Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:19](=[O:21])[CH3:20]>C1COCC1>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:19](=[O:21])[CH3:20])[CH:10]=2)[CH:6]=[N:7]1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cn[nH]c2c1
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of 6-bromo-1H-indazole (5.0 g, 25.4 mmol) in 40 mL THF was added dropwise n-BuLi (2.5M, 30 mL, 76.2 mmol) at −65° C., and the mixture was stirred for 2 h. Then, N-methoxy-N-methylacetamide (2.9 g, 27.9 mmol) was added. The reaction mixture was stirred for another 2 h at −65° C., then quenched with 40 mL H2O. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 100 mL brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EA=40/1) to give the title compound 24-a (370 mg, 9%) as a yellow solid. [M+H] Calc'd for C9H8N2O, 161; Found, 161.
Reaction SMILES: [CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([O:8][C:9]3[CH:14]=[N:13][C:12]([CH:15]4OCC[O:16]4)=[CH:11][N:10]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CC(C)=O>[CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: c1cc(C2CC2)ccc1Oc1cnc(C2OCCO2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cnc(Oc2ccc(C3CC3)cc2)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a solution in acetone (107 mL) of the compound (2.46 g) obtained in step (3) above, p-toluenesulfonic acid monohydrate (2.04 g) was added and the mixture was stirred at 50° C. for two hours. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to it under cooling with ice and two extractions were conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate; thereafter, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-80:20) to give the titled compound as a colorless solid (0.67 g).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].S(=O)(=O)(O)O.O.OO.[CH2:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>[Cu].C(#N)C>[CH:21]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C1CCCCC1
Agent: [Cu]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Yield: 70 %

Procedure:
Copper powder (0.060 g, 0.944 mmol) is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 44 ml of acetonitrile, and 30 ml of cyclohexane that has been heated to 40 degrees. A portion of a solution of 0.457 g of concentrated sulfuric acid in 3 mol of water is carefully added to the reaction mixture after the mixture is brought to reflux. To the refluxing reaction mixture is added dropwise over 2.5 hours a solution of 7.32 g (108 mmol) of 50% aqueous hydrogen peroxide. The remainder of the sulfuric acid solution is carefully added in portions to the reaction mixture during the first 15 minutes of the peroxide addition. After work up and purification according to the procedure of Example 54, the yield of the title compound is 5.22 g (70% yield), GC assay 94%.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH2:11][CH2:10]2.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=4)[CH:17]=3)[O:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)COC1
Product: NC1=N[C@@]2(CCOc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)COC1
Yield: 54 %

Procedure:
The condensation of (R)-6′,6′-difluoro-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.2) and 5-chloropicolinic acid yielded the title compound (54% yield) as a pale yellow solid. MS (ISP): m/z=423.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=4)[CH:7]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.29) (0.300 g, 0.80 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.230 g, 1.17 mmol) according to the general procedure VI. Obtained as a white solid (0.100 g, 28%). MS (ISP) 434.1 [(M+H)+]; mp 242-245° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Yield: 94.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-methanesulfonylbenzoic acid (10.2 g) and piperazine-1-carboxylic acid tert-butyl ester (7.49 g), the title compound (15.4 g) was obtained.
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20].[C:25]([O-:28])(=[S:27])[CH3:26].[Na+]>>[C:25]([S:27][CH:3]([C:2]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)=[O:1])[CH2:4][C:5]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:7])(=[O:28])[CH3:26]
Reactant: O=C(O)CCC(=O)c1cc2ccccc2s1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC([O-])=S
Agent: [Na+]
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1cc2ccccc2s1

