Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH3:7])[O:5][CH:4]([CH3:8])[C:3]1=NO.[OH:11]S(O)(=O)=O>>[O:1]=[C:2]1[CH:6]([CH3:7])[O:5][C:4]([CH3:8])=[C:3]1[OH:11]
Reactant: O=S(=O)(O)O
Reactant: CC1OC(C)C(=NO)C1=O
Product: CC1=C(O)C(=O)C(C)O1

Procedure:
10 g of 4-oxo-3-oximino-2,5-dimethyl-tetrahydrofuran and 50 ml of 10% strength H2SO4 are heated at 80° C and the hydrolysis is followed by thin layer chromatography. The oxime has been converted after 3 hours. In its place, 4-oxo-3-hydroxy-2,5-dimethyl-4,5-dihydrofuran has been formed, as established by isolating the product and comparing the chromatographic and spectroscopic data with those of a comparative substance.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH:20]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][CH2:24][O:23][CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)OCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 3-isopropoxypropylamine (0.197 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 30% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid tip in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.395 g, 71%): TOF MS ES+ 363.2 (M+H)+, HRMS calcd for C18H24N4O3F 363.1832 (M+H)+, found 363.1821, time 0.57 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.8 ml, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH2:11][CH3:12])[CH3:10])[CH:5]=[CH:4][C:3]=1[OH:13].[CH2:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([CH2:14][CH3:15])=[CH:17][CH:18]=2)=[C:2]([Cl:1])[CH:7]=1)([CH2:11][CH3:12])[CH3:10]
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Reactant: CCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(COc2ccc(OC(C)CC)cc2Cl)cc1
Reaction time: 48 h
Yield: 60.7 %

Procedure:
A mixture of 0.74 g of 2-chloro-4-sec-butoxyphenol, 0.50 g of p-ethylbenzyl alcohol, 1.00 g of triphenylphosphine, 0.65 g of diethylazadicarboxylate and 100 mg of tetrahydrofuran was stirred at room temperatur for 48 hours. The reaction mixture was concentrated, and 50 ml of diethyl ether was added thereto. The precipitates were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to give 0.71 g of 1-sec-butoxy-3-chloro-4-(4-ethylbenzyloxy)-benzene. Yield, 60%. nD22.6 1.5529.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(N(CC)CC)C>ClCCl>[CH:12]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1)=[O:11]
Reactant: N#Cc1ccc(CO)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C=O)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (936 mg, 7.38 mmol) is dissolved in dichlormethane (8 ml) under an argon atmosphere and cooled to −78° C. in an acetone dry-ice bath. Dimethylsulfoxide (1.153 g, 14.76 mmol) is added dropwise and the mixture is stirred for 20 minutes at −78° C. The compound of Example 32A (900 mg, 6.71 mmol) is added dropwise as a dichloromethane (7 ml) solution. The reaction is stirred for an additional two hours at −78° C. Triethylamine (3.05 g, 30.19 mmol) is added and the reaction is kept at −78° C. for 10 minutes, then allowed to warm to room temperature. The reaction is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate phase is washed with bicarbonate and brine, dried over magnesium sulphate monohydrate, filtered and concentrated to afford a yellow oil. The crude oil is purified by column chromatography on silica gel with dichloromethane as eluent.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:18]>C1(C)C=CC=CC=1>[Br:18][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Br
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Solvent: Cc1ccccc1
Product: BrCCC=C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
To a vigorously stirred solution of 250.g (1.1 mol) of cyclopropyl diphenyl carbinol in 2.5 liters of toluene at ambient temperature was added rapidly 3.1 liters of 48% aqueous hydrobromic acid. After stirring for several hours, the layers were separated, the organic phase was washed with 1 liter of water, 1 liter of 10% aqueous sodium bicarbonate, and dried over sodium sulfate. The resulting crude oil residue was subjected to high-vacuum short path distillation to give 300 .g (95%) of 4-bromo-1,1-diphenyl-l-butene as a clear oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[OH-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1cn(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
The obtained 2-chloro-4,6-dimorpholino-1,3,5-triazine (1.44 g, 5.04 mol) was dissolved in DMF (40 ml), added with sodium hydroxide (430 mg, 10.2 mmol) and imidazole (694 mg, 10.2 mmol) and stirred at 110° C. -120° C. for 30 minutes. The reaction mixture was evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was recrystallized from ethanol to obtain 1.37 g (yield: 85.1%) of the titled compound as colorless crystals.
Reaction SMILES: CC([S@]([NH:7][C@@H:8]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[F:21][C:20]([F:22])([F:23])[CH2:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH2:7]
Reactant: CC(C)(C)[S@@](=O)N[C@H]1CCCc2c(OCC(F)(F)F)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCCc2c(OCC(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of Intermediate 13B (245 mg, 0.701 mmol) in DCM (1 mL) was added 4 N HCl (175 μl, 0.701 mmol) in dioxane. The resulting mixture was stirred at rt for 0.5 h. The solvents were evaporated and DCM (3×) was added and evaporated. The resulting white solid was vacuum dried for 1 h to give Intermediate 13 (140 mg, 0.571 mmol, 81.0% yield) as a HCl salt which was used directly without further purification. LCMS=1.48 min [M+1-17]=229 (Method B).
Reaction SMILES: C([Li])CCC.S1CCCSC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([C:20]#[N:21])[CH:14]=1.[CH3:22][O:23][C:24]([CH3:26])=[CH2:25].[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:38])([CH3:37])[N:34]=[C:33]([CH:39]3[S:44][CH2:43][CH2:42][CH2:41][S:40]3)[C:32]=2[CH:45]=1>CCCCCC.O1CCCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH:24]([O:23][CH3:22])[CH3:26])=[C:15]([CH:14]=1)[C:20]#[N:21].[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:37])([CH3:38])[N:34]=[C:33]([CH:39]3[S:40][CH2:41][CH2:42][CH2:43][S:44]3)[C:32]=2[CH:45]=1
Reactant: N#Cc1cc(Br)ccc1O
Reactant: C=C(C)OC
Agent: C1CSCSC1
Agent: CC1(C)N=C(C2SCCCS2)c2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(C)COc1ccc(Br)cc1C#N
Reaction time: 0.5 h

