Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:24]=[CH:23][C:9]2[C:10](=[O:22])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]I)([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:25][CH2:26][CH3:27].[CH3:29][CH2:30][CH2:31][C:32]1[C:37]([OH:38])=[C:36]([C:39]([CH3:41])=[O:40])[CH:35]=[CH:34][C:33]=1[OH:42].C(=O)(O)[O-].[K+].Cl>CN(C)C=O.CC(C)=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:24]=[CH:23][C:9]2[C:10](=[O:22])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:33]3[CH:34]=[CH:35][C:36]([C:39](=[O:40])[CH3:41])=[C:37]([OH:38])[C:32]=3[CH2:31][CH2:30][CH3:29])([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCC(=O)OC)ccc2c1OC(C)(CCCCCCI)CC2=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCC2(C)CC(=O)c3ccc(OCC(=O)OC)c(CCC)c3O2)ccc(C(C)=O)c1O
Reaction time: 6 h
Yield: 83.4 %

Procedure:
A mixture of 1.25 g of the iodohexyl chromanone product from Example 4, 0.49 g of 2,4-dihydroxy-3-propylacetophenone, 0.841 g of anhydrous potassium bicarbonate, 25 ml of acetone, and 12 ml of N,N-dimethylformamide was refluxed and stirred for 6 hours. The resulting mixtures was cooled, poured into cold 1N hydrochloric acid, and extracted 3 times with ether. The combined ether extracts were washed with saturated aqueous sodium bicarbonate, water, and brine, then dried (magnesium sulfate), filtered and concentrated in vacuo giving 1.5 of an oil. This material was chromatographed on 45 g of silica gel. Elution with 2:1 hexane-ethyl acetate afforded 1.18 g (83.4%) of rac-[[2-[6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hexyl]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[C@H:10]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:5][CH:4]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[C@H:10]2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:25][CH:26]=1
Reactant: COC(=O)[C@H]1CC[C@H](NCc2ccc(OC)cc2)[C@@H]1c1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CC[C@H](N(Cc2ccc(OC)cc2)C(=O)OCc2ccccc2)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.1 g of methyl 3-(S)-(4-methoxybenzyl-amino)-2-(S)-(4-fluorophenyl)cyclopentane-1-(S)-carboxylate, prepared as in Example 61, in 50 mL of methylene chloride was added 1.36 mL of benzyl chloroformate and after 5 min 3.0 mL of DIPEA. After stirring at room temperature for 16 h, the reaction was poured into water containing 3 mL of 2N HCl and was extracted twice with methylene chloride. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to obtain 3.95 g of title compound as an oil. T.l.c. (10% ethyl acetate in hexanes) Rf =0.35
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:13][NH:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18].B(Br)(Br)Br.C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:14][CH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:3]2[OH:2]
Reactant: COc1cccc2c(CNCCC(C)C)cccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CCNCc1cccc2c(O)cccc12
Temperature: -78 °C
Reaction time: 16 h

Procedure:
To a solution of 5-methoxynaphthalene-1-ylmethyl(3-methylbutyl)amine (Preparation 13) (310 mg, 1.20 mmol) in DCM (15 mL) at −78° C., was added 1M BBr3 in DCM (3.61 mL, 3.61 mmol.). The reaction mixture was stirred at −78° C. for 16 h. NaHCO3 (0.5 mL) was added and the mixture partitioned between NaHCO3 (0.25 mmol) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combine organic phases washed with 1M NaOH (20 mL). The aqueous phase was acidified with 1M HCl to pH 7 and extracted with EtOAc (100 mL). The organic phase was washed with brine (25 mL) and dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=2.49 min; m/z (ES+)=244.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+:36].O>O1CCOCC1.C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][CH2:29][C:30]([O-:32])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Na+:36]
Reactant: CCOC(=O)CCCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CCCC(=O)[O-])no2)cc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
To a solution of ethyl 4-[4-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]butanoate (D65) (1.42 g, 3.09 mmol) in a mixture of dioxan (70 ml) and ethanol (70 ml) was treated with 2N sodium hydroxide (1.86 ml, 3.71 mmol) followed by water (35 ml). The solution was stirred at RT for 4 hours. Evaporated off most of the solvent and filtered off the white solid from the remaining solvent. Washed the solid with water followed by ether and dried to give 580 mg of the title compound. δH (400 MHz, methanol-d4) 1.45 (6H, d), 2.09-2.22 (4H, m), 4.30 (2H, t), 4.92-4.98 (1H, m), 7.15 (1H, d), 7.31 (1H, t), 7.38-7.43 (2H, m), 7.69 (1H, d), 7.95 (1H, d), 8.43-8.46 (2H, m). MS (ES) C24H22N4O4 requires 430; found 431 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]2[O:20][C:21]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:22][C:18]=2[CH:17]=1>CO>[N:1]1([CH2:15][C:16]2[CH:28]=[CH:27][C:19]3[O:20][C:21]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:22][C:18]=3[CH:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Solvent: CO
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc2cc(CN3CCOCC3)ccc2o1

