Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CC[C@H](O)C1.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:35]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:19][CH:18]=3)[C:9]=12>>[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C@@H:35]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:21][CH:22]=3)[C:9]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C)C5)c5ncnc(N)c45)cc3)nc2c1
Agent: O[C@H]1CCNC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn([C@@H]5CCN(C)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
N2-(4-{4-amino-1-[(3R)-1-methyltetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from (S)-(−)-3-pyrrolidinol in a manner analogous to that used for the preparation of rac-N2-{4-[4-Amino-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine. The compound was formed as a white solid (0.195 g, 53%). 1H NMR (DMSO-d6, 400 MHz) 1H NMR (DMSO-d6, 400 MHz) 2.31-2.35 (m, 2H), 2.32 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 2.70-2.77 (m, 3H), 3.05 (t, 1H), 5.40 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.85 (s, 1H); RP-HPLC Rt 11.090 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 455 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[N:12]([CH3:15])[CH2:11][CH2:10][N:9]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=1.Br[C:24]1[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Br:30])[N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:30][C:28]1[N:29]=[C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[C:13](=[O:14])[N:12]([CH3:15])[CH2:11][CH2:10][N:9]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=2)[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)C(c2ccc(N)cc2)C1=O
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)OC(C)(C)C)C(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with tert-butyl 2-(4-aminophenyl)-4-methyl-3-oxopiperazine-1-carboxylate 102j (880 mg, 2.88 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (770 mg, 2.88 mmol), cesium carbonate (2.06 g, 6.34 mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (166 mg, 0.288 mmol) and tris(dibenzylidene acetone)dipalladium(0) (47 mg, 0.144 mmol) were added and the reaction mixture was heated at reflux for 18 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (50 mL) and water (50 mL), and filtered, and the filter cake was washed with ethyl acetate (2×25 mL). The organic layer was separated, washed with brine (50 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography to afford 102k (850 mg, 60%) as an orange foam: 1H NMR (300 MHz, CDCl3) δ 7.28 (s, 1H), 7.16 (d, 2H, J=8.4 Hz), 6.65 (d, 2H, J=8.4 Hz), 5.65 (s, 1H), 4.02 (m, 1H), 3.51 (m, 1H), 3.30 (m, 3H), 3.05 (s, 3H), 1.47 (s, 9H), MS (ESI+) m/z 492.1 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][NH:9][N:8]=1)=[O:6].[CH3:15]I>O1CCCC1>[CH3:3][O:4][C:5]([C:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]([CH3:15])[N:8]=1)=[O:6]
Reactant: CI
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A mixture of sodium hydride (167 mg, 6.96 mmol) in tetrahydrofuran (15 mL) cooled to 0° C. was treated with a solution of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.0 g, 5.8 mmol) in tetrahydrofuran (10 mL). This mixture was stirred at 0° C. for 1 h. It was then treated with methyl iodide (0.54 mL, 8.7 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was cooled to 0° C. and was then quenched with a saturated aqueous ammonium chloride solution and diluted with ethyl acetate (200 mL). This solution was washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was slurried in 40% ethyl acetate/petroleum ether and cooled in the freezer for 15 min. At this time, the solids were collected by filtration to afford 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (889 mg, 82.8%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ8.93 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)=[CH:23][CH:22]=2)[C:17]([NH2:19])=[S:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:33](OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:33][S:18][C:17](=[NH:19])[CH:16]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=1)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[CH:23][CH:22]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1OC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After adding 170 mg of Me3O+BF4− to a solution of 385 mg of 2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 30 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 18 hours. Next, 200 ml of ethyl acetate and 100 ml of a 5% aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was washed 100 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (371 mg, crude product).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:22])=[O:21]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2,4-dichlorophenylsulfonyl chloride (0.589 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2,4-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.620 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[C:7](Br)=[N:8][CH:9]=1)=[O:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>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.O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[C:7]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnc(Br)n1C
