Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(OC(C)C)(=O)C.[F:21][CH:22]([F:25])[CH2:23][OH:24].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O:24][CH2:23][CH:22]([F:25])[F:21])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCC(F)F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CC(=O)OC(C)C
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC(F)F)c1
Temperature: 2.5 °C
Yield: 97.4 %

Procedure:
194 g 3-nitro-benzenesulfonyl chloride (1.13 equiv.) were charged in the reaction vessel followed by 1.3 l isopropyl acetate and the solution was cooled to 0-5° C. A solution of 65 g 2,2-difluoroethanol (753 mmol, 1 equiv.), 163 ml triethylamine (1.55 equiv.) and 325 ml isopropyl acetate was added dropwise over 30 min, keeping the temperature between 0-5° C. After 4 h reaction (HPLC in process control), the reaction mixture was washed with 650 ml water. The water phase was re-extracted with 650 ml isopropyl acetate. The organic phases were washed with 650 ml 1M HClaq and 650 ml 10% NaClaq solution. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness under reduced pressure to give 196 g 2,2-difluoroethyl 3-nitrobenzenesulfonate (97% yield) as a viscous oil which crystallized on standing. The product can also be crystallized from isopropanol (seeding at 30° C., concentration: ca 13 L/kg product).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1)=O.[C:17]([NH2:20])(=[O:19])[CH3:18].C(OCC)(=O)C>CN(C)C=O>[CH3:15][C:11]1[CH:10]=[C:9]2[C:14]([C:5]([C:3]3[N:20]=[C:17]([CH3:18])[O:19][CH:2]=3)=[CH:6][C:7](=[O:16])[O:8]2)=[CH:13][CH:12]=1
Reactant: Cc1ccc2c(C(=O)CBr)cc(=O)oc2c1
Reactant: CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(-c3coc(C)n3)cc(=O)oc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(bromoacetyl)-7-methyl-2H-chromen-2-one (750 mg, 2.67 mmol) in N,N-dimethylformamide (2.5 mL), acetamide (158 mg, 2.67 mmol) was added. The reaction was then stirred overnight at 100° C. After cooling, the reaction mixture was dissolved with ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was pre-adsorbed on silica gel and purified by column chromatography (EtOAc/hexanes, 30:70 to 80:20) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.52 (s, 1H), 8.21 (d, 1H), 7.23 (s, 1H), 7.21 (d, 1H), 6.52 (s, 1H), 2.57 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.[C:13]([C:17]1[C:26]([O:27][SiH:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[CH:11]=[C:10]([CH2:12][C:19]([C:18]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][SiH:28]([CH3:30])[CH3:29])[C:17]=2[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:20])[O:9][N:8]=1
Reactant: COC(=O)c1cccc(O[SiH](C)C)c1C(C)(C)C
Reactant: Cc1cc(C)on1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)c2cccc(O[SiH](C)C)c2C(C)(C)C)on1
Temperature: -20 °C
Yield: 50.4 %

