Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[O:20][CH2:21][C:22]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([O:37][CH2:38][C:39](=[O:41])[CH3:40])[CH:35]=3)[O:30][C:29]3[C:24]2=[CH:25][C:26](Br)=[CH:27][CH:28]=3)[N:23]=1.O1CCOCC1>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.O>[NH2:18][C:19]1[O:20][CH2:21][C:22]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([O:37][CH2:38][C:39](=[O:41])[CH3:40])[CH:35]=3)[O:30][C:29]3[C:24]2=[CH:25][C:26]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:11])=[CH:27][CH:28]=3)[N:23]=1
Reactant: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cc(Cl)ccc1F
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: C1COCCO1
Solvent: O
Product: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(-c3cc(Cl)ccc3F)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with 5-chloro-2-fluorophenylboronic acid (0.431 g, 2.474 mmol), palladiumtetrakis (0.057 g, 0.049 mmol), potassium carbonate (0.684 g, 4.95 mmol), and 1-(2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one (0.400 g, 0.990 mmol) was treated with 5 mL dioxane followed by 1 mL water. The vial was flushed with argon and was heated to 80° C. for 3 hours. The reaction mixture was diluted with EtOAc (25 mL) and dried over MgSO4. The organic layers were combined and concentrated, and the crude residue was purified by column chromatography yielding 1-(2′-amino-7-(5-chloro-2-fluorophenyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one. MS m/z=454.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[C:12]([C@@H:16]1[CH2:21][CH2:20][C@H:19](O)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cc(OC3CCC(C(C)(C)C)CC3)ccc2s1

Procedure:
2-Methyl-benzothiazol-5-ol (2.5 g, 0.015 mol), cis-4-tert-butylcyclohexanol (2.84 g, 0.0182 mol), and Triphenylphosphine (4.76 g, 0.0182 mol) were combined in dry Toluene (100 mL, 1 mol) and stirred under nitrogen. Diisopropyl azodicarboxylate (3.6 mL, 0.018 mol) was added dropwise. The reaction was then stirred at RT overnight. Reaction was then concentrated to dryness and then residue was dissolved in DCM and 5 g of SiO2 was added. Solvent was removed under reduced pressure and resulting powder was loaded onto a 40 g column and purified via column chromatography using a gradient of 0-60% EtOAC/Hexanes.
Reaction SMILES: N[C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].C([OH:20])C>[OH-].[Na+]>[C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:20])=[O:3]
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 24 h

Procedure:
A mixture of 4-aminocarbonylphenoxy phenyl methane (10g) in ethanol (100ml) and sodium hydroxide (100ml., 10N) was heated under reflux with vigorous stirring for 24hrs. The reaction mixture was cooled, the precipitated sodium salt was filtered off washed with a little water then converted to 4-carboxyphenoxy phenyl methane by boiling under reflux with concentrated hydrochloric acid (100ml) for 6hr. Dilution of the cooled mixture and extraction with ether yielded 4-carboxyphenoxy phenyl methane, m.p. 188°.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][O:46]C2CCC=C2)[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][OH:46])[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Reaction time: 0.58 h
Yield: 53.7 %

Procedure:
To a suspension of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio ]-3-cephem-4-carboxylate (syn isomer)(1.06 g) in anisole (2 ml) was added trifluoroacetic acid (4 ml) under ice-cooling and the mixture was stirred for 35 minutes at the same temperature. The mixture was poured into diisopropyl ether (250 ml). The precipitate was collected, washed with diisopropyl ether and dried over phosphorus pentoxide. The precipitate was dissolved in a mixture of tetrahydrofuran (50 ml), sodium bicarbonate (242 mg), water (40 ml) and ethyl acetate (50 ml). The aqueous layer was separated and adjusted to pH 2 with 1N hydrochloric acid. The resultant precipitate was collected, washed with cold water and dried over phosphorus pentoxide to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylic acid (syn isomer) (390 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[C:11](#[N:14])[CH:12]=[CH2:13].N1C=CC=CC=1>O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:13][CH2:12][C:11]#[N:14])[N:7]=1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Reactant: C=CC#N
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(=O)c(Br)nn(CCC#N)c1=O
Yield: 93.2 %

