Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Mg+2].[Cl-].[Cl-].C[CH2:13][O:14]C(C)=O>C1COCC1>[Br:1][C:2]1[C:3]([OH:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:13]=[O:14]
Reactant: Oc1ccccc1Br
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)c1O
Reaction time: 8 h

Procedure:
A solution of 2-bromophenol (48.5 g, 0.28 mol) in 500 mL of THF was added TEA (200 mL) and then MgCl2 (100 g, 1.05 mol) was added portionwise over 90 minutes. The reaction mixture was allowed to stir overnight under a nitrogen atmosphere. The reaction mixture was neutralized with phosphoric, and then exacted with EtOAc (1000 mL). The organic layers were washed with brine (200 mL), dried over Na2SO4. The solvent was concentrated in vacuo. The residue was purified with silica gel chromatography (petrol ether/EtOAc=5:1) to give product 3-bromo-2-hydroxybenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]2([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]2([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[Cl:27])=[CH:4][CH:3]=1
Reactant: COc1cc(F)c2c(c1)C(O)(c1ncc[nH]1)c1cc(Br)ccc1O2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(F)c2c(c1)C(Cl)(c1ncc[nH]1)c1cc(Br)ccc1O2
Yield: 95.4 %

Procedure:
7-Bromo-4-fluoro-9-(1H-imidazol-2-yl)-2-methoxy-9H-xanthen-9-ol (10 g, 25.6 mmol) was dissolved in 100 ml of benzene and thionyl chloride (18.66 ml, 256 mmol) was added. The solution was refluxed for 4 hours. The reaction was then concentrated to afford 2-(7-bromo-9-chloro-4-fluoro-2-methoxy-9H-xanthen-9-yl)-1H-imidazole (10 g, 24.41 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:21]1
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CN1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (2 mL), and suspended in methanol and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.0731 g, 37%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[C:11]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH3:21])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>ClCCl>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[C:11]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH3:21])[N:10]=1
Reactant: CCOC(=O)CBr
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Yield: 102.4 %

Procedure:
A mixture of ethyl 2-bromoacetate (0.23 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (0.40 g), anhydrous potassium carbonate (0.19 g) and methyl ethyl ketone was heated under reflux for 12 hrs. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil, which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}acetate (0.52 g) as a yellow crystalline solid, mp 99° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:42][OH:43].N1C=CC=CC=1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19](=[N:42][OH:43])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=NO)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
Compound 13 (10 mg, 0.018 mmol) and hydroxylamine hydrochloride (50 eqv., 0.92 mmol, 64 mg) were dissolved in 2 mL of EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45° C. for 12 h. The solvent was then removed in vacuo and the crude solid was purified via LCMS to yield 6 mg of a white solid (58% yield; mixture of isomers). Expected mass=555. Observed mass=556.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]4[N:22]=[CH:23][CH:24]=[CH:25][C:13]=4[N:12]3[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]3([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:5][N:4]=1.Cl.O1CCOCC1>CO>[NH2:37][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:26]3[N:12]4[C:13]5[CH:25]=[CH:24][CH:23]=[N:22][C:14]=5[NH:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:11]4=[N:10][C:9]=3[C:6]3[CH:7]=[N:8][C:3]([OH:2])=[N:4][CH:5]=3)=[CH:28][CH:29]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: COc1ncc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4cnc(O)nc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 19 h
Yield: 19.2 %

