Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1([C:30]2[N:31]=[CH:32][C:33]3[CH:38]([C:39](O)=O)[CH2:37][CH2:36][C:34]=3N=2)C=NN=N1.FC1C(C#N)=C(C)C([C@@H]2OC[C@@H]3CNCCN3C2)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl>[NH:31]1[C:30]2[C:34](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:33][CH2:32]1
Reactant: O=C(O)C1CCc2nc(-n3cnnn3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1c([C@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
HATU (266 mg, 0.700 mmol) was added to a solution of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid [I-67] (148 mg, 0.637 mmol) in DMF (1 mL). The mixture was stirred at RT for 5 minutes then a solution of 6-fluoro-2-methyl-3-[(3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile [I-40A] (411 mg, 0.817 mmol), and Hunig's Base (0.70 mL, 4.0 mmol) in dichloromethane (1 mL) was added. The flask was rinsed twice with dichloromethane (0.3 mL). The reaction mixture was stirred at RT for 2 hours then diluted with EtOAc and washed with saturated NaHCO3 solution, water and brine, dried (MgSO4), filtered and the solvent evaporated to afford crude title compound as a mixture of two diastereomers. This crude material was purified by preparative TLC on silica (2000 μm, eluted twice) using CH2Cl2:MeOH 95:5 (B) to afford the title compound 2 GH as a mixture of diastereomers: LC/MS 512 (M+Na), 490 (M+H). The diastereomers were separated by chiral preparative SFC HPLC (ChiralCel IC, 21×250 mm, 60% MeOH:MeCN/CO2, 50 mL/min, 100 bar, 114 mg/mL in MeCN/MeOH, 35° C., 220 nm) to afford the separated aza-indane diastereomers Isomer 2G (faster eluting) and Isomer 2H (slower eluting). Each isomer was dissolved separately in 1 mL dichloromethane and 1 equivalent of 1 M HCl in ether was added. The solvent was evaporated to yield the HCL salt of each diastereomer. Isomer 2G HCL salt: NMR 600 MHz (CD3OD)(mixture amide rotamers) 10.012 (s, 0.5H); 10.007 (s, 0.5H); 8.72 (s, 0.5H); 8.68 (s, 0.5H); 8.00 (br app t, 1H); 7.31 (dt, 1H); 5.11 (t, 1H); 4.60-4.72 (m, 2H); 4.41 (d, 0.5H); 4.09-4.31 (m, 3H); 3.91 (t, 0.5H); 3.88 (dd, 1.5H); 3.31-3.62 (m, 4H); 3.20-3.28 (m, 2.5H); 2.72-2.86 (m, 1H); 2.61 (s, 3H); 2.30-2.37 (m, 0.5H); 2.21-2.27 (m, 0.5H); LC/MS 531 (M+H+CH3CN). Isomer 2H HCl salt: NMR 600 MHz (CD3OD) (mixture amide rotamers) 10.02 (s, 1H); 8.72 (s, 0.6H); 8.69 (s, 0.4H); 8.02 (app t, 0.4H); 7.98 (aap t, 0.6H); 7.28-7.33 (m, 1H); 5.09 (d, 1H); 4.72-4.77 (m, 1H); 4.64 (d, 0.5H); 4.57 (d, 3H); 4.34 (d, 0.5H); 4.28 (d, 0.5H); 4.05-4.20 (m, 2.5H); 3.86 (t, 1H); 3.75 (q, 1H); 3.48-3.63 (m, 2H); 3.26 (t, 1H); 3.23 (t, 1H); 2.74-2.81 (m, 1H); 2.61 (s, 3H); 2.30-2.36 (m, 0.5H); 2.20-2.27 (m, 0.5H); LC/MS 531 (M+H+CH3 CN).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16][CH:15]2[CH2:25][OH:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27]N(C=O)C.CI.[H-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])[CH2:16][CH:15]2[CH2:25][O:26][CH3:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2CCN(C(=O)C3CC3)CC2CO)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COCC1CN(C(=O)C2CC2)CCN1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 1 h

