Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)(=O)=O)=CC=1.[CH2:24]1[CH:28]2[CH2:29][NH:30][CH2:31][CH:27]2[CH2:26][N:25]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:30]2[CH2:29][CH:28]3[CH2:24][N:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][CH:27]3[CH2:31]2)=[CH:21][CH:20]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCCNc3ccc(C#N)cc3)CC2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
3-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate (1.98 g, 6 mmol; see step (b) above), and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.49 g, 6 mmol; see Preparation A above) was mixed with K2CO3 (1.93 g, 14 mmol) and CH3CN (100 mL) and then stirred at 50° C. overnight. The solvent was evaporated and the product was purified by chromatography on silica (DCM:MeOH (20:1)) to give 1.83 g (82%) of the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1.CCOC(C)=O>CSC>[CH3:21][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a suspension of p-aminophenylacetic acid (56.8 g, 376 mmol) in DMS (150 mL) was added o-tolyl isocyanate (50 g, 376 mmol) dropwise. The reaction mixture was allowed to stir 1 h, and was poured into EtOAc (1.75 L) with stirring. The precipitate was collected and washed with EtOAc (400 mL) and MeCN (400 mL) to provide oMePUPA (80 g, 75%). ESMS m/z (M+H+) 285.1.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)(=[O:25])=[O:24])=[CH:15]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCCl>[Cl:32][C:28]1[CH:27]=[C:26]([S:23]([C:16]2[C:17]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:14]([CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[CH:15]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)c1cn(CC2CCCN2Cc2ccccc2)c2ncccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=S(=O)(c1cccc(Cl)c1)c1cn(CC2CCCN2)c2ncccc12
Temperature: 25 °C
Yield: 68 %

Procedure:
A stirred solution of 1-[(1-benzyl-pyrrolidin-2-yl)methyl]-3-(3-chlorophenyl -sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.812 g, 1.74 mmol) in 1,2-dichloroethane under a nitrogen atmosphere is treated with 1-chloroethylchloroformate (0.47 mL, 4.35 mmol), heated at reflux temperature until the disappearance of starting material by thin layer chromatography (3 h), cooled and concentrated in vacuo. The resultant residue is dissolved in CH2Cl2 and re-evaporated twice. This residue is dissolved in ethanol, heated at reflux temperature for 1.5 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine, and concentrated in vacuo. The final residue is purified by flash column chromatography (10-15% methanol in CH2Cl2 as eluent) to afford the title compound as an oil, 443 mg (68% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].[H-].[Na+].[CH3:23]I>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]=1[C:17]([F:20])([F:18])[F:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(F)(F)F)[nH]c2cc(OC)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C(F)(F)F)n(C)c2cc(OC)ccc12
Yield: 87.4 %

Procedure:
This material was prepared from 6-methoxy-2-trifluoromethyl-1H-indole-3-carboxylic acid ethyl ester 76d (1.64 g, 5.7 mmole) by treatment with NaH (274 mg, 60% in mineral oil, 6.84 mmole) and methyl iodide (1.21 g, 8.55 mmole) and NaH in a manner as previously described for example 16b to give 1.5 g product (87% yield). 1H NMR (300 MHz, CDCl3) δ 7.96 (1H, dd, J=3.7, 8.8 Hz), 6.94 (1H, dd, J=2.3, 9.1 Hz), 6.77 (1H, d, J=2.1 Hz), 4.40 (2H, m), 3.89 (3H, s), 3.86 (3H, s), 1.41 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cccc(-c2cccc3c2OC(CN)C3)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c1
Yield: 58.8 %

Procedure:
Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.76 g, 6.38 mmol) with diisopropylethylamine (2.47 g, 19.17 mmol) followed by benzyl chloroformate (1.19 g, 7.02 mmol) generally according to the procedure described for Intermediate 12 provided 1.4 g (58%) of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil. Rf=0.68 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C24H23NO3: C, 77.19; H, 6.20; N, 3.75. Found: C, 76.88H, 6.25; N, 3.51. Chiral HPLC separation of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=10.439 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (Rt=11.833 min, Chiralpak AD ethanol:hexane 1:1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:28]1[N:29]([CH2:36][C@:37]2([CH3:40])[CH2:39][O:38]2)[CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[N:32]=1>CN(C=O)C>[CH3:39][C@@:37]1([CH2:40][O:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)=[CH:17][CH:18]=2)[O:38][C:28]2=[N:32][C:31]([N+:33]([O-:35])=[O:34])=[CH:30][N:29]2[CH2:36]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
4-[4-(4-Trifluoromethoxyphenyl)piperazin-1-yl]phenol (1.7 g, 5.02 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (221 mg, 5.53 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (1.2 g, 5.53 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then recrystallized from ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (1.02 g, yield 39%) as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.O1CCOCC1>[CH2:20]([O:27][C:28]([NH:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc[nH]c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
To a mixture of 3-aminopyrid-2-one (24.6 g, 0.223 mol), sodium carbonate (52.1 g, 0.492 mol), THF (250 mL) and 1,4-dioxane (50 mL) was added dropwise benzyloxycarbonyl chloride (35.1 mL, 0.246 mol). The resulting mixture was stirred at room temperature for 15 h. Ethyl acetate (1200 mL) was added and the mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine. After filtering off insolubles, the filtrate was dried over anhydrous magnesium sulfate. The residue obtained by concentration of the extract solution was recrystallized from methanol-ethyl acetate (6:1) to give 21.5 g of 3-benzyloxycarbonylaminopyrid-2-one as colorless crystals. The insolubles obtained were dissolved in chloroformmethanol (10:1), and then washed with saturated brine. The aqueous layer was further extracted with chloroform, and combined with the organic layer obtained earlier. The combined extracts were dried over anhydrous magnesium sulfate. Evaporation of the solvent further afforded 16.7 g (total yield 70%) of the same product as a colorless solid.
Reaction SMILES: P([O-])([O-])(O)=O.[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Br[CH2:26][CH3:27]>O.CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:26]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH3:27]
Reactant: CCBr
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])O
Agent: O=S([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of sodium hydrogen phosphate (14.2 g, 0.1 mol) and sodium sulfite (25.2 g, 0.2 mol) in water (200 mL) was added 4-fluoro-benzenesulfonyl chloride (19.5 g, 0.1 mol). After the mixture was stirred at 60° C. overnight, a solution of bromoethane (32.7 g, 0.3 mol) in acetone (20 mL) was added dropwise, followed by the addition of tetrabutylammonium iodide (3.7 g, 0.01 mol) in one portion. The resulting reaction mixture was stirred at room temperature for 5 days, then diluted with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (elution with 20% ethyl acetate in petroleum ether) to afford 1-ethanesulfonyl-4-fluoro-benzene (11.9 g, 63%) as a yellow oil (reference: Arnold, Leggy A. A., et al., Org. Lett, 6 (2004), 3005-3007).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=2)=[CH:11][C:10]1=[O:25])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
A mixture of (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.86 g, 2.32 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was treated with lithium hydroxide monohydrate (0.12 g, 2.85 mmol). The reaction was stirred at 25° C. for 3 h. At this time, the reaction was diluted with water (75 mL) and extracted with diethyl ether (1×75 mL). The aqueous layer was acidified with a 2N aqueous hydrochloric acid solution and then extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo to afford (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.71 g, 86%) as a light orange solid: HR-ES-MS m/z calculated for C17H18NO4F3 [M+H]+ 358.1261, observed 358.1262. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H), 1.50 (m, 1H), 1.57-1.70 (m, 1H), 1.70-1.86 (m, 1H), 4.16 (d, J=17.9 Hz, 1H), 4.28 (d, J=17.9 Hz, 1H), 4.64 (dd, J=11.6, 4.2 Hz, 1H), 4.93 (s, 1H), 7.65-7.77 (m, 4H), 12.88 (br. s., 1H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][SH:14]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:12])[S:14][CH3:13])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N=C=O)on1
Reactant: CS
Product: CSC(=O)Nc1cc(C(C)(C)C)no1