Procedure:
tert-Butyl (1-{4-[2-(2-methoxypyrimidin-5-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (45 mg, 0.077 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 19 hours. The mixture was concentrated, then sat.NaHCO3 aq. was added. The mixture was extracted with CH2Cl2+MeOH (×3), dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (CH2Cl2/MeOH=4:1) to afford the desired product (7 mg, 18%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.58 (s, 1H), 8.23 (br s, 2H), 8.09 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.92 (dd, J=4.6 Hz and 1.1 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.34 (td, J=8.6 Hz and 1.7 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.23 (d, J=7.4 Hz, 2H), 7.10 (td, J=7.4 Hz and 1.1 Hz, 1H), 6.87 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.76 (dd, J=8.0 Hz and 4.6 Hz, 1H), 2.44-2.39 (m, 2H), 2.20-2.15 (m2H), 2.09-2.00 (m, 1H), 1.74-1.67 (m, 1H). LCMS: 474 [M+H].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([NH:17][NH2:18])=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)[N:14]=2)[N:24]=1
Reactant: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To a solution of 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (9.7 g, 33.7 mmol) and acetimidamide hydrochloride (4.8 g, 50.5 mmol) in dry THF (300 mL), NaOH (2.0 g, 50.5 mmol) was added at RT. The mixture was refluxed overnight. The solution was cooled, concentrated and ethane-1,2-diol (100 mL) was added. The resulting mixture was heated at 180° C. for 3 h, cooled to RT, diluted with H2O (800 mL), and extracted with EtOAc (3×400 mL). The combined organic layers were washed with H2O (300 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude solid product, which was treated with EtOAc (150 mL). The resulting suspension was stirred at RT for 15 min, and then filtered to afford 4.8 g of the pure desired compound. The remaining filtrate was concentrated and purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to afford 1.4 g of another batch of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid-overall 6.2 g, yield 59%. MS (ES+) C12H8F3N5O2 requires: 311. found: 312 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:3]=[C:4]3[N:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=24)[C:6]([CH2:13][CH3:14])=[C:5]3[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(Br)c3cccc1n32
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(-c2ccc(OC)cc2)c2cc(-c3ccc(OCc4ccccc4)cc3)c3cccc1n32
Temperature: 87.5 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
4-Bromo-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.354 g, 1.0 mmol), prepared in example 75, step 2, was dissolved in 15 ml of 1,2-dimethoxyethane under a nitrogen atmosphere. tetrakistriphenylphospine palladium(0) (0.06 g, 0.052 mmol) was added, and the mixture was stirred for 10 minutes. Sodium carbonate (0.65 g, 6.13 mmol) and water 2 ml was added and stirring was continued for 10 minutes. 4-Benzyloxyphenyl boronic acid (0.91 g, 3.99 mmol) dissolved in 10 ml of hot 1,2-dimethoxyethane was added and the mixture was heated to 85-90° C. for 18 hours. The suspension was poured into 100 ml of water and the organic material was extracted into dichloromethane (1×100 ml and 3×50 ml). The combined organic layers were washed with brine, dried overmagnesium sulfate, and evaporated. The crude product was purified by column chromatography over silica gel 60, using 3% of diethyl ether in hexane as the eluent to afford a yellow solid, which was recrystallised from dichloromethane and petroleum ether, to afford 0.31 g (68%) of 4-(4-benzyloxyphenyl)-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine as yellow crystals. MS(SP): m/z 457 (M+). 1H--NMR (CDCl3, 400 MHz) δ: 1.48 (t, 3 H); 3.25 (q, 2 H); 3.91 (s, 3 H); 5.14 (s, 2 H); 7.07-7.13 (m,4 H); 7.31-7.51 (m, 5 H); 7.67 (dd, 1 H); 7.70 (s, 1 H); 7.73-7.82 (m, 4 H); 7.92 (d, 1 H); 8.13 (d, 1 H). Analysis: Calculated for C32H27N1O2 : C, 84.00; H, 5.95; N, 3.06%; Found: C, 84.07; H, 6.02; N, 2.90%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27].O>CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:27][CH2:26][CH2:25][O:24][CH3:23])=[O:22]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: COCCN
Solvent: O
Solvent: CN1CCCC1=O
Product: COCCNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (100 mg) and 2-methoxyethylamine (314 mg) in N-methylpyrrolidone (1 ml) was heated at 120° C. overnight. Water (3 ml) was added thereto under ice-cooling, and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, and the residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-(2-methoxyethylamino)quinoline (65 mg).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[C:12]2=[O:35])[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+]>O1CCCC1>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][N:13]1[C:14]2[C:15](=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[N:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([OH:4])[CH2:10][CH2:9]2)[C:12]1=[O:35]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](OC(C)=O)CC3)c3ncc(C(F)(F)F)cc32)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ncc(C(F)(F)F)cc32)cc1OC
Temperature: 25 °C

