Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
344 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] were subjected to N-alkylation with 406 mg of ethyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride as eluent, which separated the compound into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached). Isomer A (in which the carbon attached to the phenethyl group had the R-configuration) was eluted first as an oily compound in a yield of 0.17 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>C(OC)(OC)OC>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNc1nc(Cl)ccc1N
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: Cn1cnc2ccc(Cl)nc21
Reaction time: 3 h
Yield: 2681.7 %

Procedure:
To a solution of 6-chloro-N2-methylpyridine-2,3-diamine (300 mg, 1.9 mmol) in HC(OMe)3 (10 mL) was added TsOH (10 mg) at 22° C. The mixture was stirred for 3 h under reflux until TLC (PE:EA=3:1) showed that the reaction was complete. The mixture was concentrated to get the crude material which was purified by using column chromatography on silica gel to give the desired product (261 mg, 81.6%) as an oil. LCMS (m/z): 168.1 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:12]Br>C(O)(=O)C>[Br:12][C:4]1[CH:3]=[N:2][N:1]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:5]=1
Reactant: c1cnc(-n2cccn2)nc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1cnn(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of 2-pyrazol-1-yl-pyrimidine (0.55 g, 3.7 mmol) in acetic acid (5 mL) was added bromine (1.2 g, 7.5 mmol) in acetic acid (3 mL) dropwisely. After addition, the reaction mixture was stirred at room temperature overnight. After removed the acetic acid, the crude product was purified using column chromatography (2% methanol in dichloromethane) to give 0.7 g of pure product in 85% yield. MS (ESMS, M+H 225).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(O[N:25]=O)CC(C)C>C(O)(=O)C.O1CCOCC1>[C:14]([C:13]1[N:25]=[N:1][C:2]2[C:10]3[CH:9]=[CH:8][C:7]([CH3:11])=[N:6][C:5]=3[S:4][C:3]=2[C:12]=1[OH:18])([O:16][CH3:17])=[O:15]
Reactant: CC(C)CCON=O
Reactant: COC(=O)CC(=O)c1sc2nc(C)ccc2c1N
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1nnc2c(sc3nc(C)ccc32)c1O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of 6 g (0.022 mol) of 3-amino-2-carbomethoxyacetyl-6-methyl-thieno[2,3-b]pyridine in 1.8 ml acetic acid and 180 ml dioxane was slowly added 4.8 g (4.2 ml, 0.041 mol) of isoamylnitrite and stirring continued for 24 hours. It was then poured on ice-water, filtered and washed with water. The crude product was crystallized from DMSO/H2O to give 4.0 g (64%) of 3-carbomethoxy-4-hydroxy-7-methylpyrido[3',2':4,5]-thieno[3,2-c]pyridazine; m.p., 265°-268° C.
Reaction SMILES: C[O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:6]([O:7]C)=[C:5]([CH3:13])[C:4]=1[CH2:14][Cl:15].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[Cl:15][CH2:14][C:4]1[C:3](=[O:2])[C:10]([CH3:11])=[C:9]([CH3:12])[C:6](=[O:7])[C:5]=1[CH3:13]
Reactant: COc1c(C)c(C)c(OC)c(CCl)c1C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(CCl)=C(C)C1=O

Procedure:
0.8 g (3.5 mmol) of 2-chloromethyl-3,5,6-trimethylhydroquinone dimethylether was dissolved in 20 mL of acetonitrile. After addition of 9.6 g of ammonium cerium (IV) nitrate in 200 mL of water to the solution, the mixture was extracted with ethyl acetate (100 mL and 50 mL). The combined extract dried over magnesium sulfate and the solvent was removed under reduced pressure. 50 mL of water was added to the residue and then the mixture was extracted with ethyl acetate (50 mL). The extract was washed with saturated NaCl solution (100 mL). The extract dried over magnesium sulfate and the solvent was removed under reduced pressure to give 2-chloromethyl-3,5,6-trimethylbenzoquinone as a yellow crystal. 1H NMR (300 MHz, CDCl3): 4.47 (s, 2H), 2.16 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). ESMS: Calc. for C10H11ClO2 : 198.65; Found: 199.6 (M+H)+.
Reaction SMILES: [Cl:1]C[C:3]1[CH:10]=[CH:9][CH:8]=[C:5]2[CH2:6][CH2:7][C:4]=12.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:30](OCC)C>C(Cl)(Cl)Cl>[Cl-:1].[C:24]1([P+:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:30][C:9]2[CH:10]=[CH:3][C:4]3[CH:7]=[CH:6][C:5]=3[CH:8]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1cccc2c1CC2
Solvent: ClC(Cl)Cl
Product: C1=Cc2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Product: [Cl-]