Procedure:
52 ml of 1N solution of n-butyllithium in hexane were added to a solution of 6 g of 3,5-dimethylisoxazol in 200 ml of tetrahydrofuran at -78° C. After stirring for 1 h 15 g of methyl 2-tert.butyldimethylsiloxybenzoate in 50 ml of tetrahydrofuran were added at the same temperature. The reaction mixture was slowly warmed up to -20° C. A saturated aqueous solution of ammonium chloride was added, the mixture was extracted several times with ethylacetate. The organic phase was separated, washed with water and dried over magnesium sulfate. Chromatography on silica gel with heptane/ethylacetate gave 9.4 g of the product.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@@H:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:6][CH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of (S)-1,3-butanediol (1.0 g) and triethylamine (1.12 g) in dichloromethane (30 ml) was added portionwise p-toluenesulfonyl chloride (2.12 g) at 0° C., and then the mixture was stirred at ambient temperature for 3hours and stand overnight. The resulting solution was dilueted with dichloromethane (30 ml) and the organic layer was washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded (S)-3-hyrdoxybutyl p-toluenesulfonate (2.26 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[C:13](=[O:30])[CH2:12]1)=O)C1C=CC=CC=1.[ClH:31]>C(OCC)(=O)C.CO.[Pd]>[ClH:31].[ClH:31].[ClH:31].[N:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][CH:18]([NH:17][N:14]3[CH2:15][CH2:16][NH:11][CH2:12][C:13]3=[O:30])[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(NC2CCN(c3ccncc3)CC2)C(=O)C1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CNCCN1NC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 4-benzyloxycarbonyl-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (25.29 g) and an a 4N solution of hydrochloric acid in ethyl acetate (15.5 ml) in methanol (300 ml) was combined with 10% Pd/C (50% hydrated, 5.00 g) and stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off, and the reaction mixture was concentrated. The residue was dissolved in ethanol (300 ml), and combined with a 4N solution of hydrochloric acid in ethyl acetate (31 ml). The crystals precipitated were collected by filtration and dried to obtain 1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone trihydrochloride (20.16 g) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH2:22][C:23]([F:31])([F:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:13])=[N:8][CH:7]=1.O[Li].O>C1COCC1.O>[F:31][C:23]([F:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][N:14]([C@H:15]1[CH2:16][CH2:17][C@H:18]([CH3:21])[CH2:19][CH2:20]1)[C:12](=[O:13])[NH:11][C:9]1[S:10][C:6]([S:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:7][N:8]=1
Reactant: COC(=O)CSc1cnc(NC(=O)N(CC(F)(F)c2ccccc2)C2CCC(C)CC2)s1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CC[C@H](N(CC(F)(F)c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {2-[3-(2,2-difluoro-2-phenyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester (350 mg, 0.725 mmol) in THF (50 mL) was added LiOH.H2O (183 mg, 4.35 mmol) in water (3 mL) at RT. The mixture was stirred at RT for 16 h. Water was added and the mixture was extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulfate. The solvent was removed at reduced pressure and the residue was purified by preparative HPLC to give {2-[3-(2,2-difluoro-2-phenyl-ethyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:16]2[C:17]3[N:12]([C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)=[CH:14][CH2:15]2)[N:11]=[CH:10][C:9]=3[C:8](=[O:28])[N:7]=1)=[O:4].[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>O1CCCC1>[O:28]=[C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:39]2[CH2:40][CH2:41][N:36]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:37][CH2:38]2)[N:16]2[C:17]3[N:12]([C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=4)=[CH:14][CH2:15]2)[N:11]=[CH:10][C:9]1=3
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CN1CCN(Cc2ccccc2)CC1)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1

Procedure:
A 1.000 g amount of 2-chloro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-5-yl]acetamide (prepared in the manner described in Example 31) was dissolved in 50 ml of dry tetrahydrofuran, then 430 mg of 1-benzylpiperazine was added to the mixture in one portion. The reaction mixture was heated at reflux for 16 hours. The mixture was cooled, made basic with 1N sodium hydroxide and extracted with chloroform. The solvent was evaporated and the solid was purified by conventional means to give 426 mg of the desired product as a brown solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[S:70]1[CH:74]=[CH:73][N:72]=[C:71]1[NH2:75]>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:75][C:71]2[S:70][CH:74]=[CH:73][N:72]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: Nc1nccs1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3nccs3)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 1,3-thiazol-2-amine (10.0 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 30%). LC-MS m/z 604 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C)C(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:17]2[C:18]3[C:10]4[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:31]=[CH:32][N:33]=[C:2]([N:38]6[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]6)[CH:3]=5)[CH:30]=[CH:29][C:11]=4[CH2:12][CH2:13][C:14]=3[C:15]([C:26]([NH2:28])=[O:27])=[N:16]2)=[CH:20][CH:21]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3ccnc(Cl)c3)cc1-2
Reactant: CN1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(F)cc3)CC4)ccn2)CC1
Temperature: 100 °C
Reaction time: 88 h

