Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1>O1CCCC1.CO>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]([OH:29])[CH3:28])=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: CC(=O)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(C)O)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (46 mg, 1.2 mmol) was added to a solution of 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethanone (45 mg, 0.12 mmol) in tetrahydrofuran (300 μl) and methanol (300 μl) and then the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous potassium sodium tartrate (2 mL) and diluted with dichloromethane (3 mL). The mixture was stirred for 16 hours, filtered through a CELITE pad, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-40% acetone/hexanes, linear gradient) to afford 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethanol. MS ESI calc'd. for C19H18F3N4O [M+H]+ 375. found 375. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.54 (s, 1H), 7.27 (s, 1H), 7.18 (s, 1H), 5.39 (s, 1H), 4.80-4.72 (m, 1H), 2.35 (s, 3H), 1.38 (d, J=5.5 Hz, 3H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>>[CH:1]1([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc(C(=O)C2CCCC2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(C3CCCC3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-cyclopentanecarbonyl-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:20])=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cccc2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [O-][n+]1ccc2c(Br)cccc2c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A mixture of 5-bromoisoquinoline (0.83 g, 3.0 mmol), MCPBA (1.84 g, 8 mmol) and NaHCO3 (0.672 g, 8 mmol) in CH2Cl2 (10 mL) and H2O (5 mL) was stirred overnight. The solvents were removed, and the residue was purified by silica gel column chromatography eluting with EtOAc to give 0.51 g of the title compound. MS (APCI) m/e 225 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(N3CCCC(C(=O)O)C3)nn3ccnc23)nc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 139.5 %

Procedure:
A mixture of 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid (100 mg, 0.25 mmol), tert-butyl 4-aminobenzoate (49 mg, 0.25 mmol), EDCI (192 mg, 1.0 mmol) and 1-methyl-1H-imidazole (82 mg, 1.0 mmol) in dichloromethane (3 mL) was stirred at room temperature for 16 h. The residue was concentrated to give crude tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxamido)benzoate (200 mg, crude) as brown liquid that was used directly without further purification. LC-MS: 574 [M+1]+, tR=1.720 min.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[C:5]=1[O:22][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1
Reactant: NC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(C(N)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 31.2 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 4-(bromomethyl)benzamide (106 mg, 0.496 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford the title compound as a solid (35 mg, 30.9%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH3:12])=[N:7]1)=[S:5])[CH3:2].I[CH3:14]>CO>[CH3:14][S:5][C:4]([N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH3:12])=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CI
Reactant: CCNC(=S)N1CCC(CC)=N1
Solvent: CO
Product: CCN=C(SC)N1CCC(CC)=N1
Temperature: 50 °C
Yield: 0.7 %

Procedure:
1.51 g (1 mol equiv.) 3-Ethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 30 mL methanol, 5.1 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 1 hour. Volatiles were removed in vacuo. The residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to give 1.44 g (89%) 3,N-diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.12-1.21 (m, 6H), 2.39 (q, J=7.4 Hz, 2H), 2.48 (s, 3H), 2.70 (t, J=9.7 Hz, 2H), 3.52 (q, J=7.2 Hz, 2H), 3.75 (t, J=9.7 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:10]1([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnccc1C1=CC=CCC1
Temperature: 100 °C
Yield: 27 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) was added dioxane (0.18M) and p-TSA (1.1 equiv.). The solution was heated to 100° C. for 4 h. Cooled to room temperature, worked up with sat. NaHCO3 and ethyl acetate, the organic phase was dried with Na2SO4 and concentrated. The crude was purified via silica gel column chromatography eluting with 100% DCM to give 4-(cyclohexa-1,3-dienyl)-3-nitropyridine as a yellow oil (27% yield). LCMS (m/z): 203.1 (MH+), LC Rt=3.53 min, H-NMR (CDCl3): 9.02 (s, 1H), 8.70 (d, J=5.3, 1H), 7.30 (d, J=5.3, 1H), 6.15-6.17 (m, 1H), 6.02-6.11 (m, 2H), 2.35-2.38 (m, 4H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH3:22])=[CH:20][C:14]2=[N:13]1)(=O)C.[OH-].[Na+].Cl>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH3:22])=[CH:20][C:14]2=[N:13]1
Reactant: CCc1ccc2nn(-c3cc(C)ccc3OC(C)=O)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc2nn(-c3cc(C)ccc3O)nc2c1
Temperature: 80 °C
Yield: 53.3 %

