Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C.[BH4-].[Na+]>O.C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cccnc1Cl
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
2-Chloro-3-fluoropyridine (1.51 mL, 14.9 mmol) was added under nitrogen atmosphere at −78° C. to a mixture of 2.0 M lithium diisopropylamide (in THF) (7.44 mL, 14.9 mmol) and THF (24 mL), and the mixture was stirred at 0° C. for 2 hours. DMF (11.4 mL, 149 mmol) was added to the mixture, and the obtained mixture was stirred at 0° C. for additional 2 hours. Sodium borohydride (731 mg, 19.3 mmol) was then added thereto, and the mixture was stirred at 0° C. for 1 hour. Water was then added to the reaction solution, which was then extracted with ethyl acetate. The solution was washed with 1N HCl, sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound (1.4 g, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(O)C.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Yield: 100.3 %

Procedure:
A solution of 5-benzyloxyindole-2-carboxylic acid ethyl ester (10 g, 34 mmol) in ethanol (250 mL) was treated with 10% Pd/C and hydrogenated under atmospheric pressure (double-walled balloon) for 20 h. The reaction mixture was diluted with EtOAc and filtered through Celite. Evaporation of the filtrate in vacuo gave the title compound as a tan solid (7 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.86 (br s, 1H), 7.29 (d, J=8.80 Hz, 1H), 7.11 (s, 1H), 7.06 (s, 1H), 6.94 (d, J=8.70 Hz, 1H), 4.83 (br s, 1H), 4.42 (q, J=7.09 Hz, 2H), 1.41 (t, J=7.08 Hz, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccccc2OCCC2CCN(C)CC2)c1
Yield: 90.2 %

Procedure:
Following a procedure similar to that described in Example 38, 2.15 g of 1-t-butoxycarbonyl-4-(2-{2-[2(3-methoxyphenyl)ethyl]phenoxy}ethyl)piperidine [prepared as described in Example 53 (a)] were reacted with 0.371 g of lithium aluminum hydride dispersed in 40 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.56 g (yield 90%) of 4-(2-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}ethyl)-1-methylpiperidine as an oil.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:5]1)([CH3:3])[CH3:2].[I:15]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:15][C:7]1[C:6]([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=1
Reactant: Cc1csc(-c2ccn(C(C)C)n2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2nn(C(C)C)cc2I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 1-isopropyl-3-(4-methyl-2-thienyl)-1H-pyrazole (5.6 mmol) in 16 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (5.8 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.54 g 4-iodo-1-isopropyl-3-(4-methyl-2-thienyl)-1H-pyrazole (82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
4-Bromo-2-nitrophenol (5.0 g, 23 mmol) and sodium hydride (0.6 g, 25.3 mmol) were suspended in DMF (50 ml). Methyl iodide (3.9 mL, 28 mmol) was added dropwise at room temperature and stirred for 30 minutes. Water was added slowly to reaction mixture to get precipitate of 4-bromo-2-nitroanisole (0.67 g), 90% yield. The crude solid that was used without further purification. 1H NMR (500 MHz, CDCl3): δ 3.98 (s, 3H), 7.03 (d, J=8.9 Hz, 1H), 7.68 (dd, J=2.45 Hz, 1H), 8.01 (d, J=2.45 Hz, 1H). 13C NMR (500 MHz, CDCl3): δ 56.9, 112.0, 115.3, 128.5, 137.1, 140.2, 152.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:19]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2N2CCC(CO)CC2)CC1
Agent: Cl
Solvent: CO
Product: OCC1CCN(c2nccnc2C2CCNCC2)CC1
Yield: 98.72 %

Procedure:
A solution of 4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (40) (376 mg, 1 mmol) in 4N HCl/MeOH (20 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give (41) (308 mg, 0.98 mmol, yield 98.72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([O:12][CH2:24][CH2:23][CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: OCCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCCCc1cccnc1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (6.0 g; 28 mmol), 3-(3-pyridyl)-1-propanol (5.80 g; 41.8 mmol), dicyclohexylcarbodiimide (9.20 g; 44.48 mmol), camphorsulfonic acid (21.60 g; 9.26 mmol), and 4-dimethylaminopyridine (1.12 g; 9.26 mmol) in dry methylene chloride (200 mL) was stirred overnight. The reaction mixture was filtered through Celite, concentrated, and purified on a silica gel column eluting with 40 ethyl acetate in hexane to obtain 5.0 g of the product as a clear oil (53%). 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H); 1.43-1.95 (m, 6H); 2.68 (m, 2H); 3.46-3.52 (m, 2H); 4.11-4.22 (m, 2H); 4.33 (m, 1H); 7.17-7.24 (m, 1H); 7.47 (m, 1H); 8.43 (s, 2H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:25][CH:24]=1.[CH2:35]=[O:36].Cl>C1COCC1.C(OCC)(=O)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH:31]([CH2:35][OH:36])[C:32]([OH:34])=[O:33])=[CH:27][CH:28]=1
Reactant: C=O
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CCC(CO)C(=O)O)cc1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
To a solution of lithium diisopropylamide (prepared from diisopropylamine (16.16 g, 0.16 mol and n-butyl lithium (1.6M in hexane, 100 ml, 0.016 mol) in THF (50 ml) at -78° C., was added a solution of 4-(4-methoxyphenyl)butanoic acid (13.80 g, 0.07 mol) in THF (100 ml) over 20 min. The solution was warmed to -20° C. and stirred for 2.5 h. Formaldehyde gas generated by warming paraformaldehyde (10 g) was then passed into the reaction mixture in a stream of nitrogen. After stirring for a further 2 h. at -20° C., hydrochloric acid (2N, 500 ml) was added and the reaction mixture was diluted with ethyl acetate (800 ml). After washing with water, the organic phase was extracted with sodium hydroxide solution (0.5N, 3×200 ml). The combined aqueous extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3×200 ml), the combined organic phase (MgSO4) was dried and solvent removed at reduced pressure to give the product as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:32]I>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([N:25]([CH3:32])[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C
Reactant: CI
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)cc1C

