Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][S:9][C:8]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18](OCC)=[O:19])[CH2:14][CH2:13]2)([CH3:11])[S:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC>[C:1]([CH:5]1[CH2:6][S:7][C:8]([CH:12]2[CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][CH2:17]2)([CH3:11])[S:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1CCC(C2(C)SCC(C(C)(C)C)CS2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)C1CSC(C)(C2CCC(CO)CC2)SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-t-butyl-2-(4-ethoxycarbonylcyclohexyl)-2-methyl-1,3-dithiane (0.76 g.) in dry ether (10 ml.) was added, with stirring, to a suspension of lithium aluminium hydride (142 mg.) in dry ether (15 ml.) under nitrogen at 0° C. After allowing to warm to 25° C. the reaction mixture was stirred for 2 hours. Aqueous sodium hydroxide solution was then added (1.25 ml. of a 10% solution). The ether solution was decanted and the residue washed with 2×25 ml. portions of ether. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to give 5-t-butyl-2-(4-hydroxymethylcyclohexyl)-2-methyl-1,3-dithiane.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]=[O:20])[CH:14]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]3)[CH2:5]1.C(N(CC)CC)C.[C:32](SCC)(=[S:34])[CH3:33]>CO>[CH3:22][C:21]([CH:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][NH:2][C:32](=[S:34])[CH3:33])[O:8][C:7]3=[O:9])[CH:11]=2)[N:15]1[CH:19]=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](CN)OC3=O)ccc2N1C=O
Reactant: CCSC(C)=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=S)NC[C@H]1CN(c2ccc3c(c2)CC(C(C)(C)C)N3C=O)C(=O)O1
Yield: 45.6 %

Procedure:
The amine hydrochloride salt (200 mg, 0.566 mmol) prepared in Step 12 is stirred in a mixture of methanol (4 ml) and triethylamine (0.234 ml, 1.683 mmol). To this solution is added ethyl dithioacetate (0.08 ml, 0.70 mmol) and the mixture heated to reflux for 2 hours then allowed to cool. The precipitate is filtered to afford the thioamide as white needles (97 mg, 46%): mp 219-221° C. Anal: Calcd. for C19H25N3O3S: C, 60.78; H, 6.71; N, 11.19. Found: C, 60.63; H, 6.80; N, 11.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:29]([C:30]([O:32][CH3:33])=[O:31])[CH3:34])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Then, 0.15 g of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 0.092 g of potassium carbonate and 54 μl of methyl 2-bromopropionate were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.184 g (yield, 98%) of 3-(2,4-dichloro-5-(1-methoxycarbonylethoxy)phenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-387).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-2,3-epoxypropane (13.0 g, 0.044 mol) in DMSO (100 ml), 1,2,4-triazole (7.6 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) were added and the resulting mixture was stirred at room temperature for 12 hours and at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ether and insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and distilled off under reduced pressure. The residue was recrystallized from isopropyl ether-ethyl acetate, whereby 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.0 g, yield: 12.0%) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[CH3:13].S(=O)(=O)(O)O.[Cl:19]Cl>>[Cl:19][C:4]1[C:3]([CH3:13])=[C:2]([Br:1])[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]=1[CH3:12]
Reactant: Cc1cc(C)c(S(C)(=O)=O)cc1Br
Reactant: ClCl
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(S(C)(=O)=O)c(C)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of the crude 4-bromo-6-methylsulfonyl-m-xylene obtained in Example 1 was added to 8 ml of 20% fuming sulfuric acid. A chlorine gas was flown little by little while stirring at room temperature in a reactor provided with a dry ice trap at the upper part. After one hour, the reaction liquor was added to ice, and was extracted twice with 30 ml of EDC. The EDC solution was washed with 50 ml of water and then with 20 ml of a saturated aqueous solution of common salt, and was dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to a solid, thus obtaining 2.2 g of a crude product of the above-identified aimed compound (purity measured by gas chromatography: 81.6%). A part of the crude product was recrystallized from methanol to obtain the above-identified aimed compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:28])[C:16](=[O:27])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[CH:18][C:8]2=1)=O.[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[S:42])=[O:38])=[CH:31][CH:30]=1>>[CH2:35]([O:36][C:37](=[O:38])[NH:39][CH2:40][C:41]1[S:42][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:14])[C:9]2[N:15]([CH3:28])[C:16](=[O:27])[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])=[CH:18][C:8]3=2)[N:43]=1)[C:32]1[CH:31]=[CH:30][CH:29]=[CH:34][CH:33]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Reactant: NC(=S)CNC(=O)OCc1ccccc1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CNC(=O)OCc5ccccc5)n4)ccc3n(C)c21