Procedure:
Pure 2(2-hydroxy-5-methylphenyl)-5-ethyl-2H-benzotriazole was obtained by the hydrolysis of 2(2-acetoxy-5-methylphenyl)5-ethyl-2H-benzotriazole. A solution of 2(2-acetoxy-5-methylphenyl)5-ethyl-2H-benzotriazole (5.9 g, 0.02 mole) and 10 ml of ethanol was poured into a solution of sodium hydroxide (2.0 g, 0.05 mole). The resulting fine dispersion was heated to 80° C. for 3 hours. After cooling to room temperature, the homogeneous solution was acidified with 1N aqueous hydrochloric acid solution and the solid precipitate was extracted with carbon tetrachloride. The solution was chromatographed and the eluate concentrated under reduced pressure. The residue was recrystallized from n-hexane by cooling to -78° C. White needles were obtained which were collected by filtration, washed with cold n-hexane and dried. 2.7 g (54% yield) of 2(2-hydroxy-5-methylphenyl)5-ethyl-2H-benzotriazole was obtained, which had following properties.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[CH2:7]([N:14]1[C:26]2[CH2:25][CH2:24][CH2:23][CH:22]([C:27](OCC)=[O:28])[C:21]=2[C:20]2[C:15]1=[C:16]([CH3:34])[CH:17]=[CH:18][C:19]=2[O:32][CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.ClCCl>[CH2:7]([N:14]1[C:26]2[CH2:25][CH2:24][CH2:23][CH:22]([C:27]([NH2:2])=[O:28])[C:21]=2[C:20]2[C:15]1=[C:16]([CH3:34])[CH:17]=[CH:18][C:19]=2[O:32][CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)ccc(C)c1n2Cc1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Temperature: 50 °C
Yield: 98.5 %

Procedure:
A slurry of 0.38 g of ammonium chloride in 15 ml of dry toluene was cooled in an ice bath and treated with 3.5 ml of a 2.0 M solution of trimethylaluminum in toluene. This mixture was stirred for 1 hour at room temperature, whereupon 0.762 g (2.02 mmol) of ethyl 9-benzyl-5-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylate in 10 ml of toluene and 1 ml of dichloromethane was added. The mixture was heated to 50° C. overnight, cooled and quenched with 20 ml of aqueous 5% HCl solution. Ethyl acetate extracts (3×100 ml) were washed with water and then with brine, dried over magnesium sulfate and concentrated to afford 0.693 g (98%) of the subtitle compound. ESIMS m/e 349 (M++1) NMR (300 MHz, CDCl3): δ7.25 (m, 3H); 6.83 (d, J=7.2, 2H); 6.74 (d, J=7.8, 1H); 6.40 (d, J=7.8, 1H); 5.93 (br, 1H); 5.54 and 5.45 (ABq, J=17.7, 2H); 5.42 (br, 1H); 4.14 (br, 1H); 3.87 (s, 3H); 2.65 (dt, J=16.4, 4.1, 1H); 2.55-2.36 (m,2H); 2.45 (s, 3H); 1.97-1.86 (m, 3H).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[CH2:10]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:27]1[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:29][CH2:28]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC(C)O
Solvent: Cc1ccccc1C
Product: COc1ccccc1N1CCN([C@@H]2Cc3c(OC)ccc(OC)c3C[C@H]2O)CC1
Yield: 50.4 %