Procedure:
A stirred solution of morpholine and triethylamine in methanol is treated with 5-bromomethyl-2-sulfamoylbenzo[b]furan to give the subject compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NCC2
Yield: 122.2 %

Procedure:
A solution of 6-nitroindoline (1 g, 6.1 mmol) in 50 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (100 mg) at rt for 3 h. Filtration over celite afforded 1.0 g (98%) of 6-aminoindoline. Data for 6-aminoindoline: 1H NMR (400 MHz, CDCl3) 7.40 (d,J=7.4, 1H), 6.05 (d,J=2.0, 1H), 6.03 (d,J=7.5, 1H), 3.67 (bs, 1H), 3.49 (t,J=8.1, 2H), 3.48 (bs, 2H), 2.90 (t,J=8.2, 2H).
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].BrCC1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1.Cl>CN(C)C=O>[CH2:21]([C:18]1[CH:19]=[CH:20][C:10]([CH2:8][CH:2]([Cl:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][CH:17]=1)[C:22]([CH3:23])=[O:24]
Reactant: CC(=O)Cc1ccc(CBr)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)Cc1ccc(CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 2-chloroacetoacetate (8.25 g) in dry dimethylformamide was treated with sodium hydride (1.3 g and stirred at ambient temperature for 0.5 h. A solution of 4-(bromomethyl)phenylpropan-2-one, ethylene ketal (12.0 g) in dry dimethylformamide (20 ml) was then added and the mixture was heated at 70° C. for 4 h. The reaction mixture was cooled, poured into ice/water, acidified with 2N-hydrochloric acid, extracted with ethyl acetate (4×50 ml) and the combined organic extracts dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was dissolved in ethanol and treated at 0°-5° C. with barium hydroxide hydrate (7.7 g). The mixture was stirred for 0.5 h, poured into ice/water, extracted with ethyl acetate (3×50 ml) and the combined organic extracts dried (magnesium sulphate), filtered and evaporated in vacuo to leave a red oil, which was purified by column chromatography on silica using diethyl ether: petroleum ether (60°-80°) (30:70) as eluent to give ethyl 3-(4-acetonylphenyl)-2-chloropropionate, ethylene ketal, (6.0 g).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=S)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][N:29]=[CH:28]1>C(O)C>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=[N:35][CH2:34][CH2:33][CH2:32][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C1c2cccc3cccc(c23)N1C(c1ccccc1)c1ccccc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: c1ccc(C(c2ccccc2)N2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1

Procedure:
A mixture of 1.0 g of 1-(diphenylmethyl)benz[cd]indole-2(1H)-thione (Cd), 0.35 g of 1H-imidazole-1-propanamine, 20 ml ethyl alcohol and 0.91 g of mercuric acetate is reacted as described in Example 3, giving the desired product, mp. 142°-143° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9]>C(Cl)Cl>[CH2:2]1[NH:1][C:8](=[O:9])[N:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC[C@@H]1CCCN1
Solvent: ClCCl
Product: O=C1NC[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.2 %