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[4-(3,4-dimethylphenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.72 (dd, 1H, J=1.8, 7.7 Hz), 7.33 (t, 1H, J=8.8 Hz), 7.22 (d, 1H, J=7.8 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.01 (m, 2H), 3.24 (s, 3H), 3.10 (d, 1H, J=10.6 Hz), 3.00 (t, 1H, J=7.6 Hz), 2.49 (m, 4H), 2.33 (s, 6H), 2.11 (m, 3H), 1.99 (m, 1H), 1.79 (m, 4H), 1.26 (t, 2H, J=7.6 Hz), 1.02 (d, 6H, J=7.6 Hz); ESMS m/e: 435.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[C:52]=1[C:53](O)=[O:54].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:53]([C:52]1[C:56]([CH2:60][CH3:61])=[CH:57][CH:58]=[CH:59][C:51]=1[Cl:50])=[O:54]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: CCc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.3 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.5 mmol, 184 mg), HBTU (0.7 mmol, 265 mg) and 2-chloro-6-ethylbenzoic acid (0.7 mmol, 129 mg) in DMF (2 mL) was added diisopropylethylamine (1.25 mmol, 0.22 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel column chromatography using a Biotage (40m) column to afford 175 mg (70% yield) of N-[(2-chloro-6-ethylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C26H28ClN3O5 (M+Na) 520.1611, found 520.1613.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10]/[C:9]/2=[CH:16]\[O:17][Si](C(C)C)(C(C)C)C(C)C)=[CH:4][CH:3]=1.ClC1C=CC(C2(O)CCC(C)(C)C/C/2=C\O[Si](C)(C)C)=CC=1.[Si](O/C=C1/C(C2C=CC(Cl)=CC=2)(O)CCC(C)(C)C/1)(C(C)(C)C)(C)C.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CC(C)[Si](O/C=C1\CC(C)(C)CCC1(O)c1ccc(Cl)cc1)(C(C)C)C(C)C
Agent: CC1(C)CCC(O)(c2ccc(Cl)cc2)/C(=C/O[Si](C)(C)C(C)(C)C)C1
Agent: CC1(C)CCC(O)(c2ccc(Cl)cc2)/C(=C/O[Si](C)(C)C)C1
Agent: Cl
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting (2E)-1-(4-chlorophenyl)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-1-(4-chlorophenyl)-4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tert-butyl(dimethyl)silyl)oxy)methylene)-1-(4-chlorophenyl)-4,4-dimethylcyclohexanol and hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[N:8]=1)=[O:14])[CH3:21]
Reactant: O=C(O)c1ccc2cc(O)ccc2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(O)ccc2n1