Procedure:
2.4 g (11.6 mmol) of triazine 2a and 7 ml (106 mmol) of acrylonitrile are placed in 24 ml of a solution of pyridine and water (1:1) at reflux for 3 h. After concentration the reaction medium is extracted by AcOEt, and after drying on MgSO4 the organic phases are dry concentrated. 2.8 g of solid 3a are isolated and then washed with ether (yield=93%). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 70:30, Rf=0.18.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[F:14].C[O:16][B:17]([O:20]C)[O:18]C.Cl>CCCCCC.O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:16][B:17]([OH:20])[OH:18])=[C:8]([F:14])[CH:9]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Cl)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)Oc1ccc(Cl)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, n-butyllithium (1.6 mol/L-n-hexane, 18.8 mL) was added dropwise at −78° C. to a solution of n-hexane (11 mL) and tetrahydrofuran (30 mL). Then, a solution of 1-bromo-4-chloro-2-fluorobenzene (5.24 g) in n-hexane (15 mL) and tetrahydrofuran (15 mL) was added dropwise. The mixture was stirred at −78° C. for one hour, boric acid trimethyl ester (4.0 mL) in tetrahydrofuran (15 mL) was added dropwise. The mixture was raised to room temperature. After 2 hr, aqueous hydrochloric acid solution (3 mol/L, 120 mL) was added, and the mixture was extracted with diethyl ether (100 mL). The aqueous layer was extracted again with diethyl ether (100 mL), and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure, n-hexane was added to the residue, and the precipitated solid was collected by filtration to give the title compound (2.0 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([O:17][CH2:1][O:2][CH3:3])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2
Reactant: COCCl
Reactant: O=c1ccc2cc(O)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(Br)c2oc(=O)ccc2c1
Reaction time: 8 h

