Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(N[C:10]2[N:15]=[C:14]([N:16]3[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:18]([CH3:26])=[N:17]3)[CH:13]=[CH:12][N:11]=2)C=C(C)C=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CN=[C:36]([S:40]C)N=1>C(#N)C.C(OCC)(=O)C>[CH3:26][C:18]1[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:20][N:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([S:40][CH3:36])[N:15]=2)[N:17]=1
Reactant: CSc1nccc(Cl)n1
Reactant: CCOC(=O)c1cn(-c2ccnc(Nc3cc(C)cc(C)c3)n2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ccnc(SC)n2)nc1C
Temperature: 80 °C
Yield: 707.8 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate 2 (5.0 g, 32 4 mmol) in anhydrous acetonitrile (60 mL) were added potassium carbonate (8.96 g, 64.9 mmol) and 4-chloro-2-(methylthio)pyrimidine 11 (5.47 g, 34.1 mmol) at room temperature (rt). The resulting suspension was heated at 80° C. for 8 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). It was diluted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with methanol to give 7.88 g (83%) of ethyl 3-methyl-1-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate 12; MS (ESI) m/z 279 [M+H]+. The resulting pyrazole-4-carboxylate 12 (7.44 g, 26 7 mmol) was dissolved in 30 mL of DCM and then cooled to 0° C. To this was added 3-chloroperbenzoic acid (mCPBA, 13.2 g, 58.8 mmol) at the same temperature. The reaction was warmed to room temperature, stirred for 2 hours and then quenched by addition of saturated NaHCO3 solution. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with iso-propylether to give 7.88 g (83%) of ethyl 3-methyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate 13 as a colorless solid (6.92 g, 83%); m/z 311 [M+H]+. The obtained sulfoxide 13 (3.0 g, 9.7 mmol) was mixed with acetic acid (0.42 mL, 9.7 mmol) and 3,5-dimethylaniline (1.4 mL, 9.7 mmol) in 10 mL of n-butanol. After being heated at reflux for 2 hours, the mixture was concentrated in vacou. The resulting residue was extracted with DCM, washed with a saturated NaHCO3 solution. The collected organic layer was dried over anhydrous sodium sulfate, concentrated in vacou and then recrystallized with ethyl acetate to afford 0.86 g (26%) of Compound No. 2 as a pale yellow solid; m/z 352 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]=2[CH:1]=1)(=[O:29])=[O:28]
Reactant: OCCc1ccc2c(c1)Cc1ccccc1CO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2c(c1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol (14 g) and triethylamine (6.7 g) in 200 ml of dry dichloromethane was treated with methanesulfonylchloride (5.2 ml) and stirred at room temperature for 2 hours. This solution was evaporated to a paste, taken up in ethyl acetate, washed dried, and evaporated to an oil. Passage through a short pad of silica gel with chloroform as eluent gave 13.5 g of 2-(6,11-dihydrodibenz[b,e]-oxepin-2-yl)ethanol methanesulfonate as an oil.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)([C:9]#[CH:10])[CH3:8].[CH2:18]([O:20][CH:21]([O:27][CH2:28][CH3:29])[C:22](OCC)=[O:23])[CH3:19].[NH4+].[Cl-]>CCOCC>[CH2:18]([O:20][CH:21]([O:27][CH2:28][CH3:29])[C:22](=[O:23])[C:10]#[C:9][C:7]([CH3:6])([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH3:8])[CH3:19]
Reactant: C#CC(C)(C)OC1CCCCO1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(OCC)C(=O)C#CC(C)(C)OC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 250 mL round bottom flask, 9.5 mL of n-butyl lithium (2.5 M solution in hexane, 23.8 mmol) was added via a syringe to a pre-cooled solution (−78° C.) of 2-(2-methylbut-3-yn-2-yloxy)-tetrahydro-2H-pyran 2 (4.0 g, 23.8 mmol) in 100 mL of Et2O. The resulting solution was stirred for 30 min at −78° C., then ethyl 2,2-diethoxyacetate (4.9 g, 27.7 mmol) was added with a syringe, and the stirring continued for 12 hours. The reaction mixture was poured in an ice-cold saturated aqueous solution of NH4Cl. The aqueous layer was extracted with Et2O (3×50 mL). The organic solvent was separated with a separating funnel and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the resulting pale yellow oil was purified by radial chromatography (stationary phase silica gel, hexane/AcOEt 90:10) to provide 1,1-diethoxy-5-methyl-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-yn-2-one 3 as a colorless liquid. Yield: 3.2 g (10.7 mmol; 45%). 1H-NMR in CDCl3 (δ, ppm): 5.05 (1H, q, J=5.0, 3.5 Hz, THP), 4.73 (1H, s, acetal), 3.92 (1H, m, THP), 3.69 (2H, m, CH2, acetal), 3.62 (2H, m, CH2, acetal), 3.50 (1H, m, THP), 1.82 (1H, m, THP), 1.71 (1H, m, THP), 1.58 (3H, s, CH3), 1.54 (3H, s, CH3), 1.52 (4H, m, THP), 1.25 (6H, t, J=7.0 Hz, CH3, acetal). 13C-NMR in CDCl3 (δ, ppm): 182.6, 101.1, 97.87, 96.10, 81.25, 70.57, 62.95, 62.64, 62.61, 31.47, 29.45, 28.85, 25.06, 19.92, 14.90 IR (neat, cm−1): 2978, 2937, 2872, 2214, 1687, 1074. HR ESIMS+ with acetonitrile as the mobile phase, (m/z): 299.1837 (M+, C16H26O5, 299.1853), 321.1660 (m/z) ([M+Na]+, C16H26O5Na, 321.1672).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH3:21])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:38]([NH2:42])[CH2:39][CH2:40][CH3:41]>O1CCCC1.C(Cl)Cl>[CH2:38]([NH:42][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH3:21])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CC)NC(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
2.42 g of 1-(N-(tert-butoxycarbonyl)-2(S)-aminobutyryl)-L-proline (8.05 mmol) prepared as in Example 2 c) are dissolved in dry tetrahydrofuran (15 ml). The solution is cooled in an ice/salt bath and 0.927 g of N-ethylmorpholine (8.05 mmol) and 1.10 g of isobutyl chloroformate (8.05 mmol) are then added. The solution is stirred for 45 minutes and 0.59 g (8.05 mmol) of n-butylamine is added. After stirring overnight, methylene chloride (200 ml) is added and the mixture is washed with 10% citric acid (2×100 ml) and then with 5% NaHCO3 (2×100 ml). The organic phase is dried (Na2SO4) and evaporated under vacuum. A syrup is obtained. The deprotection is carried out without characterization.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CCl)cc1

