Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CCCCCC>[CH:24]1([NH:23][C:22](=[N:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:14][N:13]=[C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: ON=C1CCCCCCCCCCC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Product: C1CCCCCC(=NOC(=NC2CCCCC2)NC2CCCCC2)CCCCC1
Temperature: 50 °C
Reaction time: 23 h
Yield: 43.1 %

Procedure:
A mixture of cyclododecanone oxime (19.73 g, 100 mmol), dicyclohexylcarbodiimide (20.63 g, 100 mmol) and potassium-t-butylate (0.12 g) in hexane (75 ml) is stirred 23 h at 50° C. under argon. The mixture is then allowed to crystallize overnight at −18° C. The solid is filtered off and recrystallized from dichloromethane-hexane to afford 17.4 g of the title compound as white solid, mp. 108-111° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH:27]=[CH:28][C:29](Br)=[CH:30][C:25]=3[O:24][C:23]=2[CH:32]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[CH:38]=[CH:39][O:40]CC)CCC.O.C1C(=O)N([Br:59])C(=O)C1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:39](=[O:40])[CH2:38][Br:59])=[CH:30][C:25]=3[O:24][C:23]=2[CH:32]=1)=[O:18])=[O:14])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)oc1cc(Br)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)oc1cc(C(=O)CBr)ccc12
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To the solution of Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzofuran-3-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (250 mg, 0.5 mmol) and tributyl(ethoxyvinyl)stannane (188 μl, 0.55 mmol) in dioxane (3.3 ml) was added PdCl2(PPh3)2 (15 mg). The mixture was heated at 80° C. for 16 hours and was cooled to 0° C. Water (1.1 ml) was added, followed by slow addition of NBS (98 mg, 0.55 mmol) over 5 minutes period. The mixture was stirred at 0° C. for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave Pyrrolidine-1,2-dicarboxylic acid 2-{2-[7-(2-bromo-acetyl)-dibenzofuran-3-yl]-2-oxo-ethyl}ester 1-tert-butyl ester (205 mg).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[C:15]([O-:18])([O-])=O.[Na+].[Na+].CO[CH2:23][CH2:24][O:25][CH3:26]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([N:4]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]2[C:2]([C:23]2[C:24]([O:25][CH3:26])=[N:6][C:5]([O:18][CH3:15])=[N:4][CH:12]=2)=[N:3]1)([CH3:14])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: COc1ncc(-c2nn(C(C)C)c3ncnc(N)c23)c(OC)n1
Temperature: 80 °C

Procedure:
A solution 2,4-dimethoxypyrimidin-5-yl-5-boronic acid (106 mg, 0.58 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.23 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA66. ESI-MS (M+H)+ m/z calcd 316.1, found 316.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:17])([F:16])[CH:13]([OH:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CC#N.O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (4.24 g, CAS Reg. No. 350-46-9), 1,1,1-trifluoro-propan-2-ol (4.56 g, CAS Reg. No. 374-01-6) and cesium carbonate (13.04 g) in CH3CN (50 mL) was heated to reflux for 10 hours. Then, the reaction mixture was cooled, acidified with conc. HCl and then distributed between ethyl acetate and water. The organic layer was separated, washed with brine and evaporated to provide the title compound (6.74 g) that was used without further purification. Rf: 0.38 (silica gel, ether/heptane 1:4).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]1[N:37]=[C:36]([CH:38]=O)[CH:35]=[CH:34][CH:33]=1.COC(=O)C.[Cl:45]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:45].[CH3:38][C:36]1[N:37]=[C:32]([CH2:31][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc(C=O)n1
Reactant: C[C@H](CNCC(c1ccccc1)c1ccccc1)COc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)=O
Product: Cc1cccc(CN(CC(c2ccccc2)c2ccccc2)C[C@@H](C)COc2cccc(CC(=O)O)c2)n1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]2-methyl-propoxy}-phenyl)acetic acid and 6-methyl-2-pyridinecarboxaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 89 mg (95%). MS (ESI) 509.4 (M+H+).
Reaction SMILES: N1C(C)=CC=CC=1C.S([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(C(F)(F)F)(=O)=O.[F:24][CH2:25][CH2:26][CH2:27]O>C(Cl)Cl>[F:24][CH2:25][CH2:26][CH2:27][O:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCCF
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(OCCCF)C(F)(F)F
Temperature: 25 °C

