Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])([OH:3])=[O:2].S(=O)(=O)(O)O.C(N(CC)CC)C.[CH2:42](O)[CH:43]=[CH2:44]>C(OCC)(=O)C>[CH2:44]([O:2][C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)=[O:18])=[O:3])[CH:43]=[CH2:42]
Reactant: C=CCO
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5.20 g) in allyl alcohol (52 ml) was refluxed in the presence of sulfuric acid (0.5 ml) for 5 hours. After cooling, triethylamine (3.14 ml) was added to the mixture. The mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in ethyl acetate (100 ml), washed in turn with water (100 ml) and brine (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give (2S,4R)-2-(allyloxycarbonylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (6.05 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:14](Br)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH:14]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC1CCCNC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1CCCN(C(c2ccccc2)c2ccccc2)C1
Yield: 78.8 %

Procedure:
5.05 g (0.05 mole) of 3-hydroxypiperidine and 13.82 g (0.1 mole) of potassium carbonate were suspended in 100 ml of dimethylformamide. 12.36 g (0.05 mole) of benzhydryl bromide were then added to the mixture, whilst stirring, and the mixture was stirred for 10 hours at room temperature. At the end of this time, the mixture was poured into 700 ml of water and extracted with ethyl acetate. The extracts were washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 10.53 g (yield 78%) of the title compound were obtained as a colorless material from the fractions eluted with a 9:1 by volume mixture of toluene and ethyl acetate.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[N+](C1C=NC=CC=1[NH:32][C@@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:34]1)([O-])=O>>[N+:20]([C:19]1[CH:18]=[CH:17][C:4]([CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:3][C:2]=1[NH:32][C@@H:33]1[CH2:34][CH2:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37][CH2:38]1)([O-:22])=[O:21]
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2ccncc2[N+](=O)[O-])CC1
Reactant: CC(C)[Si](OCc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Product: COC(=O)[C@H]1CC[C@@H](Nc2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc2[N+](=O)[O-])CC1

Procedure:
The title compound was prepared from (3-fluoro-4-nitrobenzyloxy)triisopropylsilane using the preparation for cis-methyl 4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate described above. The yield was 3.5 g (39.2% yield).
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([I:1])=[N:3]2)=[N:14][CH:15]=1
Reactant: CCOC(=O)c1c[nH]nc1I
Reactant: Fc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ccc(F)cn2)nc1I
Temperature: 100 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (8.5 g, 32.0 mmol) in DMF (160 mL) was added 2,5-difluoropyridine (11.0 g, 96.0 mmol) and potassium carbonate (13.3 g, 96.0 mmol). The mixture was stirred at 100° C. in a sealed reaction flask. After 18 h, the mixture was cooled to ambient temperature and ethyl acetate and water were added. The solid in the organic layer was filtered off and the filtrate was dried over MgSO4, filtered and concentrated. The product was recrystallized using ethyl acetate and ether to give 6.5 g of the title compound. The solution from recrystallization was concentrated and purified by silica gel chromatography (100% dichloromethane→98% dichloromethane/methanol) gave 0.8 g of the title compound (7.3 g total). MS 361.8 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([N:20]2C=CN=C2)=[O:19])[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1.N>O>[C:18]([C:4]1[C:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:2]([Br:1])[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]=12)(=[O:19])[NH2:20]
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(=O)n3ccnc3)c2C1
Agent: N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To 1.79 g (3.66 mmol) of tert-butyl 6-bromo-7-(3-fluorophenyl)-8-(1H-imidazol-1-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in an autoclave are added 30 ml of 33% aqueous ammonia. The mixture is stirred for 5 hours 30 minutes at 90° C. and, after cooling, is then poured into water, to give 1.26 g of tert-butyl 8-carbamoyl-6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate after drying over potassium hydroxide.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12](NNS(C2C=CC(C)=CC=2)(=O)=O)[C:13]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=1)[CH3:2].C(O)CO.[OH-].[Na+]>O>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[CH:12][C:13]2[N:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:14]=2[N:15]=1)[CH3:2]
Reactant: CCSc1ccccc1-c1nc(NNS(=O)(=O)c2ccc(C)cc2)c2ncc(C(F)(F)F)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCSc1ccccc1-c1ncc2ncc(C(F)(F)F)cc2n1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 39.7 %

