Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[CH:4][N:3]=1.Cl[C:10]([N+]([O-])=O)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>CCO>[C:12]1([C:11]2[C:7]3[C:6](=[O:8])[NH:5][CH:4]=[N:3][C:2]=3[O:1][CH:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cc(O)ncn1
Reactant: O=[N+]([O-])C(Cl)=Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: O=c1[nH]cnc2occ(-c3ccccc3)c12
Temperature: 60 °C

Procedure:
The title compound 10 was prepared by the method of Dauzonne, D.; Adam-Launay, A. Tetrahedron 1992, 48, 3069-3080. 4,6-Dihydroxypyrimidine (3.3 g, 29.4 mmol) and (2-Chloro-2-nitro-vinyl)-benzene (5.3 g, 26.7 mmol) were combined in EtOH (absolute, 110 mL) and the mixture was heated at 60° C. for 10 min to dissolve 4,6-Dihydroxypyrimidine. DBU (8.06 mL, 53.9 mmol) was then added drop-wise to the reaction. After addition of DBU the deep green-brown solution was heated at reflux for 3 h then at 60° C. over night. The deep red solution was then cooled to room temperature and concentrated to a thick red oil. Purification by flash chromatography (SiO2, gradient eluent: CH2Cl2 to 5% MeOH/CH2Cl2) to afford crude 10 as an orange-red semisolid/oil. This material was triturated with 1.75:1 CH2Cl2/hexanes and solid 10 was isolated by Buchner filtration. Flash chromatography of the mother liquors afforded a second crop of solid 3 (>90% pure). The two crops were combined and concentrated to afford 10.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.N1CCCCC1.[CH2:34]([OH:39])[CH2:35][CH2:36][C:37]#[CH:38].Cl>[Cu]I>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][OH:39])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCCO
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To 3.3 g (7.72 mmol) Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester in 20 ml piperidine 447.0 mg (3.9 mmol) tetrakis(triphenylphosphine)palladium and 73.6 mg (3.9 mmol) CuI were added. At 80° C. 1.43 ml (15.45 mmol) 4-pentyn-1-ol were added slowly, and the solution was stirred for an additional hour. The cooled solution was added to ice water, acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 30:1 yielded 2.7 g (96%) 5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as orange oil, MS: 361(M).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(O)CN
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Solvent: CN1CCCC1=O
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (100 mg, 255 μmol) and 1-amino-2-methyl-propan-2-ol (91 mg, 1.02 mmol) in 2 ml of NMP is heated at 150° C. by microwave for 5 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 61 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic 2-(cyclopropanecarbonyl-amino)benzothiazol-6-yl ester (beige-colored solid).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[N+:18]([O-:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)O)n[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCCc1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 76.7 %

Procedure:
5-Butyl-1H-pyrazol-3-carboxylic acid (22.6 g, 134 mmol) was added portionwise to concentrated sulfuric acid (100 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 23.7 ml, 376 mmol) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes the pale yellow precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (21.9 g) as a pale yellow solid. 1H NMR (400 MHz, DMSO-D6): δ=2.83-2.92 (2H, t), 1.56-1.64 (2H, quin), 1.22-1.36 (2H, sext), 0.84-0.90 (3H, t) ppm. LRMS (electrospray): m/z [M−H]+ 212. Anal. Found C, 30.19; H, 5.41; N, 13.12. C8H11N3O4. 6 mol H2O requires C, 29.91; H, 7.22; N, 13.08%.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][O:7][C:8]([N:10]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:13]=1[CH2:14]O)[CH3:11])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:6][O:7][C:8]([N:10]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:13]=1[CH2:14][Cl:5])[CH3:11])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N(C)c1cccc(C)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(C)c1cccc(C)c1CCl
Yield: 123.7 %