Procedure:
The material from step 1 (2.17 mmoles) and N-methyl piperazine (32.9 mmoles) were dissolved in 5.0 mL N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100° C. for 88 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was then dissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The solvent was stripped, then the solid residue was recrystallized from acetonitrile. Mp: 277–279° C. 1H NMR (400 MHz, d6-DMSO): δ 2.17 (s, 3H); 2.35 (t, 4H, J=5 Hz); 2.82–2.95 (m, 4H); 3.47 (t, 4H, J=5 Hz); 6.85 (d, 1H, J=5 Hz); 7.01 (s, 1H); 7.21–7.44 (m, 6H); 7.50–7.59 (m, 3H); 8.16 (d, 1H, J=5 Hz); 10.10 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 20.32, 29.69, 45.20, 46.46, 55.00, 105.43, 111.23, 115.50, 117.07, 117.30, 120.66, 121.37, 126.54, 128.60, 128.69, 129.48, 133.36, 136.82, 136.85, 137.70, 139.71, 143.19, 144.36, 148.89, 159.88, 161.37, 163.81, 164.44, 165.15. M+1=526.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39]C1C=C(C=CC=1F)C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[C:36]([F:39])[CH:37]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1ccc(F)c(F)c1

Procedure:
In the same manner as in Example 7, 213.3 mg of the title compound was obtained as colorless amorphous compound from 490.8 mg of Referential Compound 3 and 215 μL of 3,4-difluorobenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:13]([NH:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1NCc1ccccc1

Procedure:
Methyl 2-amino-4-fluorobenzoate (0.90 g), benzaldehyde (0.54 mL), sodium triacetoxyborohydride (1.58 g) and acetic acid (0.3 mL) in CH2Cl2 (20 mL) were stirred for 3 hours. The reaction was quenched with methanol, concentrated, and chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 2-(4-amino-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoate (1.0 g, 2.9 mmol) and NMM (0.9 g, 8.7 mmol) in DCM (10 mL) was added MsCl (0.4 g, 3.2 mmol) dropwise, Then the mixture was stirred at room temperature overnight. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: PE/EA=4/1) to afford the title compound as a yellow solid. LC/MS m/z=422.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:17]([CH3:16])[C@H:18]2[CH2:37][N:22]3[C:23]4[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]3[CH2:20][CH2:19]2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:11])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1C(F)(F)F
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1ccc(F)cc1C(F)(F)F)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from [4-fluoro-2-(trifluoromethyl)phenyl]acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 463.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[C:18]3[C:13](=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][O:29][C:30]2=[O:33])=[CH:26][CH:25]=1>>[O:33]=[C:30]1[C:31]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:2]3[N:3]=[C:4]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:18]=4[CH:17]=[CH:16][CH:15]=[C:14]5[NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[N:6][CH:7]=3)[CH:32]=2)[CH2:28][O:29]1
Reactant: CC(=O)Nc1cccc2c(Oc3cncc(Cl)n3)cccc12
Reactant: Nc1ccc2c(c1)C(=O)OC2
Product: CC(=O)Nc1cccc2c(Oc3cncc(Nc4ccc5c(c4)C(=O)OC5)n3)cccc12
Yield: 4 %