Procedure:
A mixture of 3-(trans-4-acetoxycyclohexyl)-1-(3,4-dimethoxybenzyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (125 mg) in a mixture of tetrahydrofuran (1 mL), methanol (0.5 mL) and 1N-sodium hydroxide (0.507 mL) was refluxed for an hour. After cooling to room temperature, the mixture was concentrated in vacuo. Water was added to the residue, and the resulting precipitate was collected by filtration. The obtained solid was washed with water and subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained solid was washed with a mixture of diethyl ether and diisopropyl ether to give 1-(3,4-dimethoxybenzyl)-3-(trans-4-hydroxycyclohexyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (62.9 mg) as a colorless solid.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1C=O.N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:1]=[CH:2][C:3]([OH:5])=[O:4]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A 250 ml round-bottomed flask, Teflon stirrer, reflux condenser, and gas inlet were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, flushed with dry nitrogen gas, and allowed to cool to room temperature. After cooling, the flask was charged with malonic acid (110 mmole), pyridine (75 ml), 2,3-dichlorobenzaldehyde (17.50 g, 100 mmole) and piperidine (2 ml, 20 mmole). The reaction mixture was stirred and brought to relux. After 16 hours of stirring under reflux, the reaction mixture was cooled to room temperature and poured onto a mixture of ice (100 ml) and concentrated hydrochloric acid (100 ml) resulting in the precipitation of a white solid to form a slurry. The resulting slurry was stirred for 2 hours, filtered, washed with cold water (2×250 ml), and dried in vacuo to give 20.01 g (92%) of 2,3-dichlorocinnamic acid.
Reaction SMILES: C1CCCCC1.[CH2:7]([OH:10])[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([N+:47]([O-:49])=[O:48])[CH2:34][CH2:35][C:36](=O)[CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>C1C=CC=CC=1>[CH2:7]1[O:10][C:34]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)([CH:33]([N+:47]([O-:49])=[O:48])[CH2:32][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[O:9][CH2:8]1
Reactant: COc1ccc(CC(CCC(=O)CCc2ccc(C)cc2)[N+](=O)[O-])cc1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: COc1ccc(CC([N+](=O)[O-])C2(CCCCc3ccc(C)cc3)OCCO2)cc1OC
Yield: 7.1 %

Procedure:
In a 500 mL rb flask, 200 mL cyclohexane, 50 mL benzene, 15 g.(0.242 mole) ethylene glycol, 1.5 g p-toluene-sulfonic acid and 19 g (0.049 mole) of 1-(3,4-dimethoxyphenyl)-2-nitro-7-(4-methylphenyl)-5-heptanone were combined and refluxed 24 hours with a Dean-Stark trap. The cooled reaction mixture was poured into cold, sat'd. NaHCO3 and extracted with three 200 mL portions of ethyl acetate. The organic Layer was dried over MgSO4, filtered and concentrated. The residue was triturated with ether and ethyl acetate to give some solid (1.5 g) of mp 89°-91° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:6]=1)(=O)=O.C([Li])CCC.[F:33][C:34]1[CH:35]=[C:36]([OH:41])[CH:37]=[CH:38][C:39]=1[F:40].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[F:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][C:39]=1[F:40])[O:41][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:6]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: COc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
2-Methylsulfonyl-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (93 mg, 0.19 mmol), prepared as described in Reference Example 16, was suspended in THF (500 μL) in a vial fitted with a magnetic stir bar and rubber septum. The reaction mixture was cooled to −78° and 3,4-difluorolithium phenoxide, prepared by adding n-butyl lithium (100 μL, 2M solution) to 3,4-difluorophenol (26 mg, 0.19 mmol) in 500 μL THF at 0° C., was added by syringe. The mixture was brought to room temperature, stirred for 1 h and worked up by adding 2 mL DCM and 1 mL saturated ammonium chloride. The organic layer was separated, dried over MgSO4, filtered and the solvent removed under reduced pressure. HPLC analysis showed the product to be 95% pure and it was used in the next step without further purification. Rt=4.51 min. 1H-NMR 500 MHz (CDCl3): δ 4.12 (s, 3H), 7.02 (m, 1H), 7.15 (m, 1H), 7.20-7.45 (m, 3H), 7.54 (d, J=2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27].Cl>C(Cl)Cl>[C:26]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])[CH2:33][CH2:34]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: CCOC(=O)c1cc(-c2cccc(N)c2)on1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2cccc(NC(=O)C3CCN(C(C)=O)CC3)c2)on1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To ethyl 5-(3-aminophenyl)isoxazole-3-carboxylate (0.224 mmole) and triethylamine (0.896 mmole) in methylenechloride (3 mL) was added 1-acetyl-piperidine-4-carbonyl chloride HCl salt (0.314 mmole) via syringe at ambient temperature. After two hours, 1N HCl was added and the mixture was extracted with methylene chloride (3×40 mL). The combined organics were washed with aqueous Na2CO3, dried with anhydrous Na2SO4, filtered, concentrated under vacuo and purified by flash chromatography (10–15% ethyl acetate/Hexane) to provide (68 mg) of the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Cl[CH2:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[N:1]1([CH2:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: COC(=O)COCCl
Reactant: c1c[nH]nn1
Product: COC(=O)COCn1ccnn1