Procedure:
A solution (13.8 ml) of 1.6M n-butyllithium in hexane was added dropwise to a solution of 1,3-dithian (1.5 g) in anhydrous tetrahydrofuran (35 ml) at -78° C. under an argon atmosphere over 10 minutes. After stirring for 30 minutes, a solution of 5-bromo-2-(2-methoxy-2-methylethoxy)benzonitrile, which was prepared from 4-bromo-2-cyanophenol (m.p. 148°-150° C., 2.48 g) and 2-methoxypropene (1.1 g) according to the same manner as described in Example 29, in anhydrous tetrahydrofuran (5 ml) was added to the mixture. The mixture was treated in the same manner as that in Example 29 to obtain 6-bromo-2,2-dimethyl-4-(1,3-dithian-2-yl)-2H-1,3-benzoxazine (0.90 g) (Compound 105).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[ClH:39].[N:40]1([C:45](N)=[NH:46])C=CC=N1>CN(C)C=O>[ClH:39].[ClH:39].[CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:45](=[NH:40])[NH2:46])[CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N=C(N)n1cccn1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.9 %

Procedure:
To a solution of 1-(pyridin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (8.29 g) in dimethylformamide (50 ml) were added diisopropylethylamine (4.4 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (3.69 g), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether (350 ml) and the supernatant was removed. The obtained oil was dissolved in methanol (20 ml) and thereto was dropwise added diethyl ether (700 ml) with stirring. The supernatant was removed and dried under reduced pressure. Fifty (50) mg from the obtained 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (10.0 g) was dissolved in ethanol and dil. hydrochloric acid was added. The mixture was concentrated and dried under reduced pressure to give the title compound (55 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:17]([OH:23])=[C:16]([CH2:24][CH2:25][CH3:26])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:27])[CH:3]=1.Br[CH:29]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:30]([CH:29]([CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[O:23][C:17]1[C:16]([CH2:24][CH2:25][CH3:26])=[CH:15][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:27])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:19][C:18]=1[CH2:20][CH2:21][CH3:22])([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(CCc1ccccc1)C(=O)OCC
Temperature: 60 °C
Yield: 63.6 %

Procedure:
To a stirred solution of 0.150 g (0.41 mmol) of 5,7-dimethyl-2-ethyl -3-[4-hydroxy-3,5-dipropylphenyl]methyl-3H-imidazol[4,5-β]pyridine (Step G of Example 13) and 0.127 g (0.49 mmol) of ethyl α-bromo-4-phenylbutanoate in 2 mL anhydrous DMF was added 0.290 g (0.82 mmol) cesium carbonate and the reaction mixture was stirred and heated at 60° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with methylene chloride, filtered, and evaporated in vacuo. The residue was then purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 0.145 g (64%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:13][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCCOCCO
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCOCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethyleneglycol monomethyl ether (10 mmol) and benzyl bromoacetate (11 mmol) are added to a suspension of anhydrous K2CO3 (15 mmol) in 50 ml anhydrous DMF. The suspension is stirred at room temperature overnight. Water is added and the emulsion is extracted with ethyl acetate (3×200 ml), washed with water, brine, and dried with MgSO4. The solvent is evaporated and the residual oil purified by flash chromatography to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:12])#[N:2]
Reactant: N#Cc1cccc(CN)c1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
13.2 g of m-cyanobenzylamine, 23.8 g of sodium persulfate and 200 ml of water were mixed and allowed to react at 70° C. for 2 hours while stirring. After cooling the reaction mixture to room temperature, sodium bicarbonate was added to render the solution weakly alkaline. The solution was subjected to separation, column chromatography, and crystallization operations in the same manner as in Example 19 to obtain 6.7 g (yield: 51%) of m-cyanobenzaldehyde. The purity was 98%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][C:24]=2[O:23]1>C1COCC1>[OH:1][C:2]1([C:27]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:30][C:29]=3[CH:28]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reactant: Br[Mg]c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added a solution of fleshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound (1.03 g, 72%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:19]=[CH:20][C:21]([C:24]([O:26]C)=[O:25])=[N:22][CH:23]=4)[CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[ClH:28]>>[ClH:28].[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:13][CH2:14][N:15]([C:18]4[N:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][CH:23]=4)[CH2:16][CH2:17]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cnc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Agent: Cl
Product: O=C(O)c1cnc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1

Procedure:
Methyl 5-{4-[(1-cyclobutyl-4-piperidinyl)methyl]-1-piperidinyl}-2-pyrazinecarboxylate (may be prepared as described in Example 1) (0.665 g) was dissolved in conc. HCl and heated at reflux for 1.5 h. The reaction mixture was evaporated, then re-evaporated from toluene (3×10 ml) to afford the crude acid hydrochloride salt (E5) as a yellow solid (0.705 g). MS electrospray (+ion) 359 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][C:3]=1[F:18].C[O:20][CH:21]1[CH:25]([CH:26]=O)[CH2:24][CH:23](OC)O1>C(O)C>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:1]1[CH:23]=[CH:24][C:25]([CH:21]=[O:20])=[CH:26]1)[NH:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](=[O:17])[NH:6]2
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CCOC(=O)C1Nc2cc(N)c(F)cc2NC1=O
Solvent: CCO
Product: CCOC(=O)C1Nc2cc(-n3ccc(C=O)c3)c(F)cc2NC1=O
Yield: 12.5 %

Procedure:
To a solution of ethyl 7-amino-6-fluoro-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate (2.03 g, 8.02 mmol) in ethanol (80 ml) was added dropwise 2,5-dimethoxytetrahydrofuran-3-aldehyde (1.36 ml, 9.62 mmol), and the mixture was refluxed for 3 hours. After cooling, the residue obtained by distilling off solvent was submitted to silica gel column chromatography [ethyl acetate-hexane=2:1] to obtain 333 mg of title compound as yellow powder. Yield 13%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[S:9][CH:10]=1)[CH3:2].[OH:19]C1C=CC=C(O)C=1C(=S)N.ClCC(=O)CC(OCC)=O.[Li+].[Br-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[C:16]([OH:19])=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Reactant: NC(=S)c1c(O)cccc1O
Agent: CCOC(=O)CC(=O)CCl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2c(O)cccc2O)n1
Yield: 69 %

Procedure:
The procedure used for the preparation of 4a was repeated with 2,6-dihydroxybenzenecarbothioamide 3b (1.02 g, 6.04 mmol), ethyl 4-chloroacetoacetate (1.99 g, 12.1 mmol), and LiBr (525 mg, 6.04 mmol) in dry THF (15 mL) to give 4b (1.16 g, 69%) as a white solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 0-12%) and recrystallization from EtOAc/hexane. mp 152.5°-154.0° C.; IR (KBr) 3256 (br), 1742, 1460, 1157 cm-1 ; 1H NMR (DMSO-d6) δ1.17 (3H, t, J=7.2 Hz, CH3), 3.88 (2H, s, CH2), 4.08 (2H, q, J=7.2 Hz, CH2), 6.44 (2H, d, J=8.2 Hz, Ar), 7.09 (1H, t, J=8.2 Hz, Ar), 7.51 (1H, s), 12.19 (2H, s, OH); FDMS m/z 279 (M+); Anal. Calcd for C13H13NO4S: C, 55.90; H, 4.69; N, 5.01. Found: C, 56.19; H, 4.85; N, 4.86.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[N:12][S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])#[N:2].[BH4-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@H:7]2[NH:12][S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])#[N:2]
Reactant: CC(C)(C)[S@@](=O)N=C1CCc2c(C#N)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@H]1CCc2c(C#N)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flask containing the crude suspension of (R)-N-(4-cyano-2,3-dihydro-1H-indene-1-ylidene)-2-methylpropane-2-sulfinamide INT-4 under N2 was added THF (1.0 L) and the reaction mixture cooled to −78° C. Sodium borohydride (40.9 g, 1.08 mol) was added portion-wise over 30 mins. (The internal temperature did not rise during the addition). The reaction mixture was stirred at −78° C. for 30 mins, half out of the bath for 30 mins, then warmed to 0° C. over 1 h. The 0° C. reaction mixture was placed in an ice bath and quenched with brine (100 mL) followed by saturated sodium potassium tartrate (420 mL) and the Ti salts precipitated. The reaction mixture was diluted with EA (1.5 L) and stirred at room temperature overnight. The organic layers were decanted and washed successively with saturated NH4Cl, water, and brine. The organic layers were dried over MgSO4 and filtered through a pad of MgSO4. The filtrate was concentrated to produce 52.9 g of crude (R)—N—((R)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide INT-5 as a brown oil, which was used directly in the next step. LCMS-ESI (m/z) calculated for C14H18N2OS: 262.3. found 263.1 [M+H]+, tR=2.99 min. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=7.7, 1H), 7.56 (t, J=6.8, 1H), 7.36 (t, J=7.7, 1H), 4.97 (q, J=7.5, 1H), 3.50 (d, J=7.6, 1H), 3.22 (ddd, J=16.9, 8.8, 3.9, 1H), 3.01 (dt, J=22.4, 6.9, 1H), 2.70-2.53 (m, 1H), 2.15-1.95 (m, 1H), 1.33-1.20 (m, 9H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:15](=[O:16])[N:14]2[CH:10]([S:11][CH2:12][CH:13]2[C:17]#[N:18])[CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH:8]1[C:15](=[O:16])[N:14]2[CH:10]([S:11][CH2:12][CH:13]2[C:17]#[N:18])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CC2SCC(C#N)N2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1CSC2CC(N)C(=O)N12
Reaction time: 2 h
Yield: 30.9 %

