Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:27]([C:26]1([NH:25][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:11][C:10]([CH3:22])([CH3:23])[C:9]4[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([Cl:24])[CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:31][CH2:30]1)([OH:29])=[O:28]
Reactant: CC(C)(N)C(=O)O
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (408.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-carboxy-cyclopropylamino)-phenyl]-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (78.6 mg, 18.9%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 417.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=3)[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.[NH2:22][OH:23]>>[OH:23][NH:22][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][N:10]2[CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: COc1ccc(Cn2ccc3ccc(C(=O)O)cc32)cn1
Reactant: NO
Product: COc1ccc(Cn2ccc3ccc(C(=O)NO)cc32)cn1

Procedure:
1-((6-Methoxypyridin-3-yl)methyl)-1H-indole-6-carboxylic acid was activated and coupled with NH2OH as described in Example 4, Step 3 to provide N-hydroxy-1-((6-methoxypyridin-3-yl)methyl)-1H-indole-6-carboxamide as a tan solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)([O-:27])=[O:26].[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:40][C:41]1[C:42]([C:51]([F:53])([F:52])[F:54])=[N:43][N:44]([CH2:47][C:48]([N:37]2[CH2:38][CH2:39][N:34]([C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=3)[CH2:35][CH2:36]2)=[O:49])[C:45]=1[CH3:46]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Nitrophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) 8.05 (d, 2H), 7.01 (d, 2H), 5.38 (s, 2H), 3.62 (m, 6H), 3.52 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H=432.1, found=432.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][CH:7]=[N:8][C:9](=O)[C:10]=2[N:11]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1nc[nH]c2ccc(Cl)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2ncnc(Cl)c2n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one (150 mg, 0.83 mmol) in POCl3 (2.0 mL) was added DIPEA (0.22 mL, 1.24 mmol) at room temperature. After stirring for 1 hour at 110° C., the reaction mixture was cooled to room temperature. The reaction mixture was concentrated in vacuo, and then diluted with water and extracted with dichlormethane. The combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=10:1) to give 4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 73%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.87 (1H, d, J=8.8 Hz), 8.35 (1H, d, J=8.8 Hz), 9.14 (1H, s).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C[O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([Cl:20])[N:11]=1)=O>C(O)C.C1COCC1>[CH3:19][O:18][C:16](=[O:17])[C:13]1[CH:14]=[CH:15][C:10]([CH2:8][OH:7])=[N:11][C:12]=1[Cl:20]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Cl)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(CO)nc1Cl
Reaction time: 1 h
Yield: 69.2 %

Procedure:
A cold (0° C.) suspension of calcium chloride (19.54 g, 176 mmol) and sodium borohydride (4.18 g, 110 mmol) in anhydrous ethanol (176 mL) and anhydrous THF (88 mL) was stirred for 1 hour, after which 6-chloro-pyridine-2,5-dicarboxylic acid dimethyl ester (9.97 g, 44 mmol) was added. After stirring at 0° C. for a further 6 hours, the reaction was quenched by the addition of H2SO4 (35 mL, 5M). The reaction mixture was diluted with ethyl acetate and filtered through Celite®. The filtrate was washed with 1M NaOH, water and brine, the organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in hexane) to afford the title compound as a yellow oil (6.14 g, 69%). LCMS (method B): RT=2.34 min, [M+H]+=202.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].[C:11]([O:15][C:16](=[O:44])[NH:17][C:18]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:31]([N+:40]([O-:42])=[O:41])=[C:30](Cl)[N:29]=3)=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].[NH4+].[Cl-]>CS(C)=O>[C:11]([O:15][C:16](=[O:44])[NH:17][C:18]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:10]([N+:7]([O-:9])=[O:8])=[C:30]([CH2:31][N+:40]([O-:42])=[O:41])[N:29]=3)=[CH:24][CH:23]=2)[CH2:19][CH2:20][CH2:21]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(Cl)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CCC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(C[N+](=O)[O-])c([N+](=O)[O-])cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of potassium tert-butoxide (468 mg, 4.17 mmol) in dry DMSO (20 ml) was slowly added nitromethane (225 ul, 4.17 mmol) under nitrogen. The resulting mixture was stirred for 15 min at room temperature before tert-butyl(1-(4-(6-chloro-5-nitro-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (1 g, 2.08 mmol) was added. The resulting mixture was stirred for 1 hour at room temperature. A saturated solution of NH4Cl was added and the mixture was extracted with AcOEt (3×50 ml). The combined organic phases were washed with water (3×20 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was used directly without purification. 1H NMR (500 MHz, CDCl3): 8.60 (1H, s), 7.44-7.35 (7H, m), 7.30-7.28 (2H, m), 6.21 (2H, s), 5.09 (1H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br).
Reaction SMILES: [ClH:1].[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[ClH:1].[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:9]2[CH2:10][CH2:11][C@H:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:8]2)=[O:24])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cc2ccccc2)cc1)N1CC[C@H](N2CCCC2)C1
Reaction time: 16 h

Procedure:
A mixture of the HCl salt of 3-(pyrrolidino)pyrrolidine (0.44 g, 2.1 mmol) and 4-benzyl benzoic acid (0.34 g, 1.6 mmol) CH2Cl2 is treated sequentially at room temperature with 0.85 mL of triethylamine and solid benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.2 g, 2.4 mmol), stirred for 16 h under nitrogen, diluted with CH2Cl2, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The concentrate is chromatographically purified. The purified material is treated with ethereal HCl to afford the title compound, identified by H1 NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([CH3:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)C.CCCCCC>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([CH3:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: 5 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 8.3 g (26 mmol) of ethyl 2-(2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate in 30 mL of absolute ethanol at 5° C. was added 1.64 g (29 mmol) of cyclopropylamine. The reaction mixture was stirred at 5° C. for 90 minutes and at room temperature for 2 hours. The solution was concentrated to give a brown oil which was dissolved in hexane and reconcentrated to give a tan solid. Recrystallization from hexane gave 7.2 g of colorless crystals, mp 69°-72° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C:8]2[CH:15]=[C:14]([C@:16]3([O:34][C@H:33]([CH2:35][O:36]C(=O)C)[C@@H:28]([O:29]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@H:18]3[O:19]C(=O)C)[OH:17])[C:13]([O:40]C)=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1)[CH3:2].Cl.[NH+]1C=CC=CC=1>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[CH:15]=[C:14]([C@:16]3([O:34][C@H:33]([CH2:35][OH:36])[C@@H:28]([OH:29])[C@H:23]([OH:24])[C@H:18]3[OH:19])[OH:17])[C:13]([OH:40])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:42][CH:43]=1)[CH3:2]
Reactant: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(OC)cc2C#N)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)cc2C#N)cc1
Temperature: 215 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-ethylbenzyl)-5-methoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile (0.80 g) and pyridinium hydrochloride (9.0 g) is heated at 215° C. for 1 h. After cooling to ambient temperature, water is added and the resulting solution is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is removed under reduced pressure. The residue is dissolved in methanol (10 mL) and treated with 4 M aqueous NaOH solution (2.2 mL). The solution is stirred at room temperature for 1 h and then acidified using hydrochloric acid (4 mol/L). After removal of the organic solvents, the residue is extracted with ethyl acetate, the combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by HPLC on reversed phase (YMC C18, acetonitrile/water).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20]>C(=S)=S>[Cl:5][CH2:6][C:7]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:20])[C:11]2([CH3:21])[CH3:10])=[O:8]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)C(=O)Nc2ccc(C(=O)CCl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.1 %

Procedure:
To ice-cooled carbon disulfide (77 ml) were added anhydrous aluminum chloride (61.2 g) and chloroacetyl chloride (36.5 g), and then 2,3-dihydro-3,3-dimethylindol-2-one (24.6 g) was added thereto. The mixture was stirred for 10 minutes at ambient temperature and for 4 hours at 35° to 40° C. The solvent was removed by decantation and to the residue was added ice-water. The resulting crystal was collected, washed with water and dried to give 5-chloroacetyl-2,3-dihydro-3,3-dimethylindol-2-one (37.39 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:11](O)(=O)=O>C(O)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [O-][I+2]([O-])O
Reactant: Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Product: Nc1ccc(I)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5.00 g (36.4 mmole) of 2-aminobenzoic acid, 100 ml of acetic acid and 3.56 g (14.0 mmole) of molecular iodine, 2.12 g (8.4 mmole) of a 70% by weight aqueous solution of iodic acid was added dropwise. After the reaction mixture was stirred at the room temperature for 3 hour, the reaction mixture was analyzed in accordance with the high performance liquid chromatography. The results of the reaction are shown in Table 1. It was shown by the values obtained by the analysis of the reaction mixture that the yield of 2-amino-5-iodobenzoic acid was 60% as calculated based on the amount of iodine atom (this result is shown in the parenthesis since this result is different from the yield of the isolated product). A relatively great conversion was obtained when iodic acid of the oxidizing agent was used as the iodinating agent. However, it was difficult that the selectivity of the object product as great as that obtained by using hydrogen peroxide was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: OCCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCNCC4)n3)ccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCN(CCCO)CC4)n3)ccc21

Procedure:
88 mg (0.25 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazine are irradiated in the microwave at 140° C. for 2 h with 42 μl (0.50 mmol) of 3-chloropropan-1-ol in 2 ml of ethanol and 70 μl (0.50 mmol) of triethylamine. The reaction mixture is evaporated and purified by means of preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:18]([N:20]([CH2:42][CH3:43])[C@H:21]1[CH2:24][C@H:23]([CH2:25][N:26]2[C:34]3[C:29](=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=[C:32]([I:35])[CH:33]=3)[C:28](=[O:40])[C:27]2=[O:41])[CH2:22]1)[CH3:19].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:28]1([OH:40])[C:29]2[C:34](=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[C:36]([F:38])([F:39])[F:37])[N:26]([CH2:25][C@H:23]2[CH2:22][C@H:21]([N:20]([CH2:18][CH3:19])[CH2:42][CH3:43])[CH2:24]2)[C:27]1=[O:41]
Reactant: Fc1cc(F)cc(F)c1
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(=O)c3c2cc(I)cc3C(F)(F)F)C1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cc(F)cc3F)c3c2cc(I)cc3C(F)(F)F)C1
Reaction time: 0.5 h

