Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH3:10]O.OS(O)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:10][O:8][C:7]([CH:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of DL-pyroglutamic acid (50 g, 0.387 mol) in 157 mL CH3OH (3.87 mol) and 100 mL toluene was added concentrated H2SO4 (2.5 mL). This mixture was warmed to reflux and allowed to stir for 16 h. Since starting material remained, another 4 mL concentrated H2SO4 was added and the mixture stirred at reflux for an additional 24 h then was cooled to ambient temperature and 20% aqueous NaOH was added to bring the solution to pH ˜6. The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2, filtered through Celite® diatomaceous earth, concentrated and purified via Kugelrohr distillation. The resulting material was carried on directly to the next reaction.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:26]3[CH2:27][CH2:28][C@H:23]([CH2:24][N:25]3C(OC(C)(C)C)=O)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)([CH3:10])[CH3:9]>C(Cl)(Cl)Cl>[ClH:1].[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:26]3[CH2:27][CH2:28][C@H:23]([CH2:24][NH:25]3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2NC3)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
A 4 N-hydrochloric acid-ethyl acetate solution (8.1 mL) was added to a chloroform (10 mL) solution of the compound (1.26 g, 3.24 mmol) synthesized in (3), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound (1.15 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:19]=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:21][Mg]I>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:19]([OH:20])[CH3:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2cc(C=O)cnc2c1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc2cc(C(C)O)cnc2c1
Yield: 79.6 %

Procedure:
To a solution of 7-(heptyloxy)quinoline-3-carbaldehyde (1.6 g, 5.9 mmol) in THF (30 mL) at 0° C. was added CH3MgI (2 g, 12 mmol, 2 eq.) dropwise over 10 min. The mixture was warmed to it over 8 h. Then, the reaction mixture was quenched (water), extracted (ethyl acetate), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (pet. ether:ethyl acetate, 1:5) to give 1-(7-(heptyloxy)quinolin-3-yl)ethanol as yellow oil (1.35 g, yield 80%). ESI-MS: 288 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])(O)=O.[Na+].Br[C:24]#[N:25]>C(O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[N:17]=[C:24]1[NH2:25]
Reactant: N#CBr
Reactant: Cc1cc(C)c(Nc2ncccc2N)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-n2c(N)nc3cccnc32)c(C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of N2-(2,4,6-Trimethyl-phenyl)-pyridine-2,3-diamine (3.05 g, 13.4 mmol), NaHCO3 (2.03 g, 24.1 mmol) in ethanol (40 mL) at 0° C., was added a solution of BrCN (2.55 g, 24.1 mmol) in ethanol (6 mL). The resulting mixture was stirred at 0° C. for 1 h, room temperature for 8 h, and then 80° C. for 8 h. Ethanol was removed in vacuo and the residue was taken up into a separatory funnel with methylene chloride (100 mL). The mixture was washed sequentially with 1N NaOH, water and brine, then the organic layer was dried over Na2SO4. After removing solvents, a brown solid was obtained. By LC-MS, the solid was a mixture of the desired product and the unreacted starting material in a ratio of 4:1 in favor of the desired product. Mass spec.: 253.17 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:25])[CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH3:11].[Sn](Cl)(Cl)(Cl)Cl>>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[O:9][C:3]2[C:4]([C:20]=1[OH:21])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])=[O:25])[CH3:11]
Reactant: Cc1cccc(O)c1C
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOC(=O)c1c(O)c2ccc(C)c(C)c2oc1=O
Temperature: 200 °C
Yield: 0.7 %

Procedure:
A mixture of 2,3-dimethyl-phenol (1.17 g, 9.57 mmol), 2-ethoxycarbonyl-malonic acid diethyl ester (4.1 mL, 19.1 mmol), and tin tetrachloride (23 μL, 0.19 mmol) was heated in a 200° C.-oil bath for 10 min; then cooled, the reaction mixture was directly purified on silica gel column chromatography (eluent: ethyl acetate in dichloromethane: 20% to 80%) to give the desired title product (18 mg). ESI (m/z): 263 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:14](OCC)=[O:15])[CH2:7][CH2:8][C:9](OCC)=[O:10])C.[BH4-].[Na+].CO.Cl>C(O)(C)(C)C>[OH:15][CH2:14][CH:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CCC(CC(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CO
Product: OCCCC(CO)CCO

