Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[O:12])[CH2:9][CH2:10][NH2:11].CO.C(N(CC)CC)C.[CH2:22]([O:24]C(Cl)=O)C>C(OCC)(=O)C.C(=S)=S>[CH3:6][O:7][C:8]([CH2:9][CH2:10][N:11]=[C:22]=[O:24])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CCN
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCN=C=O
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution containing 603.6 g of β-alanine-methylester sulfate and 1.5 liter of methyl alcohol, 1,256 ml of triethylamine was added at a freezing point and thereto, 235 ml of carbon disulfide was added dropwise at 10° C. or less. After the dropwise addition, the solution was stirred at 10° C. or less for 1 hour and then 288 ml of ethylchloroformate was added dropwise and in this state, the solution was stirred for 2 hours. After the reaction, the reaction solution was subjected to liquid separation with ethyl acetate and water. The extracted ethyl acetate layer was dried over magnesium sulfate and filtered and then the ethyl acetate was removed by distillation under reduced pressure to 389.1 g (yield: 89.3%) of the objective compound as an oily product.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:27](=[O:30])[CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[N:21]=[CH:22][C:23]([CH:27]([OH:30])[CH2:28][CH3:29])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(OCc2ccccc2)nc1
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)c1ccc(OCc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
In a nitrogen atmosphere at −78° C., 2.71 M n-BuLi/hexane solution (18.8 mL) was dropwise added to a THF solution of 2-(benzyloxy)-5-bromopyridine (12.2 g, 46.2 mmol) synthesized according to the method described in a reference (J. Org. Chem., 1995, Vol. 60, p. 1408), and stirred at −78° C. for 1 hour. At −78° C., propionaldehyde (4.3 mL) was dropwise added, and stirred at −78° C. for 30 minutes and then at room temperature for 3 hours. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried with magnesium sulfate and concentrated. This was purified by silica gel column chromatography to obtain the intended compound (7.15 g, 64%) as a yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.CC(C)([O-])C.[K+]>CS(C)=O>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11]([CH2:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])=[CH:10][CH2:9]3
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H]1CC(=O)CC2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 17β,19-dihydroxy-1α-methyl-4-androsten-3-one in dimethylsulfoxide is added to a solution of potassium t-butoxide in dimethylsulfoxide precooled to 20° C. The reaction mixture is stirred under nitrogen for 10 minutes at room temperature and then poured onto ice cold aqueous ammonium chloride solution with vigorous stirring. The precipitate is rapidly filtered under vacuum, washed well with water and air dried. Crystallization of this residue from an acetone-hexane solution furnishes pure 17β,19-dihydroxy-1α-methyl-5-androsten-3-one.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]([C:13]([OH:15])=[O:14])[NH:4]1.[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22]([N:4]2[C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Sodium hydroxide (13.6 g) is dissolved in water (300 ml), and therein is suspended (3R)-1,2,3,4-tetrahydro-3-isoquinolinecarboxlic acid (30.0 g) and thereto is added tetrahydrofuran (120 ml). To the resulting solution is added 4-biphenylylsulfonyl chloride (42.9 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is acidified with 10% hydrochloric acid under ice cooling, and is diluted with water, and then extracted twice with ethyl acetate. The extract is washed with water and an aqueous saturated saline solution, dried over sodium sulfate and then treated with active carbon. Undissolved materials are filtered off from the extract, and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to give (3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (36.5 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:25][C:26]([F:31])([CH2:29][NH2:30])[CH2:27][NH2:28]>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:28][CH2:27][C:26]([F:31])([F:25])[CH2:29][NH2:30]
Reactant: NCC(F)(F)CN
Reactant: O=S1CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Product: NCC(F)(F)CNc1cc(N2CCS(=O)c3ccccc3C2)nc2ccc(Cl)cc12

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.21 (s, 1 H), 7.86-7.81 (m, 2 H), 7.77-7.74 (m, 2 H), 7.58 (m, 2 H), 6.32 (s, 1 H), 5.45 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.48 (m, 1 H), 4.20 (m, 2 H), 3.68 (t, 2 H), 3.50 (m, 2 H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH2:20][CH3:21])[C:14](Cl)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH2:20][CH3:21])[C:14]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:33][CH:34]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C=CCOC(=O)c1ccc(O)cc1
Product: C=CCOC(=O)c1ccc(OC(=O)c2ccc(CC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 70.5 %

Procedure:
In a manner analogous to Example 9(e), by reacting 2.35 g (8.1 mmoles) of 3-(1-adamantyl)-4-ethylbenzoyl chloride with 1.44 g (8.1 mmoles) of allyl 4-hydroxybenzoate, 2.54 g (71% yield) of the expected ester having a melting point of 111°-113° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH3:65][O:66][C:67](=[O:71])[CH2:68][CH2:69][NH2:70].C(N(C(C)C)C(C)C)C>CN(C)C=O.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:65][O:66][C:67](=[O:71])[CH2:68][CH2:69][NH:70][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([O:19][CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[CH2:17][CH3:18])=[CH:21][CH:22]=1
Reactant: COC(=O)CCN
Reactant: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)NCCC(=O)OC)cc1
Yield: 50 %

