Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC[C@H](C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
4.0 g of p-hydroxybenzoic acid and 12.5 g of (S)-(-)-2-methylbutanol were refluxed for 6 hours in toluene in the presence of sulfuric acid, while the generated water was removed out. Subsequently, the reaction solution was washed with water to remove sulfuric acid out. After the resulting solution was dried and concentrated, the concentrate was purified by column chromatography to obtain 5.0 g of the objective ester compound (liquid state at room temperature, [α]D23 =+4.9° (CHCl3)). (Yield: 83%)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([OH:28])([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cncnc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
n-Butyl lithium (2.5 M, 1.8 mL, 4.5 mmol) was added dropwise to a solution of 5-bromo-pyrimidine (0.668 g, 4.2 mmol) in THF (10 mL), under nitrogen at −78° C. and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) in THF (5 mL) was added dropwise at −78° C. and the reaction mixture warmed to room temperature over 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10% methanol/ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). LCMS m/z 306 [M+H]+. R.T.=2.89 min (Analytical Method 3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](OC(=O)C(C)(C)C)[N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7][N:6]=1
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21
Reactant: O=C(Cl)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1ccncc1
Yield: 104.1 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) was coupled with isonicotinoyl chloride (0.4 mmol) (Aldrich, Milwaukee, Wis.) and triethylamine in DCM at 0° C. to give 120 mg of the titled compound as a light yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.IC.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1([CH2:16][N:17]([CH3:27])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCC1(CC2OCCO2)CCc2ccccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CC1(CC2OCCO2)CCc2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl [1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methylcarbamate (13.50 g, 38.9 mmole) in THF was cooled to 0° C. To this was added iodomethane (7.27 ml, 117 mmole) followed by 1M NaHMDS in THF (58 ml, 58 mmole). The reaction was then warmed to room temperature and stirred until no U16370/185/2 remained by TLC. The THF was evaporated and the residue dissolved in Et2O. The ether was washed with water and evaporated to afford 14.33 g of tert-butyl [1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methyl(methyl)carbamate as a crude oil, which was used, with no further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH:10]([CH:13]1[O:18][CH2:17][CH2:16][NH:15][CH2:14]1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][CH2:17][O:18][CH:13]([CH:10]([CH3:12])[CH3:11])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)C1CNCCO1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C1CN(Cc2ccc(Br)cc2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound could be made in the following manner: 1.5 eq. of 4-Bromobenzyl bromide and 1 eq. of 2-Isopropyl-morpholine in acetonitrile could be stirred at room temperature and 3 eq. of potassium carbonate could be added. The reaction could be stirred at room temperature overnight. The solution could be filtered through Celite and concentrated in vacuo to afford a brown solid. Purification could be done by flash chromatography to afford product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][S:13][CH2:14][CH2:15][CH2:16][NH2:17].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH2:15][CH2:14][S:13][CH3:12])=[O:6]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: CSCCCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCCCNC(=O)c1cccc(I)c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL round-bottomed flask was added 2-amino-3-iodobenzoic acid (1.50 g, 5.70 mmol, Bosche Scientific) and 3-(methylthio)propylamine (0.72 mL, 6.84 mmol, Acros) in EtOAc (15 mL) followed by DIEA (1.19 mL, 6.84 mmol) and 1-propanephosphonic acid cyclic anhydride (3.99 mL, 6.27 mmol, 50% in EtOAc, Sigma Aldrich). The reaction was stirred at RT for 4 h, and then quenched with sat. NaHCO3. The layers were separated and the organic layer was washed with sat. NaHCO3, brine, then dried (MgSO4), filtered and concentrated to give the crude product. MS (ESI, pos. ion) m/z: 350.9 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (1H, dd, J=7.6, 1.4 Hz), 7.30 (1H, dd, J=7.8, 1.4 Hz), 6.41 (1H, t, J=7.8 Hz), 6.32 (1H, br. s.), 3.54 (2H, q, J=6.7 Hz), 2.61 (2H, t, J=6.9 Hz), 2.09-2.17 (3H, m), 1.92 (2H, quin, J=6.8 Hz)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:22])[CH3:21].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)N(C)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), acetyl chloride (0.18 g, 2.22 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 1 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.20 g, 86%)
Reaction SMILES: [CH3:1][Mg]Br.[O:4]1[CH2:13][C@H:5]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.[Cu]I>[OH:4][C@@H:5]([CH2:13][CH3:1])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: C[Mg]Br
Reactant: CCCCOC(=O)[C@@H]1CO1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCOC(=O)[C@@H](O)CC
Yield: 99 %

Procedure:
Under argon, copper(I) iodide (594 mg) was suspended in anhydrous diethyl ether (20.0 mL). A solution of methylmagnesium bromide in anhydrous tetrahydrofuran (60.2 mL, M) was added dropwise to the suspension at −15° C. or lower, and the mixture was allowed to react at the same temperature for 20 minutes. After completion of reaction, a solution (8.0 mL) of n-butyl(S)-(−)-2,3-epoxypropionate (3.0 g, 97.3% ee) (product of Osaka Organic Chemical Industry Co., Ltd.) in anhydrous diethyl ether was added dropwise to the reaction mixture at −78° C., and the resultant mixture was allowed to react for 15 minutes at the same temperature. After completion of reaction, an aqueous saturated ammonium chloride solution (50.0 mL) was added to the reaction mixture, followed by filtration by means of a Celite. The filtrate was extracted twice with diethyl ether (50 mL×2), and the organic layer was washed with saturated brine (40 mL). The washed organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography including elution with methylene chloride/diethyl ether=5/1, to thereby yield 3.37 g of colorless oil (yield 99.0%). Since the compound was also able to be purified through distillation under reduced pressure, another aliquot of the residue obtained through the same procedure was distillated under reduced pressure, to thereby yield 2.73 g of colorless oil (yield 81.8%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH:8][O:9][CH3:10])=[C:5]([S:13][CH3:14])[CH:4]=1.[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22](Cl)=[O:23])[C:18](=[O:25])[O:17]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22]([N:8]([CH2:7][C:6]2[CH:11]=[CH:12][C:3]([F:2])=[CH:4][C:5]=2[S:13][CH3:14])[O:9][CH3:10])=[O:23])[C:18](=[O:25])[O:17]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)cc1SC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(Cc1ccc(F)cc1SC)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a stirred solution of N-(4-fluoro-2-methylsulfanyl-benzyl)-O-methyl-hydroxylamine hydrochloride (1.19 g, 5 mmol) and (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.953 g, 5 mmol) in CH2Cl2 (20 mL) was added diisopropyethylamine (1.9 mL, 11 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was taken up into ether (150 mL), washed with 1N HCl (10 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give product as a white solid (1.77 g, 99%). 1HNMR (300 MHz, CDCl3) δ: 7.28–7.23 (1H, m), 6.90 (1H, dd, J=9.5, 2.6 Hz), 6.78 (1H, td, J=8.4, 2.6 Hz), 6.37 (1H, s), 4.88 (2H, s), 3.62 (3H, s), 2.44 (3H, s), 1.71 (6H, s). MS calcd for C16H18FNO5S Na (M+Na): 378.078; found: 378.18.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([F:29])[C:26]([Cl:28])=[CH:27][C:19]=1[Cl:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: CCOC(=O)C=CN(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 83.3 %

Procedure:
14.3 g of ethyl 3-dimethylaminoacrylate and 10.5 g of triethylamine are added dropwise to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 100 ml of anhydrous dioxane at 10° to 20° C., with stirring. The mixture is stirred at room temperature for 3 hours, heated at 40°-50° C. for 1 hour, and the solvent is removed by distillation in vacuo and the residue is taken up in methylene chloride/H2O. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The CH2Cl2 solution is washed with water, dried with sodium sulphate, and the solvent is removed in vacuo. The crystalline residue is recrystallized from cyclohexane/light petroleum. 27.8 g of ethyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 94°-95° C. are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C(#N)C>[CH3:23][N:24]([CH3:28])[C:25]([N:9]1[CH2:10][CH:11]2[CH2:15][C:14](=[O:16])[CH2:13][CH:12]2[CH2:8]1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: O=C1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C(=O)N1CC2CC(=O)CC2C1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f obtained from the above step was dissolved in 15 mL of acetonitrile with stirring. Upon cooling by an ice-water bath, potassium carbonate (0.24 g, 1.71 mmol) was added followed by dimethylcarbamic chloride (0.14 mL, 1.56 mmol). The reaction mixture was warmed up to room temperature and reacted for 2 hours. The mixture was concentrated under reduced pressure and diluted with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N,N-dimethyl-5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxamide 1g (0.19 g, yield 68.3%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].I[CH3:21]>CN(C)C=O.CCOCC>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH3:21])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: CI
