Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:3][CH:18]=1
Reactant: COC(=O)[C@H](C)c1ccc(NC(N)=O)cc1
Reactant: O=C(CBr)C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)co2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl (2R)-2-[4-(carbamoylamino)phenyl]propanoate (2.7 g, 9.95 mmol) in dioxane (50 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (1.03 ml, 10 mmol) and the resulting mixture was refluxed for 2 h. After cooling at room temperature, the solvent was evaporated under vacuum, the crude diluted with CH2Cl2 (50 ml) and washed with a saturated NaHCO3 aqueous solution (3×30 ml), dried over anhydrous Na2SO4 and evaporated to give pure methyl (2R)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanoate (2.5 g, 7.96 mmol) as yellow oil (80%). 1H-NMR (CDCl3): δ 10.05 (bs, 1H, NH), 8.30 (s, 1H), 7.45 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 3.75 (q, 1H, J=7 Hz), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][C@H:3]([OH:19])[CH2:4][O:5][C:6]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH2:21][CH2:22][CH3:23]
Reactant: NCC(O)COc1cccc2[nH]c3ccccc3c12
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1

Procedure:
The title compound was prepared from 1-amino-3-(9H-carbazol-4-yloxy)-propan-2-ol and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 166-179° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.79 (t, 3H), 1.15-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.64 (t, 2H), 2.60-3.00 (m, 5H), 3.60-4.20 (m, 5H), 6.69 (d, 1H), 6.80-7.60 (m, 7H), 7.90 (s, 1H), 8.20 (d, 2H), 11.35 (s, 1H); MS (ES) m/z: 551.1 (MH+); HRMS Calcd. for C30H39N4O4S (MH+): 551.2692. Found: 551.2664.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:10][C:3]2[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=2[OH:1])=[CH:15][CH:14]=1
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: ClCc1ccc(CCl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc(CSc3c(O)cc(C)oc3=O)cc2)c(=O)o1
Reaction time: 15 h

Procedure:
To a stirred solution of 15.8 g. (0.100 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 100 ml. of pyridine was added 8.75 g. (0.0500 mole) of α,α'-dichloro-p-xylene in one portion at room temperature. The reaction mixture was allowed to stand at room temperature for 15 hours and then was poured into a mixture of ice and 200 ml. of concentrated hydrochloric acid. The mixture was extracted with methylene chloride, leaving the methylene chloride-insoluble, white solid product behind. This was collected on a filter and found to weigh 5.3 g., m.p. 224°C. (dec.). The extract was dried over anhydrous sodium sulfate, and the methylene chloride was removed by evaporation in vacuo. The remaining 4.1 g. of light yellow solid residue was triturated with benzene containing a little ethanol, leaving 1.7 g. more product as an insoluble white solid, m.p. 228°-229°C. (dec.). Recrystallization of the combined product fractions from nitromethane gave the pure α,α'-bis(4-hydroxy-6-methyl-2-oxo-3-pyranylthio)-p-xylene as very pale yellow crystals, m.p. 234°C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.O[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:29]([O:28][C:27]([NH:26][CH2:25][CH2:24][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:19][CH:18]=1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(Cl)cc1
Yield: 78 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)propionate (1.01 g), which is the product of Reference example 38(b), t-butyl 2-hydroxyethylcarbamate (1.27 g), triphenylphosphine (2.06 g) and diethylazodicarboxylate (1.37 g) and the reaction mixture was treated to afford the title compound (1.14 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].O=[CH:22][C@@H]([C@@H]([C@@H](CO)O)O)O.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Al](C)C>[Pd]>[CH3:22][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: [Pd]
Agent: C[Al](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Starting with commercially available 8-bromoadenosine (1), the hydroxyl groups of the ribose moiety were transiently protected by treatment with hexamethyldisilazane and catalytic ammonium sulfate. The crude intermediate underwent palladium catalyzed coupling reaction with trimethylaluminum to install the methyl group at the 8-position. The product, without purification, was deprotected directly to afford 8-methyladenosine derivative (2). Treatment of 2 with thionyl chloride in pyridine afforded the chloride derivative 3, which was subjected to reaction with excess methylamine under microwave irradiation to yields the amine 4. Allylic displacement with cis-1-(t-butoxycarbonylamino)-4-chloro-2-butene under catalytic halide exchange conditions proceeded to form amine 5, which was then deprotected with methanolic hydrogen chloride and purified by silica gel chromatography to afford the final product.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:17])[C:9]2[C:10](=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:1]1([O:7][C:8](=[O:17])[C:9]2[CH:15]=[CH:14][C:13]([NH:16][C:1](=[O:7])[CH3:2])=[CH:12][C:10]=2[O:11][C:10](=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C(=O)Oc2ccccc2)c(O)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)Oc2ccccc2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
