Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:13](=[C:16]([OH:21])[C@H:17]([OH:20])[CH:18]=O)([CH3:15])[CH3:14].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[CH:18][C@H:17]([C:16](=[C:13]([CH3:15])[CH3:14])[OH:21])[OH:20]
Reactant: CC(C)=C(O)[C@H](O)C=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(CN=C[C@@H](O)C(O)=C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 Å and, after 20 minutes, 0.7 g (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The organic solution of isopropylidene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine obtained is cooled to -20° C. under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. A solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is then added dropwise within 1 hour and the mixture is subsequently stirred at room temperature overnight. The mixture is washed three times with 100 ml of water each time and with 100 ml of sodium chloride solution and then dried ovr sodium sulphate. The organic solution is evaporated and the residue is chromatographed on silica gel (230-400 mesh) while eluting with hexane/ethyl acetate (1:1). There are obtained 1.77 g (70%) of N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [α]D =+41° (c=0.8 in chloroform); MS: 466 (M+).
Reaction SMILES: C([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH:10]([O:12]C(C)(C)C)[CH2:9][NH:8]1)(C)(C)C.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.[C:30]([S:33][CH2:34][CH2:35][C:36](Cl)=[O:37])(=[O:32])[CH3:31]>>[C:30]([S:33][CH2:34][CH2:35][C:36]([N:8]1[CH2:9][CH:10]([OH:12])[CH:11]=[C:7]1[C:6]([OH:5])=[O:17])=[O:37])(=[O:32])[CH3:31]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(OC(C)(C)C)CN1
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: CC(=O)SCCC(=O)N1CC(O)C=C1C(=O)O

Procedure:
By substituting 4-tert-butoxy-L-proline tert-butyl ester for the L-proline tert-butyl ester and 3-acetylthiopropanoyl chloride for the 3-acethylthio-2-methylpropanoyl chloride in the procedure of Example 1, 1-(3-acetylthio-1-oxopropyl)-4,5-dihydro-4-hydroxy-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[O:29]=[C:27]1[NH:12][C:11]2[C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(C(F)(F)F)c(N)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)c2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of methyl 2,3-diamino-4-(trifluoromethyl)benzoate (5.10 g, 0.022 mol) and diisopropylethylamine (6.26 g, 0.048 mol) in toluene (50 ml) was added a solution of triphosgene (2.58 g, 0.0087 mol) in toluene (20 ml) dropwise and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with 1N hydrochloric acid and extracted with ethyl acetate and tetrahydrofuran. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. A solution of 50% diisopropylether/n-hexane was added to the residue and white precipitates were filtered, washed with same solvent to give 5.00 g (0.019 mol 87%) of the title as a white powder
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:28]([C:35]([F:36])([F:37])[F:38])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 4-methoxy-2-(trifluoromethyl)phenylboronic acid (248 mg, 1.0 mmol) to afford after chromatographic purification the title compound (196 mg, 83%). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.26 (m,2H), 7.01-7.05 (m, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 3.90-4.30 (m, 3H), 3.86 (s, 3H), 3.3.64-3.75 (m, 1H), 3.25-3.50 (m, 4H), 3.05-3.12 (m, 1H), 2.85-2.95 (m, 1H), 1.80-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS-ApCI: 475 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][CH:22]=[CH2:21])[C:6]([O:8][CH3:9])=[O:7])[CH:13]=[CH2:14]
Reactant: C=CCBr
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1CC=C
Yield: 87 %

