Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([CH3:42])[C:3]([NH:5][C@@H:6]([CH3:41])[C@@H:7]([C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([O:23]CC(C)C)=[O:22])[N:13]=[CH:12]2)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(#N)C>[F:43][C:2]([F:1])([CH3:42])[C:3]([NH:5][C@@H:6]([CH3:41])[C@@H:7]([C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([OH:23])=[O:22])[N:13]=[CH:12]2)=[O:4]
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C(C)(F)F)[C@H](Oc1ccc2c(cnn2-c2cccc(C(=O)O)c2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of isobutyl 3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate (I4a) (350 mg, 0.59 mmol) in THF (5 mL) and acetonitrile (2 mL) was treated with 0.25 M NaOH (4.72 mL, 1.18 mmol). The mixture was stirred at ambient temperature for 23 hours, additional 1M NaOH (0.590 mL, 0.59 mmol) was added and the mixture was stirred at +45° C. for 2 hours. The reaction mixture was allowed to cool down and acidified to pH 2.5-3 by adding 1 N HCl. Addition of THF and MeCN until solution followed by purification by HPLC, using an Kromasil 100-10-C18, 50×250 mm column, an 30 min gradient from 50% to 90% MeCN in water+0.1% TFA in solvents with flow=40 mL/min and UV=254 nm to collect fractions. Fractions containing the product was combined and freezedried. The material was redissolved in tBuOMe, addition of Heptane gave precipitation, the formed slurry was evaporated to afford the subtitle compound as a colourless solid. Yield 315 mg (99%)
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:15]([CH3:18])(=[O:17])=[O:16].C(N(CC)CC)C>CO.O1CCCC1.[C].[Pd]>[NH2:12][C:11]1[CH:2]=[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N)cc(S(C)(=O)=O)c1
Yield: 78.9 %

Procedure:
10% Palladium-carbon (2.5 g) was added to a mixture of methyl 4-chloro-3-methylsulfonyl-5-nitrobenzoate (9.5 g) and triethylamine (5.0 ml) in methanol (150 ml) and tetrahydrofuran (100 ml), and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and adjusted to pH 9 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 5-amino-3-methylsulfonylbenzoate (5.85 g).
Reaction SMILES: [C:1]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:22])=O.S(=O)=O.Cl>C(Cl)Cl>[C:1]([NH:14][CH2:15][CH2:16][C:17]([Cl:22])=[O:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NCCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NCCC(=O)Cl
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 101 %

Procedure:
46.8 g of N-lauroyl-β-alanine was dispersed in 155 ml of methylene chloride. Then, 24.8 g of thionyl chloride was added thereto within 10 minutes under stirring while maintaining the temperature of the mixture at 20° C. After the completion of the addition, the mixture was stirred at the same temperature for 30 minutes so as to complete the reaction. When the reaction solution thus obtained was analyzed by infrared spectroscopy, a peak at 1695 cm-1 due to carboxylic acid (--COOH) disappeared while a new peak due to acid chloride (--COCl) was formed at 1782 cm-1. These facts indicated that an acid chloride was obtained. Then, the methylene chloride employed as the solvent and side products (sulfur dioxide and hydrogen chloride) were distilled off from the reaction mixture under reduced pressure. Thus, 50.5 g of N-lauroyl-3-aminopropionic acid chloride was obtained.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:14]=[C:15]([CH2:20][CH2:21][CH2:22][CH3:23])[NH:16][C:17]=1[CH:18]=[O:19].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[CH2:20]([C:15]1[NH:16][C:17]([C:18]([OH:5])=[O:19])=[C:13]([Cl:12])[N:14]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCCc1nc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
A solution of sodium chlorite (2.0 g, 21.6 mmol) and sodium dihydrogen phosphate monohydrate (1.8 g, 12.9 mmol) in water (4.8 mL) was added to a stirred solution of 4-chloro-2-butyl-1H-imidazole-5-carbaldehyde (0.400 g, 2.1 mmol), 2-methyl-2-butene (13.4 mL of a 2M solution in THF, 26.8 mmol), and tert-butanol (1.6 mL) in THF (6.7 mL). The reaction mixture was stirred at RT for 12 h. The aqueous phase was separated and extracted with EtOAc (4×40 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.411 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 12.88, (br. s., 1H), 2.58 (t, 2H), 1.59 (quint, 2 H), 1.20-1.31 (sex, 2H), 0.87 (t, 3H). ES-LCMS: m/z 203.1 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@@H:33]1[NH:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1.C([BH3-])#N.[Na+].Cl.N>O1CCOCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(OCC)(=O)C.CO>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][CH2:34][C@@H:33]3[CH3:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCNC[C@@H]3C)c2c1
Reaction time: 15 h

