Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[OH:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.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>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:43]3[CH:44]=[CH:45][C:40]([OH:39])=[CH:41][CH:42]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1ccc(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: O
Solvent: CCO
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(O)cc2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (80 mg, 0.14 mmol) in EtOH (4 mL)/H2O (1 mL) were added 4-hydroxyphenylboronic acid (38 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol) and Pd(PPh3)4 (3 mg, 0.0028 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:4][N:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cnco2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(1,3-oxazol-5-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(1,3-oxazol-5-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[OH-].[Na+]>CS(O)(=O)=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:8]=1)[C:13](=[O:15])[CH2:12][CH2:11]2
Reactant: COc1cc(CCC(=O)O)cc(OC)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(c(OC)c1)C(=O)CC2
Temperature: 90 °C
Yield: 481.2 %

Procedure:
The 3-(3,5-Dimethoxy-phenyl)-propionic acid (2 g×5) was dissolved in methanesulfonic acid (10 ml×5) in microwave process vial (20 ml×5), the mixture was heated at 90° C. for 10 minutes under microwave irradiation. The mixture was poured into ice (250 g), neutralized by 2M NaOH to PH 8-9, and extracted by EtOAc. The organic layer was concentrated to give the product (8.8 g, 96.2%). LC-MS: m/e 193 (MH+)
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([C@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=O)[CH:11]=[CH2:12].Cl.[NH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[CH2:10]([C@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:16])[CH:11]=[CH2:12]
Reactant: COC(=O)CN
Reactant: C=CC[C@H](CCCC)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC[C@H](CCCC)C(=O)NCC(=O)OC
Reaction time: 18 h
Yield: 82.5 %

Procedure:
Step B (1): DIEA (1.35 mL, 9.9 mmol) was added to a mixture of (S)-2-allylhexanoic acid (300 mg, 1.92 mmol), methyl 2-aminoacetate hydrochloride (254 mg, 2.02 mmol), EDC (387 mg, 2.02 mmol), HOBt (273 mg, 2.02 mmol) in DMF (15 mL) at room temperature. The mixture was stirred for 18 h. Poured the reaction mixture into 200 mL 1 M HCl. Extracted with EtOAc/Hex (95:5) (2×200 mL). Washed combined organic extracts with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (5-50% EtOAc/hexanes linear gradient) to give (S)-methyl 2-(2-allylhexanamido)acetate 360 mg (83% yield) as white solid: ESI (M+H)+=228.2; 1H NMR (500 MHz, CDCl3) δ 5.90 (s, 1H), 5.64-5.85 (m, 1H), 4.95-5.14 (m, 2H), 4.04 (dd, J=5.04, 2.29 Hz, 2H), 3.75 (s, 3H), 2.28-2.46 (m, 1H), 2.07-2.29 (m, 2H), 1.62-1.64 (m, 1H), 1.46-1.47 (m, 1H), 1.18-1.36 (m, 4H), 0.87 (t, J=6.87 Hz, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:20]=[CH2:21])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:34].[Na+].OO>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][OH:34])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(F)cccc1Cl)[C@H]2C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(CCO)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethan-1-one (1.54 g, 3.15 mmol) in THF (31 mL). Cool to 0° C. Add BH3 (6.3 mL, 6.3 mmol, 1M in THF). Stir 4 h at room temperature. Cool to 0° C. Add NaOH (12.6 mL, 3 M in water) and H2O2 (1.92 mL, 30% wt/wt % in water). Stir overnight at room temperature. Add ethyl acetate, wash with saturated NaHCO3 solution and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethan-1-one as a white foam (1.08 g, 2.13 mmol). MS (m/z): 506.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1C=CC=CC=1>[CH3:1][N:2]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CNc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)N(C)c1ccccc1
Yield: 54.4 %

Procedure:
N-methylaniline (15.1 g), diethyl bromomalonate (16.9 g) and dry benzene (90 ml) were mixed and heated under reflux for 16 hours with stirring. The reaction mixture was washed, dried and concentrated by the same procedure as in Example 2, (1). The residue was purified by silica gel column chromatography using benzene/hexane (2:1) as an eluent to give 10.2 g (yield 54%) of diethyl N-methylanilinomalonate having the following NMR data.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[C:36]3[O:35][CH2:34][CH2:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)O1>>[O:35]1[C:36]2[C:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=4)[N:3]=3)=[CH:29][CH:30]=[CH:31][C:32]=2[CH2:33][CH2:34]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: CC1(C)OB(c2cccc3c2OCC3)OC1(C)C
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cccc4c3OCC4)n2)c1