This compound was prepared using the General Structural Outline for Synthesis of para-Aminosalicylic Acid Phenyl Ester Diacyl Derivatives. In a 50 mL pear shaped flask fitted for reflux were mixed para-aminosalicylic acid phenyl ester (1.45 g) and acetic anhydride (10 mL). Over 10 minutes, the mixture was brought to the boil, and refluxing was continued for 20 minutes. The mixture was allowed to cool to room temperature and stand for two hours, then poured out into a watchglass and allowed to dry. The resulting residue was ground with ether (10 mL) and the process repeated. The resulting white crystalline solid was the title compound (0.75 g, 38%), mp 142-143° C. (uncorr); IR v 3323, 1767, 1734, 1673, 1613, 1590, 1506, 1268, 1207, 1185, 1163, 1134, 1056, 1014, 1002, 944, 895, 862, 844, 748, 691 cm−1; NMR δ 10.5 (1H, br s), 8.2-7.1 (m, 8H), 2.2 (3H, s), 2.1 (3H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.CN(C)[CH:15]([CH3:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[CH2:24][CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C(=O)c1ccccc1)N(C)C
Reactant: O=c1cc(O)c2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCc1c(O)c2ccccc2oc1=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.81 g (5.0 mmol) of 4-hydroxycoumarin, 1.07 g (5.0 mmol) of 2-dimethylaminopropiophenone, and 20 mL of acetonitrile was treated with 0.2 mL (5.0 mmol) of triethylamine and then refluxed for 4 hours. The mixture was cooled to room temperature and poured into 5% sodium hydroxide. The aqueous solution was extracted with ether and acidified to pH 3 with 6N hydrochloric acid. The mixture was extracted with chloroform, and the extract was washed with water, dried, and concentrated to give the title compound, m.p. 149°-151° C. NMR (CDCl3) δ2.99 (m, 2H), 3.52 (m, 2H), 7.26 (m, 2H), 7.48 (m, 3H), 7.60 (m, 1H), 7.94 (dd, 1H), 8.02 (d, 2H), 10.65 (bs, 1H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].S(=O)(=O)(O)O.[CH3:12][C:13](=[CH2:15])[CH3:14]>O>[F:3][C:2]([F:5])([F:4])[CH2:1][O:6][C:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: OCC(F)(F)F
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OCC(F)(F)F
Temperature: 20 °C
Yield: 51 %

Procedure:
Approximately 55 g (0.55 mol) trifluoroethanol and 2 g concentrated sulfuric acid were placed in a 300 ml glass pressure bottle equipped with a magnetic stir bar and pressure gauge. The pressure bottle was evacuated briefly and the stirred contents were cooled in a water bath at about 20° C. in order to moderate the temperature of the somewhat exothermic reaction with isobutylene. Isobutylene was then added to a pressure of about 20 psig. The isobutylene supply was turned off and the reaction was monitored by the decrease in pressure in the glass reactor. After the pressure had fallen to 0 psig, additional isobutylene was charged. In this manner, a total of 20.1 g (0.359 mol) isobutylene was added. The mixture was then poured into 300 ml of cold water and extracted with 50 ml of dodecane. The organic layer was separated, washed with three (3) 50 ml portions of water and dried over anhydrous powdered magnesium sulfate. The organic layer was distilled affording 28.5 g (51%) tertiary butyl 2,2,2-trifluoroethyl ether, bp 82.5°-84° C. 1H NMR (CDCl3): δ 3.77 (q, 2H, J=8 Hz), 1.25 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[N:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].O>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[C:7](=[O:8])[NH:9][C:10](=[O:11])[CH2:12][NH:13]1
Reactant: Cc1cccc(Cn2ncc(=O)[nH]c2=O)c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(CN2NCC(=O)NC2=O)c1
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Into a three-necked flask equipped with a mechanical stirrer and a reflux condenser was placed 1 g of 1-(3-methylbenzyl)-6-aza-uracil, 100 ml of water was added and a vigorous stirring commenced. 1.1 g of zinc powder was added in one portion, and was followed by dropping in 20 ml of glacial acetic acid. The mixture was then vigorously stirred and refluxed for 24 hours. The mixture was thereafter cooled and the precipitate was filtered off with suction. The mass of crystals was dissolved in hot methanol, the solution filtered and the filtrate was left to stand overnight and filtered to yield 0.6 g of 2-(3'-methylbenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 158°.