Procedure:
To a cold (−25° C.), stirred solution of 2,6-lutidine (4.60 mL, 39.5 mmol) in DCM (30 mL) was added triflic anhydride (6.00 mL, 35.5 mmol) over 3 min. Then 3-fluoropropane-1-ol (1.61 g, 20.6 mmol) was added. The reaction mixture was warmed to room temperature for 2.5 h. The reaction mixture was then concentrated to half its volume and purified by flash chromatography (Teledyne ISCO CombiFlash, isocratic DCM, REDISEP® SiO2 120 g, detecting at 254 nM, and monitoring at 220 nM). Concentration of the appropriate fractions provided Intermediate S-3A (2.92 g, 67.4%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.69 (2 H, t, J=6.16 Hz), 4.65 (1 H, t, J=5.50 Hz), 4.54 (1 H, t, J=5.61 Hz), 2.25 (1 H, dt, J=11.39, 5.86 Hz), 2.19 (1 H, dt, J=11.44, 5.94 Hz)
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([C:21]([CH:24]=O)=[N:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:26]1([CH2:24][C:21]2[N:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH2:14][CH2:13][CH:12]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:11][CH2:10]4)=[C:3]([C:1]#[N:2])[C:4]3=[N:23][N:22]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(C=O)nnc12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(CN3CCOCC3)nnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of D9 (0.065 g, 0.196 mmol) in DCM (2.5 ml) were added morpholine (0.026 g, 0.294 mmol) and sodium triacetoxy-borohydride (0.062 mg, 0.294 mmol). The resulting mixture was stirred at r.t. for 1 day. The reaction mixture was washed with H2O, dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield final compound E11 (0.04 g, 51%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][C:4]#[CH:5].I[C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:8][CH2:7][CH2:6][N:2]([CH2:3][C:4]#[C:5][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)=[CH:17]\[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1)[CH3:1]
Reactant: C#CCN(C)CCO
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)CCO)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
2-(N-Methyl-N-propargylamino)ethanol (440 mg, 3.89 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.68 mmol; prepared as described in example 25) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL). The solution was cooled to 0° C. and tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[4-[3-[4-[3-[N-(2-hydroxyethyl)-N-methylamino]-propynyl]phenyl]-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:18])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2].[CH2:19]([N:21]1[C:25](O)=[CH:24][CH:23]=[N:22]1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(NC2CCCCC2)=O)CCCCC1>C(O)(CC)(C)C.CCCCCC.C(OCC)(=O)C>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:18])[CH:10]=[C:11]([C:15]([O:17][C:25]3[N:21]([CH2:19][CH3:20])[N:22]=[CH:23][CH:24]=3)=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CCSC1CCSc2c(Cl)cc(C(=O)O)c(C)c21
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCSC1CCSc2c(Cl)cc(C(=O)Oc3ccnn3CC)c(C)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.9 %

Procedure:
1.0 Gram (3.3 mmol) of 4-ethylthio-5-methyl-6-carboxy-8-chlorothiochroman was dissolved in 5 ml of t-amyl alcohol, and 0.45 g (4.0 mmol, 1.2 eq.) of 1-ethyl-5-hydroxypyrazole and 0.83 g (4.0 mmol, 1.2 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 2.5 hours. After the completion of the reaction, ethyl acetate and hexane were added, and liberated N,N'-dicyclohexylurea was filtered off. The filtrate was concentrated and purified by column chromatography (silica gel/hexane+ethyl acetate=5:1) to give 1.4 g (yield 100%) of 4-ethylthio-5-methyl-6-(1-ethylpyrazol-5-yl)oxycarbonyl-8-chlorothiochroman.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]([Cl:19])[N:13]=1)=[N+:6]=[N-:7]>CC(C)=O>[N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([Cl:19])[N:15]=[C:16]([NH:4][CH2:3][CH2:1][OH:2])[N:17]=1)=[N+:6]=[N-:7]
Reactant: NCCO
Reactant: [N-]=[N+]=NCCCNc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: [N-]=[N+]=NCCCNc1nc(Cl)nc(NCCO)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
Ethanolamine (2.47 g, 40.4 mmol) in acetone (20 mL) was added to a solution of 1 (2.0 g, 8.1 mmol) in acetone (30 mL). The reaction was stirred at room temperature for 24 hours. The acetone was removed by rotary evaporation and the residue was suspended in CH2Cl2. The mixture was filtered off. The solid collected was washed with CH2Cl2 with H2O and dried under reduced pressure to afford 2 as a white solid (1.86 g, 85%). The product is sufficiently pure for further reactions. ESI-MS m/z 273.1 (M+H+) calculated for C8H14ClN8O 273.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])[CH2:5][C:6]2=[O:12].[N+:14]([O-])([OH:16])=[O:15]>CCOCC>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[C:6](=[O:12])[CH:5]([N+:14]([O-:16])=[O:15])[C:4]2=[O:13]
Reactant: Cc1ccc(C)c2c1C(=O)CC2=O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: Cc1ccc(C)c2c1C(=O)C([N+](=O)[O-])C2=O

Procedure:
4,7-Dimethyl indane-1,3-dione (0.52 g; 0.003 mole) in dry ether (5 ml) was nitrated with fuming nitric acid (1.0 ml) as described in Example 12 to give 4,7-dimethyl-2-nitro-indane-1,3-dione, m.p. (water, hydrochloric acid) 108°-110°C, (Found: C, 60.07; H, 4.20; N, 6.29; C11H9NO4 requires: C, 60.28; H, 4.14; N, 6.39%).
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:5].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Br:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]2[C:2]=1[NH:1][C:19](=[O:21])[N:6]([CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)CCNC(=O)c1cccc(Br)c1N
Solvent: C1COCCO1
Product: CS(=O)(=O)CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Temperature: 100 °C
Yield: 330.4 %