Procedure:
A mixture of 156 mg of 1-[2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidin-4-yl]-2-tosylhydrazine and 12 ml of ethylene glycol was added to a mixture of 4 ml of an 8% aqueous sodium hydroxide solution and 2 ml of ethylene glycol at 80° C., and the mixture was stirred at 100° C. for 40 minutes. Water was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 40 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine (Compound of Present Invention 18).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.Cl.[N:13]([O-])=O.[Na+].C(NC1C=CC(O)=CC=1)(=O)C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>CCOCC.O>[NH:9]1[C:4]2[CH:3]=[CH:2][CH:8]=[CH:7][C:5]=2[N:6]=[N:13]1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: O
Product: c1ccc2[nH]nnc2c1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a cooled (0°-5° C.), well stirred suspension of 4-chloro-2-nitroaniline, 34.4 g. (0.2 mole) in 80 ml. of concentrated hydrochloric acid was added, dropwise, 18.0 g. (0.26 mole) of sodium nitrite in 10 ml. of water. The addition required approximately 30 minutes. After the addition was complete, the reaction mixture was filtered and the filtrate placed in an addition funnel containing approximately 100 g. of crushed ice. This solution was used immediately in the next step. The solution was added, dropwise, over 30 minutes to a well stirred suspension of 30.2 g. (0.2 mole) of p-acetamidophenol in 600 ml. of water containing 60 g. of sodium bicarbonate and 8 g. sodium hydroxide. The addition took about 20-30 minutes. The reaction was run most conveniently in a large beaker and small portions of ether were added to reduce foaming. The mixture was stirred for two hours and the dark red azo dye was collected by filtration and washed with a little water. The wet filter cake was suspended in 2,000 ml. of 5% sodium hydroxide and stirred well under nitrogen for 30 minutes. While maintaining a nitrogen atmosphere, 140 g. of Na2S2O4 was added in portions over one hour. The mixture was then boiled for one hour, cooled and filtered under nitrogen. The filtrate was acidified, under nitrogen, to a pH of 5. The yellow-grey precipitate was collected by filtration under nitrogen and dried in a vacuum desiccator to give 20 g. (38% yield) crude benzotriazole.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=1)[CH3:5].[OH-].[Na+]>C(OCC)(=O)C>[S:12]1[C:8]2[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:15])=[O:2])[CH:14]=[CH:13][C:9]=2[N:10]=[CH:11]1
Reactant: COC(=O)C(C)c1ccc2ncsc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc2ncsc2c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A mixture of 2-benzothiazol-6-yl-propionic acid methyl ester (6.6 g, 30.0 mmol) and aqueous 2 N NaOH (23.0 ml) was heated at reflux for 1 hour until the reaction mixture became a dark red solution. The mixture was then cooled to room temperature and the mixture extracted with dichloromethane (×2) and the aqueous layer was acidified with conc.hydrochloric acid to pH4-5. The resulting solid was filtered off to afford the crude product, which was stirred in ethyl acetate the filtered and dried in vacuo to provide the title compound (4.3 g, 69.2%) as an off white solid. (300 MHz, DMSO-d6): δ 12.41 (s, 1H), 9.35 (s, 1H), 8.09-8.08 (d, J=1.5 Hz, 2H), 8.05-8.02 (d, J=8.7 Hz 2H), 7.48-7.45 (dd, J=1.5 Hz, 8.7 Hz, 1H), 3.89 (q, 1H), 1.45 (d, 3H). MS m/z 208 (M++1).
Reaction SMILES: [CH:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([O:12]C/C=C(/CCC=C(C)C)\C)=[O:11])=[O:7])([CH3:3])[CH3:2].II.[Mg].IC1C=CC=CC=1C(C)C>IC1C=CC=CC=1C(C)C.C(OCC)C.C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)=CCC/C(C)=C/COC(=O)c1ccccc1C(=O)c1ccccc1C(C)C
Agent: CC(C)c1ccccc1I
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1C(=O)c1ccccc1C(=O)O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 28.1 %