Procedure:
Example 13 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran (ChemBridge Corporation). The batch was purified by preparative HPLC:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.[OH-].[Na+:42]>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:4]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O-:40])=[CH:36][CH:35]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1.[Na+:42]
Reactant: Nc1ncccc1C(=O)O
Reactant: NCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1C(=O)NCc1ccc([O-])cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 119.9 %

Procedure:
Then, a solution of 2-aminonicotinic acid (3.0 g, 21.7 mmol) in N,N-dimethylformamide (30 mL) was cooled with an ice water, 1-hydroxybenzotriazole (3.51 g, 26 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide (4.04 g, 26 mmol) and a solution of the resulting 4-aminomethyl-phenol (3.0 g, 21.7 mmol) in N,N-dimethylformamide (20 mL) were added, and the solution was stirred for 18 hours at this temperature. The reaction solution was partitioned into brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate, filtration was carried out using NH silica gel, and the filtrate was concentrated. The residue was dissolved in methanol (90 mL), 1N sodium hydroxide (17.8 mL, 17.8 mmol) was added thereto, followed by stirring at room temperature for an hour and a half. The reaction solution was concentrated in vacuo, and the title compound (5.66 g) was obtained as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])=[O:4].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][CH2:2][C:3]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])=[O:4])(=[O:31])[CH3:30]
Reactant: CC(=O)[C@@]1(OC(=O)CO)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
The above alcohol is acetylated with acetic anhydride in pyridine to give 17α-acetoxyacetoxypregn-4-ene-3,20-dione, which shows the following significant NMR signals: δ(ppm) 0.69 (s, 3H, H-18), 1.19 (s, 3H, H-19), 2.07 and 2.17 (singlets, 3H each, 2-COCH3), ##STR28## 5.76 (broad s, 1H, H-4).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)=[CH:8][C:4]=2[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:4]1[CH:5]=[CH:6][N:7]=[C:2]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3ccnc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5 mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190° C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents hexane and acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61% yield) as a yellow solid MS (m/z) 487.0 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.CC(C)([O-])C.[K+].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=[O:18]>CS(C)=O>[Br:14][C:15]1[C:16]([CH:17]=[O:18])=[C:19]([N:1]2[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]2)[CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1cn[nH]c1
Reactant: O=Cc1c(F)cccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cnn(-c2cccc(Br)c2C=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
1H-pyrazole-4-carbonitrile (935 mg, 10.0 mmol, Eq: 1.00) was dissolved in 15 mL of dry DMSO and potassium tert-butoxide (1.19 g, 10.0 mmol, Eq: 1.00) was added. The mixture was stirred at room temperature for 20 minutes and 2-bromo-6-fluorobenzaldehyde (4.08 g, 20.1 mmol, Eq: 2) was added. The mixture was stirred at room temperature overnight and then extracted with ethyl acetate and water. The organic layer was dried and concentrated. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 40% EtOAc in hexanes) to give 1-(3-bromo-2-formylphenyl)-1H-pyrazole-4-carbonitrile (1.53 g, 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:21][NH2:22].O>CN(C)C=O>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][C:10](=[O:20])[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[N:22]2[CH3:21])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2)cc1
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C2CC(=O)CC(c3ccc(C)cc3)N2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
1,5-Bis(4-methylphenyl)-1,4-pentadien-3-one (20aa, 0.32 g, 1.2 mmol) was dissolved in dimethyl formamide (9 ml). Methylamine (51, 0.5 ml, 5.8 mmol, 40% in water) was added and the mixture stirred for 72 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.26 g (75%) of a white solid: mp 120-121° C. [expected mp 105-107° C.]; 1H NMR δ 1.79 (s, 3H), 2.36 (s, 6H), 3.10 (d, 2H, J=14.9 Hz), 2.79 (t, 2H, J=13.1 Hz), 3.35 (dd, 2H, J=11.9, 2.4 Hz), 7.15 (d, 4H, J=8.0 Hz), 7.21 (d, 4H, J=7.9 Hz); 13C NMR: δ 21.2, 40.7, 50.9, 70.0, 126.9, 129.4 137.2, 140.2, 207.1.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[F:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: OC1CCNCC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: CC1COc2c(N3CCC(O)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 5.5 h
Yield: 36.6 %

Procedure:
140 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and 404 mg of 4-hydroxypiperidine were added to 2 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100° to 110° C. (bath temperature) for 5.5 hours and the reaction mixture was concentrated to dryness in vacuo. Water was added to the residue and the mixture was neutralized with diluted hydrochloric acid to yield precipitate. The precipitate was collected by filtration, washed with water, and then recrystallized from ethanol to provide 66 mg of 9-fluoro-10-(4-hydroxy-1-piperidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with m.p. 220°-240° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.C(C1C2C=CC=CC=2ONC1=O)#[N:29].[OH-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH2:29])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Reactant: N#CC1C(=O)NOc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyano-benzoxazinone product of Example 3, Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 55 mg of the title compound, a compound of the present invention, as a white solid that decomposes in the melting apparatus above 255° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.C(C1C=C(C=C(C)C=1O)C#[N:18])C>>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:18])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: COc1cc(O)ccc1C=O
Product: COc1cc(O)ccc1C#N

Procedure:
The title compound is prepared from commercially available 4-hydroxy-2-methoxy-benzaldehyde in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: tR=0.74 min. 1H NMR (D6-DMSO): δ 3.84 (s, 3H), 6.47 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 10.6 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[N:4]=1.[O-][C:42]#[N:43].[K+].C(OCC)(=O)C.CCCCCC.O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=1)[N:4]=[C:3]2[CH2:2][C:42]#[N:43]
Reactant: N#C[O-]
Reactant: COc1cc2c(CCl)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(CC#N)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Temperature: 25 °C

Procedure:
3-Chloromethyl-5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazole (165.0 g) was suspended in dimethyl sulfoxide (1,200 ml) and stirred at room temperature. To this was added potassium cyanate (43.6 g) which has been made into powder using a mortar. When the reaction solution was stirred at 70° C. for 1 hour, the reaction solution became uniform and transparent, and it was observed that the spot of the material almost disappeared on a thin layer chromatography (ethyl acetate/hexane=2/1). The reaction solution was cooled to room temperature and poured into water (15,000 ml) which was vigorously stirred, and the mixture was stirred for 1 hour. The thus precipitated solid substance was collected by suction filtration, washed with water (1,000 ml×3) and dissolved in chloroform (5,000 ml), the resulting solution was dried with sodium sulfate and filtered, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was separated and purified by a silica gel column (ethyl acetate) to obtain 108.7 g of light brown solid. This solid substance was directly used in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([Cl:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([Cl:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(Cl)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(Cl)c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144.5 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.24 g) was dissolved in ethanol (30 ml), and to the solution, sodium borohydride (0.065 g) was added under ice-cooling and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 5) (0.3 g) as yellow amorphous.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]([CH:31]([CH3:33])[CH3:32])=[N:29][O:30][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]([CH:31]([CH3:32])[CH3:33])=[N:29][O:30][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2cccc3onc(C(C)C)c23)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3onc(C(C)C)c23)nc1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl((1R)-1-{[(6-{[3-(1-methylethyl)-1,2-benzisoxazol-4-yl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 43, 2.0 mg) was dissolved in dichloromethane (1.0 mL) and, at 0° C., TFA (0.05 mL, 0.65 mmol) was added. The reaction mixture was stirred at that temperature for 2 hours. After removal of the volatiles, the residue obtained was charged on a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M in MeOH) to afford the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:7]1[CH:8]=[C:9]2[CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=3[C:14](=[O:15])[C:10]2=[C:11]([OH:13])[CH:12]=1>C1C=CC=CC=1.N1C=CC=CC=1>[OH:22][C:21]1[C:16]2[C:14](=[O:15])[C:10]3[C:9](=[CH:8][CH:7]=[CH:12][C:11]=3[OH:13])[CH:23]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: CCCC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21

Procedure:
28.6 g (0.27 moles) butyryl chloride is added, while stirring, to a mixture containing 50.9 g (0.225 moles) anthraline in 1575 ml benzene and 27.5 ml pyridine. The reaction mixture is cooked using a return condenser for 10 hours while stirring. The solution is filtered and the filrate is evaporated dry under a lowered pressure. The residue is crystallized out from acetic acid. Yield 17.0 g (25.5% of the theoretical).