Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[S:7](=[O:9])(=[O:8])[CH:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CCOC(C)=O.CCO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][CH:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:31])([CH3:1])[C:3]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCCC2S(=O)(=O)C1(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl ((11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (190 mg, 0.419 mmol) (1.9:1 mixture of trans/cis epimers) in EtOAc (3 ml) and EtOH (1.000 ml) was hydrogenated (balloon) in the presence of palladium (10% wt. on activated carbon) (44.6 mg, 0.042 mmol) for 2 hr at rt. Additional palladium, 10% wt. on activated carbon (44.6 mg, 0.042 mmol) was added and hydrogenation continued for additional 2 h. The mixture was filtered through the plug of celite and washed 3 times with 3 ml portions of EtOAc. The filtrate was concentrated in vacuo to give tert-butyl ((11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate as a mixture of diastereomers which was used in the next step without purification.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C1OC1CO.Cl.[OH-].[Na+]>CS(C)=O.OCC(CO)O>[C:8]([OH:10])(=[O:9])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: OCC1CO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: OCC(O)CO
Product: O=C(O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
1.74 g of p-hydroxy cinnamic acid and 4.0 g of glycidol were dissolved in 2 ml of DMSO, and catalytic amount of hydrochloric acid was added. The solution was heated to 90° C., heating and agitation were carried out for 1 hour, neutralized by adding sodium hydroxide and then the adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[N:10][S:9]2(=[O:35])=[O:34])[CH:5]=[CH:6][CH:7]=1.[CH3:36][Al](C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[Si:21]([O:20][CH2:19][CH2:18][C@H:17]([NH:16][C:11]1[O:12][C:13]([CH3:15])([CH3:14])[CH:8]([C:4]2[CH:3]=[C:2]([CH3:36])[CH:7]=[CH:6][CH:5]=2)[S:9](=[O:35])(=[O:34])[N:10]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: C[Al](C)C
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3)=NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under inert gas, 100 mg of [5-(3-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine, 8 mg of bis(dibenzylideneacetone)palladium and 19.6 mg of 1,2,3,4,5-pentaphenyl-1-(di-tert-butylphosphino)ferrocene were initially charged, dissolved in 3 ml of toluene and stirred at room temperature for 5 minutes. After the addition of 0.17 ml of a 2 N solution of trimethylaluminum, the reaction mixture was stirred at 70° C. for 1.5 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (51.7 mg) with a molecular weight of 516.8 g/mol (C27H40N2O4SSi); MS (ESI): m/e=517 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CCCCCC.CO.O>C1COCC1>[S:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][CH:2]=2)[CH:8]=[CH:9]1
Reactant: Brc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: c1cnc2ccsc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
3.69 g of 7-Bromo-thieno[3,2-b]pyridine (17 mmol) is dissolved in 20 ml of dry THF and cooled to −78° C. 21.2 ml of n-BuLi 1.6M in hexane (34 mmol) is added slowly to the mixture at −78° C. and stirred at −78° C. for 20 min, and 20 ml of MeOH/H2O=1/1 is added and stirred at room temperature for 1 h. The reaction mixture is extracted with CHCl2. The separated CH2Cl2 layer is washed with sat. NaCl, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane→Hexane:AcOEt=−10:1) to give 1.44 g of the title compound. Yield 62%. mass spectrum (m/e): 136 (M+1); 1H-NMR (CDCl3): 8.73 (m, 1H), 8.22 (m, 1H), 7.79 (m, 1H), 7.61 (m, 1H), 7.29 (m, 1H) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:26](=[CH:27][CH:28]=1)[C:25]1[C:16](=[C:17]3[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:30])([CH3:29])[CH:19]=[C:18]3[CH3:31])[C:15](=[O:32])[O:14]2.Cl>O1CCCC1.C(OCC)(=O)C.O>[OH:14][C:13]1[CH:12]=[C:11]([O:10][CH2:9][O:8][CH3:7])[CH:28]=[CH:27][C:26]=1[C:25]1[C:16]([CH2:15][OH:32])=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:30])([CH3:29])[CH:19]=[C:18]2[CH3:31]
Reactant: COCOc1ccc2c(c1)oc(=O)c1c3c(ccc12)NC(C)(C)C=C3C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(O)c1
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (167 mg, 4.40 mmol) was suspended in anhydrous tetrahydrofuran (3 mL). A solution of 8-methoxymethoxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-(5), 744.1 mg, 2.12 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the suspension at 0° C., the reaction mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (2 mL) and water (1 mL) were added to the reaction mixture successively, and then ethyl acetate (150 mL) was added thereto. 1N aqueous HCl solution (6 mL) was added, the mixture was washed with water (100 mL, twice) and saturated brine (50 mL) successively, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the titled reference compound (750.6 mg) as a pale yellow amorphous product. (Quantitative)
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1)(=[O:14])=[O:13].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([S:12]([CH3:11])(=[O:14])=[O:13])=[CH:20][N:19]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: CS(=O)(=O)c1ccc(N)nc1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Temperature: 90 °C

Procedure:
4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1 g, 4.48 mmol, Eq: 1.00), 5-(methylsulfonyl)pyridin-2-amine (771 mg, 4.48 mmol, Eq: 1), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (388 mg, 671 μmol, Eq: 0.15) and cesium carbonate (5.1 g, 15.7 mmol, Eq: 3.5) were suspended in dioxane (80.0 ml). Finally tris (dibenzylideneacetone)dipalladium(0) (307 mg, 336 μmol, Eq: 0.075) was added. The reaction mixture was heated to 90° C. over night.