Procedure:
(1-(4-tert-Butylphenylsulfonyl)piperazin-2-yl)methanol (97 mg, 0.255 mmol, 1.0 equiv, prepared as described in example 17) was dissolved in 5 mL THF under N2 followed by the addition of 0.1 mL DMF, 0.079 mL methyl iodide (0.765 mmol, 3.0 equiv) and 18 mg sodium hydride (1.28 mmol, 5.0 equiv). The solution was allowed to stir for one hour, at which time the solution was diluted with a saturated NaHCO3 solution. The resulting solution was extracted (3×CH2Cl2), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 0.5-2% MeOH/CH2Cl2) gave the product as a white solid. 1H NMR (DMSO, 400 MHz) δ 7.79 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.5 Hz, 2 H), 4.21-3.90 (m, 3 H), 3.65 (m, 1 H), 3.45-2.65 (m, 8 H), 1.82 (m, 1 H), 1.30 (s, 9 H), 0.683 (broad s, 4 H).
Reaction SMILES: C(Cl)Cl.[NH2:4][CH:5]([CH:11]([OH:23])[C:12]1[S:13][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Na+]>C(N(CC)CC)C>[C:24]([NH:4][CH:5]([CH:11]([OH:23])[C:12]1[S:13][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(N)C(O)c1ccc(CN2CCCC2)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1ccccc1)C(O)c1ccc(CN2CCCC2)s1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To methylene chloride solution (5 ml) of 180 mg ethyl 2-amino-3-hydroxy-3-[5-(1-pyrrolidinyl)methyl-2-thienyl]propionate diastereomers (A form and B form) was added triethylamine (300 μl), followed by dropwise addition of 80 mg of benzoyl chloride. After 30 minutes, a saturated sodium chloride aqueous solution was added to effect separation of layers, the thus separated organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Then, the residue was subjected to silica gel column chromatography and elution was carried out with chloroform:methanol (30:1) mixed solution to obtain 110 mg of ethyl 2-benzoylamino-3-hydroxy-3-[5-(1-pyrrolidinyl)methyl-2-thienyl]propionate (diastereomer A form and B form).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(SCc2ccccn2)cc1
Yield: 40.9 %

Procedure:
An ethanol/water mixed solution (2/1, 60 mL) of 4-mercaptobenzenecarboxylic acid (1.0 g), 2-chloromethylpyridine hydrochloride (2.1 g) and potassium carbonate (4.5 g) was heated under reflux for 4 hours. The organic solvent was evaporated off under reduced pressure, and aqueous 5 N hydrochloric acid solution was added to the residue until it became acidic. Water was evaporated off under reduced pressure, and DMF was added to the resulting residue and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=9/1 to 4/1) to obtain the entitled compound (650 mg).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22].[Na]>ClCCCl>[ClH:18].[CH3:2][N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][C:12]([C:21](=[O:22])[CH:20]=[CH2:19])=[CH:13][C:6]=2[CH2:5][CH2:4]1
Reactant: CN1CCc2ccccc2CC1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: C=CC(=O)c1ccc2c(c1)CCN(C)CC2
Temperature: 0 °C

Procedure:
In 30 ml of 1,2-dichloroethane, was dissolved 1.28 g of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. To the solution were added, at room temperature, 2.1 g of aluminum chloride and 0.66 ml of 3-chloropropionyl chloride, then the mixture was stirred for 2 hours. The reaction mixture was poured into 50 ml of ice-water, then the pH of the aqueous solution was adjusted to not lower than 9 with a 40% aqueous solution of sodium hdyroxide, followed by extraction with 50 ml of dichloromethane. The organic layer was washed with 50 ml of pure water, which was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give an oily residue, which was crystallized from dichloromethane-ether to afford 0.83 g of the title compound as pale yellow crystals, m.p.120°-123° C.
Reaction SMILES: C(OP([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=2)[CH:11]=1)[F:9])OCC)C.[Li+].CC([N-]C(C)C)C.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.Cl>O.C1COCC1>[CH:36]1([CH:39]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([F:26])[F:27])=[CH:22][CH:23]=3)[CH:11]=2)[F:9])[CH2:38][CH2:37]1
Reactant: O=CC1CC1
Reactant: CCOP(OCC)C(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: FC(=CC1CC1)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 0.5 h