Procedure:
4-[1-(4′-Trifluoromethyl-biphenyl-4-ylmethyl)-propoxy]-benzoic acid (0.018 g, 0.04 mmol), PyBOP (0.027 g, 0.05 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.011 g, 0.08 mmol), and ethyl-diisopropyl-amine (0.03 mL, 0.18 mmol) are dissolved in N,N-dimethyl-formamide (1 mL) and stirred for sixteen hours. The mixture is diluted with ethyl acetate, washed with water two times then brine. Organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel with 0-70% ethyl acetate/hexane gradient affords 0.012 g (0.02 mmol, 60%) of title compound.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[N:10][C:9]2[CH:14]=[N:15][CH:16]=[CH:17][C:8]1=2.FC(F)(F)C(O)=O>>[O:13]=[C:12]1[CH:11]=[N:10][C:9]2[CH:14]=[N:15][CH:16]=[CH:17][C:8]=2[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: O=c1cnc2cnccc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)cnc2cnccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To 95 mg of 1-(1,3-dioxolan-2-ylmethyl)pyrido(3,4-b)pyrazin-2(1H)-one, 4.0 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 2 hours, and then left overnight. Thereto was added 4.0 mL of an 80% aqueous trifluoroacetic acid solution, and the mixture was stirred at 50 to 70° C. for 6 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was charged with chloroform and water and adjusted to pH 7.0 with a 1 mol/L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 40 mg of (2-oxopyrido(3,4-b)pyrazin-1(2H)-yl)acetaldehyde as a light brown oily substance.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc(Br)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2Br)CC1
Yield: 97.5 %

Procedure:
To a mixture of 2,3,5-tribromopyridine (10 g), 1-Boc-piperazine (6 g) and potassium carbonate (20 g) was added 2-butanone (80 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g). To a mixture of the obtained 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g), bis(tricyclohexylphosphine)palladium(II)dichloride (1.3 g), tripotassium phosphate (38 g) and cyclopropylboronic acid (8.4 g) were added toluene (100 mL) and water (5 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g). The obtained 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in ethyl acetate (50 mL), 4N hydrogen chloride/ethyl acetate (8 mL) was added, and the precipitate was collected by filtration to give the title compound (3.2 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)NC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 55.5 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-isopropyl-4-(piperazin-1-yl)benzamide (129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 25-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 15 mL) and dried in vacuum to afford (S)-3-chloro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (122.1 mg, 0.253 mmol, 55.4% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6.57 Hz, 6 H) 1.84-2.03 (m, 3 H) 2.12-2.25 (m, 1 H) 2.50-2.59 (m, 4 H) 3.02 (br. s., 4 H) 3.35-3.45 (m, 3 H) 3.53-3.64 (m, 1 H) 3.94-4.09 (m, 2 H) 6.98 (d, J=1.52 Hz, 1 H) 7.17 (d, J=8.59 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.89 (d, J=2.02 Hz, 1 H) 8.18 (d, J=7.58 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C25H31ClN6O2, 483; found, 483.
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:25]#[N:26].[Na+]>O>[C:25]([C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:26]
Reactant: [C-]#N
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(C#N)c(OC)cc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A 1.00 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in 5 ml of water, 0.50 ml of concentrated sulfuric acid was added and then 356 mg of sodium nitrite dissolved in 2 ml of water was added dropwise under ice-cooling, followed by a short period of stirring. Separately, 1.00 g of cuprous cyanide was dissolved in 4 ml of water and, with ice-cooling, 2.00 g of sodium cyanide dissolved in 4 ml of water was added dropwise thereto, followed by 1 hour of stirring. This was mixed with the previously prepared solution and heated at 80° C. to effect the reaction, the resulting reaction solution was mixed with water, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and then the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1 to chloroform:methanol=50:1) to give 0.65 g of methyl 5-cyano-2,4-dimethoxybenzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[H][H]>[Rh]>[CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH:6]([CH3:13])[CH2:7][CH2:8]2)[NH:3]1
Reactant: [H][H]
Reactant: CC1=CC(C)(C)Nc2cc(C)ccc21
Agent: [Rh]
Product: CC1CCC2C(C)CC(C)(C)NC2C1
Reaction time: 24 h