Procedure:
Add BBr3 (0.75 mL, 8 mmol) to preparation 3(662 mg, 2.0 mmol) in 20 mL of dichloromethane at 0° C. Let stir for 15 min. Add 8 mL of methanol and then concentrate. Adsorb to 6 g of silica gel and purify by flash chromatography (40 g, 10-50% A/B, A=10% MeOH in EtOAc, B=hexanes) to give 476 mg of 8-Bromo-6-hydroxy-chromen-2-one (3). Add chloromethyl methyl ether (0.18 mL) to a solution of 8-bromo-6-hydroxy-chromen-2-one (476 mg, 1.97 mmol) and K2CO3 (660 mg, 4.77 mmol) in 10 of DMF. Let the solution stir overnight, add 0.09 mL more chloromethyl methyl ether, let stir 2 hrs, dilute with EtOAc, wash with water, 1:1 water:brine, brine, dry (Na2SO4), filter and concentrate to yield 524 mg (1.84 mmol, 93%) of preparation 5. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, 1H, J=9.2 Hz), 7.50 (d, 1H, J=2.6 Hz), 7.12 (d, 1H, J=2.6 Hz), 6.46 (d, 1H, J=9.7 Hz), 5.20 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc3n(c2c1)CCC3
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2nc3n(c2c1)CCC3
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
8.65 g of 7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (2A00) prepared according to W. Reppe Ann. 596 (1955) p. 209 are suspended in 50 cm3 of benzene. To this suspension is added dropwise 6.2 g of acetic anhydride. The mixture is boiled for 15 min and after cooling the precipitated acetyl compound is sucked off. Recrystallization from ethanol yields 7.3 g of 7-acetylamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole. Melting point: 250°-255°C. Two further recrystallizations from ethanol raise the melting point to 260°-262°C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][C:13]#[CH:14]>C1COCC1.CCOC(C)=O.[Cu]I>[Br:8][C:6]1[N:7]=[C:2]([C:14]#[C:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C#CC[Si](C)(C)C
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CC#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
3,5-Dibromo-pyrazin-2-ylamine (1.70 g, 6.70 mmol), TEA (1.1 mL, 8.04 mmol), PdCl2(PPh3)4 (28 mg, 0.040 mmol), and CuI (15 mg, 0.080 mmol) were dissolved in THF (17 mL), cooled to RT and Trimethyl-prop-2-ynyl-silane (1.0 mL, 6.7 mmol) was added at 0° C., allowed to warm up to RT and stirred overnight. The reaction mixture was diluted with EtOAc, washed with H2O and saturated aqueous NaHCO3, dried (MgSO4) and concentrated, and purified by SiO2 chromatography (80 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 1.66 g of 5-bromo-3-(3-trimethylsilanyl-prop-1-ynyl)-pyrazin-2-ylamine as a yellow semi-solid contaminated by starting material (87% yield, 66% purity).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl-].[C:22]1([CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](Cl)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:32])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccccc1Cc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
To 3.03 g of methyl 4-aminobenzoate and 3.12 g of N,N-diisopropylethylamine in 75 ml of methylene to chloride is added 5.54 g of 2-(phenylmethyl)benzoyl chloride and the reactants stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 5.04 g of the desired product as a crystalline solid, m.p. 138°-139° C.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35]>CCOCC>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1)=[O:35]
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Reactant: OCc1cccc(Oc2ccccc2)n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)n1)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of (6-phenoxy-2-pyridyl)methanol (0.2 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20% ether/hexane, gives (6-phenoxy-2-pyridyl)methyl 2-(2-napthyl)-3-methyl-butanoate, MS m/e 411(M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[C:8]2\[CH2:9][N:10]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12][CH:13]\2O)[CH:2]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[C:46]([O-:49])(=[S:48])[CH3:47].[K+]>ClCCl.C(OCC)(=O)C>[C:46]([S:48][CH:13]1[CH2:12][CH2:11][N:10]([C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]/[C:8]/1=[CH:7]\[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:49])[CH3:47]
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cccnc1
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
To a solution of (E)-3-[(pyridin-3-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (5.40 g) in dichloromethane (85 ml) were added successively methanesulfonyl chloride (1.93 ml) and triethylamine (3.49 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated in vacuo, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in dimethyl sulfoxide (75 ml) was added potassium thioacetate (7.10 g) at room temperature, and the resulting mixture was stirred at 40° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (2.68 g, yield: 42%) as a pale brown amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].[CH:18]([N:21]([CH:24]([CH3:26])C)[CH2:22]C)([CH3:20])C.C(Cl)(Cl)=[O:28].N1CCCC1>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:17][C:22]([N:21]1[CH2:18][CH2:20][CH2:26][CH2:24]1)=[O:28]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cl
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1c(NC(=O)N2CCCC2)cccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a cooled solution of 2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (233 mg, 1.00 mmol) in 6 mL of dichloromethane were added 0.52 mL (3.00 mmol) of diisopropylethylamine and 0.55 mL of a 20% solution of phosgene in toluene at 0 C. The reaction mixture was stirred at 0 C for 10 minutes and pyrrolidine was added. The reaction mixture was stirred at 0 C for 1 hour then applied to column chromatography without workup. Chromatography (20->50% in hexanes/ethyl acetate in 20 minutes->100% in 30 minutes) gave 195 mg (0.591 mmol, 59%) of the title compound.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:21])[C:14]([C:19]#[N:20])=[CH:15]OCC)[CH3:11].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:19]=1[NH2:20])=[O:21])[CH3:11]
Reactant: NNC1CCCCC1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 80 °C