Procedure:
(S)-2-(Aminomethyl)pyrrolidine (250 mg) and carbonyldiimidazole (400 mg, 1.0 equiv.) were dissolved in DCM (50 mL). The resulting mixture was stirred at room temperature for 18 hours, then concentrated under vacuum. The residue was purified by flash column chromatography (SPE cartridge, SiO2), using DCM-methanol (95:5) as eluent to afford the title compound as colourless solid (150 mg, 50% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH2:32]([N:39]=[C:40]=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N#N>C(Cl)Cl>[CH2:32]([NH:39][C:40]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Reactant: O=C=NCc1ccccc1
Agent: N#N
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ccc(CNC(=O)NCc3ccccc3)cc2CO)C2CCCc3cccnc32)c(C)c1
Temperature: 0 °C
Yield: 91 %

Procedure:
A solution (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was cooled down to a temperature of 0° C. Benzyl isocyanate (0.03 g, 0.26 mmol) was added and the solution was stirred at 0° C. for 16 hours under a positive pressure of N2. The reaction was quenched using a saturated NaHCO3 solution (25 mL). Extract with CH2Cl2 (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a light yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 99:1, v/v) afforded the product as a white solid (0.13 g, 91%). 1H NMR (CDCl3) δ 1.38 (m, 1H), 1.89 (m, 2H), 2.04 (m, 1H), 2.09 (s, 3H), 2.19 (s, 3H), 2.47 (m, 1H), 2.67 (m, 1H), 3.49 (d, 2H, J=11.8 Hz), 3.65 (d, 2H, J=12.7 Hz), 4.06 (m, 7H), 5.94 (m, 2H), 7.04 (m, 11H), 8.10 (s, 1H), 8.17 (d, 1H, J=3.9 Hz); 13C NMR (CDCl3) δ 18.28, 18.48, 21.06, 21.90, 29.63, 44.07, 44.23, 53.89, 54.05, 54.33, 57.51, 62.87, 122.05, 127.01, 127.57, 128.60, 130.86, 131.33, 132.27, 133.57, 134.94, 136.03, 137.01, 139.35, 140.11, 140.30, 142.03, 146.55, 146.87, 153.54, 156.99, 159.26; HPLC (98.05%); ES-MS m/z 550 (M+H). Anal. Calcd. for (C34H39N5O2) 0.1(CH2Cl2): C, 73.37H, 7.08 N, 12.55. Found: C, 72.95H, 7.07 N, 12.43.
Reaction SMILES: [C:1]1([SH+]C2C=CC=CC=2)C=CC=C[CH:2]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[O:19]>O1CCCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]1[O:19][CH:1]1[CH3:2]
Reactant: c1ccc([SH+]c2ccccc2)cc1
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C2OC2C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) in tetrahydrofuran (one liter) is slowly added 2,5-dimethoxybenzaldehyde (1.0 mole). The reaction mixture is stirred at -78° C. for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether phase separated. The ether phase is washed with water, dried (MgSO4) and evaporated. Fractional distillation of the residue gives the title product.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].C(N1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(OCC)=O.O1CCCC1>O>[C:21]1(=[O:30])[N:2]([CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) in water (60 ml) was brought to pH 8 with aqueous sodium bicarbonate solution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was added followed by tetrahydrofuran (until homogenous solution was obtained). The clear solution was stirred at room temperature overnight. During this time a white solid was precipitated. The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate until the solution was clear. The ethyl acetate extracts were combined, washed with water, dried (MgSO4) and concentrated to give 4-phthalimido cyclohexanol as a white solid (7.1 g).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: C1CNCCN1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 170 mg of N,N-dimethylformamide were added 50 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of piperazine, and the mixture was stirred at 90° C. for 1 hour. After adding about 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively-to obtain 33 mg of the title compound as a colorless powder.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[NH:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12
Reactant: N#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)C(F)(F)F)[C@H]1C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1)[C@H]1CCCN[C@H]1C2