Procedure:
As for Example 4, γ-oxo-benzo[b]thiophene-2-butyric acid is coupled to L-proline. The coupled product is brominated and reacted with sodium thioacetate to give the product of the Example as a glass.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:4]=1.[CH2:17](Cl)Cl>CO.CCCCCC>[F:16][C:2]([F:15])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([O:13][CH3:17])=[O:12])[CH:4]=1
Reactant: ClCCl
Reactant: CC(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)C(C)Oc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-trifluoromethyl-2-pyridyloxy)propionic acid (Step A, 15 g, 55 mol) in 100 mL CH2Cl2 and 100 mL MeOH at 0° C. was added trimethylsilydiazomethane (2 M solution in hexane) until a yellow color persisted. After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluted with 0 to 10% EtOAc in hexane to give methyl 2-(4-trifluoromethyl-2-pyridyloxy)propionate (10 g), which was used immediately for methylation following the procedure described in Reference Example 39, Step B substituting ethyl iodide with methyl iodide. 1H NMR (500 MHz, CD3OD): δ 8.25 (d, 1H), 7.18 (d, 1H), 7.15 (s, 1H), 3.65 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C-:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13].CN([S+](N(C)C)N(C)C)C.FC(F)=C(C(F)(F)F)C(F)(F)F>C(#N)C>[F:9][C:10]([F:20])([F:21])[C:11]([C:12]([F:13])([F:14])[F:15])([C:16]([F:19])([F:18])[F:17])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: FC(F)=C(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: FC(F)(F)C(Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Benzyl bromide, 18.8 g (0.11 mol), was added dropwise at 10° to a solution of tris(dimethylamino)sulfonium 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-2-propanide, prepared by dissolving 24.4 g (0.122 mol) of octafluoroisobutylene and 33.6 g (0.122 mol) of tris(dimethylamino)sulfonium difluorotrimethylsilicate in 75 mL of acetonitrile. The reaction mixture was warmed to 25°, stirred overnight, and then poured into ice water. The aqueous mixture was extracted with ether, and the ether extracts were washed three times with water, dried (MgSO4), and distilled to give 27.35 g (81%) of 3,3,3-trifluoro-2,2-bis(trifluoromethyl)propylbenzene as a colorless liquid, b.p. 53°-54° (12 mm), that solidified on cooling to a white solid: m.p. 32°-33°; 1H NMR (CDCl3) δ 3.39 ppm (s, 2H), 7.28 ppm (s, 5H); 19F NMR (CDCl3) δ -62.3 ppm (s). Anal. Calcd. for C11H7F9 : C, 42.59; H, 2.28; F, 55.13. Found: C, 42.45; H, 2.23; F, 55.00.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[SH2:10].C[OH:12]>ClCCl>[OH:12][C:2]1([CH2:1][SH:10])[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: S
Reactant: CO
Reactant: C=C1CN2CCC1CC2
Solvent: ClCCl
Product: OC1(CS)CN2CCC1CC2
Reaction time: 0.21 h

Procedure:
A solution of the epoxide of 3-methylene quinuclidine (100 g, 0.719 moles) in dichloromethane was cooled to a temperature between about 0 to 5° C. The solution was charged with methanol (100 ml). The mass was stirred for 10 to 15 minutes at this temperature range. To this cold solution hydrogen sulfide gas (50 g, 1.4 mol) was passed and after the passing was complete, the reaction was continued at this temperature for 2 to 3 hours, monitored by gas chromatography, whereupon the peak of epoxide of 3-methylene quinuclidine disappeared. After completion of the reaction, a dichloromethane solution of 3-hydroxy 3-mecapto methylquinuclidine in methanol was obtained. This solution was used for the next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12]([N:15]2[CH2:20][CH2:19][C:18]3[O:21][CH:22]=[CH:23][C:17]=3[CH2:16]2)(=[O:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[CH2:29]=O>C(O)(=O)C>[CH2:24]([N:26]([CH2:29][C:22]1[O:21][C:18]2[CH2:19][CH2:20][N:15]([S:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:14])=[O:13])[CH2:16][C:17]=2[CH:23]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCNCC
Reactant: C=O
Reactant: O=S(=O)(CCCCCc1ccccc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc2c(o1)CCN(S(=O)(=O)CCCCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.269 g (0.807 mmol) of 5-(5-phenylpentylsulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.10 ml (0.97 mmol) of diethylamine and 79 mg (0.97 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=9/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29].C(N([CH2:37][CH3:38])CC)C>ClCCl>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([N:19]([S:28]([C:38]1[CH:37]=[CH:22][C:21]([Cl:20])=[CH:26][C:25]=1[Cl:27])(=[O:30])=[O:29])[C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: CCN(CC)CC
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1Cl)N(c1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)S(=O)(=O)c1ccc(Cl)cc1Cl
Temperature: 45 °C

