Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: CC(=O)c1ccccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 1-(2-fluorophenyl)ethanone (15.1 g) in acetic acid (150 mL) was added bromine (5.8 mL). The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 22.9 g, yield 97%).
Reaction SMILES: Cl[N:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3]1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3][N:2]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[C:16]([F:15])[CH:17]=2)[CH:11]=1
Reactant: COc1ccc2c(c1)CN(Cl)C=C2Cl
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CN(c1ccc(OC(C)C)c(F)c1)C=C2Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.25 g, 1.1 mmol), 3-Fluoro-4-isopropoxyphenylboronic acid (0.21 g, 1.1 mmol) in 1,4-Dioxane (5 ml) and water (1 ml) was added K2CO3 (0.3 g, 2.2 mmol). The reaction mass was degasified for 20 min. Pd (Ph3P)4 (0.06 g, 0.05 mmol) was added to the above reaction mass and degasified again for 5 min at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 90° C. for 18 h. The reaction mass was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.2 g, 54%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 8.08 (d, J=9.26 Hz, 1H) 7.93 (dd, J=12.51, 2.25 Hz, 1H) 7.80 (dt, J=8.50, 1.00 Hz, 1H) 7.74 (s, 1H) 7.45 (d, J=2.50 Hz, 1H) 7.09 (t, J=8.50 Hz, 1H), 3.99 (s, 3H), 3.95 (m, 1H), 1.41 (d, J=6.25 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
Methyl 4-hydroxy-2-methyl-5-nitrobenzoate (12.9 g) was dissolved in dimethylformamide (200 ml), and thereto were added potassium carbonate (20.1 g) and benzyl bromide (13.7 g), and the mixture was stirred at 70° C. for 4 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The obtained organic layer was washed with 1N aqueous hydrochloric acid solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The obtained solid was washed with hexane/ethyl acetate=10/1 to give the title compound (13 g).
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.Br[Si](C)(C)C>ClCCl>[OH:5][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
(S)-7-[[Ethoxy(4-phenylbutyl)phosphinyl]-acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester (3.4 g) in dry dichloromethane is treated with bromotrimethylsilane (1.5 ml) under argon at room temperature. After 3 hours the dichloromethane and excess bromotrimethylsilane are removed in vacuo and the residue taken up in water and ethyl acetate and stirred for 5 minutes. The layers are separated and the organic phase is washed with brine and dried (MgSO4). The solvent is stripped yielding 3.3 g of the title compound as a foam.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[O:5].[OH-].[Na+]>CN(C=O)C>[N:17]1[C:2]2[O:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:4](=[O:5])[C:3]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccccc1O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2Oc2ncccc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
Title compound 13 (3.65 g, 14.7 mmol) was dissolved in DMF (25.0 mL) and sodium hydroxide (0.706 g, 17.7 mmol) was added. The reaction mixture was stirred at 130° C. for 5 hours. The mixture was cooled down to room temperature and an ice/water mixture was added. The precipitate was filtered then triturated in ethanol to afford title compound 14 (1.798 g, 58%) as a white solid. LRMS (ESI): (calc) 212.06. (found) 213.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:28](=[O:29])[N:27]([CH3:31])[CH3:26]
Reactant: CN(C)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: CN(C)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 399.9 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C:14]3([C:30]([N:32]4[CH:37]5[CH2:38][CH2:39][CH:33]4[CH2:34][CH:35]([N:40]4[C:44]([CH3:45])=[N:43][N:42]=[C:41]4[CH:46]([CH3:48])[CH3:47])[CH2:36]5)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C:14]3([C:30]([N:32]4[CH:33]5[CH2:39][CH2:38][CH:37]4[CH2:36][CH:35]([N:40]4[C:44]([CH3:45])=[N:43][N:42]=[C:41]4[CH:46]([CH3:47])[CH3:48])[CH2:34]5)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:51])[CH3:52]
