Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:13]([NH2:15])=[O:14].[Cl-].[NH4+]>[Fe].CC1C=CC=CC=1>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([CH:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:13]([NH2:15])=[O:14])[C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: NC(=O)C(Nc1ccc(Cl)cc1)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: NC(=O)C(Nc1ccc(Cl)cc1)c1c(Cl)ccc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred and refluxed mixture of 37.5 parts of 2,6-dichloro-α-[(4-chlorophenyl)amino]-3-nitrobenzeneacetamide, 500 parts of an ammonium chloride solution 1 N and 800 parts of methylbenzene are added 28 parts of iron powder. Upon completion, stirring at reflux is continued for 50 minutes. The reaction mixture is filtered and the crystallized product is filtered off from the filtrate. It is boiled in 1000 parts of methylbenzene: one part dissolves, but crystallized again upon cooling to room temperature. It is filtered off and dried, yielding 7.1 parts of 3-amino-2,6-dichloro-α-[(4-chlorophenyl)amino]benzeneacetamide; mp. 231.8° C.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][CH2:6][O:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:21])=[N:15]2)=[CH:10][CH:9]=1>O1CCOCC1.CO>[CH3:4][O:5][CH2:6][O:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH:21]=[O:2])=[N:15]2)=[CH:10][CH:9]=1
Reactant: O=[Se]=O
Reactant: COCOc1ccc2ccc(C)nc2c1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CO
Product: COCOc1ccc2ccc(C=O)nc2c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 20 h
Yield: 58.8 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere, selenium dioxide (11 mg, 0.099 mmol) was added to a solution of 8a (22.1 mg, 0.089 mmol) in dioxane (2 mL) at 85° C. The reaction was stirred for 20 h at 85° C., then cooled, diluted with methanol, and vacuum filtered. The filtrate was collected and concentrated, leaving a yellow solid, which was purified by column chromatography (4:6 EtOAc/hexane) to provide 9a (13.7 mg, 0.0523 mmol, 59%) as a yellow solid: 1H NMR (CDCl3) δ 10.15 (1H, s), 8.35 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=8 Hz), 8.00 (1H, d, J=9.6 Hz), 7.76 (1H, d, J=9.2 Hz), 5.43 (2H, s), 3.56 (3H, s); 13C NMR (CDCl3) δ 193.25, 154.14, 149.28, 140.47, 137.83, 137.55, 130.64, 125.26, 119.33, 117.34, 95.45, 57.24; FTIR (neat) 2858, 1715, 1529, 1263, 1197, 1155, 1061, 935, 918, 849, 806, 771, 658 cm−1; MS (ESI) m/z calculated for (C12H10N2O5+H)+ 263, found 263; HRMS (ESI) m/z calculated for (C12H10N2O5+H)+ 263.0668, found 263.0662.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH:8]=CC2C=CC=CC=2)[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]1=[O:24])=[N+:2]=[N-:3].C([OH:27])C.ClCCl.[BH4-].[Na+].Cl>C(O)C>[N:1]([C@H:4]1[C@@H:7]([CH2:8][OH:27])[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]1=[O:24])=[N+:2]=[N-:3]
Reactant: CCO
Reactant: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2C=Cc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2CO)cc1
Reaction time: 0.08 h