Procedure:
Method JJ. This method is identical to Method II, but uses microwave heating. Using Method JJ (heating time: 30 minutes) with 2-chloro-6-(5-acetamidonaphtyl-oxy)-pyrazine (150 mg, 0.48 mmol) and 6-amino-1,3-dihydroisobenzofuran-1-one (89 mg, 0.60 mmol), the title compound was obtained (8 mg). Yield: 4%. 1H NMR (250 MHz, DMSO-d6) δ 2.21 (s, 3H), 5.24 (s, 2H), 7.17 (d, 1H, J=8.5 Hz), 7.45-7.51 (m, 3H), 7.63 (d, 1H, J=8.2 Hz), 7.68-7.75 (m, 3H), 7.92 (s, 1H), 7.98 (s, 1H), 8.05 (d, 1H, J=8.7 Hz), 9.92 (bs, 1H), 10.00 (bs, 1H). m/z 427.1 [(M+H)+ calcd for C24H18N4O4 426.1].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([OH:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].I[CH2:30]CC.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([O:26][CH3:30])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCCI
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(O)nn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OC)nn(C)c1=O
Yield: 69.7 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxy-5-benzyloxy-2-methyl-3(2H)-pyridazinone (500 mg, 2.35 mmol) in acetone (10 ml) was added iodopropane (443 mg, 2.59 mmol) and cesium carbonate (920 mg, 2.59 mmol), and stirred under reflux for 2.5 hours. The reaction mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 643 mg of Compound (I-8-1) (yield: 70%).
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-][CH2:16][CH3:17].[Na+].C(Br)C=C>C(O)C.C(=O)(O)[O-].[Na+]>[C:2]1([C:1](=[O:8])[CH2:9][CH2:10][CH:16]=[CH2:17])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C=CCBr
Solvent: CCO
Product: C=CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl benzoylacetate (38.4 g, 0.2 mole, Aldrich) was added to a mixture of sodium ethoxide (13.6 g, 0.2 moles) in 200 mL ethanol. The mixture was stirred magnetically and slowly brought to reflux. After 30 minutes, the reaction mixture was cooled and allyl bromide (26.6 g, 0.22 moles, Aldrich) was added via a syringe with care (10 minutes), and the mixture was refluxed for another 2 hours. After cooling to room temperature, the mixture was transferred to a separatory funnel and diluted with 300 mL saturated sodium bicarbonate and extracted with ether (200 mL×3). The combined ether layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation resulting in a brownish oil. Without further purification, the crude product was suspended in 250 mL 1 normal sodium hydroxide solution and brought to gentle reflux overnight. After cooling, the oil that floated on top was separated and was combine with the organic layer from the extractions that followed. The aqueous layer was acidified with 50% sulfuric acid to pH 1 and heated to reflux for 5 hours. The mixture was extracted with ethyl acetate (200 mL×3). The organic layer was dried over sodium sulfate and the solvent removed by rotary evaporation to yield a yellow oil. Yield: 19.7 g (61.5%) with boiling point 70-80° C. at 0.8 mmHg. 1H-NMR (CDCl3, δ): phenyl ring (7.97, d, 2H, 7.55, m, 1H, 7.4, m, 2H); vinyl group (5.8, m 2H, 5.1 q, 1H); 3.08 (t, 2H); 2.5 (m, 2H). See also, Vogel et al., Vogel's Textbook of Practical Organic Chemistry. Fifth Edition, revised by Furniss et al., 1989, Pearson Prentice Hall).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc2c(Cl)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(Cl)cccc5s4)cc3CC[C@@H]12
Yield: 49.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,4-dichlorobenzothiazole (94 mg, 0.46 mmol) and 1 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 80 mg (49%) of the title compound as an amorphous solid. mp 207°-209°. FDMS: m/e=429 α[D]589 =+63.86 (c=0.57, chloroform).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][C:5](=[CH2:15])[CH2:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][CH2:2][C@@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][C:5](=[CH2:15])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C1C[C@H](CO)[C@H](c2cccc(F)c2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C1C[C@H](COCc2ccccc2)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 3-(S)-(hydroxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane (3.11 g, 16.5 mmol) from Example 65, Step C in DMF (100 mL) was added benzyl bromide (4.24 g, 24.8 mmol) and then sodium hydride (60% in mineral oil, 0.73 g, 18.2 mmol) portionwise over 5 min. The reaction was stirred at rt for 16 h, then diluted with ether (100 mL) and quenched slowly into aq. sodium bicarbonate (200 mL). The layers were separated and the aqueous was extracted with ether. The organic layers were washed 3× with water, then brine, dried over sodium sulfate and concentrated. The residue (7 g) was purified by FC using 0.5-1% ethyl acetate in hexanes to afford the title compound (2.32 g).