Reactant: C=C(C)[C@@H]1CCC2(C(=O)N3C4CCC3CC(n3c(C)nnc3C(C)C)C4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CCC2(C(=O)N3C4CCC3CC(n3c(C)nnc3C(C)C)C4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 22, 0.2 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.05 g in 4 ml water) was added and the contents were stirred for about for about 6 hours at room temperature and completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.76-0.99 (m, 16H); 1.25-1.85 (m, 35H); 2.03-2.28 (m, 6H); 2.47 (s, 3H); 2.86-3.10 (m, 3H); 3.18 (s, 1H); 4.60 (s, 1H); 4.74 (s, 1H); ES Mass: [M+] 672 (100%), [M+1] 673; HPLC: 95.5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15][CH2:16]Cl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28].[I-].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15][CH2:16][N:27]([CH3:28])[CH3:26])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(CCCCl)c2ccc(F)c(Cl)c2)C1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCN(c1ccc(F)c(Cl)c1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.24 mmol), 50% dimethylamine solution (1 ml) and sodium iodide (0.37 g, 2.5 mmol) were suspended in DMF (3 ml), followed by stirring at 60° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. The organic layer was dried over sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate), and the purified product was then concentrated under reduced pressure to thereby obtain 0.36 g of oily colorless 3(S)-[(3-chloro-4-fluorophenyl)-(3-dimethylamino propyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([NH:14][C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:4]=1[C:5]([OH:7])=[O:6])(=[O:17])[CH3:16]
Reactant: Nc1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(F)c(F)c(F)c(F)c1C(=O)O

Procedure:
Compounds of the Formula II may be prepared by a series of reactions starting with 3,4,5,6-tetrafluoroanthranilic acid. The acid is reacted with acetic anhydride and acetic acid to form 2-acetylamino-3,4,5,6-tetrafluorobenzoic acid. This compound is reacted with oxalyl chloride and dichloromethane in the presence of N,N-dimethylformamide catalyst to form 2-acetylamino-3,4,5,6-tetrafluorobenzoyl chloride. This product is treated with n-butyl lithium and malonic half acid ester to form 2-acetylamino-3,4,5,6-tetrafluoro-β-oxobenzene-propanoic acid ethyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]([CH3:21])([CH3:20])[CH2:10][CH2:11][CH:12]1[CH2:17][C:16]([CH3:18])=[CH:15][C:14](=[O:19])[CH2:13]1.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]([CH3:21])([CH3:20])[CH2:10][CH2:11][CH:12]1[CH2:17][C:16]([CH3:18])=[CH:15][CH:14]([OH:19])[CH2:13]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(C)=CC(O)C1
Reaction time: 16 h

Procedure:
To a suspension of lithium aluminum hydride (0.1 g, 0.0024 mol) in tetrahydrofuran (5 mL) cooled to 0~C was added 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohex-5-en-1-one (1.0 g, 0.0048 mol) in tetrahydrofuran (5 mL). The mixture warmed on standing 16 hours and was treated with 10% sodium hydroxide solution. Subsequent workup yielded 3-(3-methoxy-3-methylbut-1yl)-5-methylcyclohex-5-en-1-ol as a mixture of two diastereoisomers (ratio: 6.5:93.5, 0.853 g). This material was determined to possess green, woody notes NMR(CDC13)δ0.8-1.1(m,2H),1.2(s,6H), 1.3-1.6(m,5H), 1.7(s,1H), 1.9-2.2(m,5H), 3.2(s,3H), 4.2(brs,1H), 5.4(s,1H); IR(neat) 3400, 2975, 2925, 1670, 1380, 1360, 1090 cm-1 ; MS(m/e) 43, 73, 91, 106, 124, 147, 162, 180, 194.
Reaction SMILES: [CH2:1]1[C:21]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:20]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:27]O>>[CH2:1]1[C:21]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]([O:19][CH3:27])=[O:18])[CH:15]=[CH:16][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:20]=2)[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)Sc1cc3c(cc1CC2)CCC3
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)Sc1cc3c(cc1CC2)CCC3

Procedure:
A suspension of crude 2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid (8.276 g, 28 mmole) in methanol (200 ml) containing concentrated sulfuric acid was stirred under reflux for 20 hours. The suspension was evaporated, water was added and the product was extracted with chloroform. The crude ester was purified by chromatography (250 g Merck silica gel eluted with 1:1 hexane/methylene chloride) The title compound had m.p. 110°-111° C. (from acetonitrile).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)Oc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 3-isopropoxybenzoic acid (50 mmol) and dichloromethane (100 mL). Cool in an ice bath. Add in dropwise fashion, oxalyl chloride (55 mmol). Allow the reaction mixture to warm to ambient temperature. After 2 h, concentrate in vacuo to obtain a residue. Use the title compound without further purification.