Procedure:
A solution of (cis)-3-azido-1-(4-methoxyphenyl)-4-(2-phenylethenyl)-2-oxoazetidine (6 g, 18.75 mmole) in 1:1 ethanol-dichloromethane (180 ml) was cooled to -78° C. and ozonized until the mixture retained a purple hue. The reaction was purged with nitrogen, and sodium borohydride (2.835 g, 75 mmole) was added as a solid followed by 85 ml of ethanol. The mixture is allowed to stand at -78° C. for five minutes and then stirred at ice-bath temperature for one hour. The reaction was acidified to pH 4 with 3N hydrochloric acid, and the solvents were removed in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate and the organic extracts were washed with saturated potassium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated to a solid which was treated with ether. After standing under ether for three hours at 5° C., the white solid was filtered, washed with fresh ether, hexane, and dried under high vacuum. The yield of the title compound was 3.333 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.Cl.[NH2:15][C:16]1[N:27]=[CH:26][C:25]([Br:28])=[CH:24][C:17]=1[C:18](N(OC)C)=[O:19]>C1COCC1>[NH2:15][C:16]1[C:17]([C:18]([C:2]2[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=2)=[O:19])=[CH:24][C:25]([Br:28])=[CH:26][N:27]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: Fc1ccc(Br)cn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (5.6 ml, 54.2 mmol) in THF (50 ml) at 0° C. under nitrogen was added dropwise a 2 M solution of iso-propylmagnesium chloride in THF (27 ml) over a period of 10 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting slurry was added dropwise via cannula to a solution of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide hydrochloride (3.0 g, 11.5 mmol) in THF (50 ml) at room temperature under nitrogen over a period of 30 minutes. After stirring for 3 hours, the reaction was quenched by addition of a saturated aqueous solution of ammonium chloride (50 ml) at 0° C. and the mixture was stirred at room temperature for another 20 minutes. Water was added and the mixture was extracted with ethyl acetate (three times). The combined organic layers were dried over sodium sulfate, then filtered and concentrated. Crystallization from methanol (ca. 60 ml) afforded the title compound as dark yellow crystals (1.48 g, 49% yield). 1H NMR (DMSO-d6): δ 8.49 (s, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.23 (dt, J=2.5, 8.0 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.74 (broad s, 2H), 7.36 (dd, J=2.0, 8.0 Hz, 1H); MS: m/z 295.9, 297.9 [MH]+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].S(=O)(=O)(O)[O-].[K+]>CS(C)=O.ClCCl>[CH:9]([CH:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:8]
Reactant: CC(C)C(CO)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(C=O)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.97 ml of triethylamine are added dropwise at 0° C. to the solution of 3.0 g of tert-butyl 4-(2-hydroxymethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate in 11 ml of dimethyl sulphoxide and 55 ml of dichloromethane. 5.23 g of sulphur trioxide-pyridine complex are added in 3 portions at intervals of 10 minutes and the reaction mixture is stirred at 0° C. for a further 3 hours. The reaction mixture is poured onto ice-water, adjusted to pH=2.5 with saturated aqueous potassium bisulphate solution and extracted with diethyl ether (3×)—the combined organic phases are washed successively with water and 5% aqueous sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue as a yellow oil. Rf=0.46 (1:2 EtOAc-heptane).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=3)[N:7](COCC[Si](C)(C)C)[C:6]=2[C:5](=[O:34])[N:4]([CH2:35][CH2:36][CH2:37][O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[C:3]1=[O:45].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:23])[F:25])[CH:16]=3)[NH:7][C:6]=2[C:5](=[O:34])[N:4]([CH2:35][CH2:36][CH2:37][O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[C:3]1=[O:45]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2[nH]c(OCCOc3cccc(OC(F)(F)F)c3)nc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.2 g, 1.82 mmol) in THF (15 mL) was added TBAF (3.7 mL, 3.64 mmol). The mixture was stirred at 80° C. overnight. Then it was cooled, partitioned between ethyl acetate and water. The organic layers were combined, washed with water, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether and ethyl acetate (2:1) to give 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (900 mg, 93.7% yield) as a white solid. LCMS retention time 1.613; LCMS MH+-THP 445.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:13]([CH3:14])[CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)OC(=O)Cc1ccc(F)cc1

Procedure:
A mixture of 4-fluorophenylacetic acid (123.0 g), 2-propanol (96.0 g), p-toluenesulphonic acid (9.6 g) and benzene (1.3 l) is refluxed for 7 hours with a Dean-Stark separator. The solution is washed with a 10% aqueous solution of sodium carbonate (2×500 ml) and with water (2×500 ml). After drying over magnesium sulphate, the solvent and the excess 2-propanol are evaporated in vacuo. The residue is distilled (51°-53°/3·10-2Torr) to yield isopropyl 4-fluorophenylacetate.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[C:15]([CH3:25])[C:14]=1[NH2:26].C(N(CC)C(C)C)(C)C>ClCCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:26][C:14]1[C:15]([CH3:25])=[CH:16][C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:18][C:13]=1[CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCOCC2)cc(C)c1NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 47 %