Procedure:
A glass microwave reaction vessel was charged with 2-amino-3-bromo-N-(2-(methylsulfonyl)ethyl)benzamide (480 mg, 1.494 mmol) and triphosgene (0.078 mL, 0.523 mmol, Fluka) in 1,4-dioxane (6 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The mixture was cooled to RT and the solvent was removed to give the crude product 600 mg. MS (ESI, pos. ion) m/z: 347 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(OC(C)=O)c([N+](=O)[O-])c1
Reaction time: 5 h

Procedure:
A mixture of 1.5 g of ethyl 4-(4-hydroxy-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate and 7.5 ml of acetic anhydride in 7 ml of tetrahydrofuran was stirred for 5 hours. The reaction mixture was evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to give ethyl 4-(4-acetoxy-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate (0.23 g).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>C(#N)C>[Si:20]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL of acetonitrile there are added, at ambient temperature, 6.7 g of imidazole (97.05 mmol) and 11.7 g of tert-butyl(dimethyl)silyl chloride (77.64 mmol). The batch is stirred at 70° C. for 4 hours. The reaction mixture is then poured into water and extracted with ether. The organic phase is then dried over MgSO4, then filtered and evaporated to dryness. The crude product thereby obtained is then purified by chromatography over silica gel using petroleum ether and dichloromethane as eluants. The title product is obtained in the form of a powder.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14]1[C:23]2[C:22](=O)[CH2:21][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:18]=2[N:17]=[CH:16][CH:15]=1>C(O)C>[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[NH:4]([N:5]=[C:22]1[CH2:21][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][C:18]2[N:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[C:23]1=2)[C:1]([NH2:3])=[NH:2]
Reactant: N=C(N)NN
Reactant: COc1ccnc2c1C(=O)CC(c1ccccc1)C2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Product: COc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 112.4 %

Procedure:
To a solution of aminoguanidine hydrochloride (0.023 g) in ethanol (10 ml) was added methanesulfonic acid (0.02 g), and the mixture was refluxed for 30 minutes. To the solution was added 4-methoxy-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.05 g), and the mixture was stirred at room temperature for 2 hours and 20 minutes and at 50° C. for 25 minutes. To the mixture was added methanesulfonic acid (0.02 g), and the mixture was stirred at 50° C. for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methoxy-7-phenyl-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 78) (0.09 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][CH3:17])[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])C.[OH-].[Na+]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]([CH2:16][CH3:17])[C:6]=1[C:4]([OH:5])=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnn(CC)c1C(=O)O
Temperature: 25 °C
Yield: 78.5 %

Procedure:
2-Ethyl-2H-pyrazole-3,4-dicarboxylic acid diethyl ester (280 mg, 1.2 mmol) was suspended in a NaOH solution (0.5M in water, 2.8 ml) and stirred at r.t. until HPLC analysis indicated the consumption of the starting material (4 h). HCl (1N, 1 ml) was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), evaporated, and the title compound (200 mg, 81%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=211.1 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][O:14][CH2:15][C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][N:23]=[CH:24][C:16]=1[CH2:15][O:14][CH3:13]
Reactant: COCc1cnccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
A mixture of 0.40 g of 2-amino-4-(trifluoromethyl)phenol, 0.38 g of 3-methoxymethyl isonicotinic acid, 1.30 g of BOP reagent, 0.30 g of triethylamine, and 20 ml of DMF was stirred at room temperature for four hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.64 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3 (methoxymethyl)isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.[N:17]1[C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1[C:26](Cl)=[O:27].CN1CCOCC1.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]([C:23]([C:22]3[N:17]=[C:18]([C:26]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[O:27])[CH:19]=[CH:20][CH:21]=3)=[O:24])[C:4]=2[CH:3]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)n1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1O2
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: Cl
Product: O=C(NCc1ccncc1)c1cccc(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)n1
Reaction time: 16 h

Procedure:
A solution of 8-chloro-dibenz[b,f][1,4]oxazepine (0.77 g), 2,6-pyridine-dicarbonyl chloride (0.68 g) and 4-methylmorpholine (0.367 mL) in CHCl3 (33 mL) was allowed to stand at ambient temperature for 16 hours. To this solution was added 4-(aminomethyl)pyridine (0.34 mL) and the mixture was allowed to stand at ambient temperature for 16 hours. The mixture was concentrated and the residue was extracted with ethyl acetate and saturated NaHCO3. The organic extract was concentrated and the residue chromatographed over silica gel using 50% ethyl acetate in hexane. Appropriate fractions were pooled and concentrated to give the free base of the title compound as a white solid. The HCl salt of the free base was made as described in Example 3.