Procedure:
A solution of cis-1-(2,2,2-trifluoroacetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (5.50 g) and 4 M NaOH solution (5.6 mL) in methanol (30 mL) is stirred at room temperature for 2 h. Brine (150 mL) is then added and the resulting mixture is extracted with ethyl acetate (3×75 mL). The combined extract is dried (MgSO4) and concentrated to give the title compound as an oil that solidified upon standing. Yield: 3.70 g (quantitative); Mass spectrum (ESI+): m/z=295 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([NH:21][CH:22]([CH3:24])[CH3:23])[CH3:20]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:21]([CH2:19][CH3:20])[CH:22]([CH3:24])[CH3:23])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CCNC(C)C
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)C(C)C)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 33.9 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 87 mg of N-ethylisopropylamine, followed by stirring at 60° C. for 7 hours. Then, 166 mg of potassium carbonate and 435 mg of N-ethylisopropylamine were added, and the mixture was stirred at 80° C. for 8 hours. Then, 166 mg of potassium carbonate and 435 mg of N-ethylisopropylamine were added, and the mixture was stirred at 120° C. for 5 hours. The reaction mixture was then left for cooling to room temperature and subjected to phase separation three times between ethyl acetate and an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to preparative silica gel thin layer chromatography to give 79 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-isopropylamino)pyrimidine (the present compound (105)).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,4-Dichloro-benzoic acid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1O[C:6](=[O:8])[CH2:5][CH2:4]1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.Cl>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]2[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]2=[O:8])=[CH:12][CH:11]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C1CC[C@H](CO)N1c1ccc(F)cc1
Yield: 109.8 %

Procedure:
To (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (500 mg, 4.31 mmol), 4-fluoroaniline (574 mg, 5.17 mmol) was added and the resultant mixture was stirred at 150° C. for 3 days. After completion of the reaction, chloroform and hydrochloric acid were added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound (990 mg).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)([CH3:6])[C:3](O)=[O:4].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+].[N:47]1C=CC=CC=1>C(OCC)(=O)C.O1CCOCC1.CN(C=O)C>[CH3:15][C:14]([S:16]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:17])=[O:18])([CH3:25])[C:13]([NH:12][C:10]1[O:9][N:8]=[C:7]([C:2]([CH3:6])([CH3:1])[C:3]([NH2:47])=[O:4])[CH:11]=1)=[O:26]
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C(N)=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.6 %

Procedure:
To a solution of 2-methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (35 mg, 0.09 mmol), di-tert-butyl dicarbonate (26 mg, 0.12 mmol), and ammonium bicarbonate (14 mg, 0.18 mmol) in the mixture of DMF (0.035 mL) and 1,4-dioxane (0.5 mL) is added pyridine (0.022 mL, 0.27 mmol). The reaction mixture is stirred at room temperature for 1.5 h. After this time, the reaction mixture is diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC provides 3.0 mg of the title compound. Yield: 9%; m/z 388 [M+H].
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH3:8][N:9]([CH3:20])[N:10](C1C=CC=CC=1)[C:11](=O)[O-:12]>N1C=CC=CC=1>[Br:1][CH:2]1[CH2:6][CH2:5][N:4]([C:11](=[O:12])[NH:10][N:9]([CH3:20])[CH3:8])[C:3]1=[O:7]
Reactant: CN(C)N(C(=O)[O-])c1ccccc1
Reactant: O=C1NCCC1Br
Solvent: c1ccncc1
Product: CN(C)NC(=O)N1CCC(Br)C1=O
Yield: 63.7 %

Procedure:
Substantially in the same manner as in Example 39 (1), 8.2 g (50 mmol) of 3-bromopyrrolidin-2-one and 9.91 g (55 mmol) of N-dimethylaminophenylcarbamate in 100 ml of pyridine were treated to give 7.96 g of the objective compound as white crystal in 63.6% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH2:24][OH:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH:24]=[O:25])=[CH:14][CH:13]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(CO)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
To a solution of 4 tert-butyl(4-butoxy-2-cyclopropylmethyl-6-hydroxymethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.45 g, 3.5 mmol) in tetrahydrofuran (10 mL) was added manganese dioxide (0.12 g) and the mixture was stirred at room temperature for 12 h. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.33 g, 76.7%) as crystals.