Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)no2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)no2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
Prepared using General Procedure 4: To a solution of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate (710.0 mg, 1.19 mmol) in MeOH (20 mL) was added 1 N NaOH (10 mL). The reaction mixture was stirred at 50° C. for 3 h. The resulting mixture was purified by chromatography (DCM/MeOH) to afford 218 mg (31%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid as white solid. LCMS-ESI (m/z) calculated for C35H41N3O5; 583.3; no m/z observed, tR=12.16 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.69 (d, J=8.3 Hz, 1H), 8.16-8.02 (m, 2H), 7.98 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.18 (d, J=9.0 Hz, 2H), 4.70 (ddd, J=10.8, 8.4, 4.5 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.30 (dd, J=13.8, 4.2 Hz, 1H), 3.17 (dd, J=13.8, 10.7 Hz, 1H), 1.74 (dd, J=14.5, 6.7 Hz, 2H) 1.42 (dd, J=13.8, 6.1 Hz, 2H), 1.37-1.14 (m, 14H), 0.87 (t, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 175.16, 173.00, 167.96, 166.19, 162.55, 154.18, 142.11, 131.08, 129.95, 129.89, 127.14, 126.92, 125.01, 124.39, 115.49, 115.37, 67.98, 53.72, 36.19, 34.58, 31.19, 30.89, 28.46, 28.37, 25.36, 22.01, 13.92.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:28]([CH3:35])[CH:27]=5)[CH:23]=[CH:22][N:21]=4)=[C:12]([O:36][CH3:37])[CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[C:12]([O:36][CH3:37])[C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:28]([CH3:35])[CH:27]=5)[CH:23]=[CH:22][N:21]=4)=[CH:14][C:15]=3[NH2:16])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 82.7 %

Procedure:
A mixture of N-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 124, 256 mg, 0.51 mmol), iron powder (172 mg, 3.07 mmol) and NH4Cl (19.19 mg, 0.36 mmol) were heated in ethanol (3 mL) and water (1 mL) at reflux for 18 h. The crude mixture was then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and concentrated in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (198 mg, 82%) as a yellow foam; 1H NMR (CDCl3) 1.78 (1H, td), 2.07-2.13 (1H, m), 2.15 (1H, dd), 2.29 (3H, s), 2.47 (1H, dd), 2.57-2.65 (2H, m), 2.82-2.95 (2H, m), 3.45 (1H, dt), 3.85 (3H, s), 3.88 (3H, s), 4.07 (1H, ddd), 6.74 (1H, s), 7.01 (1H, d), 7.27-7.35 (2H, m), 7.38 (1H, dd), 7.55 (1H, s), 7.79 (1H, s), 8.14 (1H, s), 8.33 (1H, d), 8.45-8.52 (1H, m); m/z: ES+ MH+ 470.29.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:30])[CH2:8][S:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N[C@H](C(NCCSC(=O)C)=O)CS)(=O)C.C(Cl)Cl.CCOCC.C(Cl)(Cl)Cl>CCCCCC>[C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:30])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)c1ccccc1
Agent: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)N[C@@H](CS)C(=O)NCCSC(=O)c1ccccc1

Procedure:
This compound is obtained by the S-detritylation of 17 (2.68 mmol). The protocol used is the same as that described in example 1 for the synthesis of I-152. After the various treatments, a gum is collected, which gum is purified by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 25%). I-219 is isolated in the form of a gum which, after trituration in hexane, provides a colorless powder (Yd=58%). Rf (CH2Cl2/ether, 6/4): 0.35. M.p.=127-130° C. [α]D20=−20.8° (c 1.06, CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C([Li])CCC.CCCCCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25].O>O1CCCC1>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1cc(C=O)oc1C
Reactant: Cc1ccncc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccncc1C(O)c1cc(C)c(C)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
3-Bromo-4-methylpyridine (500 mg) was dissolved in tetrahydrofuran (15 ml) under an argon atmosphere to prepare a solution. A 1.6 M n-butyllithium/hexane solution (2 ml) was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (350 mg) in tetrahydrofuran (2 ml) was added dropwise thereto, and the temperature of the reaction solution was raised to room temperature while stirring. Water was added to the reaction solution to stop the reaction, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanol (174 mg, yield 28%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[C:15](=[O:16])[NH:14][CH2:13][CH2:12][N:11]1[C:17]([C:19]1[CH:39]=[CH:38][C:22]([C:23]([NH:25][CH:26]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:30]=3[N:29]=2)[CH3:27])=[O:24])=[CH:21][C:20]=1[Cl:40])=[O:18])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>>[NH2:8][CH2:9][CH:10]1[C:15](=[O:16])[NH:14][CH2:13][CH2:12][N:11]1[C:17]([C:19]1[CH:39]=[CH:38][C:22]([C:23]([NH:25][CH:26]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:30]=3[N:29]=2)[CH3:27])=[O:24])=[CH:21][C:20]=1[Cl:40])=[O:18]
Reactant: CC(NC(=O)c1ccc(C(=O)N2CCNC(=O)C2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1ccc(C(=O)N2CCNC(=O)C2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 91 %