Procedure:
Into a cold solution of diethyl[(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)(fluoro)methyl]phosphonite (2.0 g, 4.08 mmol) and THF (20 mL) was added dropwise LDA (14.64 mL, 1.0M). The mixture was stirred for 30 minutes and then cyclopropanecarbaldehyde (410 mg, 5.8 mmol) was added and the mixture was allowed to come to room temperature and stirred for 24 hours. Then, HCl (5 mL, 2N) was added and the mixture was stirred for 30 minutes, poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 20/1) gavel-(2-cyclopropyl-1-fluorovinyl)-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene 1:1 Z/E isomers as a yellow oil (0.72 g); MS m/e (M)+ 328.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2([CH3:29])[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27]C)=[O:26])=[CH:24][C:19]=3[O:18][CH2:17]2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[Na+].[OH-].[Li+].CCOC(C)=O>CCCCCCC>[CH3:1][C:2]1[C:3]([C:16]2([CH3:29])[C:20]3[CH:21]=[CH:22][C:23]([C:25]([OH:27])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17]2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc2c(cc1C1(C)COc3cc(C(=O)O)ccc31)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2H-1-benzofuran-6-carboxylate (140 mg, 0.36 mmol), sodium hydroxide (0.06 g, 1.54 mmol) and lithium hydroxide (0.06 g, 1.54 mmol) is stirred at room temperature for 24 h. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. 10 ml of water and 10 ml of ethyl ether are added. The mixture is acidified with concentrated hydrochloric acid solution to pH 1. After separation of the phases by settling, the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is obtained by recrystallization from a heptane/ethyl ether mixture (3/1). (90 EtOAc, 10 heptane) (Rf: 0.56).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=O)[NH:6][C:7]=1[CH3:8].[Cl:11]C1NC(=O)C(C)=C(C)N=1>>[Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([Cl:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)[nH]c(=O)c1C
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Product: Cc1nc(Cl)[nH]c(=O)c1Br
Yield: 63 %

Procedure:
The title compound was prepared in 63% yield from 5-Bromo-6-methyl-1H-pyrimidine-2,4-dione utilizing a method analogous to the preparation of 2-chloro-5,6-dimethyl-3H-pyrimidin-4-one (see Lee, et al., WO 9605177). 1H NMR (400 MHz, DMSO-d6): δ 2.38 (s, 3H). MS (ES) [m+H] calc'd for C5H4N2OBrCl, 223, 225, 227; found 223, 225, 227.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Li+].[OH-]>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.9 %

Procedure:
To methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (3.51 g, 7.54 mmol) in methanol (22.6 mL) and water (11.30 mL), was added LiOH.H20 (1.582 g, 37.7 mmol). This was stirred at room temperature for 19 h. MeOH was removed under vacuo. The aqueous layer was acidified with HCl (1 N) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford the title compound (2.2082 g, 65%). LC-MS m/z 452 (M+H)+.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[Cl:22][C:23]1[N:28]=[C:27](/[CH:29]=[CH:30]/[C:31]#[N:32])[CH:26]=[CH:25][CH:24]=1>>[Cl:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH2:32])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Reactant: N#C/C=C/c1cccc(Cl)n1
Product: Nc1cc(-c2cccc(Cl)n2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):323 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and E-3-(6-chloro-pyridin-2-yl )-acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(CC1CCCCC1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(CC2CCCCC2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 38 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (118.9 mg) and ethyl 4-aminophenylacetate hydrochloride (88.98 mg) were condensed in THF (3 ml) in the presence of triethylamine (135.67 mg) and pivaloyl chloride (66.33 mg), and then the resulting crude product was purified by column chromatography (silica gel 20 g, hexane/ethyl acetate=3/1) to obtain as a colorless oil (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide (66.2 mg).
Reaction SMILES: [S:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH2:6]2)[CH2:4][N:3]=[C:2]1[C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:15][C:14]=2[N:25]([CH3:35])[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)(=[O:28])=[O:27].[OH:36]OS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>CO.O.ClCCl>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([N:25]([CH3:35])[S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)(=[O:27])=[O:28])[CH:15]=1)[NH:12][C:11]([C:2]1[S:1][C:5]3([CH2:6][CH2:7][S:8](=[O:36])[CH2:9][CH2:10]3)[CH2:4][N:3]=1)=[CH:19]2
Reactant: O=S([O-])OO
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC4(CCSCC4)S3)cc2c1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC4(CCS(=O)CC4)S3)cc2c1
Reaction time: 18 h
Yield: 20 %

Procedure:
To a solution of N-[2-(1,8-dithia-3-azaspiro[4.5]dec-2-en-2-yl)-5-(2-methoxyethoxy)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (50.7 mg) in methanol (2 mL), water (1 mL) and dichloromethane (1 mL) was added OXONE (registered trade mark, 29 mg) at room temperature, and the mixture was stirred for 18 hr. Aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred for 30 min. The organic solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate to give two steric isomers (10.3 mg, yield 20% (retention time: shorter), and 1.7 mg, yield 3% (retention time: longer)) of the title compound as a colorless amorphous solid, respectively.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.S(O[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)(=O)C>C(O)C>[ClH:1].[ClH:1].[O:39]([CH2:38][CH2:37][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: CS(=O)(=O)OCCOc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(CCOc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
Synthesis of N-[1-(2-phenoxyethan-1-yl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Under nitrogen gas, 0.37 ml (4.78 mM) of methanesulfonyl chloride was added to a solution of 0.44 g (3.18 mM) of phenoxyethanol and 0.89 ml (6.39 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 35 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate and the reaction mixture was extracted with diethyl ether. The organic layer was washed serially with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.6989 g (<3.18 mM) of phenoxyethyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol (6.0 ml) was added 0.6989 g (<3.18 mM) of the above phenoxyethyl mesylate at room temperature and the mixture was refluxed under nitrogen for 17 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-40%) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][C@H:29]([NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 92.8 %

Procedure:
(R)-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (7D) (0.387 mmol, 0.120 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (3 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.387 mmol, 0.127 g) and N-methylmorpholine (1.55 mmol, 0.170 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.426 mmol, 0.162 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (7E) as a clear oil (0.359 mmol, 0.210 g, 93% yield). ESI-MS: m/z 585.5 (M+Hr.
Reaction SMILES: [C:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].[Si:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[CH2:34][CH2:35][CH3:36])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]2=[O:15])=[CH:28][C:27]=1[CH2:34][CH2:35][CH3:36])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20]
Reactant: CCCc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1O[Si](C)(C)C(C)(C)C
Yield: 64 %

Procedure:
To a solution of 0.295 g (1.43 mmol) of 1-carboethoxy-2-benzimidazolinone dissolved in 5.0 mL DMF was added 0.063 g (1.57 mmol) of a 60% oil dispersion of sodium hydride and the resulting mixture was stirred under a nitrogen atmosphere and gently warmed with a heat gun until the solids had dissolved and gas evolution had ceased. A solution of the product of step A in 2.0 mL DMF was then added and the reaction mixture was stirred for an additional 0.5 hours. The mixture was then quenched with 10% aqueous citric acid and extracted into ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and evaporated, and then the residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.088 g (64%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:19]=3[CH:37]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)([CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[C:19]=3[CH:37]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: OO
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.