Procedure:
To a round bottom flask is added cyclohexyl-hydrazine hydrochloride (4.5 g, 30 mmol), 2-cyano-3-ethoxy-acrylic acid ethyl ester (5.1 g, 30 mmol), sodium bicarbonate (2.6 g, 30.9 mmol) and 40 mL of ethanol. The mixture is heated to 80° C. for 1 hour, cooled down to room temperature and concentrated. The residue is dissolved in chloroform and washed with water, dried over sodium sulfate. After removal of the solvent, the solid is recrystallized from ethyl acetate: 1HNMR (CDCl3): δ 7.40 (1 H, s), 4.77 (2 H, brs), 4.05 (2 H, q, J= 7.2 Hz), 3.50 (1 H, m), 1.61-1.71 (6 H, m), 1.50 (1 H, m), 1.02-1.21 (3 H, m), 1.11 (3 H, t, J= 7.2 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41]([N:19]([CH2:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH3:17])[CH:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]1)=[O:42]
Reactant: CCOc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: CCOc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 39 (613 mg, 1.32 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (366 mg, 1.58 mmol) using Method D to give the title compound.
Reaction SMILES: C=C.[C]=[O:4].O=O.N([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=O.[C:14]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:26])[CH2:15][CH2:16][CH2:17]CC(OCC(C)C)=O>C(O)C(C)C.[Pd](Cl)Cl>[C:14]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:26])[CH2:15][CH2:16][C:17]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:4]
Reactant: CC(C)CON=O
Reactant: CC(C)COC(=O)CCCCC(=O)OCC(C)C
Reactant: [C]=O
Agent: Cl[Pd]Cl
Agent: C=C
Agent: O=O
Solvent: CC(C)CO
Product: CC(C)COC(=O)CCC(=O)OCC(C)C
Temperature: 105 °C
Reaction time: 1 h

Procedure:
An autoclave made of stainless steel, equipped with a rotary stirrer and having a capacity of 300 ml. was charged with 50 ml. of isobutanol, 50 ml. of diisobutyl adipate as a solvent and 0.19 mmol. of palladium chloride. After sealing, 20 atm. of a gas mixture consisting of 78 vol.% of ethylene, 18 vol.% of carbon monoxide and 4 vol.% of oxygen was pressured thereinto. Subsequently, after the contents of the autoclave was heated to 105° C. with stirring, the reaction was carried out for one hour while supplying the above-mentioned gas mixture at a rate of 0.6 l./min. and isobutyl nitrite dissolved in a mixed solvent of isobutanol and diisobutyl adipate (1:1, volume ratio) at a rate of 40 mmol./hr. as the result, it was found that 22.5 mmol. of diisobutyl succinate was produced and 0.54 mmol. of diisobutyl oxalate was produced as by-product.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](=O)[CH3:22])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.O.[NH2:25]N.COC(OC)[N:30]([CH3:32])C>>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]3[NH:25][N:30]=[CH:32][CH:22]=3)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: CC(=O)c1sc(-c2c(C)nn3ccsc23)nc1-c1ccccc1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(-c2ccn[nH]2)s1
Temperature: 90 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
A solution of 1-[2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazol-5-yl]ethanone (170 mg, 0.5 mmol) obtained by similar manner with Example 110-8 (ii) in N,N-dimethylformamide dimethylacetal (10 mL) was refluxed at 90° C. for 4 h. The reaction mixture was allowed to cool to rt, and the solvent was evaporated. The residue was suspended in EtOH (5 mL), and then was added hydrazine monohydrate (50 mg, 1.0 mmol). The mixture was stirred at 80° C. for 5 h. The mixture was allowed to cool to rt, and then concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=30/70→100/0) to give the title compound (143 mg, 79%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:21]([Cl:34])[CH:20]=1)=[O:4].[C:35](O)(=[O:38])[CH:36]=[CH2:37].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:34][C:21]1[CH:20]=[C:19]([NH:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([NH:5][C:3]([CH2:2][NH:1][C:35](=[O:38])[CH:36]=[CH2:37])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: C=CC(=O)O
Reactant: COc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)NCC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OC
Temperature: 0 °C
Yield: 27 %

Procedure:
170 mg of 2-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acetamide as a starting material was dissolved in 5 ml of THF, and cooled to 0° C. The solution was reacted with 0.04 ml of acrylic acid, 0.06 ml of pyridine and 134 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 1 hour and at room temperature for 5 hours. The reacted solution was extracted with chloroform after adding saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate methanol=10:1) to obtain the title compound (51 mg, 27%).