Procedure:
The product of Example 75 step i) (200 mg), (S)-3-methyl-piperazine-1-carboxylic acid, tert-butyl ester (287 mg) and titanium(IV) isopropoxide (3 mL) were stirred at room temperature for 15 hours. Methanol (10 mL) was then added followed by sodium cyanoborohydride (90 mg) and the mixture stirred for 15 hours. Methanol (10 mL) was then added followed by 4M HCl in 1,4-dioxane (10 mL) and the mixture stirred overnight at room temperature. The mixture was then poured into aqueous dilute ammonia and ethyl acetate added. The organics were decanted and evaporated to dryness. The residue was purified by HPLC to give the title compound as a solid (40 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]=[O:11].CCO>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]([NH:9][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CNC(=O)Nc1cccc(I)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 3-iodoaniline (9.39 g) in dichloromethane (75 ml) was treated with ethyl isocyanatoacetate (7.21 ml) at 0° C. and the mixture was stirred for 2 h and allowed to warm to 20° C. EtOH (10 ml) was added and the mixture was stirred for 15 h. The solvents were evaporated under reduced pressure and the residue was triturated in Et2O to give the title compound (12.9 g)LCMS RT=3.08 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O.[OH-].[Na+].[C:11](=[S:13])=[S:12]>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:11]([S:13][S:13][C:11]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[S:12])=[S:12])[CH2:4][CH2:3]1
Reactant: S=C=S
Reactant: CN1CCNCC1
Agent: [Fe+3]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CN1CCN(C(=S)SSC(=S)N2CCN(C)CC2)CC1

Procedure:
5 parts of N-methylpiperazine are reacted in 100 parts of water with 2 parts of sodium hydroxide and 4.2 parts of carbon disulfide and oxidized with 16.5 parts of potassium hexacyanoferrate(III). Obtained are 8.6 parts of the compound with 41.1% C, 6.5% H, and 15.7% N (calculated: 41.1% C, 6.3% H, 16.0% N, 36.6% S).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(I)n[nH]c2c1
Reactant: COC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCCCn1nc(I)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
to a solution of 6-fluoro-3-iodo-1H-indazole (1.5 g) and methyl (3-bromopropyl)carbamate (1.68 g) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.58 g), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/20→3/2) to give methyl [3-(6-fluoro-3-iodo-1H-indazol-1-yl)propyl]carbamate [REx(102-1)] (836 mg) as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[C:36](=[O:37])[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccc(OC)cc2)c2ccc(Cl)cc2)CC1

Procedure:
To a stirred solution of 15 parts of ethyl 4-[(4-chlorophenyl)-amino]-1-piperidinecarboxylate, 5.4 parts of N,N-diethylethanamine and 160 parts of benzene is added dropwise 11.07 parts of 4-methoxybenzeneacetyl chloride at a temperature between 32° to 40° C. After the addition is complete, the whole is stirred and refluxed for 3 hours. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, dried, filtered and evaporated in vacuo. The oily residue is crystallized from a mixture of 56 parts of 1,1'-oxybisethane and 40 parts of hexane. The crude solid product is filtered off and recrystallized from a mixture of benzene and 1,1'-oxybisethane, yielding 3 parts of ethyl 4-{N-(4-chlorophenyl)-N-[(4-methoxyphenyl)acetyl]amino}-1-piperidinecarboxylate; mp. 137° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=[N:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=[N:6][C:7]=1[S:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:28]
Reactant: Cc1nc2cccnc2nc1SCc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccnc2nc1S(=O)Cc1ccccn1
Yield: 28.3 %