Procedure:
A solution of 3.04 g (15.8 mmol) of methyl 4-hydroxy-3-propenylbenzoate (Example 42, Step B) was refluxed with anhydrous potassium carbonate (4.37 g, 2 equiv) and allyl bromide (3.5 mL, 2.5 equiv) in acetone overnight. The mixture was filtered through Celite and the filter cake was washed with more acetone and dichloromethane. After removing the solvents, the resulting oil was distilled under high vacuum to give 3.2 g (87%) of the title compound.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[CH:20][C:21]=1[NH2:22])=[O:16].C1([SiH3])C=CC=CC=1>C([Sn](Cl)(Cl)CCCC)CCC>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[CH:20][C:21]=1[NH:22][CH:9]1[CH2:10][CH2:11][CH:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:7][CH2:8]1)=[O:16]
Reactant: O=C1CCC(n2cncn2)CC1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: COC(=O)c1sc(C2=CCCCC2)cc1NC1CCC(n2cncn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
A mixture of intermediate 1, 4-[1,2,4]triazol-1-yl-cyclohexanone (257 mg, 1.55 mmol) and 3-Amino-5-cyclohex-1-enyl-thiophene-2-carboxylic acid methyl ester (compound x, see Irina) (368 mg, 1.55 mmol) was treated by dibutyltin dichloride (24 mg, 0.078 mmol). The resulting mixture was stirred 5 min at room temperature and phenylsilane (210 μl, 1.70 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 40 h. Solvent was removed and the crude was purified by silica gel column chromatography using a gradient from 50% EtOAc:hexanes to 100% EtOAc as eluent to give 5-cyclohex-1-enyl-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (555 mg, 92%) as a yellow mixture of cis and trans isomers.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])(=O)C.[Se](=O)=[O:34]>C(OCC)(=O)C.CCCCCC>[OH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCO)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (120 mg, 0.27 mmol) was added selenium dioxide (120 mg, 1.08 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-hydroxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (40 mg, 37% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of ˜80% pure 2-(bromomethyl)-1-fluoro-4-nitrobenzene (0.956 g, 3.27 mmol) in THF (10 mL) was added slowly drop-wise to a −20° C. solution of 1-methylpiperazine (0.393 g, 3.92 mmol) and DIEA (1.142 mL, 6.54 mmol) in THF (20 mL), the mixture allowed to warm slowly to RT and stirred overnight. The resulting solid was removed via filtration and the filtrate was concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford 1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine (577 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.28 (dd, J=6.2, 3.0 Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.47 (t, J=9.1 Hz, 1H), 3.60 (s, 2H), 2.48-2.25 (br m, 8H), 2.14 (s, 3H); MS (ESI) m/z: 254.1 [M+H]+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C@@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:11][C@@H:10]1[CH2:33][OH:34])(C(C)(C)C)(C)C.N1C=CC=CC=1.Cl[S:42]([NH2:45])(=[O:44])=[O:43]>C(#N)C>[S:42](=[O:44])(=[O:43])([O:34][CH2:33][C@H:10]1[CH2:11][C@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:13][C@H:9]1[OH:8])[NH2:45]
Reactant: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reactant: NS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](COS(N)(=O)=O)[C@H](O)C2)ncn1
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of {(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methanol (0.112 g, 0.231 mmol) (azetroped with toluene) and pyridine (0.0374 mL, 0.462 mmol) in anhydrous acetonitrile (2.3 mL) was cooled to 0° C. A 2 N solution of chlorosulfonamide in acetonitrile (0.116 mL) was added dropwise and the reaction was stirred for 3 h. Additional 2 N solution of chlorosulfonamide in acetonitrile (0.026 mL) and pyridine (0.0041 g, 0.052 mol) were added and the reaction was stirred for 1 h then quenched with methanol. The solution was concentrated in vacuo and purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound as a white solid (0.059 g, 57%). 1H NMR (CD3OD, 400 MHz, δ): 8.26 (s, 1H); 8.01 (s, 1H); 7.26-7.16 (m, 3H); 5.70 (s, 1H); 5.47-5.33 (bs, 1H); 4.35 (t, J=4.5 Hz, 1H); 4.31 (d, J=7.5 Hz, 1H); 4.28 (d, J=7.5 Hz, 1H); 4.25-4.21 (m, 1H); 4.15-4.11 (dd, J=7.3 Hz; J=2.5 Hz, 1H); 3.36 (s, 3H); 3.16-3.00 (m, 2H); 2.54-2.45 (m, 1H); 2.26-2.19 (m, 1H); 2.10-1.98 (m, 1H); 1.87-1.78 (m, 1H); 1.77-1.69 (m, 1H). LC/MS: Rt=1.11 min, ES+ 450 (FA standard).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:6]=1[F:16])[CH3:2].[OH:18]OS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.O>[CH3:14][C:12]([S:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:17])=[O:18])([CH3:13])[CH3:15]
Reactant: O=S([O-])OO
Reactant: CCNC(=O)c1c(F)cccc1SC(C)(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNC(=O)c1c(F)cccc1S(=O)C(C)(C)C
Reaction time: 0.03 h
Yield: 60 %