Procedure:
A solution of 4.12 g of 6,7-epoxy-5,6,7,8-tetrahydro1,4-dimethoxynaphthalene, 4.81 g of 1-(o-methoxyphenyl)piperazine, and 1.53 ml of isopropyl alcohol in 20 ml of xylene is refluxed under nitrogen for 19 hours. The xylene is removed in vacuo and the residue triturated with ether to give 4.01 g of crude material. Two recrystallizations of this material from ethyl acetate yield 2.5 g of the title compound, melting point 182°-183° C.
Reaction SMILES: [CH3:1][C:2]12[CH2:31][CH:5]([C:6]3([CH3:30])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:29])[C:17]#[C:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.O.[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]12[CH2:31][CH:5]([C:6]3([CH3:30])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:29])[C:17]#[C:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)C#Cc4ccc(C(=O)O)cc4)cc3C21C

Procedure:
0.66 g of methyl ester obtained in Example 10 dissolved in 10 ml of tetrahydrofuran was treated with 200 mg of lithium hydroxide monohydrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][CH2:9][C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O)=[O:5])[CH3:2].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[NH:22][NH2:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH2:26]([O:25][C:21]([NH:22][N:23]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][S:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:24])[CH3:27]
Reactant: CCOC(=O)NN
Reactant: CCOC(=O)CCSCC(=O)CSCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CCOC(=O)CCSCC(CSCCC(=O)OCC)=NNC(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
A solution of 1,3-bis[(2-ethoxycarbonylethyl)thio]acetone (6.22 g, 19.3 mmol), ethyl carbazate (2.40 g, 23.1 mmol) and a catalytic amount of p-toluenesulfonic acid in anhydrous acetonitrile (50 mL) containing molecular sieve was stirred for 2 days at room temperature. The reaction was quenched with water/ethyl acetate and filtered. The filtrate was extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was triturated with hexane, affording 7.2 g of 1,3-bis[(2-ethoxycarbonylethyl)thio]acetone ethoxycarbonylhydrazone. 1H NMR (CDCl3) δ 2.2-2.4 (m, 9H), 2.6-2.8 (m, 8H), 3.42 (s, 2H), 3.54 (s, 2H), 4.1-4.3 (m, 6H), 8.82 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Temperature: 60 °C
Yield: 91 %

Procedure:
To a solution of methyl 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylate (390 mg, 1.299 mmol) in MeOH (2.127 mL) was added a solution of NaOH (649.5 μL of 2 M, 1.299 mmol) in H2O (2.127 mL). The resulting solution was heated to 60° C. for 2 hours and then allowed to cool and neutralised with HCl. The resultant precipitate was collected and washed with ether and dried (340 mg, 91% Yield). MS (ES+) 287.08
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[Si:25]([O:15][CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(-c2cccc(CO)c2)cn1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
4.99 g of [3-(6-aminopyridin-3-yl)phenyl]methanol are placed in a round-bottomed flask and dissolved in 240 ml of tetrahydrofuran. 2.2 g of 1H-imidazole are added thereto, followed by 4.51 g of tert-butylchlorodimethylsilane, and the mixture is left to stir at ambient temperature for 48 hours. The reaction mixture is then hydrolyzed with water and the organic phase, extracted with ethyl acetate, is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 7.0 g of compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH3:13])=[N:7]2.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([NH2:21])[CH:20]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:21][C:19]3[CH:20]=[C:15]([CH3:14])[CH:16]=[CH:17][C:18]=3[S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCc1ccc2c(Cl)ccnc2n1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 8f (88 mg, 0.46 mmol) was reacted with the product from Example 7f (100 mg, 0.46 mmol) for 24 h following the procedure from Example 7f giving the title compound as a hydrochloride salt which was triturated with ether giving (134 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (t, J=7.35 Hz, 3 H) 3.02 (q, J=7.35 Hz, 2 H) 6.69 (d, J=6.99 Hz, 1 H) 6.97 (d, J=8.82 Hz, 2 H) 7.10 (dd, J=7.35 Hz, 1 H) 7.15 (d, J=8.82 Hz, 2 H) 7.30 (dd, J=8.09 Hz, J=7.72 Hz, 2 H) 7.56 (dd, J=2.94 Hz, J=9.19 Hz, 1 H) 7.71 (d, J=2.57 Hz, 1 H) 7.88 (d, J=8.82 Hz, 1 H) 8.52 (d, J=6.99 Hz, 1 H) 9.02 (d, J=8.45 Hz, 1 H) 11.16 (br s, 1 H) 14.56 (br s, 1 H); MS (ESI+) m/z 376 (M-Cl)+; (ESI−) m/z 374 (M−HCl)−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:15])/[C:11](=[N:13]/[OH:14])/[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29](OC(=O)C)(=O)[CH3:30]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:15])[C:11]1[N:12]=[C:29]([CH3:30])[O:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(COCc1ccccc1)(NS(=O)C(C)(C)C)/C(N)=N/O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(COCc2ccccc2)NS(=O)C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of (Z)-3-(benzyloxy)-2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide (Example 112b, 1.25 g, 3.82 mmol) in dry DMF (25 ml) was added potassium carbonate (633 mg, 4.58 mmol) followed by addition of acetic anhydride (390 mg, 360 uL, 3.82 mmol). The reaction mixture was stirred at room temperature for 1 hour and was then stirred at 120° C. for 2 hours. DMF was removed in vacuo and the residue was dissolved in ethyl acetate which was extracted with a 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (1.20 g, purity: 80%, 72%) as a light yellow oil. MS (ESI, m/z): 352.6 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:17](Br)([CH3:19])[CH3:18].Cl>>[CH:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CC(C)Br
Agent: Cl
Product: CC(C)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and i-propylbromide: m.p. 220° C. (HCl); MS m/z (rel. intensity, 70 eV) 281 (M+, 4), 266 (bp), 187 (5),129 (5), 115 (5)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[OH-].[NH4+].[H][H]>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1
Reactant: N#CCc1cccnc1
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCc1cccnc1
Yield: 90.8 %

Procedure:
A mixture of 2-(pyridin-3-yl)acetonitrile (1 g, 8.47 mmol, 1.00 equiv), Raney nickel (1 g, 17.24 mmol, 1.00 equiv) and ammonium hydroxide (3 mL) in methanol (15 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight. The catalyst was removed by filtration through a pad of Celite and washed with several portions of methanol. The filtrate and washings were combined and concentrated under vacuum to give 940 mg (45%) of 2-(pyridin-3-yl)ethanamine as a yellow oil. LC-MS: (ES, m/z): 164 [M+CH3CN+H]+, 123 [M+H]+, 106.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl.[N:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Under anhydrous conditions (positive nitrogen pressure, presence of 3Å molecular sieves), a mixture of N-hydroxyphthalimide (15.0g, 0.091mole), 4-picolylchloride hydrochloride (15.0g, 0.091mole), and triethylamine (27.7g, 0.273 mol) in 125 ml of anhydrous acetonitrile was refluxed for 2 hours. After stirring overnight at ambient temperature, TLC showed that the starting materials were practically consumed. Ethyl acetate (500 ml) was added, mixture stirred for 15 min and filtered. The solvent was evaporated and the residue dissolved in 1L of EtOAc. The filtrate was washed with water (2×500 ml), brine (1×500 ml), dried (MgSO4), and evaporated to a smaller volume (100ml). The mixture was cooled down to -18° C., precipitate filtered and recrystallized from EtOAc/hexane to afford 13.2g (56.8%) of title product.
Reaction SMILES: [N+:1]([CH:4]=[C:5]([S:11][CH3:12])[NH:6][CH2:7][CH2:8][CH2:9]Br)([O-:3])=[O:2].[H-].[Na+]>O1CCCC1>[CH3:12][S:11][C:5]1[NH:6][CH2:7][CH2:8][CH2:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1=C([N+](=O)[O-])CCCN1
Yield: 28.7 %

Procedure:
A mixture of 1-nitro-2-methylthio-2-(3-bromopropylamino)ethylene (3.2 g, 0.012 mol) and sodium hydride (50% in oil, 0.9 g, 0.019 mol) in dry tetrahydrofuran (50 ml) was refluxed for 18 hours. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was chromatographed on a silica gel column, the product being eluted with ethyl acetate. Recrystallisation of the product from methanol/propan-2-ol gave 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.6 g, 29%) m.p. 230.5°-231.5°.