Procedure:
A solution of methanesulfonyl chloride 1.7 g) in methylene chloride (3 ml) was added dropwise to a solution of 2-(N-methoxycarbonyl-N-methylamino)-6-methylbenzyl alcohol (1.04 g) and triethylamine (2.5 g) in methylene chloride (15 ml) at room temperature and the mixture was refluxed for 3 hours and the cooled. To the mixture was added an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 2-(N-methoxycarbonyl-N-methylamino)-6-methylbenzyl chloride (1.4 g).
Reaction SMILES: [NH2:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1([NH:35][C:36]([NH:1][CH:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:12])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)NC(c1ccccc1)C(NC(=O)NC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [R-(R*,R*)] and [S-(R*,R*)]N-(2-amino-1,2-diphenylethyl)-N'-(4-nitrophenyl)urea (0.1 g, 0.27 mmol) in dichloromethane (10 mL) is added cyclohexyl isocyanate (0.03 g, 0.27 mmol) in one portion. The resulting mixture is stirred 1 hour at room temperature before filtering off the solid product. The product is suspended in hot diethyl ether, filtered, and dried in vacuo at 114° C. for 4 hours, mp 244°-245° C. IR (KBr): 3337, 2931, 1639, 1559, 1507, 1330, 700 cm-1 ; NMR (DMS-d6): 0.97-1.66 (m, 10H), 4.94 (m, 2H), 5.94 (d, 1H, J=7.5 Hz), 6.42 (d, 1H, J=7.5 Hz), 7.03-7.19 (m, 12H), 7.60 (d, 2H, J=9.2 Hz), 8.12 (d, 2H, J=9.2 Hz), 9.51 (s, 1H). Analysis calculated for C 28 H31N5O4 : C, 67.05; H, 6.23; N, 13.96. Found: C, 66.74; H, 6.22; N, 13.98.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([O:12][CH3:13])[C:5]=1[NH2:14].[CH:16](OCC)(OCC)[O:17][CH2:18][CH3:19]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([O:12][CH3:13])[C:5]=1[N:14]=[CH:16][O:17][CH2:18][CH3:19]
Reactant: COC(=O)c1c(Cl)cc(Cl)c(OC)c1N
Reactant: CCOC(OCC)OCC
Product: CCOC=Nc1c(OC)c(Cl)cc(Cl)c1C(=O)OC
Temperature: 25 °C

Procedure:
A solution of the 2-amino-4,6-dichloro-3-methoxybenzoic acid methyl ester (2-3) (6.35 g, 25.4 mmol) and triethyl orthoformate (60 mL, 361 mmol) was heated under reflux for 5 days. The solution was cooled to room temperature and evaporated under reduced pressure to afford the imidate, 4,6-dichloro-2-ethoxymethyleneamino-3-methoxybenzoic acid methyl ester (5-2), and starting material (7.80 g) as a brown oil; 5-2:2-3-9:1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Mg].[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1cc(F)c(Br)cc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(F)c(F)cc2F)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A three neck flask (2 L) under an atmosphere of nitrogen with Mg turnings (9.8 g) was stirred for 15 rain and tetrahydrofuran (90 m1L) was added and stirring continued for an additional 15 min. 1-Bromo-2,4,5-trifluorobenzene (85 g) was dissolved in tetrahydrofuran (340 mL). A portion of this solution (75 mL) was added to the stirred magnesium turnings and then heated to 50° C. The rest of the solution was added and stirring continued at the same temperature for an additional 1 h. The reaction mixture was cooled to 40° C., a solution of 1,4-dioxaspiro[4.5]decan-8-one (57.3 g) in tetrahydrofuran (275 mL) was added, and stirring continued for 10 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (970 mL) and extracted with toluene (700 mL). The organic layer was washed with water (3×700 mL), dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a red-orange oil which was used in the next step without further purification.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18].Cl>>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[NH:6])[NH2:18]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccccn1
Agent: Cl
Agent: [Li+]
Product: N=C(N)c1ccccn1
Reaction time: 2 h
Yield: 82549.2 %

Procedure:
To the solution of LiHMDS (5.18 g, 0.026 mmol, 1.3 equiv.) was added picolinonitrile (2.08 g, 0.02 mmol, 1 equiv.) at ice-bath and kept stirred for 2 h. Then, the reaction mixture was acidified with aqueous HCl (4N) to pH2, cooled at ice-bath and kept stirred. Then, the mixture was extracted with EA (200 mL×5). The combined organic phase was washed with brine, dried (Na2SO4), and evaporated to get picolinimidamide (2.0 g, 83%). LC-MS (m/z)=122 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][C:5]([F:11])=[C:4]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:11][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH3:9])[CH:2]=[N:3][C:4]=1[O:12][CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: [H][H]
Reactant: CC(=O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of 1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.23 g, 0.86 mmol, Step-3) and triethylamine (0.17 mL, 1.20 mmol) in ethanol (9 mL) is stirred at room temperature for 1 hour. Then 10% palladium on carbon (0.03 g, 0.28 mmol) is added to the mixture. The mixture is stirred at room temperature under a balloon of hydrogen gas for 5 hours. After filtration through a pad of celite, the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (5:1) to give 0.15 g (76% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.I[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Cc1cccc(B(O)O)c1
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: Cc1cccc(-c2ccccc2C(=O)O)c1
Yield: 41.5 %

Procedure:
In an oven dried flask flushed with N2 was combined 2.7 g (20.0 mmol) of 3-methylbenzeneboronic acid, 3.64 g (15 mmol) of 2-iodobenzoic acid, 150 mL of DME, 26 mL of 10% Na2CO3 and 600 mg (0.5 mmol) of Pd(PPh3)4. The mixture was warmed to reflux for 24 h and partitioned between 100 mL of NaHCO3 and 100 mL of ether. The ether layer was extracted with 2×50 mL of NaHCO3 and the combined NaHCO3 fractions were washed with 2×50 mL of ether, acidified with 10% HCl and extracted with 3×75 mL of ether. The combined ether extracts were washed with 50 mL of H2O, 50 mL of brine, dried (MgSO4) and concentrated in vacuo. The oil was crystallized from ether/hexanes (1/1) at -20° C. as a white precipitate, which after filtration, provided 1.32 g (41% yield) of 3'-methyl-2-biphenylcarboxylic acid as a brown oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[C:5]([C:25](=[O:44])[NH:26][C:27]1[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=1[O:42][CH3:43])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:33]([C:31]1[CH:32]=[C:27]([N:26]2[C:3](=[O:2])[CH:4]=[C:5]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:8][CH:7]=3)[C:25]2=[O:44])[C:28]([O:42][CH3:43])=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:30]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: COC(=O)C=C(C(=O)Nc1cc(C(C)(C)C)cc(NS(C)(=O)=O)c1OC)c1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NS(C)(=O)=O)cc(C(C)(C)C)cc1N1C(=O)C=C(c2ccc(OCCN3CCOCC3)c3ccccc23)C1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
In a 40 mL scintillation vial was placed 3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-acrylic acid methyl ester 51 (25 mg, 0.04 mmol), DIEA (13.6 mL, 0.08 mmol), and 5 mL THF. The reaction was heated to 80° C., stirring for 16 hours. The resulting reaction mixture was concentrated under vacuum and the crude residue purified by reverse phase preparative LC-MS to afford (10.2 mg, 39%) of the desired compound. Calculated mass=607. Observed mass=608.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[CH2:7][CH2:6][CH:5]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2ccc3oc(=O)[nH]c3c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4oc(=O)[nH]c4c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 5-(1-hydroxy-4-oxo-cyclohexyl)-3H-benzooxazol-2-one (as prepared in Example 5, Step A) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][NH2:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=O)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CCO.C(O)(=O)C>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2/[CH:25]=[N:11]/[NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cc2ccccc2C=O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Cc2ccccc2/C=N/NC(=O)Cc2ccccc2)cc1
Reaction time: 2.5 h
Yield: 78 %

Procedure:
To a solution of-phenylacetic acid hydrazide (0.24 mmol) in absolute EtOH 10 mL and acetic acid 0.4 mL is added 2-{[(4-methylphenyl)sulfonyl]methyl}benzaldehyde (0.22 mmol). The reaction is stirred at room temperate for 2.5 hr with white ppt formation. The reaction mixture is then filtered. The solid is triturated with MeOH to give N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)methylene]-2-phenylacetohydrazide in 78% yield. 1H NMR (400 MHz, DMSO-d6) □ 11.50–11.25 (2s, 1H), 8.22–8.13 (2s, 1H), 7.79 (m, 1H), 7.56 (m, 2H), 7.31 (m, 10H), 4.93–4.80 (2s, 2H), 3.95–3.57 (2s, 2H), 2.36–2.31 (2s, 3H). ESI− for C23H22N2O3S, m/z 405 (M−H)−.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.[Cl:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1Cl>C1(C)C(C)=CC=CC=1.[Cu]>[C:1]1([O:11][C:21]2[CH:20]=[CH:19][C:18]([N+:23]([O-:25])=[O:24])=[CH:17][C:16]=2[Cl:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 144 g (1 mol) of α-naphthol in 1 liter of xylene were added 65 g (1 mol) of finely powdered 88% potassium hydroxide. The mixture thus obtained was boiled under N2 -atmosphere in an apparatus equipped with an effective water trap under constant stirring until no water was separating any more and the head temperature had risen to 137° C. Then, 500 ml of dimethylformamide were added, The solution thus obtained was boiled for a further two hours under nitrogen in the apparatus equippped with an effective water trap; then, 500 ml of solvent were distilled therefrom. The residue was allowed to cool off under nitrogen to 100° C., and 211 g (1 mol) of 3,4-dichloronitrobenzene and 1 g of copper powder were added. Then it was refluxed under nitrogen while stirring for 8 hours (approx. 140° C. bottom temperature). Afterwards it was allowed to cool off to ~50° C., approx. 30 g of kieselguhr were added, the mixture thus obtained was stirred, and the undissolved substance was removed by suction filtration and washed with xylene. The filtrate united with the wash liquid was evaporated in vacuo to dryness. The residue was dissolved in warm toluene. The obtained solution was extracted thrice with separate portions of 500 ml of 1 N sodium hydroxide solution and, subsequently, twice with separate portions of 500 ml of water. Then, the toluene phase was evaporated to dryness in vacuo (crude yield: 290 g, 96% of theory). The residue was stirred with 1.7 liter of gasoline (boiling range 80°-110° C.) at approx. 85° C. Most of the crude product dissolved; some resin remain undissolved. The solution decanted therefrom was allowed to cool off slowly. First, the product precipitated oily; however, by trituration at approx. 50° C., crystals were obtained. Then it was cooled for several hours to 5° C. and the crystalline product was removed by suction filtration.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:20][O:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH:17][C:23]([N:22]([O:21][CH3:20])[CH3:26])=[O:24])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1Cc2cc(COc3ccc(N)cc3)ccc2O1
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(OCc2ccc3c(c2)CC(C)O3)cc1
Yield: 83.7 %

Procedure:
6.5 g of 4-(2,3-dihydro-2-methyl-5-benzofuranylmethyloxy)aniline was dissolved into 30 ml of pyridine, and 3.8 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto under cooling with ice. After 2-hours' continuous stirring, pyridine was distilled off under a reduced pressure, and the residual oily matter was dissolved into 100 ml of toluene. After the reaction mixture was subsequently washed with water, diluted hydrochloric acid and saturated sodium chloride aqueous solution, toluene was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 7.3 g of Compound No. 40 shown in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=2[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cccc(F)c1F
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(F)c1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 2,3-difluorophenol: 1H-NMR (CDCl3) δ 7.94 (1H, d, J=2.6 Hz), 7.47 (1H, dd, J=8.7, 2.6 Hz), 7.05–6.86 (3H, m), 6.72–6.60 (1H, m), 3.85 (3H, s).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O>[CH2:23]([O:22][C:20]([O:16][C:4]1[CH:3]=[C:2]([F:1])[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[CH:5]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CC1OB(O)c2cc(O)cc(F)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1cc(F)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.1 %

Procedure:
To a mixture of 2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)-acetic acid (113 mg, 0.5 mmol) and sodium hydroxide (0.06 g, 1.5 mmol) in water (3 mL) was added ethyl chloroformate (59 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 15 min and then acidified to pH=2 with 1N HCl. The mixture was extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (21 mg, Yield: 14%). 1H NMR (400 MHz, DMSO-d) δ9.57 (s, 1H), 7.32-7.37 (m, 2H), 5.59-5.62 (m, 1H), 4.25-4.30 (m, 2H), 2.95-3.00 (m, 1H), 2.36-2.42 (m, 1H), 1.29-1.32 (t, J=6.8 Hz, 3H). MS (ESI) m/z=299 [M+H]+.