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:57])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:46][C:47]=3[CH3:48])=[C:37]([O:55][CH3:56])[CH:36]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:56][O:55][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[O:41][CH2:42][C:43]1[N:44]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:46][C:47]=1[CH3:48])[C:34]([NH:33][C:23]1[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:24]=1)=[O:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(C(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (215 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 38 mg), and the mixture was stirred at room temperature for 20 min. A solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzamide (433 mg) in N,N-dimethylformamide (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless amorphous form (205 mg, yield 38%) from a fraction eluted with ethyl acetate-hexane (1:1 to 1:0, v/v).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1(C(OC(C)(C)C)=O)[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:51]6[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCNCC4)c3)ccc2OC)c1
Reaction time: 3 h
Yield: 60.3 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (24 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 uL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The residue was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [36.6 mg (60%)]. LC-MS m/z 760 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:36]=[CH:35][C:22]3[NH:23][C:24]([S:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:36]=[CH:35][C:22]3[NH:23][C:24]([S:26][CH2:27][C:28]([OH:30])=[O:29])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc3[nH]c(SCC(=O)O)nc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of tert-butyl [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1H-benzimidazol-2-yl)sulfanyl]acetate obtained in Example 29 (763 mg) and trifluoroacetic acid (3 mL) was stirred at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (475 mg, 70%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:3]=1.B.[CH3:24]SC>C1COCC1.[Ni].CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][N:12]([CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(NC(=O)CNc2ccc([N+](=O)[O-])cc2)c1
Reactant: CSC
Agent: [Ni]
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NCCN(C)c2ccc(N)cc2)c1

Procedure:
From 1-fluoro-4-nitrobenzene by heating with glycine at reflux in a mixture of aqueous sodium bicarbonate and dioxane to give (4-nitro-phenylamino)-acetic acid, followed by treatment with formaldehyde and formic acid at reflux to give [methyl-(4-nitro-phenyl)-amino]-acetic acid. Treatment with thionyl chloride and catalytic DMF to give the acid chloride followed by amide formation with 2-amino-4,6-dimethylpyridine in triethylamine and chloroform gives N-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenylamino)-acetamide. The amide is the reduced with borane-dimethylsulfide in THF at reflux then catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[Cl:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([Cl:42])[CH:44]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(Cl)c2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 3-chlorophenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>CN(C=O)C.OS([O-])=O.[Na+]>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: II
Reactant: c1cnc2[nH]ncc2c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.00 g (8.40 mmol) of 1H-pyrazolo[3,4-b]pyridine in 15 mL of DMF was treated with 4.26 g (16.80 mmol) of iodine, followed by 1.77 g (31.50 mmol) of solid KOH. The resulting reddish-brown mixture was stirred at ambient temperature for 1 hour. The reaction was diluted with 5× its volume with a solution of aq. 10% NaHSO3, and the mixture stirred. The yellow solid precipitate was filtered off, washed with water, and dried in vacuo to give the desired product. The crude product was used as is in the next reaction. MS M+1=246.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[C:9]2[CH2:32][N:33](C(OC(C)(C)C)=O)[C:34]([CH3:36])([CH3:35])[C:8]2=[N:7]1)=[O:5].[ClH:44]>O1CCOCC1>[ClH:44].[CH2:2]([O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[C:9]2[CH2:32][NH:33][C:34]([CH3:35])([CH3:36])[C:8]2=[N:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CN(C(=O)OC(C)(C)C)C2(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CNC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (1.5 g, 2.5 mmol) in 1,4-dioxane (20 mL) was added 4N HCl in 1,4-dioxane (14 mL, 56 mmol). After stirring at room temperature overnight the volatiles were removed under reduced pressure and the residue triturated with diethylether affording the title compound as white solid (1.24 g).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[N:16]1[C:25]2[C:20](=[CH:21][C:22]([NH:26]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc2ncccc2c1
Temperature: 110 °C
Yield: 82.5 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), quinolin-6-ylamine (72.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 130 mg (82%) of greenish yellow solid mp 277-278° C.; MS (ESI) m/z 316.10 (M+1); Analysis for C19H13N3O2: Calcd: C, 72.37; H, 4.16; N, 13.33. Found: C, 71.86; H, 4.02; N, 13.25.