Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(O)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(O)C2
Temperature: 80 °C

Procedure:
A solution of (2SR,9aRS)-9a-butyl-2-hydroxy-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (73 mg, 0.22 mmol) in methanol (5 mL) was placed under a nitrogen atmosphere, treated with 2N aqueous HCl (0.33 mL, 0.66 mmol), and stirred with heating in an oil bath at 80° C. for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with 5% aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil. The crude product was purified by PLC on a 0.1×20×20 cm silica gel GF plate, developing twice with 4:1 hexanes-EtOAc. The band at Rf 0.12-0.20 was eluted with EtOAc and the eluant evaporated under vacuum to a gum (50 mg). This material crystallized from benzene to afford (2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:26])[CH:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]C1CCCCO1)[C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+]>C(O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:26])[CH:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8]
Reactant: NCCNC(=O)C(CCCCCCOC1CCCCO1)C(=O)NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCNC(=O)C(CCCCCCO)C(=O)NCCN
Temperature: 72.5 °C

Procedure:
N,N′-Bis(2-aminoethyl)-2-[6-(tetrahydro-pyran-2-yloxy)-hexyl]-malonamide (3.9 g, 10.6 mmol), p-toluenesulphonic acid monohydrate (8.5 g, 3 mmol) and ethanol (50 ml) were heated under reflux at 70-75° C. for 16 hours. After cooling, concentrated ammonium hydroxide (0.880) was added dropwise until a permanent pH of 9 was achieved. The precipitated white solid was removed by filtration through Celite and the filter cake washed with ethanol (30 ml). The ethanol was removed under reduced pressure (15 mm Hg, 40° C.) to leave a semi-solid wax. This residue was subjected to chromatography on silica-gel eluting with CH2Cl2/MeOH/NH4OH (100:50:10) and the title compound found to have an rf=0.2. This product was collected and co-evaporated with ethanol (100 ml×3) to remove any residual water. A pale green viscous residue was obtained which solidifies on standing. (Yield 2.1 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(N(CC)CC)C.C(O)(=O)C(C)(C)C.CC(O[CH2:26][C:27]1[CH2:36][S:35][C@@H:30]2[C@H:31]([NH2:34])[C:32](=[O:33])[N:29]2[C:28]=1[C:37]([OH:39])=[O:38])=O>O>[NH2:34][CH:31]1[C:32](=[O:33])[N:29]2[C:28]([C:37]([OH:39])=[O:38])=[C:27]([CH2:26][S:7][C:5]3[S:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH2:36][S:35][C@H:30]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: CC(C)(C)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 82 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of 30 g of 5-methyl-2-mercapto,1,3,4-thiadiazole, 32 ml of triethylamine and 5 g of pivalic acid in 2 liters of water was heated to 82° C. Thereafter there was added in one shot 40 g of 7-aminocephalosporanic acid (92%) and 5 g of pivalic acid were added in one shot to the resulting solution. Precipitation started after a few minutes and increased with time. After 30 minutes of vigorous stirring at the same temperature, the mixture was cooled to 65° C. The solid was isolated by filtering, washed with water and acetone to give 35 g of the compound of the title. The liquors were cooled to 20° C. and filtered and gave a further 5 g fraction, with an overall yield of 87%. The infrared and proton magnetic resonance spectra are consistent with the technically pure product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 70 °C
Reaction time: 9 h
Yield: 28.3 %

Procedure:
To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol) in chloroform (20 ml) were successively added p-toluenesulfonyl chloride (2.27 g, 11.9 mmol) and triethylamine (1.66 ml, 11.9 mmol) at 0° C., and the mixture was stirred at 70° C. for 9 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1) to give tert-butyl 3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (1.00 g, yield 28%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[F:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[CH:24]=[CH:25][CH2:26]Cl>>[F:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[CH:24]=[CH:25][CH2:26][N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: Fc1ccc(C=CCCl)c(F)c1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(F)cc2F)c1=O
Yield: 92 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2,4-difluorocinnamyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 92.0%.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[C:10]3[C:14]([O:18][CH2:19][CH2:20][CH2:21]Cl)=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38].C(N(CC)CC)C>CN(C)C=O.[Br-].C([N+](CC)(CC)CC)C>[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][O:18][C:14]3[C:10]4[C:11](=[O:13])[CH2:12][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[CH:17]=[CH:16][CH:15]=3)[CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38]
Reactant: O=C1CC(c2ccccc2)Oc2cccc(OCCCCl)c21
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCCOc3cccc4c3C(=O)CC(c3ccccc3)O4)CC2)cc(=O)n(C)c1=O

