° C. for 20 minutes then submitted to aqueous workup to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14]C=[CH:12][CH:11]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH:2]1([CH:1]2[CH2:14][CH2:15][CH:10]([NH2:9])[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1ccccc1
Reactant: CC1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC1CCC(C2CCCCC2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-cyclohexanone (112 g, 1.0 mol), aniline (186 g, 2 mol) and ethanol (26 mL) was stirred at room temperature and 12 M hydrochloric acid (167 mL) was added during 30 min. The dark yellow solution was refluxed at 85° C. for seven days. The solution was cooled and diluted with ethyl acetate. The mixture was stirred in an ice bath and made alkaline (pH=9) with a 27% sodium hydroxide solution, keeping the temperature below 30° C.