Procedure:
A solution of 4-chloromethylbenzocyclobutene (24.4 g, 160 mmol) and triphenylphosphine (41.9 g, 160 mmol) in 120 ml of chloroform was heated at reflux for 24 h. Addition of diethyl ether followed by filtration gave tripheny(4-benzocyclobutenyl)methyl phosphonium chloride as a white powder: 1H NMR (CDCl3) δ 3.03 (m,4H), 5,36 (d, 2H), 6.82 (m, 3H), 7.6-7.8 (m, 15H). To a solution of the phosphonium salt in 500 ml of 37% formaldehyde in water was added dropwise 75 ml of 50% aqueous sodium hydroxide. The mixture was stirred at ambient temperature for 2 h and then extracted with diethyl ether. The ether extract was washed with brine and dried over magnesium sulfate. Fractional distillation gave 14.5 g of 90% pure 4-vinylbenzocyclobutene: bp 63°-66° C. (6 torr); 1H NMR (CDCl3) δ 3.11 (s, 4H), 5.11 (d, 1H), 5.63 (d, 1H), 66.6 (dd, 1H), 6.95 (d, 1H), 7.10 (s, 1H), 7.18 (d, 1H); 13C NMR (CDCl3) δ 29.29, 29.44, 112.27, 119.87, 122.52, 125.70, 136.72, 137.97, 146.66, 146.01. ##STR6##
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:28](N(CC)CC)[CH3:29].ClC(OCC)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:28][CH3:29])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A stirred solution of 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid (Example 1c) (10 g, 0.026 mol) and triethylamine (3.0 g, 0.03 mol.) in dichloromethane (100 ml, dried over 4 A molecular sieves) at -50° C. was treated dropwise with ethyl chloroformate (3.2 g, 0.029 mol.). The solution was allowed to warm up to 0° C. over 0.5 hours, cooled back to -50° C. and treated with ethanol (6 ml, 0.1 mol). The solution was allowed to warm up and then stirred for 15 hours at 18° C. The mixture was then shaken with an aqueous solution of saturated sodium carbonate (500 ml). The organic layer was separated, dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 5% ethanol in chloroform) to give ethyl 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoate as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 24 h

Procedure:
To a stirred mixture of 2.5 g of 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and 2.8 g of powdered potassium carbonate in 25 mL of dry N,N-dimethylformamide was added methyl iodide (0.94 mL) at 5° C. Stirring was continued for 24 hours at room temperature. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and the solvent was removed in vacuo The crude product (2.7 g; oil) was used in the next step without further purification. EI-MS: 263 (M+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[Cl-].[CH:25]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]([S:32]([N-:35][C:36]2[S:40][CH:39]=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:26]=1.[Na+].C(Cl)(Cl)Cl.CCCCCCCCCCCCC[N+](CC1C=CC=CC=1)(C)C>O.CS(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[CH:29]1[C:30]([NH2:31])=[CH:25][CH:26]=[C:27]([S:32]([NH:35][C:36]2[S:40][CH:39]=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:28]=1
Reactant: Nc1ccc(S(=O)(=O)[N-]c2nccs2)cc1
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C

Procedure:
Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating. Sulfathiazole sodium (0.003 mol) was dissolved in 60 mL of distilled water by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred and heated for 1 h. The reaction mixture was cooled to room temperature and 60 mL of chloroform was added to the reaction mixture. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride ions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and an orange wax was obtained in a 50.04% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=40-50° C. Thermal data was determined by thermalgravimetric analysis: Tonset5%=156° C. and Tonset=173° C. The benzalkonium ion is a known antibacterial and the other ion is used to treat, for example, gonorrhea and other bacterial infections.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:52][C@@H:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([O:43][CH3:42])[CH:45]=2)[CH3:51])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cccc([C@@H](C)NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 100.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1R)-1-(3-methoxyphenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (53 mg, yield 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C(OC)(=O)CS.C1CCN2C(=[N:37]CCC2)CC1>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:37])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Agent: COC(=O)CS
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Reaction time: 5 h

Procedure:
To a solution of cis,trans-4-chloro-4-(4-fluorophenyl)-3-(4-(methylthio)phenyl)-3-buten-2-one (13.8 g) (Example 6, Step 3) and methyl thioglycolate (5.8 mL) in 350 mL of CH3CN was added 8 mL of DBU. After stirring for 5 h, the reaction was quenched with 250 mL of sat. NH4Cl and 50 mL of 1N HCl. The mixture was then extracted with 800 ml of 2:1 EtOAc/hexane. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluted with 10:1 hexane/EtOAc to provide 8.58 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-:39].[Na+].O.[O:42]1[CH2:46]CCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:14][CH:13]([F:15])[O:12][C:9]1[C:8]2[N:7]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=[CH:4][C:3]=2[C:2]([C:46]([OH:42])=[O:39])=[CH:11][CH:10]=1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: FC(F)Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c2nc(C(F)(F)F)ccc12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromo-8-difluoromethoxy-2-trifluoromethylquinoline (6.0 g), triphenylphosphine (0.3 g), bis(triphenylphosphine)palladium (II) chloride (0.15 g), 47% sodium hydroxide solution (4.5 g) and water (12 ml) in tetrahydrofuran (50 ml) was purged with carbon monoxide gas in a Parr pressure reactor at 7 bar. This was heated to 100° C. for 24 h. After cooling and venting the reaction mixture was partitioned between sodium hydroxide solution (1.5 g in 50 ml) and tert-butyl methyl ether (100 ml). The organic solution was extracted with sodium hydroxide solution (2×5 g in 50 ml). The combined aqueous extracts were stirred with activated charcoal (1.5 g) for 15 minutes and then filtered. The filtrate was acidified to pH 4 using 37% hydrochloric acid solution and the resultant cream precipitate isolated by filtration and washed with water (20 ml). The crude product was purified by recrystallisation from toluene to give the product (1.8 g) as a cream solid.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]([F:38])([F:37])[F:36])=[C:31]([CH:34]=1)[CH:32]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=3[C:35]([F:37])([F:36])[F:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(Cl)cc1CNc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 5-chloro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 538.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]CC#N.[OH-:13].[Na+].C(OCCO[CH2:21][CH2:22][OH:23])C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:21][C:22]([OH:23])=[O:13]
Reactant: CCOCCOCCO
Reactant: N#CCCCc1ccccc1F
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CCCc1ccccc1F
Temperature: 25 °C

