Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([N:24]([CH2:31][CH3:32])[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH3:23])=[CH:20][C:14]=2[O:13]1)C1C=CC=CC=1>[Pd].CO>[NH2:10][CH2:11][CH:12]1[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([N:24]([CH2:31][CH3:32])[C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH3:23])=[CH:20][C:14]=2[O:13]1
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2
Agent: [Pd]
Solvent: CO
Product: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CN)O2
Yield: 79.5 %

Procedure:
To 987 mg (2.1 mmol) of 2I was added 50 mL of anhydrous methanol followed by 150 mg of 10% Pd—C. This mixture was hydrogenated under atmospheric pressure 18 hours, filtered and the residue was washed with 50 mL of methanol. The combined filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography using 5% methanol in ethyl acetate to give 558 mg (1.67 mmol, 79%) of 2J as a colorless gum (M+H, 333).
Reaction SMILES: [NH2:1][C:2]([CH2:4][NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:3]>CO>[C:14]1([C:13]2[N:5]([CH2:4][C:2]([NH2:1])=[O:3])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1ccccc1
Solvent: CO
Product: NC(=O)Cn1c(-c2ccccc2)nc2cccnc21
Yield: 45 %

Procedure:
A 7.62-g (0.028 mole) sample of N-[2-[[(aminocarbonyl)methyl]-amino]-3-pyridinyl]benzamide heated in glass in a Wood's metal bath under a flow of nitrogen at 200° C. for 7 minutes. The green solid residue was broken up with a glass rod in methanol and the solid was filtered off. The filtrate was concentrated and the precipitate which formed, was separated by filtering twice. The solids were combined and recrystallized from boiling water to give 3.19 g (45%) of white needles which were dried under high vacuum at room temperature overnight, mp. 226°-7° C.
Reaction SMILES: [BH4-].[Li+].[CH:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][C:4]=1[C:16](OCC)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH:3]1[N:7]2[C:8]3[C:13]([NH:14][CH2:15][C:6]2=[N:5][C:4]=1[CH2:16][OH:17])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCOC(=O)c1cn2c(cnc3ccccc32)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: OCc1cn2c(n1)CNc1ccccc1-2
Yield: 70.7 %

Procedure:
2.8 g of lithium borohydride were added to a solution of 10 g of ethyl imidazo-[1,2-a]-quinoxaline-2-carboxylate of Step B in 230 ml of anhydrous tetrahydrofuran and the mixture was stirred at reflux for 18 hours. The resulting yellow suspension was poured into dilute hydrochloric acid to react with the boron complex and the mixture was made alkaline with sodium carbonate addition. The mixture was extracted with ethyl acetate and the organic phase was evaporated to dryness to obtain 5.9 g of 4,5-dihydro-imidazo-[1,2-a]-quinoxaline-2-methanol in the form of a buff crystaline solid melting at 172°-174° C. after crystallization from ethyl acetate to obtain a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Br:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:29]2[CH2:30][CH2:31][C@H:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Br:19])[CH:21]=3)[C@H:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: Brc1cccc([C@H]2CCNC[C@H]2c2ccccc2)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=556.0 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-4-(3-bromo-phenyl)-3-phenyl-piperidine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:29]=[O:30])=[C:5]([C:25]([O:27][CH3:28])=[O:26])[N:6]2[CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCCC1.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]>[CH:29]([C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:40])[N:6]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26])=[O:30]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1c(C=O)c2c(Br)cccc2n1CCCOc1cccc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1c(C=O)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of EXAMPLE 107B (0.5 g) and o-tolylboronic acid (175 mg) in tetrahydrofuran (5 ml) was added tris(dibenzylideneacetone)dipalladium(0) (25 mg), tri-t-butyl-phosphonium tetrafluoroborate (16 mg) and CsF (489 mg). The mixture was purged with Argon and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. After filtration, concentration of the solvent and column purification (5% ethyl acetate in hexane) provided EXAMPLE 107C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(O)=O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:23])[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccc3c(N)ncnn23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(Cc2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 3 h
Yield: 192.3 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 3-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]azetidine-1-carboxylate (325 mg, 1.07 mmol) in DMF (5 mL) and AcOH (1 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (153 mg, 0.54 mmol) in 3 portions over 10 min. The mixture was stirred at −20° C. for 3 h. Aqueous K2CO3 (5%, 20 mL) was added and the mixture was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide 397 mg (97%) of the desired product, which contained minor impurities. ES-MS m/z 382.08 [M+H]+, HPLC RT (min) 3.05.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][CH:7]=1.[CH:33](/B(O)O)=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2](/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:3]=2)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:9]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:24])[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: OB(O)/C=C/c1ccccc1
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(/C=C/c3ccccc3)nc12