Procedure:
6-Hydroxy-quinoline-2-carboxylic acid (2.3 g, 0.012 mol) was dissolved in absolute ethanol (150 ml). Sulfuric acid (0.550 ml, 0.0096 mol) was added and the mixture was refluxed for 16 hours. After cooling to room temperature the ethanol was evaporated and 60 ml of ethyl acetate, 50 ml of cooled water were added. The pH was adjusted to 7 with solid NaHCO3. Extraction and concentration of the organic phase gave the title product as a light yellow solid that was used for the next steps without purification (2.1 g, 81% of theory). MS (m/e)=218.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH3:24][S:25][C:26]1[N:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][N:27]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:32]([C:29]1[CH:28]=[N:27][C:26]([S:25][CH3:24])=[N:31][CH:30]=1)=[O:33])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: CSc1ncc(C(=O)O)cn1
Product: CCOC(=O)C(C(=O)c1cnc(SC)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (0.7 g, 32%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 2-methylsulfanyl-pyrimidine-5-carboxylic acid (Arukwe, J.; Undheim, K. Acta Chem. Scand. Ser. B; 1986; 764-767). MS: 484.2 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]3)[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNC(=O)N(c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCNC(=O)N(c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1)C1CCCCC1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)-cyclohexylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: S(Cl)(Cl)=O.BrC1SC(C(O)=O)=CC=1.BrC1SC(C(Cl)=O)=CC=1.[Br:23][C:24]1[S:28][C:27]([C:29]([N:31]=[C:32]=[S:33])=[O:30])=[CH:26][CH:25]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][C:43]1[C:52]2[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=2)[N:46]=[CH:45][CH:44]=1)[NH2:38]>C(O)C.C1(C)C=CC=CC=1>[Br:23][C:24]1[S:28][C:27]([C:29]([NH:31][C:32]([NH:38][C:37]2[CH:39]=[CH:40][C:41]([O:42][C:43]3[C:52]4[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=4)[N:46]=[CH:45][CH:44]=3)=[C:35]([Cl:34])[CH:36]=2)=[S:33])=[O:30])=[CH:26][CH:25]=1
Reactant: O=C(N=C=S)c1ccc(Br)s1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)s1
Agent: O=C(O)c1ccc(Br)s1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)s4)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 5-bromo-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 5-bromo-2-thiophene isothiocyanate was prepared using the resultant 5-bromo-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 5-Bromo-2-thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 75%).
Reaction SMILES: Cl[C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([Cl:10])([F:9])[CH2:3]2.ClC1(F)CCCC(Cl)([F:18])C1O.[OH-].[Na+]>O>[Cl:10][C:4]1([F:9])[CH2:5][CH2:6][CH:7]2[C:2]([F:18])([O:8]2)[CH2:3]1
Reactant: OC1C(F)(Cl)CCCC1(F)Cl
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC1(Cl)CCC2OC2(F)C1
Reaction time: 0.25 h

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 0.18 g (0.88 mmol) of pure alcohol 1g, 3 cm of distilled water and 0.12 g (3 mmol) of sodium hydroxide, reaction time was 1 h 15 min; ether extraction (3×12 cm). After treatment, 0.13 g of epoxide 2f were obtained (macrobore GC purity>98%). The yield of epoxide 2f was 81%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].[H-].[Na+]>CN(C=O)C.O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH2:13]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)OC)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (2.0 g, 7.2 mmol) is dissolved in DMF (25 ml) in a dry flask under nitrogen. Allyl bromide (0.65 ml, 7.55 mmol) is added drop-wise, followed by the careful addition of 60% NaH (303 mg, 7.55 mmol). The reaction is stirred overnight at RT and then is diluted with H2O (30 ml). The mixture is extracted with EtOAc (3×30 ml), and the combined organics are washed with 50% saturated NaCl (4×25 ml), dried (MgSO4), filtered, and concentrated under high vacuum to an oil that solidified upon standing. The volatiles are removed in vacuo to obtain 2.28 g (100%) of methyl 3-(allyloxy)-4-iodobenzoate as a tan solid. HRMS (FAB) calcd for C11H11IO3+H: 318.9833, found 318.9831 (M+H)+.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[C:13]1([CH3:20])[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[O:19][C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1
Reactant: Cc1ccccc1O
Reactant: C=CCSc1ccc(Cl)nn1
Agent: [Na]
Product: C=CCSc1ccc(Oc2ccccc2C)nn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of dry o-cresol. To the resulting solution was added 1.87 g(0.01 mol) of 3-chloro-6-allylthiopyridazine. The reaction solution was stirred for 5 hours at 100±5° C. and then treated according to the same manner as Example 23 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][O:22][C:18](=[O:21])[CH:19]=[CH:20][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: C=CC(=O)OC
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC(=O)/C=C/c1cccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-indol-2-one (from Example 63) (500 mg, 1.49 mmol) in DMF (8 mL) and TEA (3 mL) was added methyl acrylate (0.26 mL, 2.98 mmol) (Aldrich), tri-o-tolylphosphine (361 mg, 1.19 mmol) (Aldrich) and Pd(OAc)2 (67 mg, 0.30 mmol) (Aldrich). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 3-[2,3-dihydro-(Z)-3-[(1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-(E)-2-propenoic acid methyl ester as a yellow solid. (Yield 363 mg, 83%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].C([O-])(=O)C.[Na+]>O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:13]([OH:16])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Yield: 134.9 %

Procedure:
A 3 L one neck flask fit with a reflux condenser, magnetic stirrer, and nitrogen inlet was charged with p-t-butylbenzaldehyde (145.5 g, 0.90 mol), acetic anhydride (106 mL, 1.12 mol), and sodium acetate (7.36 g, 0.90 mol). After refluxing for 48.5 hours the reaction was cooled and water was added slowly to roughly triple the total volume as a yellow solid formed. The solids were filtered and washed with water (200 mL), reslurried in water and refiltered and washed again with water (750 mL total). The product was partially dried in the vacuum oven to give 4-t-butlycinnamic acid (248 g). 1HNMR (CD3SOCD3, 500 MHz) mostly trans isomer δ7.58 (d, JAB=8.5 Hz, 2H); 7.54 (d, J=15.5 Hz, 1H); 7.41 (d, JAB=7.5 Hz, 2H); 6.46 (d, J=16.0 Hz, 1H); 1.26 (s, 9H).