Procedure:
Dry dichloromethane (15 mL) was added to 5-Chloro-6-(quinolin-3-yloxy)-pyridin-3-yl amine (250 mg, 1 mmol) obtained in preparation 1. To the stirred solution was added 2,4-dichlorobenzenesulfonyl chloride (492 mg, 2.2 mmol) followed by the addition of triethylamine (2.2 mmol). The reaction mixture was then maintained at 45° C. for 15 hours, cooled to room temperature (25° C.) and diluted with dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulfate and concentrated under vacuum to get the crude, which was further purified by column chromatography (silica gel).
Reaction SMILES: [NH:1]([C:25]([CH3:27])=[O:26])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CC(=O)OCC.[OH-].[OH-].[Pd+2]>[NH:1]([C:25]([CH3:27])=[O:26])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Yield: 87.7 %

Procedure:
To a stirred solution of N-Ac-L-Leu-L-Leu-OBn (9.09 g, 23.9 mmol) in EA (100 mL) at R.T. was added 20% palladium hydroxide on carbon (Pd (OH)2 /C) (0.9 g, 10% by weight). The reaction mixture was placed under 20 psi hydrogen (H2). After 1 h the reaction mixture was filtered through celite and concentrated in vacuo to give N-Ac-L-Leu-L-Leu-OH as a white solid (6.0 g, 87.67%): 1H NMR (300 MHz, CDCl3) δ0.82-0.90 (m, 12 H), 1.39-1.82 (m, 9 H), 4.18-4.34 (m, 2 H), 7.94-8.13 (m, 2 H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:13]([OH:17])(=[O:16])[C:14]#[CH:15].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>[O-]S([O-])(=O)=O.[Cu+2].O.CC(O)(C)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[CH:15]=[C:14]([C:13]([OH:17])=[O:16])[N:7]=[N:6]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C#CC(=O)O
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Difluorobenzyl azide (III) (7.0 g, 41.4 mmoles) is suspended in a H2O-tBuOH 1:1 mixture (120 ml), then propiolic acid (3.19 g, 45.6 mmoles), an ascorbic acid 1M solution (4.2 ml) and a CuSO4 0.3 M solution (1.4 ml) are added thereto. The reaction mixture is kept at 25° C. under stirring and is completed after 2 h. The mixture is left to cool at room temperature thereby precipitating the product. The solid is filtered off on a Buchner filter, washed with ethyl ether and dried under vacuum.
Reaction SMILES: [C:1]([NH:4][C:5]([C:19]([OH:21])=[O:20])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH2:17][CH3:18])[CH:8]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][C@H:5]([C:19]([OH:21])=[O:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH2:17][CH3:18])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C=C(NC(C)=O)C(=O)O)cc1OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOc1ccc(C[C@H](NC(C)=O)C(=O)O)cc1OCC
Yield: 69.5 %