Procedure:
Prepared analogously to Example 17 from 4-(2-tert-butoxycarbonylaminomethyl-3-oxopiperazin-1-ylcarbonyl)-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and trifluoroacetic acid. Yield: 91%; C22H22Cl2N6O3 (489.36); mass spectrum: (M+H)+=489/491/493 (chlorine isotope).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C@H:23]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22](SC)=[CH:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=[O:46]>O.CN(C=O)C.CC(C)=O>[Si:26]([O:25][CH2:24][C@H:23]1[C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][C:22]1=[O:46])([C:39]([CH3:40])([CH3:41])[CH3:42])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CSC1=C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)(C)[Si](OC[C@@H]1CC(=O)[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 6 h

Procedure:
To 29.00 mg of cupric oxide (CuO) and 42.65 mg of cupric chloride (CUCl2) were added 5 ml of acetone, one drop of distilled water and two drops of DMF. To the suspension thus obtained was added 44 mg of (-)-(3R,4R)-3,4-bis(t-butyldiphenylsilyloxymethyl)-1-methylthio-1-cyclobutene. After stirring the obtained mixture at 30° to 40° C. for 6 hours, 24.25 mg of cupric oxide (CuO) and 88.75 mg of cupric chloride (CuCl2) were further added thereto. The obtained mixture was stirred at 30° to 40° C. for 5 hours. Then a phosphate buffer solution was added to the reaction mixture. After filtering through Celite, water was added thereto, followed by extracting with ether. The ether extract was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by thin layer chromatography. Thus 30.40 mg of (-)-(2R,3R)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclobutanone was obtained. [α]D =-13.8° (c 0.608, CH2Cl2)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.C(O)C>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (1.78 g), 5% palladium-carbon (2.0 g), ethanol (20 ml), and tetrahydrofuran (20 ml) was stirred at room temperature for one hour under a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.57 g, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](O)[C:7]3[CH2:12][CH2:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:6]1[C:7]2[CH2:12][CH2:11][NH:10][C:8]=2[N:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: Oc1nc(C2CC2)nc2c1CCN2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc(C2CC2)nc2c1CCN2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-ol 48 (0.5 g, 2.8 mmol) is suspended in phosphorus oxychloride (0.7 ml). A mixture of N,N-diethylaniline (0.46 g, 3.1 mmol) and phosphorus oxychloride (0.7 ml) is added dropwise to the suspension at room temperature. The resulting mixture is stirred at 120° C. for 3 h. The solution is poured onto crushed ice and extracted two times with dichloromethane. The aqueous layer is alkalinized (pH 10) and extracted four times with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude mixture (370 mg, 68%, 91% purity) is used in the next step without further purification due to the unstability of the compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:9]=[C:10](Cl)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of combined batches of methyl 3-amino-5-chloro-2-nitrobenzoate (39 g), morpholine (29.5 g) and K2CO3 (47 g) was stirred in DMF (200 ml) at 110° C. for 5 h. The mixture was cooled to room temperature and poured into water (1 L). It was extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo to afford the desired product as a yellow solid (22 g, yield 46%). 1H NMR (300 MHz, CDCl3): δ ppm 3.31 (t, 4H, J=4.8 Hz), 3.82 (t, 4H, J=4.8 Hz), 3.89 (s, 3H), 6.03 (d, 1H, J=2.4 Hz), 6.34 (d, 1H, J=2.4 Hz); LC-MS: m/e=282 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=2[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(CO)ccc1Br
Product: COc1cccc(-c2ccc(CO)cc2C)c1

Procedure:
Following the procedure described for Example 13, step A, but using the product from step A above and 3-methoxybenzene-boronic acid as starting materials the title product was obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH3:24][O:25][C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:27]=1[NH2:28].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH3:24][O:25][C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: CCOC(=O)CCCn1c(Cl)nc2cccc(C(CC)CC)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2ccc(OC)cc2OC)nc2cccc(C(CC)CC)c21
Temperature: 110 °C
Reaction time: 14 h
Yield: 89.4 %