Procedure:
Benzyl chloroformate (32 mg) was added to a solution of 0.15 M 2,6-dimethyl-4-morpholin-4-yl-phenylamine and 0.30 M N,N-diisopropyl-ethylamine in 1,2-dichloroethane (1 mL). The vial was shaken for 16 hours and concentrated in vacuo. Aqueous sodium hydroxide (1 M, 2 mL) was added and the crude mixture was extracted with isopropyl acetate/tetrahydrofuran (4:1, 2.5 mL). The organic phase was concentrated in vacuo and redissolved in dimethyl sulfoxide (0.5 mL) of which 0.2 mL was subjected to preparative LC-MS purification to furnish 9.5 mg (47% yield) of the title compound as an oil. LC-MS (m/z) 341 (MH+); tR=2.28, (UV, ELSD) 100%, 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[C:29](=O)([O-:31])[O-:30].[Cs+].[Cs+].Cl.[CH3:36][NH:37][CH2:38][CH2:39]Cl>C(#N)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:39][CH2:38][NH:37][CH3:36])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH:29]([O-:31])=[O:30]
Reactant: O=C([O-])[O-]
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CNCCCl
Agent: Cl
Agent: [Cs+]
Solvent: CC#N
Product: CNCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Product: O=C[O-]
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (246 mg, 0.754 mmol) and 2-methylaminoethyl chloride hydrochloride (65.4 mg, 0.503 mmol) in acetonitrile (1.3 ml) was heated at 70° C. for 20 h. After addition of further portions of cesium carbonate (246 mg, 0.754 mmol) and 2-methylaminoethyl chloride hydrochloride (65.4 mg, 0.503 mmol) the mixture was heated at 70° C. for another 20 h. The reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound as formate salt. The salt was partitioned between ethyl acetate (15 ml) and 1 M aqueous sodium hydroxide solution (10 ml). The layers were separated. The aqueous layer was extracted with two 15 ml-portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (14 mg, 25%) as off-white solid. MS m/e: 455 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](Br)=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(NC(C)C)(C)C.[Cu](I)I>[CH3:13][Si:14]([C:17]#[C:18][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:4][C:3]=1[O:11][CH3:12])([CH3:16])[CH3:15]
Reactant: COc1cc(Br)c(OC)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: COc1cc(C#C[Si](C)(C)C)c(OC)cc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
100 g (0.338 mol) of 1,4-dibromo-2,5-dimethoxybenzene, 7.12 g (0.01 mol) of bistriphenylphospine palladium dichloride and 1.93 g (0.01 mol) of copper iodide were put into a 1 litter 3-neck round-bottom flask equipped with a stirrer, a thermometer and a reflux condenser under an argon atmosphere, and dissolved in 600 ml of diisopropylamine. 99 g (1 mol) of trimethylsilylacetylene was then slowly added dropwise at room temperature, and stirred at 80° C. for 12 hours. When the reaction was completed, the reaction mixture was cooled down to room temperature, generated salt was filtered off, and then the solvent was removed under a reduced pressure. The residue was dissolved in chloroform, and resultant was washed with water several times and then dried with anhydrous magnesium sulfate, which was then filtered off. The solvent was removed, and the residue was recrystallized from ethyl acetate/hexane mixture to obtain pale yellow crystal, which was sufficiently dried in a vacuum oven at 40° C. to give 82.5 g (yield: 73%) of the desired product, and its melting point was 164° C.–165° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:17])=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[NH3:4].[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:18][C:16](=[O:17])[C:15]1[CH:26]=[CH:27][C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[CH:3][N:4]=2)=[CH:13][CH:14]=1)[CH3:23]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cc1
Product: N
Yield: 139.1 %

Procedure:
In the same way as described for Compound 85, step 1, using 4-(5-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-N-(2-diethylamino-ethyl)-benzamide (0.12 g, 0.28 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (65 mg, 0.33 mmol), Pd(PPh3)4 (32 mg, 0.028 mmol) and NaOtBu (0.11 g, 1.11 mmol) in DMF/water. Purification by silica gel column chromatography eluting with 92:8 DCM:NH3 (7M in MeOH) affords the title compound (0.0815 g, 70%). LCMS Rt 1.93 min (99%), m/z (APCI) 419 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 0.82-0.95 (6H, t), 1.64 (2H, s), 2.37-2.43 (2H, m), 3.17-3.22 (4H, m), 6.55 (1H, br s), 7.20 (1H, br s), 7.55 (1H, s), 7.65-7.69 (3H, m), 7.98-8.09 (4H, m), 9.67 (1H, s), 13.30 (1H, br s).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:22]5[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=5)[C:20]=4[CH3:21])[CH:13]=3)[C:8]2=[O:29])[CH2:3]1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:3][CH:4]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:22]5[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=5)[C:20]=4[CH3:21])[CH:13]=3)[C:8]2=[O:29])[CH2:5]1
Reactant: Cc1c(-c2ccc3c(c2)CN(CC2CC(O)C2)C3=O)nnn1-c1cccnc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(-c2ccc3c(c2)CN(CC2CC(=O)C2)C3=O)nnn1-c1cccnc1F
Reaction time: 1 h
Yield: 60.3 %

