Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[C:2]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([OH:28])=[O:1]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1CCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1CCC(=O)O
Yield: 74 %

Procedure:
A solution of 1.01 g of 3-(hydroxypropyl)-4-pivaloyloxybenzophenone in 40 ml of acetone was treated with 1.5 ml of 8N Jones' Reagent at 0° C. for 1 h. The reaction mixture was treated with 5 ml of isopropyl alcohol and filtered to remove inorganic material. The filtrate was evaporated and the residue was taken up with toluene. The toluene phase was extracted with 3% KHCO3 solution and the aqeuous extract was acidified to pH 2. The acidic product was extracted with ethyl acetate. The ethyl acetate extact was washed with brine dried (MgSO4), and concentrated to give 0.784 mg (74%) of product.
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].[S:41]1[CH2:45][C:44](=[O:46])[NH:43][C:42]1=[O:47]>O.C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([CH:39]=[C:45]4[S:41][C:42](=[O:47])[NH:43][C:44]4=[O:46])=[CH:37][CH:38]=3)=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)c3cccc([N+](=O)[O-])c3)cc2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)c4cccc([N+](=O)[O-])c4)cc3)cc2)S1
Yield: 65.5 %

Procedure:
0.25 g (2.9 mmole) piperidine, 0.174 g (2.9 mmole) acetic acid, 120 ml toluene, 2.5 g (5.8 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl 3-nitrobenzenesulfonate and 0.86 g (7.3 mmole) 2,4-thiazolidinedione were refluxed with water separation in a Dean-Stark apparatus. When the reaction mixture was allowed to cool yellow crystals formed. The crystals were collected by filtration and stirred in methanol. Filtration gave 2 g (yield 65.5%) of 5-(4-[2-(4-(3-nitrophenylsulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: F[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([N:14]=2)=[C:12](F)[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH:17]1[CH:22]=[CH:21][C:20]([P-:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.[K+].O>O1CCOCC1.O1CCCC1>[C:24]1([P:23]([C:20]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)[C:2]2[C:15]3[C:6](=[CH:7][C:8]4[C:13]([N:14]=3)=[C:12]([P:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Fc1cccc2cc3cccc(F)c3nc12
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: c1ccc(P(c2ccccc2)c2cccc3cc4cccc(P(c5ccccc5)c5ccccc5)c4nc23)cc1
Yield: 79 %

Procedure:
To a solution of 0.51 g (2.37 mmol) of 4,5-difluoroacridine (XIII) in 50 ml of 1,4-dioxane was added dropwise 9.3 ml (4.65 mmol) of a 0.5 M solution of potassium diphenylphosphide (Ph2P−K+) in tetrahydrofuran at room temperature. After the addition was completed, the mixture was heated at reflux for one hour. After cooling, 30 ml of distilled water was added to the brown reaction solution. The resulting precipitate was filtered off, washed thoroughly with distilled water, ethanol and n-pentane, and dried under high vacuum to obtain 1.02 g (79% of theory) of 4,5-bis(diphenylphosphino)acridine (Ia) as a yellow powder which will decompose from 255° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][C@H:38]([CH2:41][CH3:42])[CH2:39][OH:40]>>[OH:40][CH2:39][C@H:38]([NH:37][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1)[CH2:41][CH3:42]
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 87.8 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 50 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: C([NH:8][S:9]([C:12]1([C:15]#[CH:16])[CH2:14][CH2:13]1)(=[O:11])=[O:10])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:15]([C:12]1([S:9]([NH2:8])(=[O:11])=[O:10])[CH2:14][CH2:13]1)#[CH:16]
Reactant: C#CC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC1(S(N)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of compound 81 (200 mg, 0.81 mmol) and TFA (0.3 mL) in DCM (5 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and the crude material was purified by chromatography on silica gel (MeOH/DCM) to yield compound 82 in 70% yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: O=C(NCCCOC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl chloroformate (47 ml.) was added dropwise to a stirred solution of 3-aminopropanol (11.4 ml) in pyridine (150 ml) at 0°. The mixture was then stirred at room temperature overnight. This was poured into ice-water (300 ml.) and extracted with ethyl acetate (3×200 ml). The organic extract was washed with hydrochloric acid (5m, 3×400 ml), dried with anhydrous sodium carbonate-magnesium sulphate and evaporated to give the desired compound as an oil contaminated with a little dimethylcarbonate (30.23 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:22][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:35]
Reactant: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(N)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 0.075 g (0.25 mmol) of 5′-methyl-4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine in methylene chloride (5 mL) is added 0.050 mL (0.30 mmol) of triethylamine followed by 0.044 g (0.25 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature then purified by preparative reverse phase HPLC to give 0.033 g (30%) of the title compound (3) as a white solid. [M+H]+=441.3.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:13]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:13]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(CCn1c2c(c3ccccc31)CCNCC2)c1ccccc1
Yield: 11.3 %

