Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:18][CH3:19].O>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:9][C:8]1[C:3]([CH2:2][OH:1])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1)[CH3:19]
Reactant: CCI
Reactant: Cc1ccc(O)c(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C)nc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(hydroxymethyl)-6-methyl-3-pyridinol (1.5 g, 10.78 mmol, available from Sigma-Aldrich #144428), K2CO3 (7.45 g, 53.9 mmol) and iodoethane (1.724 ml, 21.56 mmol) were dissolved in DMF (15 ml). The mixture was left stirring at room temperature overnight. Water and EtOAc were added and the two layers were separated. The aqueous one was back-extracted several times with EtOAc. The combined organic phases were washed with brine/ice, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the crude title compound D13 (1.67 g) as a pale yellow solid which was used in the next step without any further purification. MS: (ES/+) m/z: 168 (M+1). C9H13NO2 requires 167. 1H-NMR (400 MHz, CDCl3) δ (ppm): 6.96-7.07 (m, 2 H), 4.71 (s, 2 H), 4.04 (q, 2 H), 2.50 (s, 3 H), 1.43 (t, 3 H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10]/[CH:11]=[CH:12]/[C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1.Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:29]1([CH2:28][CH2:27][CH2:26][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][S:10]/[CH:11]=[CH:12]/[C:13]3[S:23][C:22]4[N:24]5[C:15](=[CH:16][N:17]=[C:18]5[CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH2:5][CH2:4]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCCc1ccccc1
Reactant: C1=C(/C=C/SCC2CCNCC2)Sc2cccc3ncc1n23
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C1=C(/C=C/SCC2CCN(CCCc3ccccc3)CC2)Sc2cccc3ncc1n23

Procedure:
A solution of 0.314 g (0.780 mM) of (E)-4-[2-(piperidin-4-ylmethylthio)vinyl]-5-thia-1,8b-diazaacenaphthylene dihydrochloride, 0.19 g (0.94 mM) of 1-bromo-3-phenylpropane, and 0.38 ml (2.73 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 4/1) to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: -11 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
(2S,4S)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (70.0 g) was dissolved in tetrahydrofuran (700 mL) and then cooled to −11° C. To this solution, triethylamine (33.4 g) and ethyl chlorocarbonate (35.8 g) were slowly added and stirred at −15° C. for 30 minutes. Subsequently, 28% aqueous ammonia (73 mL) was added to the reaction mixture. After stirring at −10° C. for 40 minutes, a mixture of ethyl acetate and tetrahydrofuran (4:1, 1400 mL) and water (230 mL) were added and stirred. The reaction mixture was separated into organic and aqueous layers, and the aqueous layer was further extracted with a mixture of ethyl acetate and tetrahydrofuran (4:1, 350 mL). The combined organic layers were washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude crystal was recrystallized from a mixed solvent of acetonitrile and diisopropyl ether to give the titled compound (57.7 g, white powder).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([NH:17][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[C:11]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-2,6-difluoro-benzoic acid benzyl ester (43, 6.00 g, 22.8 mmol) in methylene chloride (150 mL) was added pyridine (2.76 mL, 34.2 mmol) and propane-1-sulfonyl chloride (3.80 mL, 33.8 mmol). The reaction was stirred at room temperature overnight. Then the reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography to give a colorless oil (44, 7.0 g, 83.1%). MS (ESI) [M+H+]+=370.1.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C[Si](C)(C)N[Si](C)(C)C>O1CCOCC1>[N:16]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CONC(=O)N1
Reactant: C1CCNC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: O=C1N=C(N2CCCC2)CON1
Yield: 47 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg of ammonium sulfate, 2.06 (0.029 mole) of pyrrolidine and 20 ml of hexamethyldisilazane in 40 ml of dry freshly distilled dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 0.8 g (47 percent) of 5-(1-pyrrolidinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1.O>C(Cl)Cl>[CH:28]1([S:31]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:6][CH2:5]2)(=[O:33])=[O:32])[CH2:30][CH2:29]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(CCNS(=O)(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
At 15° C., to a solution of tert-butyl (1-(2-aminoethyl)piperidin-4-yl)methylcarbamate (2.00 g, 7.78 mmol) and DIPEA (3.00 g, 23.3 mmol) in CH2Cl2 (40 mL) was added slowly cyclopropylsulfonyl chloride (3.40 g, 25.0 mmol) under Ar. The reaction mixture was stirred at room temperature for 2 hrs. Water (30 mL) was added, and the mixture was extracted with CH2Cl2 (3×30 mL). The combined extract was washed with saturated NaHCO3 (40 mL) and dried over anhydrous Na2SO4. After filtration the solvent was removed in vacuo, and the residue was applied to flash column chromatography (3-7% CH3OH in CH2Cl2) to provide tert-butyl (1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamate as pale yellow oil (2.2 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(Br)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]([NH:34][C:35]([C:37]2[CH:46]=[C:45]([OH:47])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[O:36])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12].[C:48](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:11]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([CH:24]([NH:34][C:35]([C:37]2[CH:46]=[C:45]([O:47][C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9][CH2:8][CH2:7]3)[C:44]3[C:39](=[CH:40][C:41]([CH3:48])=[CH:42][CH:43]=3)[N:38]=2)=[O:36])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])[CH2:20][CH2:21]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h
Yield: 45.2 %

Procedure:
1-Ethoxycarbonyl-1-bromocyclobutane (0.62 g, 3.03 mmol) was added to a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline (0.8 g, 1.52 mmol) and cesium carbonate (1.00 g, 3.03 mmol) in N,N-dimethylformamide (DMF) (15 mL) and stirred at 90–100° C. At every 2 hours, excess equimolar amounts of 1-ethoxycarbonyl-1-bromocyclobutane and cesium carbonate were added to the solution to a total of 8 equivalents of each reagent. After 10 hours, the reaction mixture was filtered, the solvent was evaporated and the residue was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-(1-(ethoxycarbonyl)cyclobut-1-oxy)quinoline (0.45 g , 38%) as a white solid (TFA salt); NMR (DMSO-d6) 1.04 (t, 3), 1.14 (t, 3), 1.32 (s, 9), 1.82 (m, 1), 2.00 (m, 3), 2.26 (m, 2), 2.52 (s, 3), 2.58 (m, 2), 2.78 (m, 2), 3.5 (m, 8), 4.04 (q, 2), 4.15 (q, 2), 5.00 (m, 1), 6.94 (s, 1), 7.52 (d, 1), 7.88 (s, 1), 8.14 (d, 1), 8.84 (d, 1) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([O:13][CH3:14])[CH:5]=1.[CH3:16][I:17]>O1CCOCC1>[I-:17].[CH3:15][N+:2]([CH3:16])([CH3:1])[CH2:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([OH:12])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: CI
Reactant: COc1cc(CN(C)C)cc(OC)c1O
Solvent: C1COCCO1
Product: COc1cc(C[N+](C)(C)C)cc(OC)c1O
Product: [I-]
Yield: 99 %

Procedure:
2,6-Dimethoxyphenol (70 g, 0.45 mol) dissolved in 150 ml ethanol was added dropwise to a mixture of formaldehyde (68.5 ml of a 37.5% aqueous solution, 0.91 mol) and dimethylamine (148 ml of a 40% aqueous solution, 1 mol) and the resulting mixture was refluxed for 4 h. Ethanol was evaporated, the residue was partitioned between water and dichloromethane, the organic phase was dried over MgSO4 and evaporated to yield 95 g (99%) of a white solid, mp=78-80° C. To a dioxane solution (600 ml) of the dimethyl(3,5-dimethoxy-4-hydroxybenzyl)amine thus obtained (95 g, 0.45 mol) was added methyl iodide (61 ml, 0.98 mol) and the resulting mixture was refluxed for 2 h. The solid formed was filtered and washed with dioxane to yield 156 g (99%) of the trimethyl(3,5-dimethoxy-4-hydroxybenzyl)ammonium iodide salt. This latter was suspended in 600 ml xylene, triethyl phosphite (110 ml, 0.66 mol) was added dropwise and the resulting mixture was refluxed for 16 h. The solid formed was filtered and the solvent and excess of phosphite were evaporated under vacuum to yield diethyl (3,5-dimethoxy-4-hydroxybenzyl)phosphonate as a viscous oil (130 g, 97%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC

Procedure:
A mixture of 3-trifluoromethylbenzyl bromide (5.74 g, 24.0 mmol) and triethyl phosphite (4.98 g, 30 mmol) was heated at reflux under nitrogen for 3 hours. The excess triethyl phosphite was removed by distillation and the crude product obtained was distilled at 140°-145° C. at 4 mm to yield 6.44 g (90.7%) of analytically pure product as a clear liquid. 300 MHz 1H NMR (CDCl3): δ, 3.20 (d,2H J=21.78 Hz, PCH2). D.C.I.M.S.[MH+, 297].
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[S:10][C:11]([S:14]([N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:18]3)(=[O:16])=[O:15])=[CH:12][CH:13]=2)C=CC=CC=1.Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]([OH:52])([C:48]([F:51])([F:50])[F:49])[C:44]([F:47])([F:46])[F:45])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:8][C:9]1[S:10][C:11]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:37]3[N:38]=[CH:39][C:40]([C:43]([OH:52])([C:44]([F:45])([F:46])[F:47])[C:48]([F:50])([F:51])[F:49])=[CH:41][N:42]=3)[C@@H:19]([CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:18]2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1ccc(N=C(c2ccccc2)c2ccccc2)s1)N1CCN[C@@H](CC2CCOCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)[C@@H](CC3CCOCC3)C2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
In a 20-mL vial was charged with N-(diphenylmethylidene)-5-(((3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)sulfonyl)-2-thiophenamine (170 mg, 0.334 mmol)), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (187 mg, 0.667 mmol, Intermediate D), and Hünig's base (175 μL, 1.001 mmol), and dioxane (5 mL). The vial was sealed and heated to 90° C. for 16 h. Afterwards, the mixture was concentrated in vacuo. The crude material was dissolved in THF (20 mL) and 4 N HCl in dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated, absorbed onto silica gel, and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (88 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[C:7](Cl)[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1>C(O)C.O.[Zn]>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1
Reactant: Cc1c(C(=O)O)cc(Cl)c2c1C(C)(C)CCS2(=O)=O
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)ccc2c1C(C)(C)CCS2(=O)=O
Yield: 77.1 %

Procedure:
0.88 Gram (2.90 mmol) of 4,4,5-trimethyl-8-chlorothiochroman-6-carboxylic acid-1,1-dioxide was dissolved in ethanol having a water content of 60%, 0.55 g (8.70 mmol) of a zinc powder was added, and the mixture was refluxed under heat for 5 hours. After the completion of the reaction, 50 ml of water was added, the zinc powder was removed by filtration, and the remainder was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to give 0.60 g (yield 78%) of 4,4,5-trimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:15][CH:16]1[CH2:44][CH2:43][CH:19]2[CH:20]([CH3:42])[NH:21][C:22]3[C:27]([CH:18]2[CH2:17]1)=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25]=[C:24]([S:32][CH:33]([CH:35]([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])[CH:23]=3)(=[O:14])[CH3:13].C(Cl)(Cl)Cl>C(O)(=O)C>[C:12]([NH:15][CH:16]1[CH2:44][CH2:43][CH:19]2[CH:20]([CH3:42])[NH:21][C:22]3[C:27]([CH:18]2[CH2:17]1)=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25]=[C:24]([S:32]([CH:33]([CH:35]([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])=[O:9])[CH:23]=3)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCC(C)C(C)Sc1cc2c(c(OC(C)=O)c1)C1CC(NC(C)=O)CCC1C(C)N2
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCC(C)C(C)S(=O)c1cc2c(c(OC(C)=O)c1)C1CC(NC(C)=O)CCC1C(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Equimolar amounts of m-chloroperbenzoic acid and dl-9-acetamido-1-acetoxy-6-methyl-3-(3-methyl-2-octylthio)5,6,6a,7,8,9,10,10a-octahydrobenzo[c]quinoline are added to a mixture of chloroform and acetic acid (2:1 v/v) and the mixture stirred at room temperature for one hour. The reaction mixture is washed with water, the organic phase dried over magnesium sulfate and evaporated to dryness at reduced pressure to give the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([CH3:7])[CH3:6].C(N(CC)CC)C.[ClH:21]>C(Cl)Cl>[Cl:21][CH2:12][CH2:11][CH:10]1[O:13][C:1](=[O:2])[N:8]([CH:5]([CH3:7])[CH3:6])[CH2:9]1
Reactant: Cl
Reactant: CC(C)N1CCC(O)C1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CC(CCCl)OC1=O
Reaction time: 1 h
Yield: 70 %