Procedure:
To a solution of 3-ethoxycarbonylhexanedioic acid diethyl ester (10 g, 0.036 mol) in tert-butanol (100 mL) was added sodiumborohydride (6 g). The mixture was heated to reflux. Methanol (10 mL) was added in 3 aliquots over 30 minutes. The solution was heated at reflux for a further 30 minutes and allowed to cool. The solution was neutralised with 5 M hydrochloric acid with care. The solution was filtered and extracted with ethanol (2×50 mL). The solutions were combined and the solvent was removed at reduced pressure. The residue was extracted with ethanol (60 mL), filtered and concentrated at reduced pressure to yield the desired product as a clear, colourless liquid. This was analysed by NMR in D2O and found to be 3-hydroxymethylhexane-1,6-diol in a yield of 4.5 g (85%).
Reaction SMILES: CS([O-])(=O)=O.[O:6]([CH:13]1[CH2:16][NH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].[CH3:19][N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([N:15]1[CH2:16][CH:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:22]
Reactant: c1ccc(OC2CNC2)cc1
Reactant: CN=C=O
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccccc2)C1

Procedure:
The methanesulfonate of 3-phenoxyazetidine (10.5 g., 0.043 mole) was partitioned between 50 ml of benzene and 25 ml. of dilute sodium hydroxide. The benzene layer was dried over calcium sulfate and filtered. The filtrate was treated with 2.6 g. (0.043 mole) of methylisocyanate and the solution was stirred at room temperature for 18 hours. The resulting mixture was concentrated at reduced pressure and the residue was crystallized from a mixture of ethyl acetate-isopropyl ether to give 1.2 g. (14%) of product (m.p. 139°-141° C.).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][C:35]([O:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:36][C:30]=4[S:29](=[O:45])(=[O:44])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.FC(F)(F)C(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][C:35]([O:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:36][C:30]=4[S:29](=[O:44])(=[O:45])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(Oc5ccccc5)ccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(Oc5ccccc5)ccc4C3)cc(NCC3(N)COC3)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.2 %

Procedure:
A mixture of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (90 mg, 0.13 mmol), palladium hydroxide on carbon (40 mg) and trifluoroacetic acid (0.1 mL) in methanol (30.0 mL) was stirred at room temperature under hydrogen (2 bar) for 14 hours. Then the reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford 10.5 mg of the desired product as a white solid (yield was 15.2%). MS obsd. (ESI+) [(M+H)+] 531, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J=8.34 Hz, 1 H), 7.69 (s, 1 H), 7.52 (d, J=2.53 Hz, 1 H), 7.45 (d, J=8.59 Hz, 1 H), 7.42-7.35 (m, 2 H), 7.31 (dd, J=8.46, 1.64 Hz, 1 H), 7.25-7.13 (m, 2 H), 7.06-6.97 (m, 2 H), 6.21 (s, 1 H), 5.14 (brs, 2 H), 4.70-4.46 (m, 6 H), 3.68 (s, 2 H), 3.60 (brs, 2 H), 2.44 (s, 3 H).
Reaction SMILES: C[O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[C:8](=[O:23])[NH:9][C:10](=[O:22])[N:11]([C@H:13]2[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:14]2[F:21])[CH:12]=1)=[O:4].[OH-].[Na+].CCOCC>O>[C:3](/[CH:5]=[CH:6]/[C:7]1[C:8](=[O:23])[NH:9][C:10](=[O:22])[N:11]([C@H:13]2[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:14]2[F:21])[CH:12]=1)([OH:4])=[O:2]
Reactant: COC(=O)/C=C/c1cn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)/C=C/c1cn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2F)c(=O)[nH]c1=O
Yield: 83.7 %

Procedure:
Compound 15 (560 mg, 1.70 mmol) was stirred in a NaOH solution (2 N, 5 mL) at rt for 1.5 h, then diluted with water (20 mL) and neutralized with Dowex 50 w×8 (H+) resin. The mixture was filtered and washed with water and acetone. The combined filtrate was evaporated to dryness to give a pale-white solid, which was trituated with Et2O to give 16 as an off-white solid (450 mg, 84%): UV (MeOH) λmax 298.0,0 267.0 mn (sh); 1H NMR (CDCl3) δ 11.70 (s, 1H, NH, D2O exchangeable), 8.49 (s, 1H, H-6, j=8.1 Hz 7.22 (d, 1H, Ha, J=15.9 Hz), 6.73 (d, 1H, Hb, J=15.9 Hz), 5.89 (d, 1H, H-1′, J1′,F=16.8 Hz), 5.86 (d, 1H, 3′-OH, D2O exchangeable), 5.62 (bs, 1H, 5′-OH, D2O exchangeable), 5.05 (dd, 1H, H-2′, J2′,F=52.9 Hz), 4.18 (dm, 1H, H-3′, J3′,F=24.1 Hz), 3.89 (m, 3H, H-4′), 3.74 (m, 2H, H-5′).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=O)[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:30][NH2:31].C([O-])(=O)C.[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:31]/[OH:30])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Reaction time: 3 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 48) (150 mg) in tetrahydrofuran (3 mL) and ethanol (3 mL) was added an aqueous solution (2.5 mL) of hydroxyamine hydrochloride (112 mg) and sodium acetate (133 mg), and the mixture was stirred at 70–80° C. for 3 hours. The organic solvent was removed by evaporation, water and ethyl acetate were added for separation/extraction. The organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate; ethyl acetate 10–40%). Among the 2 spots detected by TLC (the solvent system; hexane-ethyl acetate=1:1), the polar fractions (low Rf value on TLC) were collected, and the title compound (116 mg) was obtained as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=O)=O>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:5]2[CH:4]=[CH:3][C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:12][CH:13]=1
Reactant: O=S(=O)(Oc1ccccn1)C(F)(F)F
Reactant: Cc1ccc(Sc2ccc(Br)cc2C=O)cc1
Product: Cc1ccc(Sc2ccc(-c3ccccn3)cc2C=O)cc1
Yield: 39.3 %