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li]CCCC.[CH3:38][CH:39]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH:41]=O>>[CH3:38][CH:39]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH:41]=[C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)[CH3:13]
Reactant: CC(CC=O)CC(C)(C)C
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCC(C)CC(C)(C)C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
Starting from (1-(2-naphthyl)ethyltriphenylphosphonium bromide (2.80 g, 5.63 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.5 mL, 5.63 mmol, 1.0 equiv.) and 3,5,5-trimethylhexanal (1.20 g, 8.44 mmol, 1.5 equiv.), and after stirring the mixture at 25° C. for 3 h, 0.73 g (46%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: C1(S([N:10]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:20])(=O)=O)C=CC=CC=1.[OH-].[Na+]>CO>[C:23]1([CH3:28])[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([C:11]1[NH:10][CH:14]=[CH:13][C:12]=1[C:15]([F:16])([F:17])[F:18])=[O:20]
Reactant: Cc1ccccc1NC(=O)c1c(C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1NC(=O)c1[nH]ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of 1-(phenylsulfonyl)-N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide (560 mg of crude material) in 12 mL of methanol was added 2 mL of an aqueous 1N solution of sodium hydroxide and the mixture was stirred at room temperature during 1 h. At the end of this period, no starting material was detected and the reaction was elaborated in the following way: methanol was evaporated and water was added basifying the mixture with saturated aqueous solution of potassium carbonate. This mixture was extracted with ethyl acetate and this organic phase was washed with water and brine, dried (Na2SO4) and concentrated to dryness affording a reddish residue. This residue was purified by flash chromatography silica (hexane/ethyl ether). Concentration of the fractions containing the compound afforded 120 mg (50%) of the title compound.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([C:17]2[O:18][C:19]([NH:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])=[N:20][N:21]=2)=[O:16])[CH:11]=[CH:10][C:9]=1[C@H:32]1[CH2:37][CH2:36][C@H:35]([CH:38]([CH3:44])[C:39]([O:41]CC)=[O:40])[CH2:34][CH2:33]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([C:17]2[O:18][C:19]([NH:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])=[N:20][N:21]=2)=[O:16])[CH:11]=[CH:10][C:9]=1[C@H:32]1[CH2:33][CH2:34][C@H:35]([CH:38]([CH3:44])[C:39]([OH:41])=[O:40])[CH2:36][CH2:37]1
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2Cl)CC1
Agent: C[Si](C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)O)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2Cl)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Potassium trimethylsilanolate (1.29 g, 9.98 mmol) was added in one portion to a stirred solution of rac-ethyl 2-(trans-4-{2-chloro-4-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)propanoate (Example 641, 550 mg, 1.0 mmol) in THF (10 mL) and the reaction mixture was heated in the microwave at 90° C. for 20 min. The reaction mixture was concentrated in vacuo to leave a yellow solid and then a 1M aqueous solution of citric acid (40 mL) was added and the mixture was stirred for 30 mins. The mixture was filtered to leave a solid, which was washed with H2O (20 mL) to give the title compound (570 mg, 97%) as an off-white solid. The individual isomers may be separated by chiral chromatography under standard conditions and recrystallised from EtOH/water to give
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24](O)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCNCC1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCC(O)CC2)n[nH]1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 4-hydroxypiperidine. The crude product was purified by flash chromatography using CH2Cl2-MeOH (95:5) as an eluent. 1H NMR (400 MHz, CDCl3): 1.62 (1H, d), 1.65 (2H, m), 1.95 (2H, m), 3.00 (2H, t), about 3.57 (2H, m), 3.77 (2H, q), about 4.1 (3H, m), 6.20 (1H, d), 6.58 (1H, d), 7.03 (1H, s), about 7.6 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.74 (1H, d), 11.6 (1H, broad s).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH:23]([CH3:25])[CH3:24])[C:14]=2[CH:26]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:26][C:14]1[C:15]([CH:23]([CH3:25])[CH3:24])=[N:16][C:17]2[C:22]([C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h

Procedure:
A solution of carbon tetrabromide (12.620 gm, 38.0 mmol) in CH2Cl2 (20 ml) was added over a 10 minute period to a cold (-10° C.) solution of 4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde (7.394 gm, 25.2 mmol) and triphenylphosphine (19.86 gm, 75.7 mmol) in CH2Cl2 (140 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to 50 ml. The residue was triturated with Et2O and the precipitated triphenylphosphine oxide was removed by filtration. The filtrate was stripped and the residue was chromatographed (flash, Merck SiO2, 10% EtOAc in hexane) to give 3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1 -methylethyl)quinoline as a light yellow foamy oil (11.556 gm, 102% theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:18])[N:14]=[CH:15][C:16](I)=[C:11]2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:25](=[O:27])=[O:26].[O-]S([O-])(=O)=O.[Ca+2]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:18])=[N:14][CH:15]=[C:16]([C:25]([OH:27])=[O:26])[C:11]=2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(I)c12
Agent: CC(C)[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-chloro-4-iodo-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (2 g) in dry tetrahydrofuran (40 ml) was added 4 A molecular sieves. The solution was stirred at room temperature for 15 minutes then cooled to 40° C. Under an atmosphere of nitrogen was added dropwise, a solution of isopropylmagnesium chloride (2M in tetrahydrofuran, 5.4 ml) and the solution stirred at −40° C. for 10 minutes. The solution was saturated with a stream of carbon dioxide gas which had been passed through a column of Drierite and then diluted with ethyl acetate. The organic was extracted with 1N sodium hydroxide solution until complete extraction and the combined aqueous was then acidified to pH1 with concentrated hydrochloric acid. The acidified aqueous was extracted twice with ethyl acetate which was combined and washed with water until neutral. The ethyl acetate layer was then dried (MgSO4) and evaporated to give a solid. The solid was triturated with isohexane, filtered off and washed with isohexane. The solid was sucked dry then dried at 50° C. under vacuum to afford the title compound (1.22 g).