Procedure:
The process is carried out as for Example 8 above, using the compound from preparation 1.2, 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and N-benzyloxycarbonylglycine thioamide.
Reaction SMILES: Cl.N=CCO[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.[NH2:14][CH:15]([C:19]([NH2:21])=[O:20])[C:16]([NH2:18])=[O:17]>CO>[C:19]([C:15]1[N:14]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:18][C:16]=1[OH:17])(=[O:20])[NH2:21]
Reactant: CCOC(=O)CC(=O)OCC=N
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: CO
Product: CCOC(=O)Cc1nc(C(N)=O)c(O)[nH]1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Ethyl iminoethoxycarbonylacetate hydrochloride (49.59 g) and aminomalonamide (24.7 g) were added to anhydrous methanol (500 ml) under ice-cooling while stirring. After stirring was continued for 1 hour, the mixture was refluxed for 41/2 hours and then cooled with ice. The precipitated crystals were collected, washed with ethanol and diisopropyl ether and dried under vacuum to give ethyl 4-carbamoyl-5-hydroxy-1H-imidazole-2-acetate (32.69 g, 72.7%). m.p. 241°-241.5° C. (decomposition)
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[NH:31][C:30]=2[CH:40]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH:34]3[CH2:35][CH2:36][N:37]([CH2:20][C:19]4[CH:22]=[CH:23][C:16]([C:8]5[C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:12][N:11]6[N:13]=[CH:14][CH:15]=[C:10]6[N:9]=5)=[CH:17][CH:18]=4)[CH2:38][CH2:39]3)[NH:31][C:30]=2[CH:40]=1
Reactant: Fc1ccc2nc(C3CCNCC3)[nH]c2c1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Fc1ccc2nc(C3CCN(Cc4ccc(-c5nc6ccnn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Reaction time: 8 h
Yield: 59 %

Procedure:
250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 258 mg (1 mmol) 6-fluoro-2-piperidine-4-yl-1H-benzimidazole hydrochloride salt were treated as previously described. Additional NaBH(OAc)3 has been added after one, two and three hours (two equivalents each). After a further hour stirring at room temperature additional 26 mg 6-fluoro-2-piperidine-4-yl-1H-benzimidazole hydrochloride salt and two equivalents NaBH(OAc)3 were added. After stirring overnight and two further additions of NaBH(OAc)3 the solvents were evaporated. Workup and purification yields 249 mg of the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1.[C:13](#N)C.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>>[Br:1][C:2]1[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CC#N
Reactant: Cn1cc(Br)c(NS(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CN(c1nn(C)cc1Br)S(C)(=O)=O
Temperature: 50 °C

Procedure:
Into a 8-dram vial, N-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-methanesulfonamide (1.38 g, 5.43 mmol), Acetonitrile (20 mL, 400 mmol), Potassium carbonate (1.50 g, 10.9 mmol), and Dimethyl sulfate (1.03 mL, 10.9 mmol) were added. The reaction mixture was heated at 50° C. overnight. The solid was filtered and washed DCM. The solvent was removed under vacuum to give a solid. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant. The collected fractions afforded N-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-N-methyl-methanesulfonamide as a white solid (1.20 (82%).
Reaction SMILES: [Br:1][O-].[Na+].[C:4]1([C:10]#[CH:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:11]#[C:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]Br
Reactant: C#Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrC#Cc1ccccc1
Reaction time: 5 h
Yield: 1001.3 %

Procedure:
To a solution of sodium hypobromite [prepared by slow addition of bromine (11 ml) to 10M sodium hydroxide solution (50 ml) and crushed ice (100 g)] was added a solution of phenylacetylene (20.4 g, 19.97 mmol) in THF (10 ml). The two phase mixture was stirred vigorously for 5 hours. Saturated aq. ammonium chloride was added and the mixture was extracted with diethyl ether (3×30 ml). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to provide 1-bromo-2-phenyl-acetylene (36.2 g, 99%) as a yellow oil. 1H-NMR; δ (CDCl3), 7.50 (m). IR: Vmax (neat) 2200 cm-1.
Reaction SMILES: [F:1][C:2]1(F)[CH2:5][N:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3]1.FC1CNC1>>[F:1][CH:2]1[CH2:3][N:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1
Reactant: FC1(F)CN(C2CCNCC2)C1
Agent: FC1CNC1
Product: FC1CN(C2CCNCC2)C1