Procedure:
The reaction was performed in accordance with a document (Tetrahedron Lett. Vol. 36, No. 50, pp. 9085-9088, 1995) and the product was treated by using 5-bromo-2-[(4-methyphenyl)thio]-benzaldehyde (0.06 g, 0.2 mmol) and 2-pyridyl trifluoromethanesulfonate (0.03 g, 0.2 mmol). The residue was purified by thin-layer chromatography (hexane: ethyl acetate=8:1)) to obtain 2-[(4-methylphenyl)thio]-5-(2-pyridyl)benzaldehyde (0.024 g, 38.5%).
Reaction SMILES: CS[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C[O-:13].[Na+].CO>>[CH2:6]([O:5][P:4]([CH:3]=[O:13])([O:8][CH2:9][CH3:10])=[O:11])[CH3:7]
Reactant: C[O-]
Reactant: CCOP(=O)(CSC)OCC
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(C=O)OCC

Procedure:
Oxydation of diethyl methylthiomethylphosphonate include anodic oxidation in NaOMe/MeOH (saturated with CO2) to give the O, S-acetal of diethoxyphosphinylformaldehyde, which upon oxidation may give the corresponding sulfone as Diethyl methoxy(methylsulfone)phenyl phosphonate (Shankaran, K et al. 2001).
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:8]([C:11]1[N:16]2[N:17]=[C:18]([CH3:28])[C:19]([C:20]3[S:24][C:23]([CH2:25][O:26][CH3:27])=[N:22][CH:21]=3)=[C:15]2[N:14]=[C:13]([CH3:29])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[Cl:30]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1>[Cl:30][C:21]1[N:22]=[C:23]([CH2:25][O:26][CH3:27])[S:24][C:20]=1[C:19]1[C:18]([CH3:28])=[N:17][N:16]2[C:11]([CH:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[CH:12][C:13]([CH3:29])=[N:14][C:15]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(COC)s3)c(C)nn12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(COC)nc3Cl)c(C)nn12
Reaction time: 0.5 h
Yield: 4.3 %

Procedure:
Add n-butyl lithium (2.5 M in hexanes, 174 mL, 0.43 mmol) to a stirred solution of 7-(1-ethyl-propyl)-3-(2-methoxymethyl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (150 mg, 0.43 mmol) in THF (3 mL) at −78° C. Stir for 30 min and add N-chlorosuccinimide (87 mg, 0.653 mmol). Stir 30 min and then warm the reaction slowly to room temperature allowing the reaction to continue overnight. Quench the reaction by adding saturated ammonium chloride solution, extract with ethyl acetate, dry over sodium sulfate, filter, and concentrate to a residue. Purify by flash chromatography, eluting with hexanes/ethyl acetate (10/2) to give the title compound (7 mg). MS (APCI) m/z (35Cl) 379.3 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7](OC)=[O:8])[CH:2]=[CH2:3].O.[NH2:16][NH2:17]>C(O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([NH:16][NH2:17])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(=O)OC)ccc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: C=CCc1cc(C(=O)NN)ccc1C

Procedure:
A solution of methyl 3-allyl-4-methylbenzoate (2.84 g, 15 mmol) and hydrazine hydrate (2.1 mL, 37.5 mmol) in ethanol (5 mL) was heated to 100° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water, and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 3-allyl-4-methyl-benzoic acid hydrazide as a white solid. (Yield 2.80 g, 98.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[C:6]([NH2:30])[CH:5]=1.[CH3:32][CH:33]([CH3:37])[C:34](Cl)=[O:35]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[C:6]([NH:30][C:34](=[O:35])[CH:33]([CH3:37])[CH3:32])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1
Reactant: CC(C)C(=O)Cl
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1