Procedure:
The precursor to Example #W.1,8-ethyl-1-methyl-7-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine, was prepared as shown in Scheme B. 2-Bromo-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (Preparation #5) and (E)-styreneboronic acid are reacted following conditions given in D to give (E)-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-2-styryl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine. This alkene is then cleaved following the conditions given in E to give an aldehyde, reduced using conditions described in F to give an alcohol, converted to an azide following G, and then reduced following conditions given in I to give (7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine. The amine is then coupled with Ac2O following conditions described in J.2 and then cyclized using the conditions described in L.1 with mercury(II) trifluoroacetate as the mercury salt to give the precursor to Example #W.1. The reaction sequence detailed above is translated in the preparations and examples section to “prepared using D from Preparation #5 with (E)-styreneboronic acid, E, F, G, I, J.2 with Ac2O and L.1 with mercury(II) trifluoracetate.”
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)O1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)=[CH:7][CH:6]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:21]([CH3:27])[CH:22]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (−)-5-[3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (CAS RN 214360-51-7). The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 100:0). Light brown solid. MS (ESI+): m/z=521.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][S:5][C:6]=1[Cl:7].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[C:3]([CH:8]=[O:9])=[N:4][S:5][C:6]=1[Cl:7]
Reactant: OCc1nsc(Cl)c1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1nsc(Cl)c1Cl
Yield: 65 %

Procedure:
Dissolve (4,5-dichloroisothiazol-3-yl)-methanol (300 mg, 1.63 mmol) in dichloromethane (10 mL). Add pyridinium chlorochromate (703 mg, 3.26 mmol) and stir for 2 h. Pour the mixture onto a column of silica gel, eluting with dichloromethane and concentrate to give 4,5-dichloroisothiazol-3-carbaldehyde as a white solid (193 mg, 65%). 1H NMR (400 MHz, MeOH-d4) δ 9.96 (s, 1H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Na].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:9])([CH3:8])[CH2:10][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Yield: 78.4 %

Procedure:
A mixture of 2.6 g (0.010 mol) of (1,1'-biphenyl-4-yl)chloromethyldimethylsilane and 1.1 g (0.012 mol) of 1,2,4-triazole sodium salt in 5 ml of dimethylformamide was warmed to 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.3 g of colorless solid, m.p. 79°-86°. Recrystallization from a mixture of 25 ml of hexanes and 2 ml of ethyl acetate gave 1.1 g (38%) of the title compound: m.p. 92°-93°; ir (Nujol®) 1255, 1130, 1000, 825, 760, 695 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 3.9 (2H, s), 7.2-7.7 (9H, m), 7.8 (1H, s), 7.9 (1H, s); analysis for C17H19N3Si (mw 293.43):
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([S:25][CH3:26])[C:19]=2[O:18][CH2:17][CH2:16][CH:15]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:26][S:25][C:24]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:14][C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCOc2c(SC)cccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1=Cc2cccc(SC)c2OCC1
Yield: 85.7 %

Procedure:
A solution of p-toluenesulfonic acid monohydrate (109 mg) and ethyl 5-hydroxy-9-methylthio-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (cis and trans mixture, 1.62 g) in toluene (32 ml) was heated to reflux for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and evaporated in vacuo to give 1.60 g of crude product, which was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (30:1) to afford ethyl 2,3-dihydro-9-methylthio-1-benzoxepin-4-carboxylate (1.30 g, colorless needles).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:23])(=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][C:6]=2[CH:28]=1.B([O-])([O-])O[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:41]([O:40][CH2:39][CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:13]=[CH:14][C:15]([S:18](=[O:23])(=[O:22])[N:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=4)[CH2:10][CH2:9][C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][C:6]=3[CH:28]=2)=[CH:36][CH:35]=1)[CH2:42][CH2:43][CH3:44]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccc(S(=O)(=O)N(C)C)cc2)CC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A mixture of methyl 7-bromo-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g), 4-(2-butoxyethoxy)phenyl borate (0.19 g), 1M potassium carbonate solution (2 ml), ethanol (2 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH:25]=[CH:24]2>CO>[OH:1][C@@H:2]([CH2:18][N:34]1[CH2:33][CH2:32][CH:31]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:27]=2)[CH2:36][CH2:35]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: COc1ccc2cc(C3CCNCC3)ccc2c1
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Solvent: CO
Product: COc1ccc2cc(C3CCN(C[C@H](O)COc4ccccc4C=C4CCOC4=O)CC3)ccc2c1
Yield: 42.1 %