Procedure:
A 0° C. solution of N-ethyl-2-fluoro-6-(1,1-dimethylethylthio)benzamide (3.45 g, 13.51 mmol) in methanol (100 mL) was combined with a 0° C. solution of OXONE® (8.31 g, 13.51 mmol) in water (100 mL). This mixture was stirred for 2 min, then was poured into 25% aq sodium metabisulfite (100 mL) and extracted with ether (3×100 mL). The combined organics were washed with brine followed with water, then was dried (MgSO4), concentrated, and recrystallized from ethyl acetate—hexanes to afford 2.2 g of the title compound as a white solid, a 60% yield. m.p. 114-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(Br)CCC>>[CH3:19][CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[CH:15][CH:16]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC
Reactant: CCOC(=O)NCCOc1ccc(O)cc1
Agent: CCCC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)Oc1ccc(OCCNC(=O)OCC)cc1

Procedure:
In the same manner, ethyl N-{2-(4-hydroxyphenoxy]ethyl}carbamate (1.25 g, 5.5 mmol) and sodium hydride, prewashed with pentane, (0.132 g, 5.5 mmol) are reacted together, followed by addition of 1-methylbutyl bromide. The mixture is heated at 50° for 20 hours, then worked up and purified by prep. TLC to give ethyl N-{2-[4-(1-methylbutoxy)phenoxy]ethyl}carbamate (compound 14, Table A).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].O[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:25]=[C:16]1[C:17]2[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:20])[N:15]1[O:13][CH:10]1[CH2:9][CH2:8][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
4-Hydroxy-piperidine-1-carboxylic acid isopropyl ester (3.09 g, 17 mmol), N-hydroxyphthalimide (2.69 g, 17 mmol), and triphenylphosphine (4.32 g, 17 mmol) were combined in THF (30 mL). DEAD (2.6 mL, 17 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated under vacuum and the residue was purified by flash LC(elution with 10-50% ethyl acetate and 0.1% TEA in hexanes) to afford 3.31 g (60%) of 2a as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.85-7.81 (m, 2 H), 7.83-7.29 (m, 2 H), 4.91 (quintet, J=6.3 Hz, 1 H), 4.43 (septet, J=3.9 Hz, 1 H), 3.94-3.86 (m, 2 H), 3.32-3.23 (m, 2 H), 1.99-1.78 (m, 4 H), 1.24 (d, J=6.6 Hz, 6 H); LC-MS 333.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CC([O-])(C)C.[K+].I[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1)[CH3:19]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
57.1 To a stirred, cooled (0° C.) solution of the 1.6 g 3-aminopyrazole in DMF under an argon atmosphere was added potassium tert-butylate. After 30 min. stirring at 0° C., ethyl iodoacetate was added in one portion. After 2 h stirring at 0° C., the ice bath was removed and stirring at r.t. was continued for 22 h. The mixture was concentrated in order to remove as much DMF as possible. The residue was taken up in EtOAc and washed with H2O. The aqueous phase was extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica using a gradient from cyclohexane to EtOAc in 40 min to give 366 mg (3-amino-pyrazol-1-yl)-acetic acid ethyl ester as viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH:11]=[C:10]([CH2:13]O)[C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[BrH:20]>>[Br:20][CH2:13][C:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[CH:11]=1
Reactant: Br
Reactant: OCC1=Cc2c(Cl)cccc2Oc2ccccc21
Solvent: O
Product: Clc1cccc2c1C=C(CBr)c1ccccc1O2
Yield: 38.7 %