Procedure:
20 mg of 4-[2-(3-hydroxy-cyclobutylmethyl)-1-oxo-isoindoline-5-yl]-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole obtained in Example 132 was dissolved in 1 ml of dimethylsulfoxide, and 100 μl of triethylamine followed by 40 mg of sulfur trioxide/pyridine complex were added at room temperature and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were purified by preparative thin-layer silicagel chromatography (chloroform:methanol=20:1) to obtain 12 mg of the above compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)(C)(C)C.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[C:33](Cl)=[N:32][C:31]([Cl:35])=[CH:30][N:29]=1)(=[O:26])=[O:25]>>[NH2:7][C:8]1[O:9][CH:10]=[C:11]([CH2:13][O:14][C:33]2[C:28]([NH:27][S:24]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=3[Cl:16])(=[O:26])=[O:25])=[N:29][CH:30]=[C:31]([Cl:35])[N:32]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CO)co1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: Nc1nc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)co1

Procedure:
Prepared by the method of Example 112 using (4-hydroxymethyl-2-oxazolyl)carbamic acid tert-butyl ester (Example 212a) (0.12 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.21 g). Purification was by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures to give the title compound with the BOC (tert-butyl carbonyl) attached (0.11 g). This compound was dissolved in trifluoroacetic acid (1.5 mL) and dichloromethane (1.5 mL). After 2 h, the solution was evaporated. Purification was by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures to give the title compound. Yield 0.08 g.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Clc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 27.7 %

Procedure:
Using the procedure of example 1, 4-chloro-aniline (103 mg) was reacted with compound 1f (100 mg) to provide compound 11 (24 mg, 28%). 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.0 Hz, 1H), 8.32 (d, J=5.6 Hz, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.14 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.24 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.16 (d, J=4.8 Hz, 1H). MS (ESI) m/z: 322 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[S:20][C:19]([C:21]#[N:22])=[CH:18][C:17]=1[CH3:23]>>[CH3:23][C:17]1[CH:18]=[C:19]([C:21]#[N:22])[S:20][C:16]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(C)N2

Procedure:
Prepared according to the procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-4-methyl-2-thiophenecarbonitrile. A yellowish solid: mp 145-146° C.; 1H-NMR (DMSO-d6) δ 7.79 (s, 1H), 7.18 (d, 1H, J=2.0 Hz), 7.13 (dd, 1H, J=8.4, 2.0 Hz), 6.68 (s, 1H), 6.54 (d, 1H, J=8.3 Hz), 4.83 (m, 1H), 2.26 (s, 3H), 1.49 (s, 3H), 1.46 (s, 3H), 1.28 (d, 3H, J=5.5 Hz); MS (ESI) m/z 299 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:33])[C:30]([OH:32])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][O:59][C:60]1[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[CH:64][C:61]=1[CH2:62][NH2:63].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:33])[C:30]([NH:63][CH2:62][C:61]3[CH:64]=[CH:65][C:66]([O:68][CH3:69])=[CH:67][C:60]=3[O:59][CH3:58])=[O:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(O)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)N1C(=O)[C@@](C)(CC(O)C(=O)NCc2ccc(OC)cc2OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.1 h

Procedure:
To a solution of 43 mg (0.09 mmol) of 3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoic acid (Example 81, Step B) in DMF (5 mL) was added 67 mg (0.18 mmol) of HATU, 58.5 mg (0.35 mmol) of 2,4-dimethoxybenzylamine and 36 μL (0.26 mmol) of triethylamine. The resulting yellow solution was stirred at room temperature for 1.1 h, and then was partitioned between saturated aqueous sodium bicarbonate and EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of alcohol epimers) was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2=[O:16].S(Cl)([Cl:20])(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:20])[C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:14])([CH3:15])[CH2:6][C:5]2=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 2.80 g, 9.8 mmol) in methylene chloride (50 nL) at 0° C. were added sulfuryl chloride (1.59 g, 11.7 mmol) followed by treatment with pyridine (0.87 g, 11.7 mmol). After stirring at 0° C. and slow warning room temperature over 3 h, the reaction was quenched with ice water. The resulting mixture was extracted with dichloromethane and then the combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) to afford the title compound as a colorless oil.