Procedure:
(S)-α-(2′-(2,3-Epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (1.2 g) and 4-(6-methoxynaphthalen-2-yl)piperidine (1.2 g) were dissolved in methanol (50 ml), and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.0 g), melting point 148–150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.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.CN(C)C(=O)C>[O:25]=[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:3]=1)[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(Br)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 15.7 %

Procedure:
To a 25 ml of flask was added ethyl 2-((S)-1-(3-bromophenylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 107.1.B (165 mg, 0.41 mmole), pyridine-4-yl boronic acid (53 mg, 0.43 mmole), tetrakis(triphenylphosphine)palladium (94 mg, 0.081 mmole), potassium carbonate (112 mg, 0.81 mmole), 0.2 ml of water and 2 ml of N,N-dimethylacetamide. The reaction mixture was stirred at 80° C. for 5 hours. Then, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 107.1.C (26 mg, 16% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.53 (s, 1H), 8.67 (d, J=5.8 Hz, 2H), 8.01 (s, 1H), 7.70-7.27 (m, 10H), 4.17-4.10 (m, 2H), 3.50 (dd, J=9.0, 4.3 Hz, 1H), 3.36 (s, 2H,), 3.35 (dd, J=14.1, 4.3 Hz, 1H), 2.92 (dd, J=14.1, 9.0 Hz, 1H), 1.99 (brs, 1H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>CO.O>[CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
In 6 ml of methanol is dissolved 0.57 g of methyl 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetate. After adding 0.72 ml of 5 mol/L solution of sodium hydroxide, the mixture thus obtained is stirred at ambient temperature for one hour and thereafter at 50-60° C. for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.45 g of 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetic acid is obtained as a colorless crystalline product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=O)[O:8][C:7](=[O:12])[C:6]=2[C:13]=1[O:14][CH3:15]>CO>[NH2:10][C:5]1[C:6]([C:7]([O:8][CH3:9])=[O:12])=[C:13]([O:14][CH3:15])[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COc1c(Br)ccc2[nH]c(=O)oc(=O)c12
Solvent: CO
Product: COC(=O)c1c(N)ccc(Br)c1OC
Yield: 87 %

Procedure:
A solution of Example 385B (6.83 g, 25.2 mmol) in anhydrous methanol (300 mL) was refluxed for 48 hours. The solution was concentrated and the residue was purified by chromatography on a silica gel column eluting with 20% ethyl acetate/hexane to give the desired product 5.7 g, 87.2% yield. 1H NMR (DMSO-d6) δ 3.70 (s, 3H), 3.82 (s, 3H), 5.92 (s, 2H), 6.45 (d, 1H), 7.30 (d, 1H); MS (ESI(−)) m/e 258, 260 (M−H)−.
Reaction SMILES: CO[C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([CH3:21])[C:18]([OH:20])=[O:19].C(OC(=O)C)(=O)C>I>[CH3:21][CH:17]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:3]=2[O:19][C:18]1=[O:20]
Reactant: COc1c(Sc2ccccc2Cl)cccc1C(C)C(=O)O
Agent: I
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)Oc2c(Sc3ccccc3Cl)cccc21
Yield: 81.8 %

Procedure:
2-[2-Methoxy-3-(2-chlorophenylthio)phenyl]propionic acid (1.9 g), acetic anhydride (5 ml) and hydriodic acid (58%, 10 ml) were treated in a similar manner to that of Example 21-(9) to give oily 3-methyl-7-(2-chlorophenylthio)-2,3-dihydrobenzofuran-2-one (1.4 g). This product was subjected to column chromatography (silica gel 30 g, benzene), and the resultant oily substance was crystallized with ethanol to give crystaline product (1.2 g), mp. 63°-64° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:21]=[CH2:22])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:23][CH3:24])=O)(C)(C)C.Cl.[CH2:26](Cl)Cl>O1CCOCC1>[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:21]=[CH2:22])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:23][CH3:24])(=[O:5])[CH3:26]
Reactant: ClCCl
Reactant: C=Cc1ccc2c(c1CCCN)OC(CC)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1CCCN)OC(CC)N2C(C)=O
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of N-t-butoxycarbonyl 7-(3-aminopropyl)-6-vinyl-2-ethylbenzoxazole (30 mg, 0.091 mmol), in methylene chloride (1 mL) was treated with 4 M HCl in dioxane (1 mL) and stirred for 2 hours. The solvent was evaporated and the residue was taken up in pyridine (2 mL) and treated with acetic anhydride (100 μL). After stirring for 2 hours, the reaction was diluted with EtOAc (5 mL) and washed with saturated aqueous copper (II) sulfate (2×5 mL). The organic layer was dried with magnesium sulfate and evaporated. The product was purified on a silica gel column and eluted with 25% EtOAc/hexanes to give a clear oil (16 mg, 64%).