Procedure:
Prepared by general procedure E but using 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-3-aminobenzoic acid methyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester and 2-methylpropionyl chloride instead of propionyl chloride.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([F:20])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[CH2:7])CCC.[Br:21]N1C(=O)CCC1=O>C1COCC1.O>[Br:21][CH2:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([F:20])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCCCC)c1ccnc2c(F)cc(OC)cc12
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c2nccc(C(=O)CBr)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
9.0 g (32.7 mmol) of 4-(1-Butoxy-vinyl)-8-fluoro-6-methoxy-quinoline was dissolved in 200 mL of 3:1 THF/water. 6.4 g of N-bromosuccinimide was added and the contents stirred at rt for 3 hrs. Solvent was then removed by rotary-evaporation. The crude material was purified by flash chromatography on silica gel using 20% ethyl acetate/hexanes as the eluent to give 8.5 g (88%) of the desired product. 1H NMR (CDCl3, 400 MHz) 8.92 (d, 1H), 7.71 (m, 2H), 7.18 (d, 1H), 4.55 (s, 2H), 3.94 (s, 3H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)[CH3:14].CI.Cl>O1CCCC1>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:1])[C:23]#[N:24])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOc1ccc(CC#N)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1ccc(C(C)C#N)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 8.8 g of diisopropylamine in 150 ml of dry tetrahydrofuran were added 50 ml (1.5 mmole/ml) of n-butyl lithium at -50° C. After stirring at -20° C. for 30 minutes, 10.0 g of 4-ethoxyphenylacetonitrile was added thereto at -50° C. After stirring at the same temperature for 1 hour, 10.1 g of methyl iodide was added dropwise at -50° C. After stirring at the same temperature for 3 hours and then at 20° C. for 10 hours, the reaction solution was poured into 10% aqueous hydrochloric acid and extracted with ethyl acetate. After concentrating the ethyl acetate layer, the residual oil was column-chromatographed on silica gel (developing solvent, n-hexane: ethyl acetate=20:1) to obtain 9.50 g of the desired 2-(4-ethoxyphenyl) propionitrile [corresponding to the compound represented by the foregoing formula (II) wherein R1 is an ethoxy group, R2 is a hydrogen atom and R4 is a methyl group] as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine 1,1-dioxide (1.09 g, 8.0 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.90 g, 74%). 1H NMR (CDCl3, 300 MHz): 7.50-7.44 (m, 2H), 7.22-7.16 (m, 2H), 3.60 (s, 2H), 3.09-3.02 (m, 4H), 3.00-2.94 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH3:10].[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([S:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:17](=[O:18])[CH2:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CSc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl

Procedure:
2',3'-Dichloro-4'-methylthio-2-cyclopentylacetophenone is prepared following substantially the same procedure described in Example 10, Step A, using the following substances: 2,3-dichlorothioanisole (63.1 g., 0.327 mole), methylene chloride (300 ml.), cyclopentylacetyl chloride (52.7 g., 0.367 mole) and aluminum chloride (48.0 g., 0.36 mole).
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][C:9]=2[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[Cl:27][CH2:14][C:12]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCCCC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a stirred solution of 78.7E (0.185 g, 0.6 mmol) in DCM (6 mL) and DMF (0.04 mL) at 0° C. was added thionyl chloride (0.08 mL, 1 mmol). The reaction was stirred at room temperature for one hour and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 78.7F as a colorless oil (0.165 g, 84% yield).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]I>C1COCC1.CCOCC>[CH2:16]1[C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]2=[O:8])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCCCCI
Reactant: O=C1CCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCCCCC12CCCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cycloheptanone (2.1 mL, 17.83 mmol) and potassium tert-butoxide (2.60 g, 23.18 mmol) in THF (10 mL) was dropwise added a solution of 1-chloro-5-iodopentane (2.74 mL, 19.61 mmol) in THF (10 mL). The mixture was stirred at ambient temperature for 16 hours. It was then diluted with ether (200 mL), washed with saturated NH4Cl and brine, dried with MgSO4, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (95:5 hexane-EtOAc, eluant) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.50 (t, 2 H), 1.55-1.79 (m, 8 H), 1.30-1.52 (m, 10 H). MS (DCI+) m/z 198 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]3)=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:28][CH:27]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Yield: 47.2 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1 g, 3.3 mmol) was reacted with tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, 5.0 mmol) to afford the desired product (720 mg, 48%) as a brown solid: ESI MS m/z 463 [C26H26N2O4S+H]+.