Reaction SMILES: CO[C:3](=[O:25])[CH:4]([C:8]1[N:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[CH2:5][CH:6]=O.[CH3:26][NH2:27].[BH4-].[Na+].O>CO.CO.CCOC(C)=O>[CH3:26][N:27]1[CH2:6][CH2:5][CH:4]([C:8]2[N:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:3]1=[O:25]
Reactant: CN
Reactant: COC(=O)C(CC=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2nc3ccc(C)cn3c2C2CCN(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a magnetically stirred solution of 2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-4-oxo-butyric acid methyl ester 36b (0.035 g, 0.0988 mmol) in methanol (1 mL) at room temperature under Ar atmosphere was added a 40% aqueous solution of methyl amine (0.009 mL, 0.0988 mmol). The reaction mixture was stirred for 1 h at room temperature. NaBH4 (0.0074 g, 0.197 mmol) was added at room temperature. After 30 min, water (30 mL) was added, and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (EtOAc, then 4:96 MeOH/EtOAc as eluent), which gave the title compound (0.006 g, 19%) as a white solid. (400 MHz, CDCl3) 2.31 (s, 3H), 2.33 (m, 2H), 2.39 (s, 3H), 3.00 (s, 3H), 3.51 (m, 2H), 4.41 (t, J=10.2 Hz, 1H), 7.02 (dd, J=1.1, 9.1 Hz, 1H), 7.24 (d, J=7.7 Hz, 2H), 7.25 (s, 1H), 7.53 (m, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2].N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39].C(=O)(O)[O-].[Na+]>ClCCl>[C:38]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:20]2[CH:19]=[C:18]([N:15]3[CH2:14][C@H:13]4[N:9]([CH2:10][CH2:11][CH2:12]4)[C:8]4[N:31]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[CH:6][C:7]=4[C:16]3=[O:17])[CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27]1)(=[O:40])[CH3:39]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(OC3CCNCC3)c1)C2=O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(OC3CCN(C(C)=O)CC3)c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Compound 147 (50.0 mg, 0.118 mmol) obtained in Example 147 was dissolved in dichloromethane (3 mL), cooled to 0° C., and stirred at 0° C. for 30 minutes after adding pyridine (0.0110 mL, 0.142 mmol) and acetyl chloride (0.0100 mL, 0.142 mmol). A saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by preparative TLC to give the title compound (Compound 150) (54.2 mg, quantitative).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([O:10]C)=[O:9])(=[O:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C)nc(NC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C(=O)O)cc(C)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.6 %

Procedure:
A mixture of methyl 2-acetamido-6-methylisonicotinate (1.99 g, 9.56 mmol, Step-1), 0.5M aqueous sodium hydroxide solution (20 mL, 10.0 mmol) and tetrahydrofuran (64 mL) is stirred at room temperature for 2.5 hours. The mixture is acidified by 2M hydrochloric acid and the organic solvent is removed by evaporation. The precipitate is collected by filtration and washed with diisopropyl ether to give 0.81 g (44% yield) of the title compound as a slight yellow solid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])O.[Na+]>C(O)C.O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(SCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.6 parts of sodium hydroxide was dissolved in ethanol. A solution of 5 parts of p-aminothiophenol in 20 parts of ethanol was added to the solution. The mixture thus obtained was cooled at 0° C. or below. A solution of 3.8 parts of chloroacetic acid and 3.4 parts of sodium hydrogencarbonate in 10 parts of water was added dropwise to the mixture, while the mixture was kept at 0° C. or below. After completion of the addition, the mixture was stirred at 0° C. for 3 hours and then adjusted at pH 3. A solid thus formed was filtered to obtain 5.4 parts of p-aminothiophenoxyacetic acid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C([OH:17])=C(F)C(F)=C(F)C=1F>>[C:1]([OH:8])(=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Product: O=C(O)c1ccccc1

Procedure:
The procedure was the same as for the polymer of Example 9(b) except that 0.125 mole (III) was replaced by a combination of 0.121 mole (III) and 0.004 mole benzoyl chloride. Inherent viscosity in pentafluorophenol was 0.57 dL/g. Thermal properties were very similar to Example 9(b).