Reactant: OB(O)c1ccc(C(F)(F)F)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: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)n1C
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To 2-bromo-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (800 mg) were added 4-(trifluoromethyl)phenylboronic acid (1.04 g), and tetrakis(triphenylphosphine)palladium(0) (422 mg), and tetrahydrofuran (9 ml), saturated sodium carbonate water (3 ml), and water (1.5 ml) as solvents, and stirred at 120° C. for 30 minutes under microwave radiation. After completion of the reaction, to the reaction solution 6 was added water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 3-methyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazole-4-carboxylic acid methyl ester (980 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29](=[O:35])[N:28]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:27]2=[O:52].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:28]2[C:27](=[O:52])[C:26]4[C:31](=[CH:32][CH:33]=[C:24]([F:23])[CH:25]=4)[N:30]([CH3:34])[C:29]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)c2cc(F)ccc2n(C)c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)c2cc(F)ccc2n(C)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 3] (200 mg, 0.524 mmol), 6-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 13] (215 mg, 0.524 mmol), Cs2CO3 (512 mg, 1.57 mmol) and PdCl2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water (1 mL) was heated at 60° C. overnight, then at 90° C. for 4 h. The cooled mixture was concentrated and the residue was purified twice by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 50-100%), to give a mixture of four atropisomers of 3-chloro-4-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (129 mg, 39% yield). This material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH-MeCN (65:17.5:17.5) at 85 mL/min; sample preparation: 15.4 mg/mL in MeOH; injection: 0.5 mL. The third peak eluting from the column provided a single atropisomer of 3-chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (33 mg). The isomeric purity was determined to be greater than 98%. Mass spectrum m/z 567 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.44 (br. s., 1H), 8.29 (dd, J=8.1, 6.4 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.56-7.49 (m, 1H), 7.36 (dd, J=15.2, 7.3 Hz, 2H), 7.22 (d, J=6.8 Hz, 1H), 7.04-6.92 (m, 3H), 3.65 (s, 3H), 1.84 (s, 3H), 1.63 (s, 6H).
Reaction SMILES: [N+]([O-])(O)=O.S(=O)(=O)(O)O.ClC1C=C(C(O)=O)C(C)=CC=1.[Cl:21][C:22]1[C:23]([N+:35]([O-:37])=[O:36])=[C:24]([C:32](O)=O)[C:25]([CH3:31])=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29].B#B.ClC1C([N+]([O-])=O)=CC(CO)=CC=1[N+]([O-])=O.P(Br)(Br)[Br:56]>>[Br:56][CH2:32][C:24]1[C:25]([CH3:31])=[CH:26][C:27]([N+:28]([O-:30])=[O:29])=[C:22]([Cl:21])[C:23]=1[N+:35]([O-:37])=[O:36]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)O
Reactant: BrP(Br)Br
Agent: B#B
Agent: Cc1ccc(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1CBr

Procedure:
The process for preparing the compound according to claim 1 which comprises: reacting a mixture of concentrated nitric acid and sulfuric acid with 4-chloro-o-toluic acid at a temperature from about 40° C. to about 60° C., reducing resultant 4-chloro-3,5-dinitro-o-toluic acid with diborane, treating resultant 4-chloro-3,5-dinitro-benzyl alcohol with phosphorus tribromide to obtain α'-bromo-4-chloro-3,5-dinitro-o-xylene, reacting the latter with an aliphatic alcohol, and recovering the resultant desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>CCO>[CH3:8][N:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:32]([C:28]4[S:27][CH:31]=[CH:30][CH:29]=4)=[NH:33])[CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC(=N)c1cccs1
Reactant: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Agent: I
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a solution of tert-butyl-3-(5-amino-1H-indol-3-yl)cyclohexyl(methyl)carbamate (0.32 g, 0.93 mmol) in dry EtOH (25 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (0.53 g, 1.86 mmol) and the reaction left to stir at room temperature for 48 h. The solvent then was evaporated and the mixture dissolved in dichloromethane (20 mL) and washed with 2N NaOH (10 mL). The organic layer was extracted and evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98 to 5:95) to give the title compound as a yellow solid (0.32 g, 75%). 1H-NMR (DMSO-d6) δ 1.38 (s, 9H), 1.46-1.68 (m, 5H), 1.84-2.00 (m, 5H), 2.69 (s, 3H), 2.79-2.87 (m, 1H), 3.78-4.09 (m, 1H), 6.20 (s, 2H, NH), 6.62 (dd, 1H, J=1.8, 8.4 Hz), 6.98 (s, 1H) 7.04 (s, 1H), 7.09 (dd, 1H, J=3.6, 3.6 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=4.8 Hz), 7.70 (d, 1H, J=3.3 Hz), 10.59 (s, 1H, NH); ESI-MS (m/z, %) 453 (MNa+, 100).