Procedure:
In 10 ml of N,N-dimethylformamide, reaction was carried out at 100° C. for 8 hours among 2.5 g of the previously obtained 2-phenyl-5-(3-chloropropoxy)-4-oxo-2,3-dihydro-4H-1-benzopyran (Compound 20), 1.2 g of 1,3-dimethyl-6-(piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (Compound 3), 1.0 g of tetraethylammonium bromide and 2.0 ml of triethylamine. The resultant reaction solution was concentrated under reduced pressure, and the residue was then dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and then purified through a silica gel column chromatograph (chloroform:methanol=40:1 in volume ratio), thereby obtaining 0.80 g of 1,3-dimethyl-6-(4-[3-(2-phenyl-4-oxo-2,3-dihydro-4H-1-benzopyran-5-yl)oxypropyl]piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (the non-oxalate of Compound 21).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]/[CH:10]=[CH:11]\[CH:12]([OH:14])[CH3:13])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:14][CH:12]([CH3:13])/[CH:11]=[CH:10]\[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(S/C=C\C(C)O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S/C=C\C(C)OC(C)=O)cc1

Procedure:
1 g (4.76 mmol) of rac-(Z)-4-[(p-methoxyphenyl)thio]-3-buten-2-ol are dissolved in 50 ml of methylene chloride. whereupon the solution is treated with 0.77 ml (9.5 mmol) of pyridine and cooled to 0° . There is added dropwise thereto a solution of 0.5 ml (7.1 mmol) of acetyl chloride in 10 ml of methylene chloride and the mixture is stirred at 0° for 1 hour. The reaction mixture is washed successively with 50 ml of 1N hydrochloric acid, 50 ml of 5 percent sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (9:1) there is obtained pure rac-4-[[(Z)-3-acetoxy-1-butenyl]thio]anisole; IR: 1735 cm-1.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@H]1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (107 mg, 93%), MS (ISP) m/z=459.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (S)-[1,4]dioxan-2-yl-acetic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(C)n2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (173 mg) in 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 79 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C@H:30]3[CH2:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.N1C=CC=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C@H:30]3[CH2:34][CH2:33][C@@H:32]([C:35]([NH:1][C:2]4[CH2:7][CH2:6][C:5]5([CH2:40][CH2:39]5)[CH2:4][C:3]=4[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:36])[CH2:31]3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1=C(N)CCCC1
Reactant: c1ccncc1
Reactant: O=C(O)[C@@H]1CC[C@H](N2CCN(c3ccc(Cl)cc3)CC2)C1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CCOC(=O)C1=C(NC(=O)[C@@H]2CC[C@H](N3CCN(c4ccc(Cl)cc4)CC3)C2)CCC2(CC2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To an ice cold solution of ethyl 2-aminocyclohex-1-enecarboxylate (1.27 g, 6.48 mmol) in pyridine (5 ml), phosphorus trichloride (0.18 ml, 2.10 mmol) was added. After 15 min, (1R,3S)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentanecarboxylic acid (0.5 g, 1.62 mmol) was added at room temperature to the mixture, followed by stirring at temperature for 6 h. Upon completion, the reaction mixture was diluted with chloroform and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using ethyl acetate in hexane as eluent to afford ethyl 6-((1R,3S)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentanecarboxamido)spiro[2.5]oct-5-ene-5-carboxylate (300 mg, 38.1%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.ClC1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=1[N+:36]([O-:38])=[O:37]>C(Cl)Cl>[Cl:34][C:33]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[CH2:12][CH2:11]2)=[C:29]([N+:36]([O-:38])=[O:37])[C:30]([NH2:35])=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Cl)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 31.3 %

Procedure:
tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.220 g, 0.79 mmol, 1.1 eq) was dissolved in DCM (2 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (2 mL). Stirring was continued at this temperature for 1 h. The solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.140 g, 0.79 mmol, 1.1 eq) was suspended in iPrOH (0.8 mL) and DIPEA (0.3 mL). To this solution, 4,5-dichloro-3-nitropyridin-2-amine (0.15 g, 0.72 mmol, 1 eq) was added and the mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.080 g, 27%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.60 (m, 4H, piperazine N(CH2)2), 3.07 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.54 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H), 9.04 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.71 min—355/357 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C:15]([CH3:30])([CH2:24][CH2:25][C@@H:26]([CH3:29])[CH2:27][CH3:28])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:30])([CH2:24][CH2:25][C@@H:26]([CH3:29])[CH2:27][CH3:28])[C:14](=[O:31])[C:13]=1[C:8]1[NH:7][C:6]2[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 43F (0.119 g, 0.240 mmol), mesyl chloride (0.075 mL, 0.970 mmol), and pyridine (0.157 mL, 1.94 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[OH-].[Na+].[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([NH:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:18]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)CCOCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCOCCCl)NCc1ccccn1
Yield: 65 %

Procedure:
A cooled solution of (2-pyridyl)methanamine (0.55 g, 5.1 mmol) in CH2Cl2 was stirred vigorously with 2% aqueous NaOH (12.2 mL, 6.1 mmol) while 3-(2-chloroethoxy)propanoyl chloride (6.1 mmol, prepared by refluxing 3-(2-chloroethoxy)propanoic acid with SOCl2) in CH2Cl2 was added dropwise. The same NaOH solution was then used to maintain pH at 9, and at costant pH the layers were separated. The organic phase was washed with 3 N HCl, with H2O, and then dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 1:1, as eluent) to afford pure compound in 65% yield. 1H NMR (CDCl3): δ 2.38-2.41 (m, 2H), 2.60-2.63 (m, 2H), 3.54-3.60 (m, 2H), 3.66-3.69 (m, 2H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 7.09-7.11 (m, 2H), 8.40-8.42 (m, 2H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH3:34][C:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)=[O:36]>O1CCCC1>[Br:1][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)=[O:36]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(O)cc1
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Phenyltrimethylammonium tribromide (276 g, 734 mmol) was added to a suspension of 4-hydroxyacetophenone (100 g, 734 mmol) in tetrahydrofuran (1000 ml) at room temperature. After stirring for 3 hours, the resulting suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether to afford 2-bromo-1-(4-hydroxyphenyl)-ethan-1-one (85 g, 54%) as white crystals.
Reaction SMILES: Br.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11]C)[C:4]=1[F:13]>C(O)(=O)C>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([OH:11])[C:4]=1[F:13]
Reactant: COc1c(C=O)ccc(Br)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc(Br)c(F)c1O
Reaction time: 16 h
Yield: 70.4 %

Procedure:
48% Hydrobromic acid (254 mL) was added to a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (52.3 g) in acetic acid (350 mL) at room temperature. The mixture was stirred at 120 C under nitrogen atmosphere for 16 hours and concentrated in vacuo. The residue was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether and collected by filtration to give the title compound (34.6 g).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:25]Br>>[CH3:21][C:22]1[CH:29]=[C:28]([CH:27]=[C:24]([CH3:25])[CH:23]=1)[CH2:30][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Cn2c(Oc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 66.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dimethylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (260 mg, yield: 66.2%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH2:35]1[O:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]3[CH2:19][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)=[CH:29][C:30]=2[O:36]1
Reactant: Cl[C@@H]1CCCCN(CCc2ccc3c(c2)OCO3)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCCN1CCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (56 mg, 1.4 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (250 mg, 1.27 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(3,4-methylenedioxyphenethyl)homopiperidine (426 mg, 1.40 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 2 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (4:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)piperidine-2-ylmethyl] dibenzo [b,e][1,4] oxazepine in the form of a light yellow oil (171 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[CH3:13])[N:3]=1.CO>[Pt]=O.CCO>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[CH3:13])[N:3]=1
Reactant: CCCCCCC=Cc1ccc2nc(N)nc(N)c2c1C
Agent: O=[Pt]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCc1ccc2nc(N)nc(N)c2c1C
Reaction time: 60 h

Procedure:
A mixture of 12.6 g of the olefin mixture of Example 5, 2.0 g of platinum oxide, and 500 ml of methanol was stirred under an atmosphere of hydrogen for 60 h. The catalyst was removed by filtration through a celite pad and the filtrate was evaporated in vacuo. The solid residue was recrystallized from ethanol to afford 10.6 g (83%), m.p. 262°-264° C.; UV (95% EtOH; pH 12). 238 (43,600), 272 (10,900), 347 (5,930); NMR (CDCl3 --CD3OD) 0.89 (3H, t, CH3CH2 --), 1.32 (12H, m, CH2), 2.72 (3H, s, 5--CH3), 2.72 (2H, t, Ar--CH2), 7.20 (1H, d, C7 --H), 7.47 (1H, d, C8 --H). Anal. calc'd for C17H26N4.HCl: C, 63.2; H, 8.43; N, 17.3; Cl, 11.0. Found: C, 63.3; H, 8.46; N, 17.3; Cl, 10.9.