Reaction SMILES: C(OC[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)C1C=CC=CC=1.C([Li])CCC.Br[C:21]1[CH:22]=[CH:23][C:24]2[N:29](CC3C=CC(OC)=CC=3)[C:28](=[O:39])[O:27][C:26]([CH2:44][NH:45][C:46](=[O:54])[C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)([C:40]([F:43])([F:42])[F:41])[C:25]=2[CH:55]=1.CN(C=O)C>C1COCC1.C(OCC)(=O)C.O.[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:53][C:50]1[CH:51]=[CH:52][C:47]([C:46]([NH:45][CH2:44][C:26]2([C:40]([F:41])([F:42])[F:43])[C:25]3[CH:55]=[C:21]([C:12]4[NH:11][N:10]=[CH:14][N:13]=4)[CH:22]=[CH:23][C:24]=3[NH:29][C:28](=[O:39])[O:27]2)=[O:54])=[CH:48][CH:49]=1
Reactant: c1ccc(COCn2cncn2)cc1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-c3ncn[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
To a stirring and cooling solution of 1-[(benzyloxy)methyl]-1H-1,2,4-triazole (41.7 mg, 0.22 mmol) in THF (0.3 mL) at −78° C., n-butyl lithium (92 μL, 2.4 M hexane solution) was added dropwise thereto. After the reaction solution was stirred at the same temperature for 10 minutes, a solution of zinc bromide (59.5 mg, 0.26 mmol) in THF (0.3 mL) was added thereto at −78° C. The solution was stirred at −78° C. for 20 minutes, and then the temperature of the solution was gradually raised to room temperature. To the reaction solution, tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (50 mg, 0.088 mmol) and DMF (0.5 mL) were added, and the solution was stirred overnight at 100° C. The temperature of the solution was brought to room temperature and the solution was diluted with ethyl acetate and water was added thereto. Then, the organic layer was separated. The organic layer was washed sequentially with an aqueous citric acid solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1), and 36.6 mg of a pale yellow liquid was obtained as a crude product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH2:16]Br)[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]=1[Br:7].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH2:16][N:33]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[S:30]([C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]=1[Br:7]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1c(Br)c(Br)n(Cc2ccc(F)cc2)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of ethyl 4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate (104.0 g, 0.209 mol) and ethyl N-[(4-methylphenyl)sulfonyl]glycinate (53.7 g, 0.209 mol, prepared by the method of: Ginzel, K. D.; Brungs, P.; Steckhan, E. Tetrahedron 1989, 45, 1691-1701) in anhydrous THF (1.5 L) was added NaH (60% in mineral oil, 8.409, 0.210 mol) in several small portions. The mixture was allowed to stir at room temperature for 16 hours. It was quenched with aq. NH4Cl solution, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and the residue was purified by column chromatography with ethyl acetate/hexane (1:4, v:v) to provide the title compound as glue-like material (124 g, 88% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:20]3[CH:21]=[N:22][O:23][C:19]=3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CCCc1cnoc1-c1ccccc1
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCc1cnoc1-c1ccccc1)Nc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 4-(1-imidazolyl)aniline (0.85 g), 4-(5-phenyl-4-isoxazolyl)butanoic acid (1.21 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.95 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.20 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(1-imidazolyl)phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide (1.68 g, yield 86%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:35]1[CH2:36][CH2:37][N:32]([C:22]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:26][CH:25]=2)=[O:23])[CH2:33][CH2:34]1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: C1CCNCC1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCCCC1
Yield: 64 %

Procedure:
4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid (89 mg) was reacted with piperidine as in General Procedure 8 to give the title compound as an orange solid (64% yield). m.p.=216° C., LCMS: m/z=515.27 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.61 (6H, m), 2.88 (1H, s), 2.95 (1H, s), 3.38 (2H, s), 3.49 (2H, m), 3.69 (2H, m), 4.62 (2H, s), 5.26 (1H, s), 6.60 (1H, s), 7.37 (5H, m), 7.51 (1H, s), 7.64 (1H, d, J=8.3 Hz), 7.75 (1H, d, J=1.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:41])[CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:49][CH2:50][CH2:51]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]([O:5][C:6](=[O:42])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:41])[CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:51][CH2:50][F:49])[CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCF)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.6 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-hydroxypyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 25e, 800 mg, 1.36 mmol) was dissolved in N,N-dimethylformamide (52 mL). Cesium carbonate (1.1 g, 3.4 mmol) and 2-fluoroethyltosylat (445 mg, 2.04 mmol) were added. The mixture was stirred at room temperature for 3.5 hours, additional cesium carbonate (70 mg, 0.21 mmol) and 2-fluoroethyltosylate (28 mg, 0.13 mmol) were added and stirring was continued for 2.5 hours at room temperature and 17 hours at 5° C. The mixture was quenched by addition of saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane 20 to 100% followed by dioxane in ethyl acetate 0 to 50%) to yield 670 mg of tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-fluoroethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat.