Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([N:28]1[CH2:41][C:31]2=[C:32]3[N:37]([N:38]=[C:30]2[CH2:29]1)[CH:36]=[C:35]([Cl:39])[C:34]([CH3:40])=[N:33]3)=[O:27])C)(C)(C)C>C(Cl)Cl>[ClH:39].[Cl:39][C:35]1[C:34]([CH3:40])=[N:33][C:32]2[N:37]([N:38]=[C:30]3[CH2:29][N:28]([C:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[O:18][CH2:17][CH2:16][NH:14][CH3:13])=[O:27])[CH2:41][C:31]3=2)[CH:36]=1
Reactant: Cc1nc2c3c(nn2cc1Cl)CN(C(=O)c1ccc(F)cc1OCCN(C)C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCOc1cc(F)ccc1C(=O)N1Cc2nn3cc(Cl)c(C)nc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (456 μL; 1.83 mmol; 10 eq.) was added to solution of {2-[2-(6-chloro-5-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (92 mg; 0.18 mmol; 1 eq.) in DCM (2 mL) and the reaction mixture was stirred at room temperature for 30 minutes then concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (15 mg, 19%) as a yellow solid. 1H NMR (DMSO-d6) δ 9.55-9.45 (d, J=5.0 Hz, 1H), 9.01-8.78 (s, 2H), 7.43 (ddd, J=8.4, 6.7, 4.5 Hz, 1H), 7.19 (dd, J=11.1, 2.3 Hz, 1H), 6.95 (td, J=8.5, 2.3 Hz, 1H), 4.82 (d, J=5.8 Hz, 2H), 4.58 (d, J=12.5 Hz, 2H), 4.36 (t, J=4.5 Hz, 2H), 3.26 (t, J=5.2 Hz, 2H), 2.60 (s, 1.5H), 2.57-2.51 (m, 4.5H). HPLC (max plot) 99.2%, Rt 2.48 min. UPLC/MS: (MS+) 404.3 ([M+H]+).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1.C1(CCCCCCC(C2OC(C3N=C([C:54]([O:56][CH3:57])=[O:55])C=CC=3)=NN=2)=O)C=CC=CC=1>CO.C(Cl)Cl>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[N:17]=[C:18]([C:54]([O:56][CH3:57])=[O:55])[CH:19]=[CH:20][CH:21]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)c1nnc(-c2cccc(Br)n2)o1
Reactant: COC(=O)c1cccc(-c2nnc(C(=O)CCCCCCc3ccccc3)o2)n1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(-c2nnc(C(=O)CCc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 48 %

Procedure:
The title compound was prepared from 30 (70 mg, 0.16 mmol) by using a procedure similar to that detailed for 8f. Flash chromatography (SiO2, 2.5×15 cm, 0-1% MeOH—CH2Cl2) afforded the title compound (32 mg, 48%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.47 (d, 1H, J=7.8 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.10 (t, 1H, J=7.8 Hz), 7.57 (d, 2H, J=7.2 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.7 Hz), 7.33 (m, 3H), 4.06 (s, 3H), 3.61 (t, 2H, J=7.5 Hz), 3.19 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ 186.1, 164.9, 164.6, 161.5, 149.3, 142.9, 141.0, 139.7, 138.9, 138.8, 129.0, 128.9, 127.9, 127.5, 127.3, 127.2, 127.1, 53.4, 41.8, 29.1; HRMS-ESI-TOF m/z 414.1451 ([M+H]+, C24H19N3O4 requires 414.1448).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:9][C:10](=[O:37])[CH:11]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)[CH2:12][P:13]([CH:16]([NH:18]C(OCC1C=CC=CC=1)=O)[CH3:17])([OH:15])=[O:14])[CH3:8])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:18][CH:16]([P:13]([OH:15])([CH2:12][CH:11]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)[C:10]([NH:9][CH:7]([CH3:8])[C:6]([OH:38])=[O:5])=[O:37])=[O:14])[CH3:17]
Reactant: CC(NC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(C)N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound obtained in step 2 is solubilised in a 50:50 CH2Cl2/TFA mixture (40 ml) and the mixture is stirred for 1 hour at ambient temperature. The residue is evaporated to dryness, taken up with water and freeze-dried. 1.0 g of the expected compound is obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[C:22]([Cl:25])(=O)C.[ClH:26].[OH-].[Na+]>C(O)(C)C.CC(C)=O>[ClH:25].[ClH:26].[CH3:1][NH:2][CH2:3][CH2:4][C@:5]([CH3:22])([O:11][C:12]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CNCC[C@](C)(Oc1cccc2ccccc12)c1cccs1
Temperature: 50 °C

Procedure:
The crude wet duloxetine free base (205.0 g) and an acetone (anti-solvent)(600.0 g) were charged in a 4-neck round flask and heated to a temperature of 50° C. while stirring. To another 4-neck round flask, isopropyl alcohol (IPA) (200.0 g) was charged, and the temperature was set to about 0 to about 5° C. while stirring. Fresh hydrochloride was prepared by dropping acetyl chloride (48.0 g) slowly to the isopropyl alcohol solution and stirring the reaction for one hour at a temperature of about 15° C. to 20° C. Then, the fresh hydrochloric acid in isopropyl alcohol was added to the duloxetine free base solution slowly, and the pH value was controlled in a range from 5.5 to 7.5 with NaOH(aq). The temperature was set at 50° C., and the reaction was gradually cooled to 0° C.˜5° C. The reaction was stirred for another one hour at about 0° C.˜5° C., and after filtration, the purified duloxetine hydrochloride was produced. (190 g, 99% ee; purity; 98% by HPLC assay).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C@:13]12[CH2:30][CH2:29][C@H:28]3[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@:26]3([CH3:27])[CH2:25][CH2:24][C@H:23]([OH:31])[CH2:22]4)[C@@H:17]1[CH2:16][CH:15]=[CH:14]2.C[C@]12CC[C@H]3[C@@H](CC[C@@H]4[C@]3(C)CC[C@H]([OH:51])C4)[C@@H]1CCC2=O.O>N1C=CC=CC=1>[CH3:12][C@:13]12[CH2:30][CH2:29][C@H:28]3[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@:26]3([CH3:27])[CH2:25][CH2:24][C@H:23]([OH:31])[CH2:22]4)[C@@H:17]1[CH2:16][CH:15]=[CH:14]2.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:51])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Methylbenzenesulphonyl chloride (20 g) was added to a stirred solution of (3β, 5α)-androst-16-en-3-ol (20 g), which was prepared from (3β, 5α)-androstan-3-ol- 17-one in a similar way as described in Examples 1 and 2, in pyridine (100 ml) at °C. The mixture was stirred at 0°-5° C. for 1 h., then set aside in a refrigerator for 3 d. Water was added to precipitate the product as off-white prisms. Recrystallisation from diethyl ether-methanol gave colourless prisms of (3β, 5α)-androst-16-en-3-ol 4-methylbenzenesulphonate, Which Was treated as described in Example 3.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[N:9][C:8](Cl)=[C:7]2[NH:12][N:13]=[CH:14][C:6]=12.[Cl-].[NH4+]>>[Br:4][C:5]1[CH:10]=[N:9][C:8]([O:2][CH3:1])=[C:7]2[NH:12][N:13]=[CH:14][C:6]=12
Reactant: C[O-]
Reactant: Clc1ncc(Br)c2cn[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1ncc(Br)c2cn[nH]c12
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Sodium methoxide (28% in MeOH) (3 ml) was added to 4-bromo-7-chloro-1H-pyrazolo[3,4-c]pyridine (126 mg) obtained in the 2nd step, followed by stirring at 90° C. for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution and an insoluble precipitate was collected by filtration. The obtained residue was washed with water and a yellow solid of 4-bromo-7-methoxy-1H-pyrazolo[3,4-c]pyridine (133 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.CCN(C(C)C)C(C)C>CCO>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)=[N:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(F)c(F)cc2[N+](=O)[O-])n[nH]1
Reaction time: 8 h

Procedure:
To a solution of 2,3,6-trifluoro-5-nitropyridine (Intermediate 40, 1.0 g) in EtOH (20 ml) at 0° C., was added 5-methyl-1H-pyrazol-3-amine (550 mg) and DIPEA (2 ml). The resulting mixture was stirred at this temperature overnight. The title compound was collected via filtration (780 mg). LCMS: 377 [M+1].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8]([OH:10])=O)[CH3:2].CCN=C=NCCCN(C)C.[CH2:34]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39])[CH3:35]>C(#N)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8](=[O:10])[NH:39][CH:38]([C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:40][OH:41])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)CO
Reactant: CCOC(=O)C(CCC(=O)O)NC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CCOC(=O)C(CO)NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.9 %

Procedure:
A suspension of acid (3) (7.6 g, 24.57 mmol) in dry acetonitrile (80 ml) was stirred under nitrogen at room temperature and Hobt (4 g, 29.6 mmol, 1.2 equiv.) was added. Stirring was continued for 10 min., and EDCI (5.1 g, 26.6 mmol, 1.1 equiv.) was added. The resulting mixture was stirred for 1.5 hrs and serine ethyl ester free base (3.27 g, 24.57 mmol, 1 equiv.) in acetonitrile (20 ml) was added. Stirring was continued at room temperature for 3 hrs. The solvent was removed in a rotary evaporator, the residue was partitioned between water (100 ml) and ethyl acetate (200 ml) and phases were separated. The organic phase was washed successively with water (50 ml), 5% potassium carbonate (2×50 ml) and water (2×50 ml), dried over sodium sulfate and the solvent removed in a rotary evaporator. The residue was dried in a vacuum oven (50° C.) to produce (4) (12.4 g, 85.5%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[N:12]1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][C:27]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)(=[O:4])=[O:3])=[O:28])[N:20]=1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: Cc1nnnn1-c1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-n2nnnc2C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To 0.48 g of 1-(2-aminosulfonylphenyl)-5-methyl-1H-tetrazole and 0.52 g of phenyl N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate in 25 mL of acetonitrile at ambient temperature and pressure was added 0.3 mL of DBU. The mixture was stirred for three hours and then added to 25 g of ice and acidified with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried in vacuo to yield 0.65 g of the desired product melting at 207°-209° C. Infrared absorption spectra showed absorption at 1700, 1600 and 1550 cm-1, consistent for the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35](=[O:36])[NH:37][CH3:38])=[CH:39][CH:40]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: CNC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (170 mg, 0.41 mmol) in 10 mL of DMF were added 4-amino-N-methyl-benzamide (81 mg, 0.54 mmol), HATU (205 mg, 0.54 mmol) and DIEA (79 mg, 0.61 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to give a solid as a crude product. It was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (66 mg, 29.7%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.66 (s, 1H), 10.21 (s, 1H), 9.39 (s, 1H), 8.93 (s, 1H), 8.59 (d, 1H, J=7.2 Hz), 8.38-8.37 (m, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.89-7.82 (m, 6H), 7.71-7.68 (m, 12H), 7.54-7.50 (m, 1H), 6.97 (d, 1H, J=8.7 Hz), 3.78 (s, 3H), 3.72 (s, 3H), 2.78 (d, 1H, J=3.9 Hz). LC-MS: 541.1 [M+H]+, tR=1.72 min. HPLC: 96.60% at 214 nm, 97.75% at 254 nm, tR=6.68 min.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][C@H:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>O.CC(C)=O>[CH3:6][C@H:7]1[CH2:12][N:11]([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH2:10][CH2:9][NH:8]1
Reactant: C[C@H]1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Sodium hydrogen carbonate (21.7 g) and acetone (50 ml) was added to a solution of (S)-(+)-2-methylpiperazine (6.0 g) in water (75 ml). The resulting suspension was cooled (0-5° C.) and a solution of 2-nitrobenzenesulphonyl chloride (15.9 g) in acetone (25 ml) was added, the reaction mixture was allowed to stir at ambient temperature overnight. Water (60 ml) was added and volatile material was removed by evaporation. The residue was acidified to pH 2 by the addition of HCl (2 M, 75 ml) and the mixture was extracted into DCM (2×100 ml). The aqueous phase was adjusted to pH 10-11 by the addition of NaOH (2 M, 50 ml) and extracted into EtOAc (2×150 ml). The organic washings were combined, dried and concentrated to leave the title compound (14.1 g) as a yellow oil. NMR: 1.06 (d, 3H), 2.35-2.43 (m,1H), 2.73-3.06 (m, 4H), 3.65-3.71 (m, 2H), 7.59-7.62 (m, 1H), 7.68-7.72 (m, 2H), 7.95-7.98 (m, 1H); m/z (+ve ESP): 286 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-7-hydroxytetralin (400 mg) was dissolved in 8 ml of N,N-dimethylformamide, 3.16 g of cesium carbonate and 650 μl of ethyl 4-bromobutyrate were added to the solution, and the mixture was stirred at room temperature for 1.5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/ethyl acetate=1/1) to give 488 mg of ethyl (S)-4-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]butyrate having a meltin(point of 96 to 98° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[CH2:27]([NH:34][C:23](=[O:25])[CH2:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:10]2[NH:11][C:12](=[O:14])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:26])[CH:4]=3)[CH:9]=2)[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)NCc4ccccc4)c3)[nH]c(=O)n2)ccc1O
Yield: 25.5 %

