Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 4 of Example 60, from 7.00 g (20.5 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 200 mL of 1:1 methanol-water mixture and 0.98 g (41.0 mmol) of lithium hydroxide with a work-up consisting only of thorough evaporation of solvents. The residue was directly taken to step 3.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[C:18]([CH3:31])=[CH:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=2)[CH:11]=3)=[O:5])[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[N:8]=[CH:9]3)=[CH:14][CH:13]=2)=[C:18]([CH3:31])[CH:19]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)ncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Yield: 12 %

Procedure:
A solution of the crude tert-butyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpyridin-2-ylcarbamate in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was stirred for 60 mins at ambient temperature and concentrated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate and brine and extracted twice with dichloromethane, and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0.5-20% methanol in dichloromethane) and subsequently repurified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to afford the title compound as a white amorphous solid (7.0 mg, 12% over 2 steps). 1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.14 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.84, (s, 1H), 7.66 (dd, J=8.8, 1.4 Hz, 1H), 6.40 (s, 1H), 5.91 (s, 2H), 2.17 (s, 3H), 2.12-2.03 (m, 1H), 0.90-0.79 (m, 4H). LCMS (Method E): RT=3.241 min, M+H+=319.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:33])N(C)[C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=2)=[CH:3]1.[OH-:34].[K+]>CCO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[O:33][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:17]=2)=[CH:3]1
Reactant: [OH-]
Reactant: CN1C(=O)C(c2cccc(OCCN3CCOCC3)c2)=C(c2cn(C)c3ccccc23)C1=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1cc(C2=C(c3cccc(OCCN4CCOCC4)c3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C

Procedure:
3-(1-Methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]-1-methylpyrrole-2,5-dione (0.22 g, 0.5 mmol) was dissolved in EtOH (10 mL) and a solution of KOH (1.5 g) in H2O (2.5 mL) was added. After the reaction mixture was refluxed for 3 h, it was cooled to room temperature, followed by evaporation of EtOH. The residue was acidified with aq. HCl to pH=4.5. The product was extracted with EtOAc and the EtOAc layer was dried over sodium sulfate and concentrated to give 3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]furan-2,5-dione which was in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[Li+:26].[OH-]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O-:15])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1.[Li+:26]
Reactant: CCOC(=O)C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Yield: 125.1 %

Procedure:
Part A: A mixture of ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3.97 g, 0.01 mol) in methanol/water is reacted with LiOH (1.3 gram, 0.054 mol) at room temperature for 16 hours. The resulting mixture is concentrated in vacuo to give crude lithium 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (4.7 gram).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1cccc(C=CC(=O)O)c1OC
Product: COc1cccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c1OC
Yield: 20.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (14.7 mmol) of 5,6-diamino-1,3-dimethyluracil and 3.37 g (16.2 mmol) of 2,3-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.03 g (yield 41%) of Compound 88 as pale yellow needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1.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.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nccc2ccccc12
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
In a 200 ml-three-necked flask, 3.40 g (25.0 mmole) of 4-methylphenyl-boronic acid (made by Aldrich Co.), 4.09 g (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 mol of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.80 g (yield=51.1%) of 1-(4-methylphenyl)isoquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH:25]1([NH:28][C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[O:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:28]([CH:25]4[CH2:27][CH2:26]4)[C:29]([CH3:34])([CH3:33])[C:30](=[O:31])[N:32]=3)[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(NC1CC1)C(N)=O
Product: Cc1c(C2=NC(=O)C(C)(C)N2C2CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 11 was synthesized from 4a (248 mg, 0.66 mmol) and 5f (148 mg, 1.05 mmol) as a white solid (122 mg, 38%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.28-7.26 (m, 3H), 7.21 (d, 1H), 7.07 (d, 2H), 2.91-2.89 (m, 1H), 2.29 (s, 3H), 1.49 (s, 6H), 0.88-0.86 (m, 2H), 0.76-0.73 (m, 2H); ESMS m/z: 487.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:20](=[O:22])[CH3:21])=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1nccc2cc(-c3ccc(F)cc3)nn12
Agent: O=S(=O)(O)O
Solvent: O
Product: CSc1nccc2c(C(C)=O)c(-c3ccc(F)cc3)nn12
Temperature: 110 °C
Reaction time: 96 h
Yield: 70 %