Procedure:
A solution of 2.0 g (12 mmol) of 4-chloromethylbenzoic acid in 50 ml of methanol was added with 5 droplets of concentrated sulfuric acid, followed by stirring under heat and reflux for 4 days. After neutralization with a 5% aqueous solution of sodium carbonate, the resultant mixture was extracted with chloroform. The chloroform extract was dried over magnesium sulfate and then concentrated under reduced pressure, whereby 1.7 g of a colorless liquid were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][O:16][CH:17]2[CH:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])=[CH:25][CH:24]=3)[CH2:21][CH2:20][N:19]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH2:18]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]#[N:13])[CH:8]=[C:7]2[CH3:14].B#B.CO>O1CCCC1>[NH2:13][CH2:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:15][O:16][CH:17]3[CH:22]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])=[CH:27][CH:28]=4)[CH2:21][CH2:20][N:19]([C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])[CH2:18]3)[C:2]=2[Br:1])[C:7]([CH3:14])=[CH:8]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CC#N)c3c2Br)cc1
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1

Procedure:
The solution of 0.240 g of benzyl 3-(7-bromo-1-cyanomethyl-3-methyl-1H-indol-6-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.5 ml of tetrahydrofuran is cooled to 0° C. with stirring and admixed with 1.22 ml of diborane (1M in tetrahydrofuran). The reaction mixture is stirred at 0° C. over 1 hour and subsequently admixed cautiously with 1.0 ml of methanol and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.46 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=5.45.
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[CH2:16]([NH:19][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH:17]=[CH2:18]
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Reactant: C=CCN
Solvent: O
Product: C=CCNC1=NS(=O)(=O)c2cnccc2N1
Temperature: 120 °C

Procedure:
A mixture of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate (0.5 g) and allylamine (4 mL) was heated in a sealed bumb for 4-5 h at 120° C. After cooling, the amine was removed by distillation under reduced pressure. The residue was dissolved in 0.5N NaOH, treated with charcoal, filtered, and the filtrate was adjusted to pH 6 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a dihydrate (yield: 0.44 g); m.p. 206°-208° C. (Compound 15).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:27])[C@H:11]([CH2:23][CH2:24][S:25][CH3:26])[NH:12][C:13](=[O:22])[C@H:14]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(=O)[C@H](CCSC)NC(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)N[C:42](=[O:68])[CH2:43][NH:44][C:45](=[O:67])[CH2:46][NH:47][C:48](=[O:66])[C@H:49]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])C1C=CC=CC=1>>[CH2:2]([O:9][C:10](=[O:27])[C@H:11]([CH2:23][CH2:24][S:25][CH3:26])[NH:12][C:13](=[O:22])[C@H:14]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[NH:15][C:42](=[O:68])[CH2:43][NH:44][C:45](=[O:67])[CH2:46][NH:47][C:48](=[O:66])[C@H:49]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)[NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1cccs1)C(=O)OCc1ccccc1
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](Cc1cccs1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of β-(2-thienyl)-L-alanyl-L-methionine benzyl ester hydrochloride is substituted for the L-tryptophyl-L-methionine benzyl ester hydrochloride of Example 7 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosylglycylglycyl β-(2-thienyl)-L-alanyl-L-methionine benzyl ester.
Reaction SMILES: [OH:1][C@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[N:24]([CH2:12][C@@H:2]([OH:1])[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CP(C)(=O)OCC(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COP(C)(=O)C[C@H](O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 4.3 g of isobutyl P-[2(R)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate and 1.5 g of sodium azide in 25 ml of dry dimethylformamide is heated to a temperature of 120° for a period of 3 hours under an inert gas atmosphere. The reaction mixture is allowed to cool to room temperature, poured onto 50 ml of water and extracted twice with 100 ml of ethyl acetate. The organic extract is dried over magnesium sulphate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate to 1 part of ethanol as eluent. There is obtained isobutyl P-[3-azido-2(R)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+54.8 and +53.7 ppm (CDCl3), [α]D25 =-15.8 (0.51% in ethanol).
Reaction SMILES: [CH2:1]([C@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[C@H:9]([OH:31])[CH2:10][N:11]([CH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][CH2:26][C:27]#[N:28])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].N.CO>[NH2:28][CH2:27][CH2:26][CH2:25][C:24]([CH3:30])([CH3:29])[CH2:23][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[CH2:10][C@@H:9]([OH:31])[C@@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Yield: 77.3 %

Procedure:
A mixture of 0.29 g (0.46 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-3-((4-cyano-2,2-dimethylbutyl)[3-(methylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate and approximately 50 mg of Raney nickel (washed with water and MeOH) in 60 mL of 2M NH3/MeOH was subjected to hydrogenation at 45 psi. After 1.5 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through celite and the filtrate concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 9:1 CH2Cl2/2M NH3 in MEOH) to afford 0.22 g (76%) of the desired amine as a white foam. NMR (CDCl3): 7.39-7.19 (m, 6H), 7.10 (d, 1H), 7.04-6.92 (m, 2H), 6.81 (dd, 1H), 5.63 (d, 1H), 5.05 (q, 1H), 4.16 (br s, 1H), 4.09-3.80 (m, 4H), 3.70 (m, 2H), 3.31 (m, 2H), 3.21-3.00 (m, 3H), 2.99-2.58 (m, 5H), 2.90 (3, 3H), 2.57-2.10 (br, 2H), 1.82-1.07 (m, 6H), 1.04 (s, 3H), 0.92 (s, 3H). MS(ESI): 619 (M+H).
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:32][CH:33]3[CH2:34][CH:35]([CH2:36][CH:37]([CH2:39]3)[CH2:38]1)[CH2:40]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccc(C)cc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccc(C)cc2)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)O

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(4-methylbenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[I:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:19]=2)[CH:16]=1>CO>[OH:3][NH:2][C:24](=[NH:25])[C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]3[CH:13]=[CH:12][C:11]([I:10])=[CH:16][N:15]3[CH:17]=2)=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N=C(NO)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 73.8 %

