Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][CH2:12]O>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncccc1N

Procedure:
A mixture of 3-aminopyridine-2-carboxylic acid (6.4 g, 46.3 mmol) in 26 mL of EtOH and 8 mL of concentrated sulfuric acid is heated to reflux for 2 days. After cooling, the mixture is concentrated to about 15-20 mL and poured into 20 g of ice. The mixture is basified to pH 8-9 with concentrated NH4OH while cooling in an ice bath. The resulting brown precipitate is filtered off, and the filtrate is extracted with ether (4×60 mL). The combined ether extracts are washed with brine (4×60 mL), dried (Na2SO4), filtered, and evaporated to give a yellow/brown solid. This solid is combined with that from the above filtration and the whole is triturated with cold ether to give the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, m), 7.21 (1H, m), 7.03 (1H, m), 5.74 (2H, bs), 4.44 (2H, q, J 7.2, 6.9), 1.45 (3H, t, J 6.9).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]1=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c([N+](=O)[O-])cc(Br)cn1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 5-bromo-3-nitro-pyridin-2-ol (5.0 g, 22.8 mmol) and K2CO3 (9.5 g, 3 equiv., 69 mmol) in DMF (25 mL) was treated with benzyl bromide (4.3 g, 1.1 equiv., 25 mmol) and heated to 50° C. After stirring overnight, the solution was poured into water (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (30-40% ethyl acetate in heptane) afforded 1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one as a yellow solid (5.56 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:34]=[CH:35][N:36]([CH2:39][C:40]#[CH:41])[C:37]=1[Cl:38]>N(CC)CC.CN(C=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:41]#[C:40][CH2:39][N:36]4[C:37]([Cl:38])=[C:33]([Cl:32])[N:34]=[CH:35]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCn1cnc(Cl)c1Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCn3cnc(Cl)c3Cl)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.1 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) and anhydrous DMF (10 mL) is added 4,5-dichloro-1-prop-2-ynylimidazole (104.8 mg). The reaction is sonicated and stirred at room temperature for 2 days. The reaction is condensed to afford a residue. The residue is adsorbed onto silica and chromatographed (eluant 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined and condensed to afford 20 mg of the title compound as a white solid.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH2:14][C:15]2[C:20]([CH:21]=1)=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:18]=[CH:17][CH:16]=2.[Cl:28][Si:29](Cl)([CH3:31])[CH3:30]>CCOCC>[Cl:28][Si:29]([CH:14]1[C:15]2[C:20](=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:13]1[CH3:12])([CH3:31])[CH3:30]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2c(cccc2-c2ccccc2)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A 2.5 M solution of n-BuLi in hexane (4.85 mL, 12.12 mmol) was added at 0° C. to a solution of 2.50 g of 2-methyl-4-phenyl-indene (Boulder Scientific Company, Mw=206.29, 12.12 mmol, n-BuLi:2-Me-4-Ph-Ind=1:1) in 30 mL of ether. The resulting mixture was stirred for additional 2 h at room temperature with final formation of an orange solution. This solution was cooled again to 0° C. and added slowly of a solution of 1.58 mL of dichlorodimethylsilane (Aldrich, Mw=129.06, d=1.064, 13.03 mmol, Me2SiCl2:2-Me-4-Ph-Ind=1.08:1) in 20 mL of ether. The reaction mixture was then allowed to warm up to room temperature and stirred for 1 h. The final straw yellow suspension was concentrated under vacuum and the residue was extracted with 50 mL of toluene. The extract was dried under vacuum to give 3.36 g of a straw yellow solid, which was characterized by GC-MS analysis and 1H-NMR spectroscopy. Yield=92.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)=[O:20])([CH3:15])[CH3:14]
Reactant: COc1cccc2c1CCNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1cccc2c1CCN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 5-methoxy-1,2,3,4-tetrahydro-isoquinoline (CA [103030-70-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:32])([C@H:23]([N:25]1[CH:29]=[C:28]([CH2:30][OH:31])[N:27]=[N:26]1)[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:32])([C@H:23]([N:25]1[CH:29]=[C:28]([CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35])[N:27]=[N:26]1)[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C[C@@H](n1cc(CO)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](n1cc(COS(C)(=O)=O)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.26 ml) was added dropwise to a solution of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-hydroxy methyl-1H-1,2,3-triazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (Compound 56, 0.6 g) and methanesulfonyl chloride (0.14 ml) in dichloromethane (20 ml) under ice-cooling. The mixture was stirred for 30 minutes at room temperature. After addition of dichloromethane (20 ml), the mixture was washed with water (20 ml) and 5% sodium hydrogen carbonate aqueons solution (20 ml). The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to give (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methanesulfonyloxymethyl-1H-1,2,3-triazol-1-yl)-1(1H-1,2,4-triazol-1-yl)-2-butanol as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][Br:31]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(Cl)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Cl)cc1CBr
Yield: 112.3 %