Procedure:
To a suspension of N-acetyl-3-(3,4-diethoxyphenyl)dehydroalanine (100.2 g) in acetic acid (1000 ml) is added 10% palladium-carbon (4 g), and the mixture is subjected to hydrogenation at 40° C. under 3 atms of hydrogen gas for 7 hours. The catalyst is removed by filtration, and the filtrate is concentrated. The residue is crystallized from ether to give N-acetyl-3-(3,4-diethoxyphenyl)alanine (70.1 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=O)C.[H][H].C(=S)=[S:18]>O.C1C=CC=CC=1.CC(N(C)C)=O>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]=[S:18]
Reactant: [H][H]
Reactant: CC(=O)Nc1c(C)cccc1C
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N=C=S
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
To a suspension of 2.5 g (0.05 mol) of sodium hydride in a mixture of 40 ml of dry-dimethylacetamide and 40 ml of dry benzene, 0.05 mole of N-(2,6-dimethylphenyl)acetamide was added. After evolution of hydrogen ceased, the mixture was cooled in ice and water, and with stirring 0.075 mole of carbon disulfide was added slowly. The mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with toluene. The organic layer, dried over sodium sulfate, was evaporated, and distillation of the residue yielded 6.1 g (74%) of 2,6-dimethylphenylisothiocyanate.
Reaction SMILES: C([O:3][C:4](=[O:62])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([CH3:61])=[C:15]([CH2:17][O:18][C:19]3[CH:58]=[CH:57][C:22]([CH2:23][O:24][C:25]4[C:29](/[CH:30]=[CH:31]/[C:32]5[N:33]=[C:34]([N:38]6[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]6)[S:35][C:36]=5[CH3:37])=[CH:28][N:27]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[N:26]=4)=[CH:21][C:20]=3[O:59][CH3:60])[N:16]=2)=[CH:8][CH:7]=1)C.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:47]([O:46][C:44]([N:41]1[CH2:42][CH2:43][N:38]([C:34]2[S:35][C:36]([CH3:37])=[C:32](/[CH:31]=[CH:30]/[C:29]3[C:25]([O:24][CH2:23][C:22]4[CH:57]=[CH:58][C:19]([O:18][CH2:17][C:15]5[N:16]=[C:12]([C:9]6[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:62])=[O:3])=[CH:7][CH:8]=6)[O:13][C:14]=5[CH3:61])=[C:20]([O:59][CH3:60])[CH:21]=4)=[N:26][N:27]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:28]=3)[N:33]=2)[CH2:39][CH2:40]1)=[O:45])([CH3:48])([CH3:50])[CH3:49]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCN(C(=O)OC(C)(C)C)CC5)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCN(C(=O)OC(C)(C)C)CC3)sc2C)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a mixture of tert-butyl 4-{4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate (0.30 g), tetrahydrofuran (6 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give [4-(4-{[4-({[4-((E)-2-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-5-methyl-1,3-thiazol-4-yl}ethenyl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)-2-methoxyphenoxy]methyl}-5-methyl-1,3-oxazol-2-yl)phenyl]acetic acid as crystals (0.14 g, yield 50%). Recrystallization from ethyl acetate-hexane gave brown prism crystals. melting point: 119-120° C.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][N:7]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8]1.C(N(CC)CC)C.[Na].O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([NH2:34])=[O:33]>C1C=CC=CC=1.O>[CH3:6][N:7]1[CH2:11][CH2:10][CH:9]([O:12][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[C:32]([NH2:34])=[O:33])[CH2:8]1
Reactant: NC(=O)c1ccc2ccccc2c1O
Reactant: CN1CCC(O)C1
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CN1CCC(Oc2c(C(N)=O)ccc3ccccc23)C1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
In another vessel, 79 g (0.69 mole) of methanesulfonylchloride was added dropwise to a solution of 69.7 g (0.69 mole) of 1-methyl-3-pyrrolidinol and 77 g (0.76 mole) of triethylamine in 500 ml of dry benzene while cooling with an ice bath. The mixture was stirred 15 minutes and filtered. The filter cake was washed with 500 ml of benzene and the benzene filtrates were combined and concentrated on the rotary evaporator to about 200 ml. The residue was added dropwise to the above prepared dimethylsulfoxide solution containing the sodium salt of 1-hydroxy-2-naphthalenecarboxamide while stirring at 75° C. The temperature was maintained at 75° C. for 18 hr with external heat. The resulting solution was cooled and an equal volume of water was added. The mixture was extracted with three portions of chloroform. The washes were combined and concentrated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted twice with ethyl acetate. The ethyl acetate washes were combined, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-isooctane. Yield of solid was 55 g (32%). A portion was recrystallized twice from ethyl acetate-isooctane, m.p. 122°-129° C.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][C:28]=1[C:37](O)=[O:38].FC(F)(F)C(O)=O>ClCCl>[CH2:19]([N:18]([C:37]([C:28]1[CH:29]=[N:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)=[O:38])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: O=C(O)c1cnc2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and quinoxaline-2-carboxylic acid as starting materials and by an operation similar to that of Example 312-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.