Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:13](=[O:24])[NH:14][C@H:15]1[CH2:21][CH2:20][C@@H:19]([CH3:22])[NH:18][CH2:17][CH:16]1[OH:23])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([N:34]=[C:35]=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]>>[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([NH:34][C:35]([N:18]1[CH2:17][CH:16]([OH:23])[C@@H:15]([NH:14][C:13](=[O:24])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:25])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:21][CH2:20][C@H:19]1[CH3:22])=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)[C@H](CC(C)C)N=C=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NCC1O
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
[(S)-3-Methyl-1-((4S,7R)-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (Example 12a–i, 500 mg, 1.4 mmol) was dissolved in TEF (7 ml), then (S)-(−)-2-isocyanato-4-methylvaleric acid methyl ester (180 mg, 1.05 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 1% to 2% MeOH/CH2Cl2) to yield the title compound as a white solid (91%, 506 mg): LC/Electrospray mass spec: M+H+=529.4.
Reaction SMILES: Cl[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:21]=[N:22][CH:23]=1
Reactant: Clc1nn2ccccc2c1-c1ccccc1
Reactant: OB(O)c1cncc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Fc1cncc(-c2nn3ccccc3c2-c2ccccc2)c1
Temperature: 100 °C

Procedure:
A solution of 2-chloro-3-phenylpyrazolo[1,5-a]pyridine (37-1; 0.2 g, 0.88 mmol), (5-fluoropyridin-3-yl)boronic acid (0.15 g, 1.05 mmol), and potassium phosphate tribasic (0.66 g, 2.64 mmol) in tetrahydrofuran (10 mL) was degassed for 10 min. Then 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.065 g, 0.16 mmol) and palladium acetate (0.02 g, 0.08 mmol) were added and heated in a sealed tube at 100° C. for 18 h. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the resulting residue by prep HPLC (Analytical Conditions: Column: Xbridge C18 (250 mm×4.6 mm×5 m), Mobile phase (A): water, Mobile phase (B): Acetonitrile, Flow rate: 1.0 mL/min, GradientT/% B:0/20, 8/50, 25/50, 27/20, 30/20) provided 2-(5-fluoropyridin-3-yl)-3-phenylpyrazolo[1,5-a]pyridine. 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.79 (d, J=8.0 Hz, 1 H), 8.57-8.56 (d, J=4.0 Hz, 2 H), 7.76-7.73 (d, J=12.0 Hz, 1 H), 7.61-7.59 (d, J=8.0 Hz, 1 H), 7.49-7.45 (m, 1 H). MS (M+1): 290.1.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[NH:17]([CH2:21][CH2:22][CH2:23]Br)[C:18]([CH3:20])=[O:19]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:23][CH2:22][CH2:21][NH:17][C:18](=[O:19])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: CC(=O)NCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 70.7 %