Procedure:
Using 3-t-butyl-5-isoxazolyl isocyanate and methyl mercaptan, the reaction is effected as in Synthetic Example 17, whereby S-methyl 3-t-butyl-5-isoxazolylthiocarbamate is obtained as crystals melting at 104.0° to 105.5° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:33][CH2:34][CH3:35])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([O:31]C)=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11]CC)=[O:10])([CH3:3])=[CH2:2].O.[OH-].[Li+]>O1CCOCC1.O>[C:1]([C:4]1[N:5]=[C:6]([CH2:33][CH2:34][CH3:35])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([OH:31])=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:8]=1[C:9]([OH:11])=[O:10])([CH3:3])=[CH2:2]
Reactant: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3C(=O)C(=O)OC)cc2)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3C(=O)C(=O)O)cc2)c1C(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.2 %

Procedure:
A solution of 279 mg of ethyl 4-isopropenyl-1-[(2'-methoxalylbiphenyl-4-yl)methyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] dissolved in 3 ml of dioxane was mixed with a solution of 123 mg of lithium hydroxide monohydrate dissolved in 3 ml of water, and the resulting mixture was stirred at 80° C. for 5 hours. At the end of this time, the dioxane was removed by distillation under reduced pressure, and 2.94 ml of 1N aqueous hydrochloric acid were added to the residual aqueous solution. The crystals which precipitated were collected by filtration, to give 214 mg of the title compound, melting at 150°-151° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:7]=1[C:8]#[N:9])(=[O:5])=[O:4])[CH3:2].[C:17](O)(=[O:19])[CH3:18].C(OC(=O)C)(=O)C>[Fe]>[C:8]([C:7]1[CH:10]=[C:11]([NH:14][C:17](=[O:19])[CH3:18])[CH:12]=[CH:13][C:6]=1[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])#[N:9]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(=O)O
Agent: [Fe]
Solvent: CC(=O)OC(C)=O
Product: CCS(=O)(=O)c1ccc(NC(C)=O)cc1C#N
Temperature: 100 °C
Yield: 83 %

Procedure:
To 5B (3.60 g, 15.0 mmol) in 1:1 acetic acid/acetic anhydride (150 mL), Fe (4.20 g, 75.2 mmol) was added. The reaction mixture was heated to 100° C. for 2 h then poured into ice. After the ice melted, the product was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated to provide 5C (3.14 g, 83%). LC-MS: 241.18 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CC(C)=O>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:20][CH:22]2[CH2:23][O:24]2)=[CH:3][CH:4]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(OCC2CO2)cc1

Procedure:
5 g of 4-hydroxybenzotrifluoride, 12.8 g of potassium carbonate, 500 mg of potassium iodide and 18 g of epichlorohydrin are stirred in 75 ml of acetone for 15 hours at 60° C. The reaction mixture is filtered and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed with water. After concentration of the organic phase and Kugelrohr distillation, 2-(4-trifluoromethyl-phenoxymethyl)-oxirane is obtained. (b.p.20 145-150° C.)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl.[I-:21].[Na+]>CCOCC>[I:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2c(I)ccnc2c1
Reaction time: 0.25 h

Procedure:
The general procedure is described in Drake, N. L.; Creech, H. J.; Garman, J. A.; Haywood, S. T.; Peck, R. M.; Van Hook, J. O.; Walton, E., Synthetic antimalarials. The preparation of certain 4-aminoquinolines. Journal of the American Chemical Society 1946, 68, 1208-13. A dry 250 mL, 1-neck round bottomed flask was charged with 4-chloro-7-methoxyquinoline (1.77 g, 9.1 mmol), and 100 mL dry dioxane. The solution was treated with 20 mL 1N HCl in Et2O. The solution was occasionally swirled over a 15 minute period, and the solvent was removed in vacuo. The residue was dried at 60° C. at 0.1 mmHg for 2 h. To the flask was added a stir bar and 20 mL dry acetonitrile. The flask was fitted with a reflux condenser, and to the stirring slurry was added sodium iodide (4.1 g, 27 mmol). The solution was heated to reflux for 48 h. The solution was cooled, and the solution was filtered. The precipitate was washed with ACN (3×20 mL), and water (3×20 mL). The solid was suspended in 70% CH2Cl2-30% MeOH. To the solution was added Si-carbonate (16 g, 11 mmol). The slurry was swirled for 1 h, and filtered. The silica was washed with EtOH (3×50 mL). The solvent was removed in vacuo to afford 4-iodo-7-methoxyquinoline. 1H NMR (300 MHz, MeOD) δ ppm 4.00 (s, 3 H) 7.35 (dd, J=10.01, 2.48 Hz, 1 H) 7.36 (d, J=2.56 Hz, 1 H) 8.00 (d, J=9.87 Hz, 1 H) 8.01 (d, J=4.75 Hz, 1 H) 8.33 (d, J=4.90 Hz, 1 H). 13C NMR (101 MHz, MeOD) δ ppm 56.46 (s, 1 C) 107.73 (s, 1 C) 113.18 (s, 1 C) 122.61 (s, 1 C) 127.31 (s, 1 C) 132.05 (s, 1 C) 134.27 (s, 1 C) 150.18 (s, 1 C) 150.86 (s, 1 C) 163.35 (s, 1 C). MS (ESI pos. ion) m/z (MH+): 286.0, calcd for C10H8INO+H+=286.0.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([CH:20]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:28][CH:27]=2)[CH2:21][CH2:22][CH3:23])[CH3:19]>>[CH3:17][CH:18]([CH:20]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:28][CH:27]=2)[CH2:21][CH2:22][CH3:23])[CH3:19]
Reactant: CCCC(c1cc2cc(/C(C)=C/C(=O)O)ccc2[nH]1)C(C)C
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCC(c1cc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc2[nH]1)C(C)C