Procedure:
Prepared according to the method used in the preparation of 4-(3,3-difluoroazetidin-1-yl)-piperidine using 3-fluoroazetidine in place of 3,3-difluoroazetidine hydrochloride. The title compound was obtained as a colourless oil (180 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)[C:2]=1[NH2:1])([O-:10])=[O:9]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 2-amino-3-nitro-phenol (18.0 g, 0.117 mol) and epibromohydrin (21.0 g, 0.15 mol) in DMF (200 mL) containing potassium carbonate (20.7 g, 0.15 mol) was stirred at 70° C. overnight. The mixture was evaporated in vacuo, water was added to the residue and the mixture was then extracted with dichloromethane (2×300 mL), the combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride) provided 15.0 g of the title compound as an orange solid. 1H NMR (DMSO-d6): δ 7.60 (dd, 1H); 7.11 (dd, 1H); 7.05 (s, 2H); 6.60 (dd, 1H); 4.40 (dd, 1H); 3.93 (dd, 1H); 3.42 (m, 1H); 2.87 (dd, 1H); 2.75 (dd, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:7]([Cl:21])[C:6]=1[Cl:22])=O.[C:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1)(=[S:25])[NH2:24]>CN(C=O)C>[Cl:22][C:6]1[C:7]([Cl:21])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]1[N:24]=[C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)[S:25][CH:2]=1
Reactant: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Reactant: CC(=O)N1CCN(C(N)=S)CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2nc(-c3ccc(Sc4ccccc4C(C)C)c(Cl)c3Cl)cs2)CC1

Procedure:
A solution of compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl-4-acetyl piperazine (20.5 mg, 0.11 mmole) in DMF (1.0 ml) was stirred at ambient temperature for two hours. The solvent was evaporated and the residue was purified on a 5-g silica gel cartridge, giving the desired product 39 as a white solid. 23 mg, 65.7%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 2.14 (s, 3H), 3.46–3.60 (m, 7H),), 3.75–3.78 (m, 2H), 6.48 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 7.21 (m, 1H), 7.44–7.51 (m, 3H), 7.57 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 506 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[CH:13]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>O.COCCOCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2/[CH:13]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=Cc1cn[nH]c1-c1ccc(F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: COCCOCCOC
Product: O=C(O)/C=C/c1cn[nH]c1-c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 9.8 %