Procedure:
To a cold (ice bath) solution of 98.5 g (10 mole) of phosgene in 500 ml of methylene chloride was added dropwise a solution of 129.2 g (1.0 mole) of 1-isopropyl-3-pyrrolidinol in 250 ml of methylene chloride at such a rate that the temperature did not exceed 10° C. After addition was complete, the mixture was stirred in the cold for 1 hr and then treated dropwise with 140 ml (101 g, 1.0 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The mixture was stirred at ambient temperature for 3 hr and then treated with 500 ml of 1N hydrochloric acid solution. The layers were separated and the organic layer was washed successively with 500 ml of a 1N hydrochloric acid solution, 500 ml of a 4% sodium hydroxide solution and 500 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give a brown oil as residue. The oil was subjected to vacuum distillation to yield 134.9 g (70%) of yellow oil, b.p. 110° C. at 0.2 mm.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[CH:16]=[CH:17][S:18][C:14]=3[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.CN(C)C=O.Cl.[CH3:27][N:28]([CH3:41])[CH2:29][CH2:30][O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[CH3:27][N:28]([CH3:41])[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:11]2[CH2:12][CH2:13][C:14]3[S:18][CH:17]=[CH:16][C:15]=3[CH:10]2[C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=2)=[O:37])=[CH:39][CH:40]=1
Reactant: FC(F)(F)Oc1ccc(C2NCCc3sccc32)cc1
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C(=O)N2CCc3sccc3C2c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 pi), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCCOC1CCCCO1
Product: CCOC(CNCCOC1CCCCO1)OCC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran (3.03 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (1.59 g, 30%).
Reaction SMILES: [CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.Cl[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1>CN(C=O)C>[CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][N:6]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Clc1ccncn1
Reactant: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(c2ccncn2)CC1
Temperature: 140 °C
Yield: 51.2 %

Procedure:
4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (10 mg, 0.035 mmol), triethylamine (0.049 mL, 0.352 mmol), and 4-chloropyrimidine (8 mg, 0.070 mmol) were dissolved in DMF (1.5 mL) and heated under microwave irradiation at 140° C. for 30 min. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 6.5 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.14 (dd, 1H, J=7.6, 1.3 Hz), 7.51 (s, 1H), 7.37 (s, 1H), 7.11 (d, 1H, J=7.5 Hz), 5.14 (s, 2H), 4.27 (m, 1H), 4.11 (m, 1H), 3.86-3.87 (m, 1H), 3.80-3.82 (m, 1H), 2.86 (m, 1H), 2.73 (m, 1H), 2.38 (m, 1H), 2.24-2.31 (m, 4H), 0.99 (t, 3H, J=7.6 Hz). MS (ES) [M+H] found 363.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]#[N:28])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])C(C#N)=[N:16]3)=[CH:11][C:10]=2[O:25][CH3:26])=[CH:4][CH:3]=1.Cl.[C:30]([OH:33])(=[O:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]#[N:28])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[C:31]([C:30]([OH:33])=[O:32])=[N:16]3)=[CH:11][C:10]=2[O:25][CH3:26])=[CH:6][CH:7]=1
Reactant: COc1cc(-n2nc(C#N)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: Cl
Product: COc1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1

Procedure:
A mixture of 4 parts of 2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile, 24 parts of concentrated hydrochloric acid and 40 parts of acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated in vacuo and the residue is stirred in water. The product is extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract is dried, filtered and evaporated, yielding 2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([O:11][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=1)=[O:10]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Br)Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2cccc(Oc3ccccc3)c2)[C@@H]1C=C(Br)Br

Procedure:
The carboxylic acid described above was converted to its acid chloride by reaction with thionyl chloride in pyridine as described in Example 17 and the resulting acid chloride reacted with 3-phenoxybenzyl alcohol in dry benzene in the presence of pyridine as described in Example 17 to give 3-phenoxybenzyl(1R)cis-2,2-dimethyl-3-(2,2-dibromovinyl)cyclopropane carboxylate, m.p. 93°, nD 1.5848 (Compound P29A).