Procedure:
The title compound was prepared from 1,2,3-triazole and methyl chloromethoxyacetate by a similar method to that of Preparation 40 as a colourless oil which was characterised by NMR. 1H-NMR (300 MHz, CDCl3): δ=3.76 (s,3H), 4.16 (s,2H), 5.84 (s,2H), 7.80 (d,2H) ppm.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=O.C([N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])(=O)C.[H-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=[C:22]1[CH2:23][CH2:24][NH:20][C:21]1=[O:25]
Reactant: CC(=O)N1CCCC1=O
Reactant: CN1CCN(c2ccc(F)cc2C=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(F)cc2C=C2CCNC2=O)CC1
Reaction time: 2.5 h
Yield: 33.5 %

Procedure:
A solution of 9.0 g (40.5 mmol) of 5-Fluoro-2-(4-methyl-piperazin-1-yl)-benzaldehyde and 5.1 g (40.5 mmol) of N-acetylpyrrolidinone in 80 mL of tetrahydrofuran is slowly added to a 0° C. solution of 5.4 g (133.6 mmol) of sodium hydride in 80 mL of tetrahydrofuran over a 2 hour period. After 2.5 hour at 0° C., the reaction is quenched with sat. ammonium chloride and extracted with methylene chloride. The organic layer is dried with magnesium sulfate and concentrated to provide a yellow solid. Recrystallization from ethyl acetate and diispropyl ether provided 3.92 g (33%) of 3-[5-Fluoro-2-(4-methyl-piperazin-1-yl)-benzylidene]-pyrrolidin-2-one as a white solid. Diagnostic C13 NMR (100 MHz, CDCl3) 26.4, 39.9, 46.1, 52.9, 55.3, 115.2, 115.5, 115.8, 116.0, 120.2, 120.3, 126.7, 131.1, 148.9, 157.3, 159.7, 172.8; MS m/z 290.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[C:30]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:38]([O:37][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:13]12[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1)[NH:11][C:10](=[O:27])[N:9]2[C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:39]
Reactant: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Reactant: CCCCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC12CCCCC1(Cc1ccc(C#N)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (500 mg) (1.25 mmol) in DMF (20 ml) was carefully dropped on a suspension of NaH 60% (65 mg) (1.3 eq) in DMF (10 ml) at RT. The reaction mixture was stirred 1 h at RT, then ethyl hexanoate (0.27 ml) (1.2 eq) was added. After 3 h, the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified on SiO2 chromatography (eluent EtOAc/cyclohexane—2/8) to give 6-[7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-hexanoic acid ethyl ester (200 mg) as an oil. 1H NMR (CDCl3): 7.55 (2H, d), 7.25 (2H, d), 7.1 (1H, m), 6.75 (2H, m), 4.95 (1H, m), 4.15 (2H, q), 3.7 (1H, m), 3.1 (1H, m), 3.0 (2H, s), 2.35 (2H, m), 2.2-1.3 (12H, m), 1.23 (3H, t).