Procedure:
A mixture of 5-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (1.0 g), malonic acid (0.67 g), piperidine (0.54 g) and bis(2-methoxyethyl) ether (10 mL) was stirred at 110° C. for 6 hrs. Water and 1N hydrochloric acid were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give (2E)-3-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]acrylic acid as colorless crystals (0.12 g, yield 10%) from a fraction eluted with hexane-ethyl acetate (1:9, v/v). Recrystallization thereof from acetone-diisopropyl ether gave colorless prism crystals. melting point: 276-277° C.
Reaction SMILES: [ClH:1].C([NH:9][C@H:10]([C:20]([OH:22])=[O:21])[CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OC(C)(C)C)=O.[CH2:23](O)[CH3:24]>>[ClH:1].[CH2:23]([O:22][C:20](=[O:21])[C@H:10]([CH2:11][S:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:9])[CH3:24]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl(g) is bubbled into a solution of BOC-S-benzyl-L-cysteine (9.33 g, 30 mmol) in ethanol (200 mL) for 15 minutes. The container is stoppered and stirred at room temperature overnight. The solvent is evaporated in vacuo and the residue stirred in diethyl ether (150 mL) for 1.5 hours to yield S-benzyl-L-cysteine ethyl ester hydrochloride as a solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]3[CH2:15][C:16]4([CH2:19][CH:12]3[C:11]2=[O:20])[CH2:18][O:17]4)=[CH:6][CH:5]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(O)C=CC=CC=1>O>[OH:17][C:16]1([CH2:18][NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:12]2[C:11](=[O:20])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:22])([F:21])[F:1])=[CH:9][CH:8]=3)[CH2:14][CH:13]2[CH2:15]1
Reactant: O=C1C2CC3(CO3)CC2CN1c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccccc1
Solvent: O
Solvent: Oc1ccccc1
Product: O=C1C2CC(O)(CNc3ccccc3)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
rac-(3aR,5S,6aS)-2-[4-(trifluoromethoxy)phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxiran]-1-one (80 mg, 0.25 mmol), aniline (5 mL) and PhOH (23 mg, 0.24 mmol) were mixed together, and the mixture was stirred for 24 h at 60° C. The solution was then poured into water (25 mL) and extracted with ether (3×20 mL). The combined ether was washed with sodium hydroxide (10%, 3×10 mL), with water (30 mL) and dried over Na2SO4. The solvent was removed and the residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) to yield the title compound (25 mg, 24%). 1H NMR (300 MHz, CDCl3): δ 7.57-7.55 (m, 2H), 7.27-7.13 (m, 4H), 7.00-6.93 (m, 3H), 5.26 (bs, 1H), 4.07 (t, 1H, J=9.3 Hz), 3.75-3.73 (m, 1H), 3.34-2.22 (m, 3H), 3.05-2.90 (m, 1H), 2.46-2.42 (m, 1H), 2.02-1.90 (m, 3H); LC-MS: 407.1 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[CH:16]1[C:24](=[O:25])[CH:23]2[CH:18]([CH:19]3[O:26][CH:22]2[CH:21]([C:27]#[C:28][Si](C)(C)C)[CH2:20]3)[C:17]1=[O:33].Cl>CO>[C:27]([CH:21]1[CH2:20][CH:19]2[O:26][CH:22]1[CH:23]1[CH:18]2[C:17](=[O:33])[CH:16]([C:9]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[CH3:7])[C:24]1=[O:25])#[CH:28]
Reactant: Cc1cc(C)c(C2C(=O)C3C4CC(C#C[Si](C)(C)C)C(O4)C3C2=O)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CC2OC1C1C(=O)C(c3c(C)cc(C)cc3C)C(=O)C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (2.58 g, 19 mmol) is added to a stirred solution of (1RS,2SR,6RS,7RS)-4-(2,4,6-trimethylphenyl)-8-trimethylsilylethynyl-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione (6.43 g, 17 mmol) in methanol (100 ml). The reaction mixture is stirred at room temperature for 2 hours and 30 minutes, then dilute aqueous hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give (1RS,2SR,6RS,7RS)-8-ethynyl-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26](O)=[O:27].C(N=C=NC(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)=[O:27]
Reactant: O=C(O)Cc1cc(F)ccc1Br
Reactant: OCc1ccc(OCc2ccccc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cc(F)ccc1Br)OCc1ccc(OCc2ccccc2)cc1

Procedure:
A suspension of 3 g (2.73 mmol) of Wang resin (p-benzyloxybenzyl alcohol resin, 100-200 mesh) in 49 ml of dichloromethane is stirred (orbital stirring) at room temperature for 15 minutes. 2.8 g (12.0 mmol) of (2-bromo-5-fluorophenyl)acetic acid dissolved in 20 ml of dichloromethane are then added, followed by addition of 0.067 g (0.55 mmol) of 4-dimethylaminopyridine and 1.88 ml (12.0 mol) of N,N′-diisopropylcarbodiimide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH2:29][CH3:30])[CH2:25][CH3:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1Cl)=NC2
Reactant: CCN(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-bromo-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine is treated with a cold mixture of N,N-diethylhydroxylamine and sodium hydride in dimethylformamide to give 8-bromo-1-[(diethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.C(OC([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1B(O)O)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:4]1[N:3]=[C:2]([C:19]2[NH:18][C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: COc1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Temperature: 60 °C
Yield: 69.6 %

Procedure:
To a degassed solution of compound 2,6-dichloro-3-methoxypyridine (8.9 g, 0.05 mol), (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (13 g, 0.05 mol) and K3PO4 (31.8 g, 3.0 mol) in DMF (100 mL) was added Pd(dppf)Cl2 (3.65 g, 5 mmol) under N2. The mixture was heated at 60° C. for about 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide the desired product of 2-(6-chloro-3-methoxypyridin-2-yl)-1H-indole (9.0 g, yield: 69.8%). 1H-NMR (CDCl3, 400 MHz) δ 9.52 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.38˜7.43 (m, 2H), 7.07˜7.26 (m, 4H), 4.03 (s, 3H). MS (M+H)+: 259/261.