Procedure:
Geranyl 2-(2'-isopropylbenzoyl)benzoate (2) Magnesium (0.46 g, 19 mmol) and a crystal of iodine were placed in a dry round bottom flask which was heated to activate the magnesium. Diethyl ether was added to cover the magnesium (50mL) and several drops of 2-iodoisopropyl benzene in diethyl ether were added to start the preparation of the Grignard reagent. When the latter was underway, a solution of 2-iodoisopropyl benzene (4.18 g, 17 mnol) in diethyl ether (20 mL) was added over 20 minutes. The reaction mixture was stirred for another 15 minutes and then refluxed for 20 minutes. Phthalic anhydricie (3.11 g, 21 mmol) in toluene (50 mL) was added dropwise to the Grignard reagent at room temperature. The reaction temperature was raised to 60° C. and the diethyl ether removed by evaporation. The reaction was allowed to stir at 60° C. for 6 hours. The reaction mixture was poured on ice and 10% HCl (lOOmL) and extracted twice with diethyl ether. The organic phase was washed twice with a 10% Na2CO3 solution (200 mL). The aqueous phase was acidified with acetic acid (120 mL) and extracted twice with diethyl ether (200 mL). The organic phase was washed three times with NaHCO3 (100 mL) and then twice with water. The ether phase was dried over Na2SO4, filtered and concentrated. The yield was 1.43 g (purity: 94.6%, isolated yield: 31%) of 2-(2isopropylbenzoyl)benzoic acid. For esterification, a solution of the thus obtained acid (3.77 g, 10 mmol), geraniol (1.4 g, 9 mmol) and 4-dimethylaminopyridine (DMAP, 0.244 g, 2 mmol) in pyridine (15 mL) was prepared under anhydrous conditions. 1,3-Dicyclohexylcarbodiimide (DCC, 2.06 g, 10 mmol) was added and the reaction was stirred under a stream of nitrogen gas for 52 hours. The reaction mixture was partitioned between IM HCl and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated under vacuum. The ester product was purified by flash column chromatography (SiO2, 7:1 cyclohexane:ethyl acetate; isolated yield: 0.7 g, 48%) to give the following analytical data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(C(C)C)CC)(C)C.Cl.[NH2:20][OH:21]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([NH:20][OH:21])=[NH:6]
Reactant: NO
Reactant: N#Cc1cccc(F)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1cccc(F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
3-Fluorobenzonitrile (2.5 g, 0.021 mol), diisopropylethyl amine (10.8 mL, 0.062 mol) and hydroxylamine hydrochloride (4.3 g, 0.062 mol) were mixed in ethanol (30 mL). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated to half the original volume. The residue was added to a mixture of dichloromethane (200 mL) and water (60 mL). The mixture was basified to pH 9 using 2N NaOH and the organic phase was separated. The aqueous phase was extracted further with dichloromethane (2×50 mL) and the combined organic phase was washed with water (75 mL), washed with brine (75 mL), dried over sodium sulfate and concentrated to give the product as a yellow solid (2.8 g, 89%). 1H NMR (300 MHz, CDCl3): δ 8.05 (bs, 1H), 7.39 (m, 3H), 7.16 (m, 1H), 4.88 (bs, 2H).
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:12](Br)=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)(=O)=O)=CC=1.[O:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.C([Li])CCC.O>C1COCC1>[O:23]1[CH:27]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]1[CH:25]=[CH:26]2
Reactant: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc3cccnc23)cc1
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C1=CC2OC1c1ccc3cccnc3c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of the tosyl ester (4a) (5.00 g, 13.2 mmol) in dry THF (150 mL) and freshly distilled furan (24.3 mL, 22.6 g, 0.33 mol, 25 equiv.) cooled at −78° C. under nitrogen was treated dropwise with n-butyllithium in hexanes (2.5 M, 5.55 mL, 13.8 mmol, 1.05 equiv.). The reaction was stirred for 1 hr at −78° C. and then allowed to warm to room temperature over 3 hours. The reaction mixture was treated with water (5 mL) and then heated under reduced pressure to remove most of the THF. This mixture was then diluted with water (150 mL), extracted with dichloromethane (3×100 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a crude brown solid (2.31 g). This material was dissolved in the minimum amount of dichloromethane/petroleum and absorbed onto a pad of neutral alumina. Gradient elution with ethyl acetate/petroleum ether afforded the product, which was recrystallized from dichloromethane/ether/petroleum ether to afford the endoxide (7,10-epoxy-7,10-dihydrobenzo[h]quinoline (6) as cream colored crystals (1.07 g, 42%). 1H NMR (CDCl3, 300 MHz) δ ppm 8.88 (dd, 1H, J=4.1, 1.7 Hz); 8.14 (dd, 1H, J=8.4, 1.7 Hz); 7.60 and 7.57 (ABq, 2H, J=7.8 Hz); 7.27–7.33 (m, 2H); 7.21 (dd, 1H, J=5.5, 1.8 Hz); 6.54 (bs, 1H); 5.95 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]([S:9]C)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:11]=[C:12]1[N:17]2[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]2[CH2:15][NH:14][CH2:13]1.O>CN(C)C=O>[CH:1]1([C:7]([N:14]2[CH2:13][C:12](=[O:11])[N:17]3[CH2:18][CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:16]3[CH2:15]2)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Reactant: CSC(=S)C1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(C(=S)C2CCCCC2)CC2c3ccccc3CCCN12