Procedure:
To a solution of ({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}oxy)acetic acid (16.9 mg, 48 μmol) and benzylamine (4.3 mg, 40 umol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 μmol) followed by 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 μmol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound N-benzyl-2-(3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)phenoxy)acetamide (4.5 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH3:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1.[H-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CN(C)C=O>[C:19]([N:10]1[CH:11]([CH3:13])[CH2:12][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:14])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C)N(C(=O)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen stream, 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (300 mg) described in Preparation Example 52 was dissolved in N,N-dimethylformamide (3 mL), sodium hydride (60 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Then, benzoyl chloride (0.17 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (220 mg).
Reaction SMILES: [CH2:1](N(CCCC)CCCC)CCC.CS(C)=O.O.[NH2:19][C:20]1[N:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[N:23]=[C:22]([C:29]([OH:31])=[O:30])[C:21]=1[Cl:32].BrC>O>[NH2:19][C:20]1[N:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[N:23]=[C:22]([C:29]([O:31][CH3:1])=[O:30])[C:21]=1[Cl:32]
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Reactant: CCCCN(CCCC)CCCC
Agent: CBr
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 5 °C
Yield: 80.8 %

Procedure:
A 200-mL reactor equipped with a 10-mL jacketed addition funnel below a cold-finger condenser at −10° C., a nitrogen inlet and overhead stirring was charged with tributylamine (20.4 g, 0.11 mol) and DMSO (45 mL). The mixture was stirred at 25° C., and 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (23.1 g, 0.1 mol) was added in portions. The reaction mixture was stirred at 30° C. while bromomethane (13.3 g, 8 mL, 0.14 mol) was condensed into the jacketed addition funnel and then added to the reaction mixture over 30 minutes. The mixture was stirred for an additional 3 h and then added over about 30 minutes to a reactor charged with water (200 mL) at 25° C. The resulting slurry was cooled to 5° C. and filtered. The filtered cake was washed with water (2×30 mL) and dried at 60° C. in a vacuum-oven for 16 h to give 18.4 g (81% yield) of the title compound as an off-white solid melting at 147-148° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[Cl:14]N(C(C)C)C(C)C>>[Cl:14][CH:5]([CH3:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCCCCC(=O)O
Reactant: CC(C)N(Cl)C(C)C
Agent: O=S(=O)(O)O
Product: CC(Cl)CCCC(=O)O

Procedure:
135 parts by mass of the caproic acid were added to 1,000 parts by mass of 84% sulfuric acid and an equivalent amount of N-chlorodiisopropylamine and were reacted for 5 hours at 25° C. to obtain 163 parts by mass of 5-chlorocaproic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc(Cl)c1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(=O)c2ccccc2)cc(Cl)c1OCc1ccccc1
Temperature: 0 °C
Yield: 90.6 %

Procedure:
To a solution of 27.3 g of 4-benzyloxy-3-chloro-5-methylphenol dissolved in 250 ml of chloroform and being stirred at 0° C. were added 15.4 g of benzoyl chloride and then 13.3 g of triethylamine. After stirring at room temperature for 2 hours, the chloroform layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 35 g of 4-benzyloxy-3-chloro-5-methyl-1-benzoyloxybenzene (90% yield).