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[NH4+].Cl>C1COCC1>[C:1]1([C:9]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:14])[CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCO1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 ml (120 mmol) of 2 M solution of phenyl magnesium bromide in THF was added dropwise to 4.33 g (50.3 mmol) of γ-butyrolactone in 60 ml of THF for the duration of 50 minutes. After stirring at room temperature overnight, a saturated aqueous ammonium chloride solution and then 2 N hydrochloric acid were added dropwise to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[C:16](OCC)=[O:17])=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][OH:17])=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CO)nc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl (1R,2R)-2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclopropanecarboxylate (31-3, 126 mg, 0.38 mmol, 1.0 equiv) was added to anhydrous THF (3.8 mL) and cooled to 0° C. DIBAL-H (1.9 mL, 1.90 mmol, 5.0 equiv, 1.0M in THF) was added dropwise and the resulting solution was stirred at 0° C. for 2 h. The reaction was then quenched by the addition of saturated Rochelle salts (20 mL), diluted with EtOAc (10 mL) and stirred at RT for 18 h. Following this duration, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. Purification by reverse-phase HPLC (10-100% 0.1% TFA in 1-120:CH3CN) provided 31-4 as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[C:3]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1c(Br)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 95 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
Into a flame-dried 25 mL round bottom flask was placed 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (25 mg, 0.05 mmol), 2-chlorophenylboronic acid (16 mg, 0.1 mmol), K3PO4 (43 mg, 0.2 mmol), Pd(dba)3 (4.6 mg, 0.005 mmol), and S-Phos (dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, 4.2 mg, 0.01 mmol). The reaction flask was purged with argon three times before toluene (1 mL) was added. The reaction mixture was stirred at 95° C. for 16 h. Analysis by HPLC/MS indicated the starting 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (15 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluted with a gradient of EtOAc (30-70%) in hexanes to afford the desired product (86% pure). The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 70% to 100% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile, frozen and lyophilized to afford 10 mg (40%) of the title compound as a light yellow powder. HPLC/MS: retention time=4.13 min, [M+H]+=529.3.
Reaction SMILES: [CH2:1]([O:3][C:4](/[C:6](=[CH:11]/[C:12]1[O:13][C:14]([CH3:17])=[CH:15][CH:16]=1)/[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C([O-])(=O)C.[Na+]>>[C:18]([O:10][C:8]1[C:16]2[CH:15]=[C:14]([CH3:17])[O:13][C:12]=2[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)/C(=C/c1ccc(C)o1)CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Temperature: 25 °C
Yield: 152.7 %

Procedure:
To a vigorously stirred solution of (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (I-1a: 326.6 g, 1.371 mol) in acetic anhydride (1.77 L, 18.72 mol) at room temperature was added sodium acetate (193 g, 2350 mmol) in one portion. The reaction mixture was then heated at reflux for 2.5 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was suspended in dichloromethane (1.5 L) and filtered, washing the solids with dichloromethane (3×500 mL). The combined filtrate and washings were then washed with sodium hydrogencarbonate (2×1 L of a saturated aqueous solution) and brine (2 L), then concentrated in vacuo to give desired ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (I-1b: 549.03 g, quantitative). 1H NMR (CDCl3, 300 MHz) δ ppm 8.00-7.99 (m, 1H), 7.64 (d, 1H), 6.32-6.32 (m, 1H), 4.38 (q, 2H), 2.47 (d, 3H), 2.37 (s, 3H), 1.39 (t, 3H).
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.[Cl:15][C:16]1[CH:41]=[CH:40][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([S:28]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]3[C:37](O)=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.C1C[C@H](C(O)=O)NCC1.[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:6][NH:7][C:37]([C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][N:31]1[S:28]([N:25]1[CH2:24][CH2:23][CH:22]([C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:41][CH:40]=2)[CH2:27][CH2:26]1)(=[O:30])=[O:29])=[O:38])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(S(=O)(=O)N2CCCC[C@@H]2C(=O)O)CC1
Reactant: CC(C)(C)ON
Agent: Cl
Agent: O=C(O)[C@H]1CCCCN1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 65 %

Procedure:
O-tert-butylhydroxylamine hydrochloride (127 mg, 1.01 mmol), 1-(3-dimethylaminopropyl)-3-ethylcaibodiimide hydrochloride (129 mg, 0.67 mmol), N,N-dimethylaminopyridine (41 mg, 0.34 mmol), and N-methylmorpholine (0.15 ml, 1.3 mmol) were added to a solution of 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (140 mg, 0.34 mmol), [prepared by proceeding as described in Example 9, but replacing D-valine and 4-(4chlorophenoxy)piperidinesulfamoyl chloride with D-pipecolinic acid and 4-(4-chlorobenzoylpiperidinesulfamoyl chloride, respectively], in methylene chloride (2 ml). After stirring overnight, the reaction mixture was diluted with ethyl acetate, washed with 1M HCl, and brine, and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexane) to give N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (65%).