Procedure:
191 mg of 3-(1-piperidinylmethyl)phenol was dissolved in 10 ml of ethanol, and 116 mg of potassium hydroxide was added. The mixture was heated under reflux, and a solution of 360 mg of 3-acetamino-1-bromopropane in 3 ml of ethanol. The reaction mixture was heated under reflux for 8 hours, and the solvent was distilled off under reduced pressure. Water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 205 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide as an oil. The resulting product coincided with the product obtained in Example 2.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:11])[C@@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:10][C:6]1([CH3:9])[O:5][C@H:4]([C:3]([Cl:11])=[N:2][O:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:8][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@H](C(Cl)=NO)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A solution of (S)—N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (9.88 g, 55.01 mmol) in THF (200 mL) at 0° C. was added methanesulfonyl chloride (4.703 ml, 60.51 mmol), followed by N,N-diisopropylethylamine (10.54 ml, 60.51 mmol) and the reaction was stirred for 1 hour at ambient temperature, filtered and concentrated in vacuo. The residue was purified over silica gel (25 to 100% ethyl acetate in hexanes) to afford (S)-2,2-dimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (12.28 g, 47.65 mmol, 86.63% yield) as colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[OH:33])=[O:19].O>CN(C=O)C>[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[O:33][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
tert-Butyl bromoacetate (0.10 ml, 0.65 mmol, 1.3 equiv) was added to a mixture of NaOt-Bu (60 mg, 1.2 equiv) and 6-chloro-1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (150 mg, 0.5 mmol) in DMF (6 ml) and stirred at 60° C. for 2.5 hr then at RT for 3 days. Water was added and the mixture was extracted with EtOAc. After removal of solvent, purification by column chromatography gave 140 mg (68%) of 1-tert-butoxycarbonylmethoxy-6-chloro-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as orange solids.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[F:15][C:16]1[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:15][C:16]1[CH:26]=[C:25]([NH:27][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(F)cc(N)cc1F
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: CCOC(=O)c1c(F)cc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1F
Yield: 67.8 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and ethyl 2,6-difluoro-4-aminobenzoate (148 mg, 0.736 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] to obtain ethyl 2,6-difluoro-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (105 mg, 68%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([OH:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH:11]1(O)[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:10][C:8]2[CH:9]=[C:4]3[CH:3]=[CH:2][NH:1][C:5]3=[N:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: OC1CCCC1
Product: c1cc2cc(OC3CCCC3)cnc2[nH]1

Procedure:
5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine P-0001 was synthesized in one step from 1H-Pyrrolo[2,3-b]pyridin-5-ol 6 and cyclopentanol 7 as shown in Scheme 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C@H:8]1[NH:11][C:10](=[O:12])[C@@H:9]1[C@H:13]([O:15]C(OCC1C=CC=CC=1)=O)[CH3:14])=[CH2:7])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[NH:11][C:10](=[O:12])[C@@H:9]1[C@H:13]([OH:15])[CH3:14])[CH3:7])=[O:5])[CH3:2]
Reactant: C=C(C(=O)OCC)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O

Procedure:
A solution of (3S,4S)-4-(1-ethoxycarbonylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (40.0 g in ethanol (600 ml) was hydrogenated under hydrogen atmosphere in the presence of 10% Pd/C (20. 0 g) at room temperature for 3 hours. The mixture was filtered, and the filtrate was evaporated in vacuo to give (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-hydroxyethyl)-2-azetidinone as a yellowish oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([Cl:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:7]1([CH3:24])[CH3:23])=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:23][C:7]1([CH3:24])[CH:8]([CH:9]=[C:10]([Cl:22])[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=2)[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)O
Yield: 68.2 %

Procedure:
30.8 g (0.085 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid ethyl ester were dissolved in 100 ml of ethanol, a solution of 4 g (0.1 mol) of sodium hydroxide in 100 ml of water was then added and the mixture was heated to the reflux temperature for 4 hours, while stirring. The ethanol was then distilled off under a waterpump vacuum, the residue was taken up in 300 ml of warm water and the mixture was extracted once with 300 ml of methylene chloride. The aqueous phase was separated off, acidified with concentrated hydrochloric acid and then extracted with 2 times 300 ml of methylene chloride. The organic phase was then separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vaccum. Last residues of solvent were removed by brief incipient distillation under 2 mm Hg at a bath temperature of 60° C. 19.4 g (68.3% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid (cis and trans, E and Z isomer mixture) were then obtained as a very viscous yellow oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C([Li])CCC.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>CCOCC>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([Sn:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: C[Sn](C)(C)Cl
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Sn](C)(C)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
2,6-Di(trifluoromethyl)-4-(trimethylstannyl)pyridine was prepared from 8.7 g 4-bromo-2,6-di(trifluoromethyl)pyridine, 12.4 ml butyllithium (24M in hexane) and 6 g trimethyltin chloride in 200 ml ether according to the procedure of Example 3, part (g), and was obtained (11 g) as a yellow semi-solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[CH:13]1[C:18]([O:19][CH2:20][CH2:21][OH:22])=[CH:17][CH:16]=[C:15]([O:23][CH2:24]CO)[CH:14]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:22][CH2:21][CH2:20][O:19][C:18]1[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH2:1][O:2][C:3](=[O:12])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: OCCOc1ccc(OCCO)cc1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(OCCOc1ccc(OCCO)cc1)c1ccc(O)c(Cl)c1
Temperature: 0 °C
Yield: 94.1 %