Procedure:
A solution of 1,3,5-trifluorobenzene (318 mg, 2.41 mmol) in tetrahydrofuran (6.0 mL) was cooled to 78° C. under nitrogen, and thereto was added dropwise 2N lithium diisopropylamide (1.53 mL, 3.06 mmol), and the mixture was stirred for 30 minutes, Then, thereto was added dropwise a solution of the compound of Example 1-1 (650 mg, 1.34 mmol) in tetrahydrofuran (16 mL), and the mixture was stirred at −78° C. for 3 hours. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate, dried over magnesium sulfate and filtered. The filtrate was evaporated and purified by silica gel column chromatography (hexane/ethyl acetate/ammonia water=50/1/0.25 to 30/1/0.16 to 20/1/0.1) to give the titled compound (223 mg, 27%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>>[O:26]1[CH2:25][CH:24]1[CH2:22][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:6]
Reactant: O=C(NCCO)NCc1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCO)NCc1ccccc1OCC1CO1
Reaction time: 6 h

Procedure:
A mixture of 29.2 g of N-(2-hydroxyethyl)-N'-(2-hydroxybenzyl)urea, 440 ml of epichlorohydrin and 38.9 g of potassium carbonate is stirred for 6 hours at 90°. The solids are then suction-filtered whilst hot, washed with acetonitrile and the filtrate is concentrated by evaporation in vacuo. The oil remaining crystallises when left to stand and is recrystallised from 320 ml of ethyl acetate, with carbon treatment. The resulting epoxide melts at 96°-99°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])O.[Na+].[C:15]([C:17]1([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](Cl)=[O:24])[CH2:19][CH2:18]1)#[N:16]>O1CCCC1>[C:15]([C:17]1([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[CH3:8])=[O:24])[CH2:18][CH2:19]1)#[N:16]
Reactant: Cc1ccc(O)cc1N
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a two-layer solution of 3-amino-4-methylphenol (5.92 g, 48.0 mmol) in tetrahydrofuran (40 mL)/1N aqueous sodium hydrogencarbonate solution (54 mL) was added a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hr. Since the reaction mixture showed pH 4-5, sodium hydrogencarbonate (900 mg, 10.7 mmol) was added to adjust the pH to 8-9, and the reaction mixture was further stirred at room temperature for 1 hr. The aqueous layer was separated, and extracted with ethyl acetate (150 mL). The combined organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained suspension was added ethyl acetate (25 mL)/hexane (50 mL), and the mixture was stirred at room temperature for 20 min. The precipitate was collected by filtration, repeatedly washed with diisopropyl ether/hexane (1:1) and air-dried to give the title compound (12.2 g, 87%) as a pale-yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][NH:10][C:23]([NH:22][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[S:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(CN)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(CNC(=S)NC(=O)c1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of (2-amino-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester [CAS 320581-09-7] (43.9 g) and benzoyl isothiocyanate (31.8 ml) in THF (400 ml) was stirred at 60° C. overnight. The mixture was concentrated. Small amounts of toluene were added. Insoluble parts were filtered off and the remaining solution was concentrated. The residue was disolved in ethyl acetate and extracted with brine. The organic layer was dried (MgSO4) and evaporated. Crystallisation of the obtained residue in toluene and hexane provided 53.0 g of white crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].[C:14]([CH:16]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]=[CH:40][N:41]([CH3:43])[CH3:42])(=[O:38])=[O:37])=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]>CC(C)=O>[C:14]([CH:16]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]=[CH:40][N:41]([CH3:42])[CH3:43])(=[O:38])=[O:37])=[CH:26][CH:25]=1)[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)C(C#N)NCc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1)C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.53 g of potassium carbonate and 3.33 ml of valeryl chloride were added to a solution of 1 g of the product of Stage C in 200 ml of dry acetone. After stirring for 20 hours at ambient temperature, the solution was filtered and dried. Purification was carried out by chromatography with dichloromethane-ethyl acetate 85-15 to obtain 11.6 g of the expected product as a white solid with a
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:16]4[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]12[C:14]3[C:10](=[CH:9][C:8]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=4)=[CH:7][C:6]=3[CH2:5][CH2:4][CH2:3]1)[CH2:11][CH2:12][CH2:13]2
Reactant: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4(C)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCCc3cc(Nc4ccc(C(=O)O)cc4)cc(c31)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A suspension of ethyl 4-[(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.250 g) in ethanol (15 ml) was added with 20% aqueous sodium hydroxide (5 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.185 g, yield: 80%) as pale brown needles (melting point: 232-234° C.).