Procedure:
Compound 6 (0.6 g, 2.12 mmol) was dissolved in 15 mL 2N HCl/dioxane with stirring. After 2 h, many white solid formed. The above clear liquid was removed and another 20 mL dry ethyl ether was added, stirred and then discarded. The product 7 (0.12 g, 26%) was obtained and dried under reduced pressure. 1H NMR (400 MHz, CDCl3) δ 1.17 (m, 1 H), 2.05-2.15 (m, 1.5 H), 3.10-3.20 (m, 1.5H), 3.40-3.50 (m, 3.5 H), 4.40-4.55 (m, 1.5 H), 4.95 (m, 1 H), 5.22 (m, 1 H), 5.31 (m, 2 H), 5.54 (m, 1 H).
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:13][CH2:14][C:15]([O:17][C@@H:18]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C:34]2[C:33]3[N:32]([CH3:40])[C:31]4[N:30]=[C:29]5[CH:41]=[CH:42][CH:43]=[CH:44][C:28]5=[CH:27][C:26]=4[C:25](=[O:45])[C:24]=3[C:23]([O:46][CH3:47])=[CH:22][C:21]=2[O:20][C:19]1([CH3:49])[CH3:48])=[O:16])=O)(C)(C)C>C(Cl)(Cl)Cl>[NH2:13][CH2:14][C:15]([O:17][C@@H:18]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C:34]2[C:33]3[N:32]([CH3:40])[C:31]4[N:30]=[C:29]5[CH:41]=[CH:42][CH:43]=[CH:44][C:28]5=[CH:27][C:26]=4[C:25](=[O:45])[C:24]=3[C:23]([O:46][CH3:47])=[CH:22][C:21]=2[O:20][C:19]1([CH3:49])[CH3:48])=[O:16]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@@H](OC(C)=O)[C@@H](OC(=O)CNC(=O)OC(C)(C)C)C(C)(C)O2
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@@H](OC(C)=O)[C@@H](OC(=O)CN)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Add 0.14 μl of iodotrimethylsilane to a solution, at ambient temperature, of 0.1 mmol of the compound of Example 10 in 1 ml of chloroform. The reaction mixture is stirred for 5 min. at ambient temperature and then evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane/methanol:85/15) allows the expected product to be isolated.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[K+].Cl[CH2:14][C:15](=[O:17])[CH3:16].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:14][C:15]([CH3:16])=[O:17])=[O:6]
Reactant: CC(=O)CCl
Reactant: O=C([O-])c1ccccc1CO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)COC(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of potassium 2-hydroxymethylbenzoate (9.45 g) and chloroacetone (5 ml) in dry dimethylformamide (100 ml) was stirred for 3 hours at room temperature. Ethyl acetate and brine were then added and the organic layer, after further washing with water, was dried and evaporated to obtain acetonyl 2-hydroxymethylbenzoate (10 g) as a white powder. A solution of this material (1 g) in dimethylformamide (20 ml) was stirred for 3 hours in the presence of tert-butyldiphenylsilylchloride (2.32 ml) and imidazole (0.864 g).