Procedure:
A 300-ml eggplant type flask was charged with 16.3 g of 3-chloro-4-hydroxybenzoic acid methyl ester, 87 g of 1,4-(2-hydroxyethoxy)benzene and further with 0.8 g of PTD (p-toluenesulfonic acid monohydrate) as a catalyst to form a mixture. The mixture was stirred with heating on an oil bath, externally regulated at a temperature of 150° C., to react the mixture for 5 hours. The reaction mixture was poured into ice water followed by extracting with ethyl acetate, drying over anhydrous magnesium sulfate, concentrating and separating with a column using ethylacetate/n-hexane to obtain 29 g of 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester (melting point: 87° to 88° C.). To 50 ml of an acetonitrile solution containing 10 g of the 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester, 13.9 g of N-methylpyrrolidone and further 8.78 g of methacrylic acid chloride were added with stirring to form a solution. The solution was stirred at 40° C. for 8 hours to react the solution. Thereafter, excess methacrylic acid chloride was removed by means of vacuum distillation. The reaction mixture remaining therein was poured into ice water and the precipitated crystals were obtained by filtration. The crystals were recrystallized with ethylacetate/n-hexane to obtain 3-chloro-4-hydroxybenzoic acid 2-[4-(β-methacryloyloxyethoxy)phenoxy]ethyl ester (melting point: 105° to 106° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][CH:43]=[CH:42][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][CH2:30][O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1.O[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57]>>[C:56]([NH:55][CH2:54][CH2:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[O:31][CH2:30][CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:42]=[CH:43][CH:44]=[CH:45][C:2]=3[Cl:1])=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)(=[O:58])[CH3:57]
Reactant: CC(=O)NCCc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOc3ccccc3Cl)cc2)cc1
Product: CC(=O)NCCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOc2ccccc2Cl)cc1

Procedure:
Analogously to Method G, 0.28 g of tert-butyl 4-{4-[3-(2-chlorophenoxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 123b) and 0.15 g of N-[2-(2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.65 (EtOAc); Rt=5.73.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.[NH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]2[S:29][C:28]3[N:30]=[CH:31][CH:32]=[N:33][C:27]=3[N:26]([CH2:34][O:35][CH3:36])[C:25]=2[CH:37]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:36][O:35][CH2:34][N:26]1[C:25]2[CH:37]=[C:21]([CH2:20][NH:19][C:7]([C:3]3[CH:4]=[N:5][O:6][C:2]=3[CH3:1])=[O:9])[CH:22]=[CH:23][C:24]=2[S:29][C:28]2[N:30]=[CH:31][CH:32]=[N:33][C:27]1=2
Reactant: COCN1c2cc(CN)ccc2Sc2nccnc21
Reactant: Cc1oncc1C(=O)O
Agent: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCN1c2cc(CNC(=O)c3cnoc3C)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of 520 mg of 5-methyl-1,2-oxazole-4-carboxylic acid and 0.75 ml of triethylamine in tetrahydrofuran (10 ml) was ice-cooled. After adding 0.8 ml of diethyl chlorophosphate, the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 5 ml of a solution of 750 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine in tetrahydrofuran and the resulting mixture was stirred at room temperature for 1.5 hours. Next, the reaction mixture was distributed into ethyl acetate and an aqueous solution of ammonium chloride. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 520 mg of N-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-5-methyl-1,2-oxazole-4-carboxamide. Further, the product was treated by the same method as the one of Example 434 to thereby give 310 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C(B(CC)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)C>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reactant: CCB(CC)c1cccnc1
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: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OC(C)(C)C
Yield: 47 %