Procedure:
tert-Butyl 6-[2-(phenylsulfonyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.139 g, 0.306 mmol) was treated with trifluoroacetic acid (1 mL) for 5 min. CH2Cl2 was added and the reaction mixture was concentrated to dryness. The salt was partitioned between CH2Cl2 and a mixture of 1 M KOH and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was chromatographed (SiO2, eluted with 1:1 EtOAc:hexane) to give 6-[2-(phenylsulfonyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.0123 g) as a white solid. 1H NMR (300 MHz, CD3OD) δ 3.13, 3.29-3.33, 3.42, 3.50, 3.71, 4.65, 7.07, 7.14, 7.22, 7.42, 7.51, 7.66, 7.70.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:3]=1
Reactant: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(CN2CCNCC2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate (800 mg, 2.40 mmol, 1.00 equiv), dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added dropwise. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to provide 590 mg (crude) of 1-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 282 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH2:19])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.Br[C:22]1[C:23]([CH3:34])=[CH:24][C:25]([CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:19][C:14]1[N:15]=[CH:16][C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:22]1[C:23]([CH3:34])=[CH:24][C:25]([CH:28]([OH:33])[C:29]([F:31])([F:30])[F:32])=[N:26][CH:27]=1)[CH:18]=2
Reactant: Cc1cc(C(O)C(F)(F)F)ncc1Br
Reactant: CC1(C)OB(c2ccc3cc(N)ncc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C(O)C(F)(F)F)ncc1-c1ccc2cc(N)ncc2c1
Temperature: 130 °C
Yield: 77.2 %

Procedure:
A mixture of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine (225 mg, 0.583 mmol), 1-(5-bromo-4-methyl-2-pyridyl)-2,2,2-trifluoro-ethanol (200 mg, 0.741 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (41 mg, 0.06 mmol) and saturated aqueous sodium carbonate solution (0.3 mL) in acetonitrile (3 mL) was heated under microwave irradiation (Biotage) at 130° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-100% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as yellow oil (150 mg, 77%), which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH3:9])[CH2:3][C:4]([OH:6])=[O:5].O[C@H](CCC)CC(O)=O>>[OH:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC(O)CC(=O)O
Agent: CCC[C@@H](O)CC(=O)O
Product: CCC[C@H](O)CC(=O)O
Reaction time: 100.5 h

Procedure:
The reaction times are suitably 1 to 1000 hours, preferably 1 to 200 hours. Namely, the reaction time depends on the kind of the racemic esters of 3-hydroxy hexanoic acid which are starting materials. The conversion of 20-80% is attained within the above preferable reaction times. In this case, in the reaction of the conversion of 50% or less, (R)-3-hydroxyhexanoic acid having optical purity over 90% ee is obtained, while in the reaction of the conversion of 50% or more, (S)-3-hydroxyhexanoic acid having optical purity over 90% ee is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:24][N:25]=[C:26]=[O:27]>ClCCl.C(#N)C.CCN(C(C)C)C(C)C>[CH3:24][NH:25][C:26]([N:21]1[CH2:20][CH2:19][CH:18]([CH2:17][N:13]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22]1)=[O:27]
Reactant: CN=C=O
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OC)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CCCN(CC1CCN(C(=O)NC)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (200 μL of a 0.25 M solution in dichloromethane, 50 μmole) was added 220 μL of a 0.25 M solution of methyl isocyanate in acetonitrile and 30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. under N2 and then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1 % TFA)) to afford 4-{[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid methylamide (17.1 mg) 25 [M+H]+=374.
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:11])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22](O)=[O:23])=[C:20]([CH3:29])[CH:19]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22]([NH:10][CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:2]([CH3:1])([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH3:11])=[O:23])=[C:20]([CH3:29])[CH:19]=1
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Reactant: CSc1cc(Cl)cc(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CSc1cc(Cl)cc(C)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 16 h
Yield: 66.3 %