Procedure:
Hydroxylamine hydrochloride (208 mg) and potassium carbonate (415 mg) were added to a solution (10 mL) of 4-(6-iodoimidazo[1,2-a]pyridin-2-yl)benzonitrile (345 mg) in methanol, followed by refluxing for 14 hours. The mixture was left to cool, and the formed crystals were recovered through filtration. The crystals were washed with water and dried, to thereby yield the title compound (279 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C>C(O)C>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:2][C:3]3[C:4](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[C:5]2=[O:7])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: CC(C)c1ccc(N)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-nitrobenzoate (1.88 g, 6.52 mmol), 4-isopropylaniline (1.11 mL, 7.83 mmol) and N,N-diisopropylethylamine (1.36 mL, 7.83 mmol) in ethanol (75 mL) was heated in a sealed tube at 110° C. overnight. After this time, the mixture was cooled to room temperature and the solid collected by filtration to afford 2-(4-isopropylphenyl)-6-nitroisoindolin-1-one (1.45 g, 75%) as a yellow solid: mp 225-227° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (d, J=2.0 Hz, 1H) 8.48 (dd, J=8.3, 2.1 Hz, 1H), 7.76-7.69 (m, 3H), 7.32 (d, J=8.6 Hz, 2H), 2.94 (sept, J=6.9 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H); ESI MS m/z 297 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[C:40](O)(=[O:42])[CH3:41].C(=O)([O-])[O-]>>[C:40]([N:37]1[CH2:38][CH2:39][CH:35]([NH:34][C:32]([C:5]2[C:6]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]5[N:21]([CH3:29])[C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=4)[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=2)=[O:33])[CH2:36]1)(=[O:42])[CH3:41]
Reactant: CC(=O)O
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Product: COc1cc(-c2csc3c(C(=O)NC4CCN(C(C)=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 20 h

Procedure:
4-Amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-pyrrolidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (100 mg, 0.185 mmol) and acetic acid (9.6 μL, 0.168 mmol) were treated according to General Procedure D. MP-carbonate (184 mg, 0.504 mmol) was added and mixture placed on shaker for 20 hours. The mixture was then filtered and solvent removed in vacuo. The product was purified via flash chromatography to furnish the title compound as a off-white powder. (3.2 mg, 0.0051 mmol): LCMS (Conditions b): MH+=583, Rt=2.85 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (1H), 8.62 (1H), 8.54 (1H), 8.00 (1H), 7.71 (1H), 7.59 (2H), 7.35 (2H), 7.19 (1H), 7.15 (1H), 7.06 (1H), 6.04 (2H), 4.46-4.56 (1H), 4.04 (3H), 3.91 (3H), 3.80 (1H), 3.61 (1H), 3.50 (1H), 3.39 (1H), 2.00-2.22 (2H), 1.96 (3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Reactant: O=C=NCc1ccccc1
Product: CC1(C)CN(Cc2ccccc2)c2ccc(OC(=O)NCc3ccccc3)cc21

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.3 mg, 36%) having the following characteristics.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:11]([C:13]1[NH:14][C:15](=[O:23])[NH:16][C:17](=[O:22])[C:18]=1[CH:19]([CH3:21])[CH3:20])=[O:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32]>CN(C=O)C>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:11]([C:13]1[N:14]([CH2:31][CH3:32])[C:15](=[O:23])[NH:16][C:17](=[O:22])[C:18]=1[CH:19]([CH3:20])[CH3:21])=[O:12]
Reactant: CCI
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C(=O)c2cc(C#N)cc(C)c2Cl)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of Compound 98 (0.067 g, 0.202 mmol) and potassium carbonate (0.0279 g, 0.202 mmol) in DMF (1.0 mL) was added iodoethane (14 μL, 0.168 mmol) and reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, dried (MgSO4) and concentrated. The resulting residue was purified by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give a white powder after lyophilization (20.5 mg, 28%). 1H NMR (300 MHz, CD3CN): 9.15 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 3.52 (br s, 2H), 2.47 (s, 3H), 2.3-2.2 (m, 1H), 1.1-1.0 (s, 9H); Mass Spectrum: 360.2, 362.2 (M+H).