Procedure:
Methyl cyclohexanecarbodithioate (0.24 g) was added to a solution of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.3 g) in dimethylformamide (5 ml). The mixture was refluxed for 4 h, cooled and poured into water. This was extracted with diethyl ether; the ether solution was dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, diethyl ether). m/e observed: 342.1770 C20H26N2OS requires 342.1766
Reaction SMILES: Cl.C(=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:30])[CH3:29])[CH2:24][CH:23]=2)[C:17]=1[F:31])(C1C=CC=CC=1)C1C=CC=CC=1.[NH4+].[OH-]>C1COCC1>[CH3:29][N:28]([CH3:30])[CH:25]1[CH2:26][CH2:27][C:22]([C:18]2[C:17]([F:31])=[C:16]([NH2:15])[CH:21]=[CH:20][CH:19]=2)=[CH:23][CH2:24]1
Reactant: CN(C)C1CC=C(c2cccc(N=C(c3ccccc3)c3ccccc3)c2F)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C1CC=C(c2cccc(N)c2F)CC1
Yield: 89 %

Procedure:
Add concentrated hydrochloric acid (2 mL) into a solution of the above benzhydrylidene-(3-(4-dimethylamino-cyclohex-1-enyl)-2-fluoro-phenyl)-amine (2.27 g, 5.7 mmol) in THF (20 mL) and heat at reflux for 1 hr. Basify the reaction mixture with conc. NH4OH and partition between saturated aqueous NaCl and DCM, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by chromatography on a silica gel column (DCM: 2M NH3 in MeOH, gradient) to give the title compound (1.189 g): MS (ES): m/z=235 (M+H)+. 1H NMR (CDCl3): δ 6.85 (m, 1H), 6.64 (m, 1H), 6.87 (m, 1H), 5.87 (m, 1H), 3.70 (br s, 2H), 2.3-2.6 (m, 4H), 2.35 (s, 6H), 2.18 (m, 1H), 2.06 (m, 1H), 1.55 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Cl)cc2)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of p-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(4-chlorophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 202°-204° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][NH:27][C:28](=O)[O:29]C1C=CC=CC=1>C1COCC1>[CH2:3]([CH:10]1[CH2:14][CH2:13][N:12]([C:28]([NH:27][CH2:26][CH2:25][C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([Cl:15])[CH:17]=3)[NH:21][CH:20]=2)=[O:29])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)Oc1ccccc1
Reactant: c1ccc(CC2CCNC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)N1CCC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
NaH in mineral oil (60%) (12.20 mg) was added to a mixture of 3-benzylpyrrolidine (0.085 g; 0.508 mmol) in THF (2 mL) and stirred at room temperature for 10 minutes. Phenyl 2-(5-chloro-1H-indol-3-yl)ethylcarbamate (0.080 g; 0.245 mmol) in THF (2 mL) was added to the above mixture and stirred at room temperature overnight. The crude material was purified by preparative HPLC (method 2) to yield 0.03 g (31%) of 3-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyrrolidine-1-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[S:23][CH2:22][CH2:21][C:19]=2[N:20]=1>C(O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:18]3[S:23][CH2:22][CH2:21][C:19]=3[N:20]=[C:15]([Cl:14])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2SCC3)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
454 mg piperazine-1-carboxylic acid tert-butyl ester in 5 mL ethanol was added to 0.5 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine in 5 mL dichlormethane. The reaction was stirred 2 h at RT, 3 h at 60° C. and over night at RT. The solvents were removed and water was added to the residue. The precipitate was filtered and dried to give 0.83 g of the desired product.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH:23]O.[OH-].[Na+]>C1COCC1.O.CCOCC>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH2:3][OH:23])[N:5]=[CH:6]2
Reactant: OO
Reactant: C=CCn1ncc2cc(Br)ccc21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCCCn1ncc2cc(Br)ccc21
Temperature: 0 °C

Procedure:
1-Allyl-5-bromo-1H-indazole (1s) (0.50 g, 2.1 mmol) was dissolved in 2 mL THF and cooled to 0° C. A solution of 9-BBN in THF (0.5 M solution, 8.9 mL, 4.4 mmol) was then added slowly via syringe under nitrogen and stirring. The reaction was warmed to room temperature over 6.5 hours. Then, a solution of aqueous H2O2 (30% wt. solution; 1.4 mL) in 1 N NaOH (14 mL, 14 mmol) was added slowly to the solution. The reaction was stirred at room temperature overnight, resulting in the formation of a white precipitate. The reaction was diluted with H2O and Et2O. The layers were separated and the organic phase was washed with brine. The aqueous phases were extracted once with Et2O. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude material (2s) was carried on to the next step without characterization.