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Reaction time: 0.17 h

Procedure:
A solution of EXAMPLE 157B (0.62 g) was dissolved in N,N-dimethylformamide (10 mL) and treated with NaH (0.062 g, 60% in mineral oil). After 10 minutes, iodomethane (0.16 mL) was added. After 1 hour, additional sodium hydride (0.5 eq.) and iodomethane (0.5 eq.) were added and stirring was continued at room temperature for 3 hours. The reaction was diluted with ether (75 mL) and washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(C)C>[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
(28 mmol, 1 eq.) of bromobenzene and 9 g (42 mmol, 1.5 eq.) of K3PO4 are added to a solution of 5.13 g (42 mmol, 1.5 eq.) of phenylboronic acid in 60 ml of isopropanol. The mixture is stirred at room temperature for 45 minutes, and 0.02 g (14.03 μmol, 0.05 mol %) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is subsequently added, and the reaction mixture is stirred at room temperature for 3 hours. After addition of 100 ml of water, the reaction mixture is extracted with 200 ml of hexane. The organic phase is washed with saturated sodium chloride solution and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 3.16 g of biphenyl are isolated as a white solid. The yield is 73%, based on the amount of bromobenzene employed.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:35]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][Br:35])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1
Reactant: BrBr
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)-5-chlorobenzotriazole was prepared from the bromination of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)-5-chlorobenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 7.042 g (0.0223 mol) 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)-5-chlorobenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)-5-chlorobenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy3′-tert-butyl-5′-bromomethyphenyl)-5-chlorobenzotriazole was 7.2 g (81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([S:24]([C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[CH3:16])(=[O:26])=[O:25])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (240 mg, 1.1 mmol), 2,4-dimethyl-benzenesulfonyl chloride (278 mg, 1.4 mmol) and di-isopropylethylamine (0.4 mL, 2.3 mmol) were dissolved into DCM (5.0 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (25 mL) and washed with 1N NaOH (10 mL) and water (2×20 mL). The organic layers were combined, dried, filtered and concentrated to yield the title compound (300 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (800 mg) obtained in Reference Example 1(2) is dissolved in chloroform (30 ml), and thereto are added morpholine (560 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.24 g) and triethylamine (650 mg) under ice-cooling. The mixture is then stirred at room temperature for 19 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=30/1) to give methyl trans-4-(morpholin-4-ylcarbonyl)cyclohexanecarboxylate (897 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (1.95 g) described in Preparation Example 17 was dissolved in a solution of tetrahydrofuran (20 mL) and methanol (20 mL), 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid, and the solvent was evaporated. To the obtained residue was added water, and the insoluble material was collected by filtration to give the title compound (1.62 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=1.[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28]([OH:35])=[C:29]([C:32](=O)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]>CO>[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28](=[O:35])[C:29](=[C:32]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=2)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CCC(=O)Nc1cc(N)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)Nc1cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)ccc1O

Procedure:
Following the procedures of Example 3, 2.0 g. (0.0096 mol) of 4-nitro-2-propionamidophenyl (prepared from propionic acid and 2-amino-4-nitrophenyl) is hydrogenated in a mixture of 100 ml. of ethanol, 0.3 g. of 10% palladium-on-carbon and 1.34 ml. of concentrated hydrochloric acid in a Parr apparatus. Filtration and evaporation of the solvent gives 4-amino-2-propionamidophenol hydrochloride. The latter (2.0 g., 0.0096 mol) in a methanol solution is treated with 1 equivalent of triethylamine under nitrogen atmosphere. The solution of the free amine is added to a refluxing mixture of one equivalent of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 30 ml. of methanol under nitrogen. The reaction mixture is refluxed for 18 hours, filtered and the solid is recrystallized from ethanol to yield 5-acetyl-4-hydroxy-3-[1-(4-hydroxy-3-propionamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 228°-229° C. (dec.).