Procedure:
0.93 g of compound 21 was obtained in a similar manner to those described in the Examples 1 and 2 using 2.20 g of ethyl 4-(2-aminophenoxy)butyrate and 1.50 g of 3-[1-(1-methylethyl)butylindol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:13][NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1.C(OCC)(=O)C.O>ClCCl>[CH3:1][S:2]([O:20][CH:18]([CH2:17][CH2:16][C:15]([NH:14][N:13]=[C:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21])[CH3:19])(=[O:4])=[O:3]
Reactant: CC(O)CCC(=O)NN=C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CCC(=O)NN=C(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
At 0° C., 0.25 ml (3.2 mmol) of methanesulphonyl chloride is added dropwise to a solution of 0.64 g (2.2 mmol) of N′-(diphenylmethylene)-4-hydroxypentane hydrazide, 0.19 ml (2.4 mmol) of pyridine and 0.01 mg of N—N-dimethylaminopyridine in 5 ml of dichloromethane. The reaction mixture is stirred at room temperature for 2 h, and ethyl acetate/water is then added. The organic phase is separated off and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 0.38 g (44% pure) of 5-[2-(diphenylmethylene)hydrazino]-5-oxopentan-2-yl methanesulphonate; (log P(HCOOH): 2.82 with LC-MS: m/z=375 [M+]+). The product is taken up again in 2 ml of tetrahydrofuran, and 0.04 g (1.0 mmol) of sodium hydride is added at 0° C. After 16 h of stirring at room temperature, ethyl acetate/saturated aqueous NH4Cl solution is added, the organic phase is separated off and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. This gives 0.21 g (61%) of the desired product; (log P(HCOOH): 2.73); 1H-NMR (ppm): δ (DMSO-d6)=1.22 (d, 3H), 2.05-2.15 (m, 4H), 3.86 (sextet, 1H), 7.24-7.26 (m, 2H), 7.40-7.43 (m, 4H), 7.48-7.53 (m, 4H); LC-MS: m/z=279 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:19](=O)([O-])[O-:20].[Na+].[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:19]=[O:20])[CH:8]=2)[N:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCN1c2ccccc2CC1(C)C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCN1c2ccc(C=O)cc2CC1(C)C
Temperature: 80 °C
Yield: 36.1 %

Procedure:
To 2,2-dimethyl-N-n-heptylindoline (12.5 g) in dimethylformamide (100 cm3) phosphorus oxychloride (15.3 g) was added at 5° C. before heating the mixture at 80° C. for 2-5 hours. The reaction mixture was cooled, poured onto ice, neutralised with solid sodium carbonate and extracted into toluene. The toluene was washed with water, separated, dried over magnesium sulphate, filtered and evaporated to leave an oil. The oil was eluted from silica using dichloromethane as eluent, evaporation of the solvent gave 2,2-dimethyl-5-formyl-N-n-heptylindoline (4.9 g, 36.1%).