Procedure:
A mixture of (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (262 mg; 1.2 mmol), 4-chloro-2-methyl-6-(methylthio)benzoic acid (388 mg; 1.8 mmol), 1-hydroxybenzotriazole hydrate (276 mg; 1.8 mmol) and EDC (345 mg; 1.8 mmol) in DCM (16 ml) was stirred for 16 h. The reaction mixture was then partitioned between DCM and saturated aqueous sodium hydrogen carbonate and the organic layer separated, washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with an ethyl acetate-hexane 0 to 100% gradient to give the title compound as a colourless oil (332 mg; 66%). 1H NMR (CDCl3) δ: 0.90 (3H, s), 0.98 (3H, s), 1.66-1.75 (4H, m), 2.31 (3H, s), 2.44 (3H, s), 2.60-2.65 (2H, m), 2.69-2.74 (2H, m), 4.82 (1H, d J=3 Hz), 7.00 (1H, m), 7.09 (1H, m), 7.11 (1H, br s), 7.23-7.33 (3H, m), 7.41-7.43 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 417 (MH+). C23H2935ClN2OS requires 416. Ret. time 2.08 min. The product was dissolved in methanol and 1M HCl/diethylether solution was added dropwise to the stirred solution. After stirring at room temperature for 5 minutes, the mixture was evaporated at reduced pressure. It was redissolved in DCM and evaporated again at reduced pressure to yield the hydrochloride salt as a white foam (320 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:39]([C:36]3[CH:37]=[N:38][C:33]([CH3:32])=[CH:34][CH:35]=3)(=[O:41])=[O:40])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: O=Cc1c[nH]c(-c2cccnc2Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cccnc2Cl)cn1
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
To a solution of 5-(2-chloropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (207 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 100 mg) at room temperature and the mixture was stirred for 10 min. 15-Crown-5 (552 mg) was added dropwise, and the mixture was stirred for 5 min. 6-Methylpyridine-3-sulfonyl chloride (250 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:7→1:4) to give the title compound as a colorless oil (yield 90 mg, 25%).
Reaction SMILES: [NH2:1][C:2](=[S:17])[NH:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].Cl>[OH-].[Na+].O>[CH3:6][C:5]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:3]=[C:2]([SH:17])[N:1]=1
Reactant: CC(=O)N(NC(N)=S)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(S)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 Parts of acetic acid, 2-(aminothioxomethyl)-1-(4-nitrophenyl)hydrazide are dissolved in a mixture of 10 parts of sodium hydroxide and 400 parts of water and the solution is stirred for 30 minutes at room temperature. The reaction mixture is acidified with concentrated hydrochloric acid. The precipitated product is filtered off, washed with water and with 2-propanol and crystallized from 1,4-dioxane, yielding 22.4 parts of 5-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole-3-thiol; mp. 202.1° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CCOC(C)=O>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[N:4]=[C:5]([O:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(C#N)cc3ccccc23)C1
Reactant: CCOC(=O)NN
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C

Procedure:
To crude (R)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate was added ethyl hydrazinecarboxylate (1.104 g, 10.60 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled and diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[CH:19][C:20](=[O:23])[NH:21][CH:22]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1.CN(C)C=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:18]=[CH:19][C:20](=[O:23])[NH:21][CH:22]=3)=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Nc2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
5-[4-(4-Nitrobenzamido)phenyl]-2(1H)-pyrazinone (1.0 g) was added to a vigorously stirred suspension of palladium on charcoal (0.3 g, 5%) in ethanol (20 ml) followed by cyclohexene (20 ml). The reaction was heated under reflux for 24 hours, hot dimethylformamide was then added and the mixture was filtered. Evaporation of the filtrate gave a solid residue which was extracted with boiling glacial acetic acid, collected and dried to give the title compound (0.6 g, m.p. >300° C.; δ(DMSO-d6) 7.99 and 8.09 (2H, 2s, pyrazinone ring protons), 9.7 and 9.9 (2H, 2 broad s, =CH--NH--CO and --NH--CO).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:23][CH3:24])([O:21][CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:27]I.[Cl-].[NH4+]>CS(C)=O>[CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:21][CH3:22])([O:23][CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH3:27])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(SC)c1cccc(C(OC)(OC)c2ccccc2)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(SC)c1cccc(C(OC)(OC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Methyl α-methylthio-[m-(α,α-dimethoxybenzyl)phenyl]acetate (444 mg) was dissolved in 4 ml of dimethyl sulfoxide, and 55 mg of sodium hydride (65% content) was added. The mixture was stirred at room temperature for 20 minutes. Methyl iodide (0.20 ml) was added dropwise over the course of 3 minutes, and the mixture was further stirred at room temperature for 30 minutes. An aqueous solution of ammonium chloride (200 mg/30 ml) was added, and the mixture was extracted three times with 20 ml of diethyl ether. The organic layer was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, and the residue was chromatographed on a column of Florisil using benzene and methylene chloride as eluents to afford 386 mg of methyl α-methylthio-α-[m-(α,α-dimethoxybenzyl)phenyl]propionate as an oil in a yield of 84%.