Procedure:
In 14 ml of chloroform was dissolved 1.4 g of 2-methyl-3-(2-pyridylmethylthio)pyrido[2,3-b]pyrazine. To the solution under chilling with ice was added portionwise 1.1 g of m-chloroperbenzoic acid (purity: 80%). The reaction mixture was then left to have room temperature, and poured into saturated aqueous NaHCO3 solution. The aqueous mixture was extracted with chloroform. The chloroform layer was washed with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), to give 420 mg of 2-methyl-3-(2-pyridylmethylsulfinyl)-pyrido[2,3-b]pyrazine as a brown crystalline powder, m.p. 120°-125° C. (decompn.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:24])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC(C)C)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (56 mg, 0.154 mmol) and TBTU (55 mg, 0.169 mmol) in DMF (2.0 mL) was added DIPEA (131 μL, 0.769 mmol). Then isopropylamine (15 μL, 0.169 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (47 mg, 75%) as a white solid. MS: m/e=406.4 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH:7]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-phenylcyclopentanone (1.3 g, 8.12 mmol) and NaBH4 (0.61 g, 16.24 mmol) in methanol (15 mL) was stirred at room temperature for 1 h. The mixture was concentrated, dissolved in CH2Cl2, washed with 10% HCl, brine, dried over MgSO4 and concentrated to afford the title compound as a white solid. MS m/z: 163 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:14][O:15][NH:16][CH3:17].C(N(CC)CC)C>>[CH3:17][N:16]([O:15][CH3:14])[C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cccnc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A flask is charged with nicotinic acid (5.0 g, 40.6 mmol). Thionyl chloride (30.0 mL) is added and the reaction is refluxed for 1 h. It is then cooled to room temperature and concentrated in vacuo. The residue is dissolved in anhydrous dichloromethane (30 mL) and O,N-dimethyl-hydroxylamine (4.35 g, 44.0 mmol) is added, followed by addition of triethylamine (14.15 g, 100.0 mmol). The reaction mixture is stirred at room temperature for 1.5 h. It is then washed with water and the aqueous phase is extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and concentrated in vacuo to afford N-methyl-N-methoxy-nicotinamide as a brown oil. MS (ESI) m/z 167.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16].O>C(O)C.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:16][CH2:15][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN
Agent: [Pt]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reaction time: 4 h
Yield: 106.6 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (15 g, 75.28 mmol) was dissolved in ethanol (150 ml) and treated with 70% ethylamine/H2O (6.06 ml, 75.29 mmol), followed by 5% Pt/C JM type 117 (2.25 g, 20 wt %). The reaction mixture was subjected to hydrogenation at 2 bar, 50° C. with stiring for 4 hours. The reaction mixture was purged with nitrogen and filtered through GF/F filter paper. The catalyst was washed with ethanol (2×15 ml). The liquors were combined and evaporated to dryness to give N-(1-tert-butoxycarbonyl-4-piperidinyl)ethylamine as a colourless oil (18.33 g, 107%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([OH:15])[C:7]=1[CH2:16][CH2:17][CH3:18])=[O:4].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[C:12]([C:9]1[C:8]([O:15][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:7]([CH2:16][CH2:17][CH3:18])[C:6]([S:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:19])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)CCCBr
Reactant: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1OCCCC(=O)OCC
Reaction time: 9 h
Yield: 84.2 %