Procedure:
2,2,4,7-tetramethyldecahydroquinoline was prepared by reacting 125 grams of 2,2,4,7-tetramethyl-1,2-dihydroquinoline with hydrogen using 3 grams of rhodium at 5% by weight on charcoal as the catalyst and operating at 185° C., a 1000 psig pressure, for 24 hours. The desired product was confirmed by NMR spectral analysis and its carbon, hydrogen, nitrogen content (calculated contents for C13H25N is the same as above and analyzed contents were 78.95% carbon, 13.30% hydrogen, and 6.80% nitrogen). The product was 95% pure as determined by vapor pressure chromotograhy and boiled at about 65° C. at 1 mm of Hg.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-].[Na+].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=[O:32].[Na+].[Na+].Cl>O.C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:32])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: -7 °C
Reaction time: 2.5 h
Yield: 53.8 %

Procedure:
A flask is charged with acetonitrile (0.1 L). Under mixing, compound VI (5 g) is added, followed by NaOH pellets (2.18 g, 4.0 eq.). The reactor is cooled to −7° C. A commercial 10.5% NaOCl solution (11.5 ml, 1.4 eq.) is diluted by a factor of 3 by adding water. The diluted NaOCl solution (34.5 ml) is added dropwise over 25 min. The two-phase mixture is stirred at room temperature for 2.5 h. Then, aqueous Na2S2O5 (20 ml) is added. The pH of the aqueous phase is adjusted to 8 with 10% HCl (10 ml). The phases are then separated. The organic layer is washed with water, and the aqueous phase is washed twice with acetonitrile. The combined organic phases are combined, dried over magnesium sulfate (MgSO4), and concentrated to one quarter of the original volume. A precipitate forms in the concentrate, which is separated by filtration to obtain pantoprazole (2.78 g, 53.8%) containing 0.07% compound VI and free of sulfone within the limited of UV detection.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:6]=1[CH2:7][OH:8]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C=O
Reaction time: 18 h
Yield: 81.8 %

Procedure:
Manganese dioxide (9.64 g) is added portion-wise to a solution of {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-yl}-methanol (3.88 g) in dichloromethane (100 ml). After 18 hours at room temperature, the reaction mixture is filtered through a plug of celite and the filtration cake is washed with dichloromethane. The filtrate is concentrated in vacuo to yield 2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-carbaldehyde (3.16 g) as a white foam. The crude product obtained is used without further purification. MS (HPLC/MS): 426 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:2]1.[OH-].[Li+].Cl>O1CCCC1.O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:17]3)=[CH:10][CH:11]=2)=[N:2]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1

Procedure:
A scintillation vial was charged with the product from Example 37B (31.3 mg, 0.100 mmol), lithium hydroxide (21 mg, 0.50 mmol) and 10 mL of 4:1 tetrahydrofuran/water and placed in a shaker overnight at room temperature. The reaction was neutralized by the addition of 4 M HCl, and the resultant mixture was concentrated and purified by RP-HPLC to provide the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.07-1.17 (m, 2H), 1.42-1.53 (m, 2H), 1.70-1.88 (m, 5H), 2.14 (d, J=6.75 Hz, 2H), 2.44-2.48 (m, 1H), 6.63 (d, J=2.15 Hz, 1H), 7.26 (d, J=7.97 Hz, 2H), 7.65 (d, J=2.15 Hz, 1H), 7.68 (d, J=7.97 Hz, 2H), 12.46 (br, s, 2H); MS (ESI) m/z 285.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[C:7]([OH:14])=[N:6]2.O=S(Cl)[Cl:17].Cl>CN(C=O)C>[Cl:17][C:8]1[C:7]([OH:14])=[N:6][C:5]2[C:10]([N:9]=1)=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: COc1ccc2nc(O)c(O)nc2c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2nc(Cl)c(O)nc2c1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution (1.53M) of the product of step 1 in DMF was treated with SOCl2 (1 eq) and heated at 110° C. After 1.5 hours, the reaction mixture was cooled and poured into aqueous HCl (1 N). The resulting precipitate was filtered and washed with H2O and Et2O. The dried solid contained predominantly the title compound as a mixture with 6-methoxyquinoxaline-2,3-diol and 2,3-dichloro-6-methoxyquinoxaline. This material was used directly in the subsequent step. MS (ES+) m/z 211 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7]2)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][CH:8]1[CH2:9][CH2:10][CH2:11][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:7]1
Reactant: CC1CCCC(O)(c2ccsc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1C=C(c2ccsc2)CCC1
Reaction time: 16.5 h
Yield: 33.9 %

Procedure:
A stirred solution of 37.6 g (0.192 mol) of 1-(3-thienyl)-3-methylcyclohexanol and 0.5 g of p-toluenesulfonic acid in 200 mL of toluene was heated under reflux, and by-product water was collected in a Dean-Stark trap attached to the reaction vessel. After about 16.5 hours, the reaction mixture was cooled and concentrated under reduced pressure to give a residual oil. The oil was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 11.6 g of 3-methyl-1-(3-thienyl)cyclohexene b.p. 105° C.±5° C./0.25 mm.