Procedure:
A solution of 2-fluoro-5-chlorobenzyl alcohol (1.28 g, 7.97 mmol) in diethyl ether (26 ml) was treated with triphenylphosphine (2.72 g, 10.36 mmol), followed by carbon tetrabromide (3.44 g, 10.36 mmol). The resultant suspension was stirred for 3.5 hours, then filtered, washing with diethyl ether. The filtrate was concentrated, then passed through a plug of silica to remove triphenylphosphate. The residue was then purified by liquid chromatography affording 2.0 grams of a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25]>>[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: Cn1cccc1C(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccn4C)cc23)CC1
Yield: 107 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.0 mg (0.15 mMol) N-methylpyrrole-2-carboxylic acid, 18.0 mg (100%) of the title compound were recovered.
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH:1]1([O:5][C:6]2[N:11]=[CH:10][C:9]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OC2CCC2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OC1CCC1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (1.17 g, colorless oil) from 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanone (1.03 g, 5.00 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (909 mg, 7.50 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccc(Sc2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccc(Sc2cccc(OCCCCBr)c2)cc1

Procedure:
A stirred mixture of methyl 4-(3-hydroxyphenylsulfanyl)benzoate (13.0 g, 50.0 mmol) and 1,4-dibromobutane (21.0 g, 0.1 mol), anhydrous potassium carbonate (16.0 g) and 4-methylpentane-2-one (150 ml) was refluxed for 13 h. The hot mixture was filtered, the filtrate was evaporated to dryness and the partially crystalline residue was dissolved in a mixture of dichloromethane-petroleum ether (1:1) and then purified by column chromatography on silica gel using the same solvent mixture. The title ester was obtained as the main fraction (15.2 g, 76.9%), m.p. 43-45° C. For C16H19BrO3S (395.3) calculated: 54.69% C, 4.84% H, 20.22% Br, 8.11% S; found: 54.71% C, 4.80% H, 20.09% Br, 8.07% S.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[NH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[C:3]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1[nH]c2cccc(-c3ccccc3C)c2c1Br
Reactant: BrCCCOc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 126B (1.14 g) and 1-(3-bromopropoxy)naphthalene (0.922 g) in N,N-dimethylformamide (20 ml) was added cesium carbonate (2.158 g). The reaction was stirred at room temperature overnight and diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-50% dichloromethane in hexane to provide the title product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN1CCc2ccc(N)cc2CC1

Procedure:
3-Ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (740 mg/3.4 mmol) was dissolved in anhydrous methanol (ca. 10 mL) and the solution added to a Parr flask. Palladium (10% on charcoal) was added carefully (WARNING: this addition should be done under a atmosphere of nitrogen to avoid ignition of methanol vapor in flask) and the mixture shaken under 40 psi of hydrogen for 2 hours. The mixture was then filtered and the colorless filtrate concentrated to afford 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo [d]azepin-7-ylamine (yellows upon standing). The material was typically used without further purification (680 mg/quantitative). 1H NMR (400 MHz, CDCl3) δ 6.9 (d, J=7.6 Hz, 1H), 6.4 (m, 2H), 2.9 (m, 4H), 2.7 (m, 6H), 1.1 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br.Br[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CO>[N:1]([CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[N+:2]=[N-:3]
Reactant: BrCCCC1CCNCC1
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCCC1CCNCC1