Procedure:
A mixture of (4-(N,N-dimethylcarbamoylthio)-2-hydroxy-3-propylphenyl)ethanone (26.6 g), ethyl 4-bromobutyrate (92.9 g), potassium iodide (1 g) and potassium carbonate (26.1 g) in acetone (200 ml) was heated and refluxed with stirring. Each of potassium carbonate (13 g) was added thereto after 9 hours and 14 hours, and the mixture was heated and refluxed with stirring for total 29 hours. Then, inorganic materials were separated and the solution was concentrated under a reduced pressure. The resultant residue was purified through silica-gel column chromatography (eluting with hexane, then benzene and finally benzene:ethyl acetate=9:1) to give ethyl 4-(6-acetyl-3-(N,N-dimethylcarbamoylthio) -2-propylphenoxy)butyrate (31.5 g, 84.2%) as light brown crystal, mp 60-63° C.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.C(N(CC)CC)C.CS([Cl:39])(=O)=O>ClCCl>[Cl:39][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2
Reactant: COCOc1ccc(-c2ccc3c(c2CO)NC(=O)C(C)(C)N3)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(-c2ccc3c(c2CCl)NC(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
8-Hydroxymethyl-7-(2-methoxy-4-methoxymethoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 9, 495 mg, 1.33 mmol) was dissolved in anhydrous dichloromethane (10 mL), and triethylamine (250 μL, 1.80 mmol) and methanesulfonyl chloride (113 μL, 1.46 mmol) were added thereto successively. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (239 mg) as a yellow amorphous product. (Yield 46%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:26])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cnc(-c2ccncc2)nc1Cl
Temperature: 25 °C
Yield: 84 %

Procedure:
A suspension of 4.78 g (19.5 mmol) 4-hydroxy-2-pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester in 20 ml POCl3 was heated at reflux for 1 h. The solution was cooled to RT and poured into 100 ml ice-water. The pH of the solution was adjusted to 8 with sat.NaHCO3-solution. The water-phase was extracted three times with 80 ml CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) to give 4.34 g (84%) 4-chloro-2-pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester as a yellow solid, MS (EI): 263.1 (M+).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+:14]>>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[K+:14]
Reactant: CCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCC(=O)[O-]

Procedure:
Potassium decanoate was prepared by thoroughly mixing decanoic acid with 2% aqueous KOH at about 70° C. until the pH passed 10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl.Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[N:14]1[CH:15]=[CH:16][C:11]([S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccncc1
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccncc2)cc1
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of 4-aminothiophenol (20.2 g, 156.5 mmol) in anhydrous DMF (200 mL) was added 4-chloropyridine hydrochloride (24.4 g, 161.0 mmol) followed by potassium carbonate (44 g, 318.4 mmol). The reaction mixture was heated at 80° C. overnight, then diluted with ethyl acetate (400 mL) and water (400 mL). The aqueous layer was back-extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with a saturated aqueous NaCl solution (200 mL), dried over anhy MgSO4, and concentrated under reduced pressure. The residue was filtered through a pad of silica with ethyl acetate and the resulting material was triturated with an ethyl ether/hexane solution to afford the desired product (24.7 g, 78%). TLC (50% ethyl acetate/50% hexane) Rf 0.25; 1H-NMR (DMSO-d6) δ 5.67 (bs, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.88 (d, J=6.2 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 8.27 (d, J=6.2 Hz, 2H), MS[M+H]+=203.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6]2)#[N:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]([CH2:12][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:8]1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCC1Cc2ccc(C#N)cc2C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1Cc2ccc(C#N)cc2C1)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{[(5-cyano-2,3-dihydro-1H-inden-2-yl)methyl]amino}ethyl)carbamate (460 mg, 1.5 mmol), chloro-acetyl chloride (180 mg, 1.6 mmol) and TEA (590 mg, 5.8 mmol) in 30 mL DCM was stirred at RT for 12 hours. The mixture was diluted with 50 mL DCM and then washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC (EA/PE=1:1) to give the title compound. MS m/z: 392 [M+1]+.