Procedure:
To a slurry of 2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (1.5 g, 5.9 mmol) in acetic anhydride (10 mL) was added 4 drops of sulfuric acid. The reaction mixture was heated to 80° C. for 2 hours, to 110° C. for 2 hours, and to reflux for 2 hours. The solution was allowed to cool to room temperature and stirred for 4 days. The mixture was poured into water (350 mL) and extracted with ethyl acetate (2×75 mL). The organic phase was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2:98 acetone:dichloromethane to yield 1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone (1.24 g, 70%). 1H NMR (DMSO): δ 8.12 (d, 1H), 7.98 (d, 1H), 7.65 (dd, 2H), 7.24 (m, 2H), 2.77 (s, 3H), 2.23 (s, 3H). MS m/z302 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[C:33](=[CH:44][CH:45]=1)[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:47]([NH:46][C:32]2[CH:31]=[C:30]([Cl:29])[CH:45]=[CH:44][C:33]=2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[O:48])(=[O:19])=[O:20])=[CH:14][C:13]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)ccc1NC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)ccc1NC(=O)OCc1ccccc1
Yield: 82.9 %

Procedure:
834 mg (2.05 mmol) of 4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide and 783 mg (2.05 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 1.18 g (yield 83%) of benzyl 2-{[(4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.56 (9H, s), 5.22 (2H, s), 5.37 (2H, s), 7.04 (1H, dd), 7.33-7.42 (10H, m), 7.97 (1H, d), 8.14 (1H, d), 8.45 (1H, d), 8.60 (1H, d), 8.65 (1H, d), 11.01 (1H, s), 11.11 (1H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:22][C:23]1[C:32](Br)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[NH2:22][C:23]1[C:32]([C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=2)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N
Temperature: 110 °C
Yield: 466.5 %

Procedure:
A mixture of 4-morpholinophenylboronic acid (5.0 g, 24 mmol), sodium carbonate (6.91 g, 65.2 mmol), tetrakistriphenylphosphine palladium (0) (1.40 g, 1.21 mmol), and methyl 3-amino-2,6-dibromoisonicotinate (7.86 g, 25 4 mmol) in a pressure flask was flushed with nitrogen. Toluene (60 mL) and methanol (20 mL) were added and the flask was sealed heated at 110° C. for 44 h. After cooling to RT, the solid was collected by filtration and washed with sat. aq. NaHCO3 solution, water, and dried to give methyl 3-amino-6-bromo-2-(4-morpholinophenyl)-isonicotinate (7.32 gm, 77%). MS (ESI) m/z 392.15 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.78 (1H, s), 7.58 (2H, d, J=8.85 Hz), 7.01 (2H, d, J=8.85 Hz), 6.00 (2H, br. s.), 3.94 (3H, s), 3.88-3.92 (4H, m), 3.22-3.28 (4H, m).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:15]#[N:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:37][CH2:2][C:3]1[CH:4]=[C:5]([C:15]#[N:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1cc(CO)ccc1-c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(CBr)ccc1-c1ccccc1
Reaction time: 16 h

Procedure:
5-Hydroxymethyl-biphenyl-2-carbonitrile from step 3 (1.3 g, 6.2 mmol) was dissolved in THF (31 ml) and treated with Ph3P (2.4 g, 9.3 mmol) followed by CBr4 (3 g, 9.3 mmol). The reaction was mixture stirred at room temp. for 16 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product. FAB MS: m/z 272 (M+ +H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:23]C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1

Procedure:
A solution of acetic acid 2,5-bis(benzyloxy)phenyl ester (1.85 g) and 5M sodium hydroxide solution (10.6 ml) in ethanol (11 ml) was heated under reflux for 6.5 hrs. After ethanol was evaporated under reduced pressure the clear solution was made acidic with diluted hydrochloric acid. The precipitated product was collected by filtration, washed with cold water and dried under reduced pressure. Yield is 0.56 g. 1H NMR (DMSO-d6) δ: 4.97 (s, 2H), 5.01 (s, 2H), 6.34 (dd, J 3.1, 8.8 Hz, 1H), 6.49(d, J 3.1 Hz, 1H), 6.85 (d, J 8.8 Hz, 1H), 7.28-7.46 (m, 10H), 9.1 (br s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[OH:10][C:11]1[CH:20]=[CH:19][C:14]2[S:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1.O>CN(C)C=O>[CH2:7]([O:10][C:11]1[CH:20]=[CH:19][C:14]2[S:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1)[CH3:8]
Reactant: CCI
Reactant: O=c1oc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2sc(=O)oc2c1
Reaction time: 4 h

Procedure:
Potassium carbonate (533 mg) and ethyl iodide (160 μL) were added to a solution of 6-hydroxy-1,3-benzoxathiol-2-one (336 mg) in N,N-dimethylformamide (10 mL) to form a reaction solution. This reaction solution was stirred for 4 hours at normal temperature. Water was added to the reaction solution. The precipitated crystals were filtered off, thoroughly washed with water and diisopropyl ether, and then dried under reduced pressure to obtain the target product (245 mg) as a colorless solid.
Reaction SMILES: C(O[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[N:12]=[C:11]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]2)[N:10]=1)C1C=CC=CC=1.[O:35]1[CH2:38][C:37]([CH2:41][NH2:42])([CH2:39][NH2:40])[CH2:36]1>>[NH2:40][CH2:39][C:37]1([CH2:41][NH:42][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[N:12]=[C:11]([N:22]3[CH2:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]3)[N:10]=2)[CH2:38][O:35][CH2:36]1
Reactant: O=C(O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(OCc3ccccc3)c2c1
Reactant: NCC1(CN)COC1
Product: NCC1(CNc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C(=O)O)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 108-1 in Scheme 54 by using 4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid and oxetane-3,3-diyldimethanamine, MS obsd. (ESI+) [(M+H)+] 484, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (brs, 1 H), 8.68 (m, 1 H), 8.04 (d, J=9.1 Hz, 1 H), 7.77-7.73 (m, 2 H), 7.68-7.63 (m, 1 H), 7.48-7.43 (m, 1 H), 7.24-7.19 (m, 1 H), 5.11 (brs, 2 H), 4.59-4.30 (brs, 6 H), 4.20 (m, 1 H), 4.0 (m, 1 H), 3.58 (brs, 2 H), 3.12 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][C:4]=1[O:12][CH3:13].C(C1C(=O)C(Cl)=C(Cl)C(=[O:19])C=1C#N)#N.C(O)(=O)C>O1CCOCC1>[CH3:13][O:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:9]=[CH:10][CH:11]=[O:19]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCc1ccc(OC)c(OC)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(C=CC=O)cc1OC
Yield: 60 %

Procedure:
In order to study the contribution of the length of the conjugation bridge to the AR activity, compound Q110 with a four-conjugated-double bond linker and compound Q111 with a five-conjugated-double bond linker were synthesized and illustrated in Scheme 13. Compound Q110 was synthesized starting from 1,2-dimethoxy-4-propylbenzene. To a solution of 3-(3,4-dimethoxypheny) propane in dry dioxane was added with DDQ (3.1 eq.) and catalytic amount of acetic acid. The mixture was sonicated for 2 h with TLC monitoring. After completion of the reaction, the solid was filtered out and the filtration was concentrated. The residue was dissolved in EtOAc and washed with water, 2% NaHCO3, and brine. The organic extract was dried over Na2SO4 and concentrated to afford a crude as yellow-brownish solid, which was purified with neutral alumina column chromatography and eluted with hexanes-ethyl acetate mixture to give a light yellow solid, 3,4-dimethoxycinnamaldehyde in 60% yield (B. P. Joshi et al., Tetrahedron, 62, 2590-2593, 2006). A solution of 2,4-petanedione (3 eq.) and B2O3 (1 eq.) in EtOAc was stirred at 40° C. for 0.5 h, 3,4-dimethoxycinnamaldehyde (1 eq.) and tributyl borane (1 eq.) were added. The resulting reaction mixture was stirred at 40° C. for 0.5 h. Butylamine (1.2 eq.) in EtOAc was added dropwise at the temperature and stirred at 40° C. for 16 h. To the red reaction mixture, 1% HCl aq was added and the mixture was stirred to 60° C. for 1 h. After cooling to rt, the aqueous was separated and the organic was washed with water to pH˜7 and dried over Na2SO4. The crude was purified by silica gel flash column chromatography to get the intermediate product 8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one as an off-white solid. A solution of the intermediate (1 eq.) and B2O3 (0.7 eq.) in EtOAc was stirred at 70° C. for 0.5 h. 3,4-dimethoxybenzaldehyde (1 eq.) and trubutyl borane (1 eq.) were added and the reaction mixture was stirred at 70° C. for 0.5 h. Piperidine (1.2 eq.) in EtOAc was added dropwise and the reaction mixture was stirred at 88-90° C. for 1 h. After cooling to 60° C., 1% HCl aq was added and the mixture was stirred at 60° C. for 0.5 h. The reaction mixture was worked-up by following the procedure described above and the crude was purified by silica gel column chromatography to afford the desired product Q110 as a red solid. Amorphous, mp. 65-68° C., ESI MS m/z: 423.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.64-7.58 (d, 2H, H-1 and 2), 7.16-7.02 (4H, aromatic ring H and trans double bond H), 6.90-6.82 (4H, aromatic ring H), 6.53-6.48 (1H, trans double bond H), 6.18-6.12 (1H, trans double bond H), 5.75 (s, 1H, H-4), 3.94-3.92 (12H, —OCH3).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].IC.[C:20](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:20])=[O:9])[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1ncnc(C(=O)O)c1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ncnc(C)c1C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 79.1 %

Procedure:
To a solution of 9.12 g (38 mmol) of the material from Step B in 100 mL of N,N-dimethyl formamide (DMF) was added 3.1 mL (50 mmol) of iodomethane and 3.7 g (50 mmol) of lithium carbonate. The reaction mixture was heated at 60° C. for 3 hours. After cooling the reaction mixture was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate) and the solvent was removed with a rotary evaporator and then a vacuum pump. The residue was purified by MPLC with a gradient of 20-30% ethyl acetate in hexanes as eluant to afford 7.58 g of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]2([C:37]([F:40])([F:39])[F:38])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([N:26]4C(=O)C5=CC=CC=C5C4=O)[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.NN>C(O)C>[NH2:26][CH:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH2:14][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)([C:37]([F:38])([F:39])[F:40])[O:17][N:16]=2)=[CH:23][CH:22]=1)[CH3:25]
Reactant: CC(c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2.80 g of N-[1-[4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl]ethyl]phthalimide in 10 mL of ethanol, 0.22 g of hydrazine monohydrate was added and the resultant reaction mixture was stirred at 80° C. for 2 hours. After the completion of the reaction, the mixture was cooled down to 0° C. and the deposited insoluble substance was filtered off, followed by cleaning the filtered substance with a small amount of chloroform. The filtrate and the resultant chloroform-cleaning liquid were combined and the solvent was distilled off under reduced pressure. The resultant residue was dissolved in 30 mL of ethyl acetate and the resultant solution was washed with water (10 mL×1). Subsequently, the washed solution was dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order, and the solvent was distilled off under reduced pressure to obtain 1.80 g of the objective substance as a yellow resinoid. This was used in the next process as it was without being further purified.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 90 %

Procedure:
To ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g) was added conc. hydrochloric acid (5 ml), water (2 ml) and acetic acid (20 ml), and the mixture is refluxed for 2 hours. After cooling, the precipitated crystals are separated by filtration, and washed with water, ethanol and diethyl ether in this order to give 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) as a white crystal, m.p. 240°-243° C.