Procedure:
4.58 g (17.70 mmol) of (1-chlorodibenz[b,f]oxepin-10-yl)-methanol are heated under reflux in 50 ml of 48% hydrobromic acid for 2 hours. The mixture is cooled, water is added and the mixture is extracted 3× with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and concentrated. 5.57 g of crude product are obtained which becomes solid on being left to stand (3 days). Recrystallisation from tert-butyl methyl ether/hexane yields 2.205 g (6.86 mmol)=38.7% of 10-bromomethyl-1-chloro-dibenz[b,f]oxepine in the form of light-beige crystals; TLC (silica gel; ethyl acetate; UV): Rf =0.73; 1H-NMR (CDCl3, 200 MHz): 4.60 (s, 2H); 7.15-7.58 (m, 8H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.Cl[CH:26](Cl)C>CN(C)C=O>[C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:26])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A mixture of 2-phenylsulphenyl-4-trifluoromethylbenzoic acid (11.5 g), thionyl chloride (11.4 g), dimethylformamide (0.2 ml) and dichloroethane was heated at reflux for 90 minutes. The solution was then concentrated under reduced pressure and the residue was dissolved in methanol and heated at reflux for one hour. The resulting solution was poured into aqueous sodium bicarbonate and extracted with ether. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. The resulting material was crystallised from hexane to give methyl 2-phenylsulphenyl-4-trifluoromethylbenzoate (10.5 g) as white crystals, m.p. 58° C.
Reaction SMILES: C1(Br)CCCCC1.Cl[C:9]1[C:14]2[S:15][CH:16]=[C:17]([CH3:18])[C:13]=2[CH:12]=[CH:11][CH:10]=1.[Mg].C1C[O:23]CC1>>[OH:23][C:9]1[C:14]2[S:15][CH:16]=[C:17]([CH3:18])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1csc2c(Cl)cccc12
Reactant: C1CCOC1
Agent: [Mg]
Solvent: BrC1CCCCC1
Product: Cc1csc2c(O)cccc12
Reaction time: 2 h

Procedure:
Cyclohexyl bromide (32.6 g.) and 7-chloro-3-methylbenzo[b]thiophene (18.3 g.) in THF (400 ml) is added to a suspension of magnesium turnings (7.3 g.) in THF. The mixture is stirred for two hours and heated on a steam bath for two hours. The reaction is cooled and oxygen is bubbled in slowly for two hours. The mixture is stirred for 18 hours at room temperature and extracted with chloroform. The organic extract is extracted with 5% sodium hydroxide. The aqueous extract is acidified with concentrated hydrochloric acid and extracted with ethyl ether. The ether extract is dried (MgSO4) and concentrated to a solid.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:9]1[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:2]=[CH:3][CH:4]=2)=[N:8]1
Reactant: Cc1ccccc1-n1ccc(=O)c(C(=O)C=CN(C)C)n1
Reactant: NNc1ccccc1
Solvent: CO
Product: Cc1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Yield: 11.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(2-methylphenyl)pyridazin-4(1H)-one (crude, 1298 mg, 4.59 mmol) in 20 mL of methanol was added phenylhydrazine (744 mg, 6.89 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-methylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (180 mg, 12% for two steps) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH2:18])=O)=[CH:13][CH:12]=1>CO>[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]2[N:2]=[C:1]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)[NH:18][N:17]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccncc1
Reactant: NNC(=O)c1ccc(N)cc1
Agent: [Na]
Solvent: CO
Product: Nc1ccc(-c2n[nH]c(-c3ccncc3)n2)cc1
Temperature: 245 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To 4-cyanopyridine (4.2 g.) in methanol (60 ml.) is added sodium (0.2 g.). The solution is allowed to stand for 0.5 hour at room temperature and is then added to a suspension of p-aminobenzhydrazide (6.4 g.) in 150 ml. of methanol. The resulting solution is heated 20 hours at reflux during which time a solid separates. The solid is filtered and heated to 245° C. over one hour and maintained at that temperature for an additional 15 minutes. After cooling the solid is recrystallized from a mixture of acetonitrile and water to yield 3-(p-aminophenyl)-5-(4-pyridyl)-1,2,4-triazole (2 g.) m.p. 251°-252.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][C:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][C:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=34)[S:5]2(=[O:17])=[O:16])[CH2:34][CH:35]=1
Reactant: Fc1ccc2[nH]cc(CC3=CCNCC3)c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CC=C(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 11.6 %

Procedure:
The procedure is as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g), 4-[(5-fluoro-3-indolyl)methyl]-1,2,3,6-tetrahydropyridine hydrochloride (2 g) and sodium bicarbonate (1.3 g) in a mixture of dimethylformamide (70 cc) and tetrahydrofuran (45 cc). The mixture is heated to boiling for 20 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with dichloromethane and then ethyl acetate as eluents, 2-{2-[4-((5-fluoro-3-indolyl)methyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (0.4 g) is obtained in the form of a yellow oil, which is converted to an acid oxalate, m.p. 128° C.