Procedure:
15.4 gm of the compound prepared in (5) above was added to a mixture of 400 ml of 5% aqueous solution of sodium hydroxide and 400 ml of diethylene glycol monoethyl ether. The mixture was heated under reflux for 3.5 hours, cooled to room temperature, and washed with ether. After the addition of concentrated hydrochloric acid to acidify, the water layer was extracted twice with 500 ml of ethyl acetate. The extract was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 15.9 gm of the title compound.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71]([C:72]([F:75])([F:74])[F:73])=[CH:70][N:69]=[C:68]([NH:76][C:77]4[CH:91]=[CH:90][C:80]([CH2:81][P:82](=[O:89])([O:86]CC)[O:83][CH2:84][CH3:85])=[CH:79][C:78]=4[O:92][CH3:93])[N:67]=3)=[C:61]([C:94](=[O:98])[NH:95][O:96][CH3:97])[CH:60]=2)[CH:56]=[N:55]1>>[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71]([C:72]([F:74])([F:73])[F:75])=[CH:70][N:69]=[C:68]([NH:76][C:77]4[CH:91]=[CH:90][C:80]([CH2:81][P:82](=[O:86])([OH:89])[O:83][CH2:84][CH3:85])=[CH:79][C:78]=4[O:92][CH3:93])[N:67]=3)=[C:61]([C:94](=[O:98])[NH:95][O:96][CH3:97])[CH:60]=2)[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NOC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NOC)n2)c(OC)c1
Yield: 98.7 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methoxycarbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 26B, 114 mg, 161 μmol) to afford 108 mg of the title compound (99%). MS (ESI): m/z=680.75 [M+H]+. UPLC: tR=1.02 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light yellow solid (67 mg, 85%), MS (ISP) m/z=316.6 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:21]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCc1cccnc1
Product: CCc1cc(-c2cncc(C(=O)NCc3cccnc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and pyridin-3-ylmethyl amine to afford the title compound. MS: m/e=349 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C@@H:9]([CH2:12][C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C@@H:10]([OH:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][S:21][CH2:22]Cl.CCOCC>CN(C)C=O>[Cl:1][C:2]1[C:7]2[S:8][C@@H:9]([CH2:12][C:13]3[NH:17][CH:16]=[CH:15][N:14]=3)[C@@H:10]([O:11][CH2:20][S:21][CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CSCCl
Reactant: O[C@H]1c2cccc(Cl)c2S[C@H]1Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSCO[C@H]1c2cccc(Cl)c2S[C@H]1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of cis-7-chloro-3-hydroxy-2,3-dihydro-2-(1'-imidazolylmethyl)benzo(b)thiophene (2.67 gms., 10 mmols) in dry dimethylformamide (30 ml.) at 0°-5° C., add sodium hydride (50% oil dispersion) (0.53 gms., 11 mmols) and stir for one hour at room temperature. Add chloromethyl methyl sulfide (1.06 gms., 11 mmols) and stir again for one hour at room temperature. Pour the reaction mixture into ether (500 ml.) and extract with three portions (500 ml. each) of water. Dry the ether solution over anhydrous magnesium sulfate and evaporate in vacuo. Chromatograph the resultant residue by high pressure liquid chromatography using two silica gel cartridges and eluting with ethyl acetate. Combine the like eluates as determined by thin layer chromatography and evaporate the combined residues to give cis-7-chloro-3-(methylthiomethoxy)-2,3-dihydro-2-(1'-imidazolylmethyl)benzo(b)-thiophene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a suspension of crude 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (846 mg, 3 mmol) in N,N-dimethylformamide (7.5 L) is added 4-(4-methyl-piperazin-1-yl)-phenylamine (573 mg, 3 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours, then evaporated to dryness and triturated with ether. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.23 g of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione.