Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=2[F:25])[CH:7]=[CH:6][CH:5]=1)[C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccc(F)c21
Product: COc1cccc(-c2cccc(C3(c4ccncc4)N=C(N)c4c(F)cccc43)c2)c1F
Yield: 28 %

Procedure:
The title compound was synthesized as described for Example 1 in 28% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (0.096 g, 0.25 mmol) and 2-fluoro-3-methoxybenzeneboronic acid (0.047 g, 0.28 mmol): 1H NMR (DMSO-d6) δ ppm 8.50-8.44 (m, 2 H) 7.65-7.60 (m, 1 H) 7.58-7.49 (m, 1 H) 7.45-7.37 (m, 3 H) 7.36-7.24 (m, 4 H) 7.22-7.11 (m, 2 H) 6.96-6.90 (m, 1 H) 6.64 (br. s., 2H) 3.85 (s, 3 H), MS (ES+) m/z 428 [M+1]+.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:20]4[C:19](=[O:25])[NH:18][N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1>CS(C)=O.C(OCC)(=O)C>[O:25]=[C:19]1[NH:18][N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:28]3[CH2:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:27]3)=[O:26])=[CH:15][CH:14]=2)[N:21]2[CH:22]=[CH:23][CH:24]=[C:20]12
Reactant: O=C(Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1)Oc1ccccc1
Reactant: c1ccc2c(c1)CNC2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1)N1Cc2ccccc2C1
Temperature: 25 °C

Procedure:
40 mg [4-(1-Oxo-1,2-dihydro-pyrrolo[1,2-d][1,2,4]triazin-4-yl)-phenyl]-carbamic acid phenyl ester (0.115 mmol) were dissolved in 0.3 ml DMSO. A mixture of 15 mg isoindoline (0.121 mmol) in 0.2 ml DMSO was added at room temperature and the reaction was stirred at room temperature over night. The reaction mixture was diluted in ethyl acetate and washed with water, aqueous HCl, water, aqueous NaOH, and water. The solvent was evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:24])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:29](Cl)(=[O:32])[CH2:30][CH3:31].Cl>[N+](C)([O-])=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:29](=[O:32])[CH2:30][CH3:31])[O:10][C:6]=2[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3ccoc23)c1=O
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCC(=O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
1.3 g (1.4 mmol) of 3-(4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 1.9 g (1.4 mmol) of aluminum chloride, were dissolved in 20 ml of nitromethane, and 0.5 g (1.4 mmol) of propionyl chloride was dropwise added thereto under cooling with ice. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into a mixture of dilute hydrochloric acid and ice and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated s odium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 56%) of the desired product as a yellow glassy substance. Refractive index: unmeasurable, 1H-NMR (solvent, CDCl3): 1.20(3H,m), 2.91(2H,q), 3.56(3H,s), 6.38(1H,s), 7.28(1H,d), 7.58(1H,s)ppm
Reaction SMILES: [Cl:1][CH:2]([C@H:13]1[C@H:15]([C:16](O)=[O:17])[C:14]1([CH3:20])[CH3:19])[C:3]([Cl:12])([Cl:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH:2]([C@H:13]1[C@H:15]([C:16]([Cl:23])=[O:17])[C:14]1([CH3:20])[CH3:19])[C:3]([Cl:12])([Cl:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1C(Cl)C(Cl)(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Cl)C(Cl)(Cl)c1ccc(Cl)cc1
Yield: 93 %

Procedure:
14 g of trans-3-(1,2,2-trichloro-2-(4-chloro-phenyl)-ethyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid were dissolved in 100 ml of carbon tetrachloride, 75 g of thionyl chloride were added and the mixture was heated under reflux for 4 hours. The solvent and excess thionyl chloride were then stripped off in vacuo. 13.7 g of trans-3-(1,2,2-trichloro-2-(4-chloro-phenyl)-ethyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid chloride were obtained as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18]C)=[O:17])[C:6]2=[O:24].[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([OH:18])=[O:17])[C:6]2=[O:24]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(OC)cc3c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2ncn(-c3cc(C(=O)O)ccc3C)c(=O)c2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a stirred suspension of methyl 3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate (19.3 g) in a mixture of methanol (650 ml) and water (150 ml) was added 2N NaOH (89 ml) and heated to 70° C. until a clear solution was formed at which point the heating stopped. Stirring was continued for a further 1.5 hours. The pH was adjusted to pH˜1 with 1N HCl and the resultant solid collected by filtration. The solid was dried in vacuo for 16 hours to yield 3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoic acid as a white solid (17.8 g); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 3.88 (s, 3H), 7.49 (m, 1H), 7.57 (m, 2H), 7.71 (d, 1H), 7.93 (s, 1H), 7.98 (m, 1H), 8.20 (s, 1H); Mass Spectrum: M+H+ 311.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C@@H:10]([NH:12][C:13](=[O:29])[NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[C:18]([NH:25]C(=O)C)[N:19]=[CH:20]3)[C:9]2[C:4](=[CH:5][C:6]([C:30]([F:33])([F:32])[F:31])=[CH:7][CH:8]=2)[O:3]1.[OH-].[Na+]>CO.O>[NH2:25][C:18]1[N:19]=[CH:20][C:21]2[C:16]([CH:17]=1)=[C:15]([NH:14][C:13]([NH:12][C@H:10]1[C:9]3[C:4](=[CH:5][C:6]([C:30]([F:33])([F:31])[F:32])=[CH:7][CH:8]=3)[O:3][C:2]([CH3:34])([CH3:1])[CH2:11]1)=[O:29])[CH:24]=[CH:23][CH:22]=2
Reactant: CC(=O)Nc1cc2c(NC(=O)N[C@@H]3CC(C)(C)Oc4cc(C(F)(F)F)ccc43)cccc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)C[C@@H](NC(=O)Nc2cccc3cnc(N)cc23)c2ccc(C(F)(F)F)cc2O1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of Example 90D (505 mg, 1.07 mmol) and NaOH (428 mg, 10.7 mmol) in MeOH (10 mL) and H2O (3.5 mL) was heated to 85° C. After 24 h the reaction mixture was cooled to ambient temperature. The precipitate was collected by vacuum filtration, washed with minimal MeOH and then water, and dried in the vacuum oven at 50° C. for 4 h to provide the title compound (238 mg, 0.553 mmol, 52% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.35 (s, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.06 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.71 (s, 1H), 5.99 (s, 2H), 5.14-5.00 (m, 1H), 2.21 (dd, J=13.3, 6.2 Hz, 1H), 1.82 (dd, J=13.1, 11.6 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H); MS (ESI+) m/z 431 (M+H)+; [α]23D +35.7° (c 0.61, CH3OH).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:2]1.[N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[N:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1CN[C@@H](C(O)=O)C1.[BH4-].[Na+]>CC#N.C(O)C>[OH:10][CH2:9][C@@H:8]([N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=CCCC1CCCOC1
Agent: O=C(O)[C@H]1CCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: O=C(NN(C(=O)OCc1ccccc1)[C@H](CO)CC1CCCOC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
To a stirred solution of 3-(tetrahydro-2H-pyran-3-yl)propanal (8.25 g, 0.058 mol) and dibenzyl azodicarboxylate (94%, 12.3 g, 0.041 mol) in MeCN (250 mL) at 0° C. was added (R-proline) (0.47 g, 0.0041 mol). After stirring the mixture at 0° C. for 15 hr. ethanol (100 mL) and NaBH4 (1.56 g, 0.041 mol) was added, and the mixture was stirred at 0° C. for 40 min. The reaction was quenched by slow addition of 10% aqueous citric acid (15 ml), and the whole solution was concentrated in vacuo. This residue was diluted with EtOAc (200 ml), washed with saturated brine (1×50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give dibenzyl 1-((2S)-1-hydroxy-3-(tetrahydro-2H-pyran-3-yl)propan-2-yl)hydrazine-1,2-dicarboxylate (14.68 g, 81%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39](=[O:45])[CH2:40][C:41](=O)[CH2:42]C>>[F:28][C:29]1[C:34]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39](=[O:45])/[CH:40]=[C:41](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:42]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1cccc(C(F)(F)F)c1F
Product: C/C(=C/C(=O)c1cccc(C(F)(F)F)c1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 190 mg (0.52 mmol) of Intermediate 45 and 120 mg (0.52 mmol) of Intermediate 37 to yield 102 mg (35% yield) of Example 26: 1H NMR (DMSO-d6, 400 MHz) δ11.36 (d, 1H, J=8.9), 7.9 (m, 3H), 7.77 (t, 1H, J=6.9), 7.46 (m, 3H), 7.42 (m, 1H), 7.11 (d, 2H, J=8.5), 6.81 (d, 2H, J=8.5), 5.22 (s, 1H), 4.14 (t, 2H, J=6.6), 4.1 (m, 1H), 3.13 (m, 1H), 2.87 (t, 2H, J=6.6), 2.78 (dd, 1H, J=13.7, 8.5), 2.31 (s, 3H), 1.68 (s, 3H); low resolution MS (ES+)m e 597.4(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[NH:7][C:6]2=[O:16].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]Cl)[CH2:29][CH2:28]1.O>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:7]2[C:6](=[O:16])[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:9][C:8]2=[O:15])[CH2:31][CH2:32]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: COc1cc2[nH]c(=O)[nH]c(=O)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2[nH]c(=O)n(CCN3CCN(c4ccccc4OC)CC3)c(=O)c2cc1OC
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
Two grams of 6,7-dimethoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione was dissolved in 30 ml of dimethylformamide. After adding 1230 mg of sodium hydride thereto under cooling, the mixture was stirred for 10 minutes. Then, 23 grams of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride was added and the stirring was continued at 70° C. for 6 hours. After the reaction was finished, water was added to the reaction mixture and the mixture was extracted with chloroform and concentrated. The resultant residue was purified through the silica gel chromatography and crystallized from methanol to obtain 1.4 g of the titled compound (yield: 35%).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:28]([NH:29]C(=O)OCC3C=CC=CC=3)=[CH:27][C:26]3[C:21](=[CH:22][C:23]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[C:42](=[O:47])[CH2:41]4)=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:29][C:28]1[C:19]([C:17]([NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:4]2[CH2:5][C@H:6]([CH3:9])[C@@H:7]([OH:8])[C@H:2]([NH2:1])[CH2:3]2)=[O:18])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[C:42](=[O:47])[CH2:41]1)[CH:22]=2
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(4-methyl-3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (0.0070 g, 0.011 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was then filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H33N8O3 [M+H]+: m/z=505.3. found: 505.3.
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([OH:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26].[NH:27]1C=N[N:29]=[N:28]1>>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:19][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[NH:26][N:29]=[N:28][N:27]=2)=[C:15]([CH2:16][CH2:17][CH3:18])[C:2]=1[OH:1])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2)c1O
Reactant: c1nnn[nH]1
Reactant: N#CCCCCBr
Product: CCCc1c(OCCCCc2nnn[nH]2)ccc(C(=O)c2ccccc2)c1O

Procedure:
The title compound was prepared by first reacting 7.68 g. of 2,4-dihydroxy-3-propylbenzophenone with 4.86 g. of 5-bromovaleronitrile according to the procedure in Example 21. The reaction afforded 8.2 g. of the nitrile intermediate of the title compound. This nitrile intermediate was then converted to the tetrazole following the procedure of Example 8 giving 1.2 g. of the title compound, m.p. about 114-°115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][S:7][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)([O-])=O.O.C([O-])(O)=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][S:7][C:8]=1[O:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2sncc2[N+](=O)[O-])CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2sncc2N)CC1
Temperature: 35 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
To a solution of tert-butyl 4-(4-nitroisothiazol-5-yloxy)piperidine-1-carboxylate (1C3) (213 mg, 0.67 mmol) in methanol (4 mL) at room temperature was added water (3 mL), saturated NaHCO3 solution (3 mL) and Na2S2O4 (340 mg, 2 mmol). The mixture was stirred at 35° C. for 3 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to afford the product tert-butyl 4-(4-aminoisothiazol-5-yloxy)piperidine-1-carboxylate (1D4) (80 mg, 0.27 mmol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:21]1[CH:25]=[C:24]([CH2:26][OH:27])[O:23][N:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[CH2:11]([C:21]1[CH:25]=[C:24]([CH:26]=[O:27])[O:23][N:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCc1cc(CO)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCc1cc(C=O)on1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of oxalyl chloride (31.7 ml) in dry dichloromethane (100 ml) cooled to -60° C., was added a solution of dimethylsulfoxide (9.8 ml) in dichloromethane (30 ml) followed by a slurry of 3-(1-decyl)-5-isoxazolemethanol (13.8 g) in dry dichloromethane (100 ml). The reaction mixture was stirred at -60° C. for 0.5 hr, quenched with triethylamine (40 ml), and allowed to warm to ambient temperature. The solution was poured into water (300 ml) and extracted with dichloromethane. The organic phases were washed with dilute citric acid, dried, and evaporated. The residue was flash chromatographed (silica, 50:1-dichloromethane:methanol). The appropriate fraction were collected and evaporated. The residue was recrystallized from ether-hexane to give 11.2 g (82%) of product, mp 46-48° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:8]2[N:9]([N:11]=[C:12]([NH2:14])[N:13]=2)[CH:10]=1)=[O:4].[OH-].[Li+]>C1COCC1.O>[NH2:14][C:12]1[N:13]=[C:8]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)=[C:6]([CH3:25])[C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]2[N:11]=1
Reactant: COC(=O)c1cn2nc(N)nc2c(-c2cccc(C(F)(F)F)c2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 1.75 h
Yield: 61.4 %

Procedure:
To a suspension of 2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (Int. 35, 1.0 g, 2.857 mmol) in THF (10 mL) and water (5 mL) was added lithium hydroxide (273 mg, 11.34 mmol) and the reaction mixture was stirred at 45° C. for 1.75 hrs. Cooled then acidified to pH 1. The resultant precipitate was collected by filtration, washing with water, to afford the title compound as a white solid (590 mg).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([OH:26])=O)[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:37][S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])=[O:26])[O:21][C:22]=3[CH3:23])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1
Product: Cc1oc(C(=O)NS(=O)(=O)c2ccccc2)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1

Procedure:
Compound (172) was prepared from compound (171) and benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt=10.38 mins, m/z (ES+)=513 (M+H for C26H22F2N2O5S).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[NH2:37][C@@H:38]1[CH2:41][C@H:40]([C:42]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[C:39]1([CH3:51])[CH3:50]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:37][C@@H:38]4[CH2:41][C@H:40]([C:42]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[C:39]4([CH3:51])[CH3:50])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.410 g, 0.823 mmol) (Prepared as described in J. Med. Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (0.71 ml, 8.232 mmol) in DCM (3.42 ml) was added at 0° C. and stirred at room temperature for about 3 hours and completion of the reaction was monitored by TLC, then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((1S,3R)-3-amino-2,2-dimethylcyclobutyl)(piperidin-1-yl)methanone (step 2, 0.328 g, 1.56 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous 1N HCl, then washed with water and brine, and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.400 g; Yield: 71.9%; 1H NMR (300 MHz, CDCl3): δ 5.85 (d, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.50-4.41 (m, 1H), 4.18-4.07 (m, 1H), 3.78-3.67 (m, 1H), 2.50-2.30 (m, 3H), 3.19-3.07 (m, 1H), 2.88 (t, 1H, J=8.1 Hz), 2.54-2.13 (m, 3H), 2.04 (s, 3H), 2.00-1.86 (m, 2H), 1.80-1.11 (m, 33H), 0.95, 0.93, 0.87, 0.83, 0.81 (s, 18H); Mass: [M+H]+ 691 (100%), [M+Na]+ 713 (25%); IR (KBr, cm−1): 3395, 2943, 2864, 1736, 1734, 1624, 1444, 1370, 1248, 1192, 1154, 1024, 979, 884; M.R: 140.2° C.-145.8° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].C[O-].[Na+].CO>>[CH2:1]([C:8]1[C:9]([O:39][CH3:38])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccccc3)c(Cl)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccccc1
Temperature: 53 °C
Reaction time: 5 h

Procedure:
A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1.10 g, 2.02 mmol, Example 109) and 0.5 M NaOMe in MeOH (13 mL, 6.5 mmol) in a sealed tube was heated at 53° C. for 1 hour. More 0.5 M NaOMe in MeOH (6.5 mL, 3.3 mmol) was added, and the mixture was stirred at the same temperature for another 5 hours. The solvent was evaporated in vacuo, and the residue was diluted with DMF and filtered through a syringe filter. The filtrate was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 9.03 (s, 1H), 8.83 (d, J=2.02 Hz, 1H), 8.22 (d, J=2.02 Hz, 1H), 8.08 (dd, J=2.02, 8.08 Hz, 1H), 7.92 (d, J=8.59 Hz, 1H), 7.88 (d, J=8.08 Hz, 1H), 7.66 (dd, J=2.27, 8.84 Hz, 1H), 7.22 (d, J=4.04 Hz, 4H), 7.10-7.18 (m, 1H), 7.06 (d, J=1.52 Hz, 1H), 4.28 (s, 2H), 4.07 (s, 3H), 3.71 (s, 3H); MS m/e 539.1 [M+H]+.