Procedure:
Sodium azide (1 g) was added to a mixture of 4-(3'-bromopropyl)-piperidine hydrobromide (2 g), water (7 ml) and methanol (7 ml). The pH of the mixture was adjusted to 6.3, and the resulting solution was refluxed for 2 hours. After cooling, methanol was evaporated, 30 percent aqueous sodium hydroxide was added and the mixture was extracted several times with ether. The ether extracts were dried and evaporated to leave the desired compound as an oil. The IR-spectrum (CHCl3) showed strong bands at 2925, 2100 and 1450 cm-1.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1C[CH2:17][CH2:16][CH:15]=1>O>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH:14]1[CH2:15][CH2:16][CH2:17][C:1]1=[O:3]
Reactant: Cc1ccc(C2=CCCC2)c(C)c1
Reactant: O=CO
Agent: OO
Solvent: O
Product: Cc1ccc(C2CCCC2=O)c(C)c1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 18 mL of 96% formic acid and 2 mL of water was added 4.5 mL of 30% hydrogen peroxide and the resulting solution was warmed to 40° C. for 10 minutes. The 1-(2,4-dimethyl-phenyl)cyclopentene (6 g) was slowly added with ice-bath cooling to maintain the internal temp at 35-40° C. The mixture was stirred at room temperature for 4 hours, diluted with water, and extracted with ether. The ether was washed with aqueous sodium bicarbonate and brine, dried, and evaporated. Purification of the residue by flash chromatography (15% ethyl acetate/hexane) afforded 2.5 g of 2-(2,4-dimethyl-phenyl)-cyclopentanone as an oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[N:18].[CH3:19][O-].[Na+].CI>CO>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:19])[N:7]=1
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(N)c(C#N)c(-c2ccccc2)c1C#N
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a stirred solution of 0.19 g (0.75 mmol) 6-amino-4-phenyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile in 25 ml methanol were added 0.14 ml (0.76 mmol) sodium methylate solutiuon (5.4M in methanol) and 0.09 ml (1.5 mmol) methyl iodide and stirring continued for 16 hours at room temperature. The reaction mixture was then cooled to 0° C. and the resulting crystals collected by filtration and washed with ether/methanol (3/1) to afford 0.1 g (50%) 2-amino-6-methylsulfanyl-4-phenyl-pyridine-3,5-dicarbonitrile as a white crystalline solid. EI-MS m/e (%): 266 (M+, 40), 265 ([M—H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.[NH2:13][C:14]1[C:19](Br)=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC=CC=1>[NH2:13][C:14]1[C:19]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: Nc1nc(Cl)cnc1Br
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
A solution of 2,3,5-trichlorobenzeneboronic acid (1.62 g, 7.18×10−3 mole) in absolute ethanol (2.05 ml) was added slowly to a mixture of 2-amino-3-bromo-6-chloropyrazine (1 g, 5.1×10−3 mole) and tetrakis(triphenylphospine)palladium(0) (0.334 g,2.89×1−4 mole) in benzene (10.20 ml)/2M aqueous sodium carbonate (5.50 ml). The mixture was refluxed for 17 hrs. The cooled reaction mixture was evaporated in vacuo and then extracted with chloroform (50 ml). The chloroform layer was washed with water (2×30 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 0.205 g (14%), M.p. 211-214° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[C:9](OCC)(=O)[CH:10]=[O:11].[OH-].[Na+].Cl>O>[OH:4][C:3]1[C:2]([C:6]([NH2:8])=[O:7])=[N:1][CH:9]=[C:10]([OH:11])[N:5]=1
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ncc(O)nc1O
Reaction time: 0.67 h
Yield: 23 %

Procedure:
In 2.1 mL of water is suspended 0.5 g of 2-aminomalonamide. Under ice-cooling, 0.43 g of ethyl glyoxalate is added to the suspension, which is then stirred for 40 minutes. Then, 0.85 mL of 5 mol/mL sodium hydroxide is added to the resulting suspension, which is then stirred at the same temperature as above for 40 minutes. The reaction mixture is adjusted to pH 12 by adding 1 mol/L sodium hydroxide, and once made into a solution. The solution is then adjusted to pH 2 by adding 6 mol/mL hydrochloric acid. The deposited crystals are collected by filtration and washed successively with water and 50% (w/w) ethanol to obtain 0.15 g of 3,5-dihydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:6].N1C=CC=CC=1.Cl.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:20]1([S:26]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[C:3]([O:2][CH3:1])=[O:12])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloroanthranilic acid methyl ester (400 mg; prepared in Reference Example 1) and pyridine (0.87 ml) in methylene chloride, benzenesulfonylchloride (0.33 ml) was added at 0° C. The solution was stirred overnight at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (664 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[O:9]1[CH2:11][C@H:10]1[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:11][C@H:10]([OH:9])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Solvent: CCO
Product: O=c1cc(Br)ccn1C[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 22.8 %

Procedure:
To a solution of 4-bromopyridin-2(1H)-one (1 g, 5.747 mmol) in EtOH (3 mL) was added (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (1.087 g, 5.747 mmol). The mixture was heated under microwave conditions at 120° C. for 0.5 h and concentrated. The crude product was purified by column chromatography eluting with DCM/MeOH (10:1). (475 mg, yield 22.8%) MS (ESI+) e/z: 363.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])([CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (170 mg, 0.687 mmol) in THF (5 mL) at 0° C. was added 3.0M methylmagnesium bromide in ether (688 mL, 2.1 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water (2 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and the solvent was removed in vacuo to give an oil that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, 7:3) to afford 120 mg (66%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline: 1H NMR (400 MHz, DMSO-d6) 7.54 (d, J=7.7, 1H), 7.50 (dd, J=7.7, 1.5, 1H), 7.14 (ddd, J=7.3, 7.3, 1.7, 1H), 7.04 (ddd, J=7.9, 7.9, 1.0, 1H), 5.14 (s, 1H), 3.69 (m, 2H), 1.87 (t, J=6.5, 2H), 1.46 (s, 9H), 1.37 (s, 3H).