Procedure:
A mixture of N-Boc-4-iodo-L-phenylalanine methyl ester (810 mg, 2 mmol, Lei, H et al, ibid) tetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol), aqueous sodium carbonate (4 mmol, 2 ml of a 2M solution) and diethyl(3-pyridyl)borane (294 mg, 2 mmol) in dimethoxyethane (30 ml) was refluxed for 6 hr. The solvent was removed in vacuo, the residue dissolved in EtOAc (100 ml) and washed with water (30 ml) aqueous sodium thiosulphate (20 ml) and brine (30 ml) dried (Na2SO4)and evaporated in vacuo. Purification by column chromatography (SiO2, EtOAc/hexane 30:70) gave the title compound (335 mg,47%) as a yellow oil. δH (CDCl3) 8.81 (1 H, d, J 1.7 Hz, PyrH), 8.56 (1 H, dd, J 4.8, 1.6 Hz, PyrH), 7.84 (1 H, dt, J 7.9, 2.0 Hz, PyrH), 7.49 (2 H, d, J 8.2 Hz, ArH), 7.34 (1 H, ddd, J 7.9, 4.8, 0.6 Hz, PyrH), 7.23 (2 H, d, J 8.2 Hz, ArH), 5.09 (1 H, br d, J 7.8 Hz, CONH), 4.62 (1 H, br q, J 6.8 Hz, CHα), 3.73 (3 H, s, CO2Me), 3.18 (1 H, dd, J 13.8, 5.6 Hz, CHAHBAr), 3.07 (1 H, dd, J 13.8, 5.8 Hz, CHAHBAr) and 1.40 (9 H, s, tBu); m/z (ESI, 15 V) 357 (MH+).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.C1COCC1.CO.[Pd].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C@H:9]1[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]2[S:4][CH:3]=[C:2]([CH:20]([CH3:22])[CH3:21])[C:11]=2[O:10]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: COCCOC
Product: CC(C)c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (1.15 g) obtained in Example 12, steps 1-4, isopropenylboronic acid pinacol ester (0.807 mL), dichlorobis(triphenylphosphine)palladium (116 mg) and potassium carbonate (1.37 g) in DME-water (1:1, 30 mL) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→12% ethyl acetate/hexane) to give a colorless oil. To a solution of the obtained oil in THF-MeOH (2:1, 30 mL) was added 10% palladium on carbon (100 mg), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction solution was filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (926 mg, 90%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[CH:21]=1.[C:28]([O-])([O-])=O.[K+].[K+].C(I)I>CN(C=O)C>[O:26]1[C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:3]3[CH:4]=[C:5]([C@H:8]4[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]4)[CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:21][C:22]=2[O:27][CH2:28]1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c(O)c3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(3,4-dihydroxybenzyl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (E055) (30 mg, 0.0756 mmole) in DMF (4 mL) were added K2CO3 and CH2I2 (7.3 μL). The reaction mixture was stirred at 100° C. overnight and filtered. The resulting crude solution was purified by reverse phase preparative HPLC to yield the title compound (16 mg, 0.0401 mmole, 53%) as a brown gum.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(OC)=C(F)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:26]1([CH2:25][N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC)c(F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1ccc(NCC2CCCC2)cc1F
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1F

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-fluoro-4-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)Nc1nccnc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)Nc1nccnc1S2
Yield: 100.4 %

Procedure:
To 50 ml of a solution of 2 g of methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate in methanol was added 0.8 g of sodium hydroxide and the resulting mixture was heated under reflux for 1 hour. After distilling off the methanol under reduced pressure, a 1 N aqueous solution of hydrochloric acid was added thereto so as to adjust the pH value to 5 to 6. Then the mixture was extracted with ethyl acetate/dichloromethane and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 1.9 g of the title compound was obtained as a yellow solid.