Procedure:
A mixture of ethyl 4-[2-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (475.2 mg, 1.41 mmol), 2,4-dimethoxyaniline (0.60 mL, 4.23 mmol) and 1-methyl-2-pyrrolidone (0.5 mL) was stirred at 110° C. for 14 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown solid (570.0 mg, 1.26 mmol, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3=[CH:16][S:17][CH:18]=[C:13]3[N:12]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3=[CH:18][S:17][CH:16]=[C:14]3[N:15]=2)=[O:27])[N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3cscc3[nH]2)n1
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cscc3[nH]2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.1 g of 2-(4-methoxy-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole were dissolved in 100 ml of dichloromethane and, at -10° C., 820 mg of m-chloroperbenzoic acid were added in portions. The mixture was then stirred at room temperature for 15 minutes, extracted by shaking with sodium bicarbonate solution, and the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography resulted in 300 mg of 2-(4-methoxy-2-pyrimidinylmethylsulfinyl)1H-thieno[3,4-d]imidazole (melting point 125° C. [decomposition]).
Reaction SMILES: NN.C(O)=O.[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[C:34]([C@H:35]([N:37]=[N+]=[N-])[CH3:36])=[CH:33][N:32]=[C:31]([F:40])[CH:30]=5)=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1>C(O)C.[Ni]>[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[C:34]([C@H:35]([NH2:37])[CH3:36])=[CH:33][N:32]=[C:31]([F:40])[CH:30]=5)=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1
Reactant: C[C@@H](N=[N+]=[N-])c1cnc(F)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O=CO
Product: C[C@@H](N)c1cnc(F)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
Add NH2NH2—HCOOH (Pre-prepared, 1 mL) to a solution of (R)—N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-4-(7-(5-(1-azidoethyl)-2-fluoropyridin-4-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (250 mg, 513.84 μmol) in ethanol (10 mL). Cool the mixture to 0° C. and add Raney Nickel (0.5 g, 8.52 mmol, wet with water as it packed). Stir the solution at RT for another 1.5 h, filter Raney Nickel out, and wash with methanol. Dilute filtrate with chloroform/IPA (3/1) and wash with saturated sodium carbonate. Dry the organic phase over sodium sulfate and concentrate in vacuo to give a brown tar. Purify the solid by passing through a FCC (10% methanol in DCM) to give the title compound as a pale brown solid (200 mg, 85%). MS (ES) m/z 461 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:34]=[C:33]([CH2:32][CH2:31][OH:35])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (581.4 mg) and PdCl2(PPh3)2 (37.9 mg) in Et3N (20 mL) is added CuI (10.3 mg) and 3-butyn-1-ol (0.082 mL). The reaction is stirred at room temperature for 2 days under N2. After 2 days the solvent evaporates. The resulting solid is dissolved in CH2Cl2 and partitioned against H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are washed with brine (1×), dried over Na2SO4, filtered, and condensed. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 3% MeOH in CH2Cl2). Product-containing fractions are combined and concentrated to yield a creme solid. The solid is recrystallized from hot acetonitrile to afford 290 mg (56%) of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as an off-white solid, m.p. 169-172° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:12]([C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[CH:13][C:14]=2[S:15][CH2:16][CH2:17][OH:18].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:12]([C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[CH:13][C:14]=2[S:15]([CH2:16][CH2:17][OH:18])=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Nc2ccc(F)c3c(SCCO)cc(-c4ccc[nH]4)c1c23
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)c3c(S(=O)CCO)cc(-c4ccc[nH]4)c1c23
Reaction time: 0.33 h

Procedure:
A solution of 6-fluoro-5-(2-hydroxy-ethylsulfanyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one (from Example 36 above) (15 mg, 0.05 mmol) in THF (approximately 7 mL) was treated with mCPBA (Acros, 14 mg, 0.06 mmol, 75%). After 20 minutes, the reaction mixture was diluted with ethyl acetate and washed with aqueous saturated Na2S2O3 and aqueous saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient), followed by precipitation out of THF with excess pentane to give 6-fluoro-5-(2-hydroxy-ethanesulfinyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 15 mg, 96%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:25])[CH:7]=1.[Br:31]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>>[Br:31][C:7]1[C:8](=[O:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (2.1 g, 5.06 mmol) and N methyl 2-pyrrolidine (10 mL). N-Bromo succinimide (1 g, 5.56 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica (1:1 hexanes; ethyl acetate) to give the title compound as an orange oil (0.77 g, 31%). 1H NMR (400 MHz, CD3OD) δ 8.16 (app qd, J=2.5 and 7.2 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H), 7.64 (m, 1H), 7.30 (d, J=9.2 Hz, 1H), 7.04 (appt, J=8.4 Hz, 2H), 6.60 (s, 1H), 5.33 (s, 2H), 3.80 (s, 6H), 1.99 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.56 (1F), −116.00 (1F) ppm. ES-HRMS m/z 494.0398 (M+H calcd for C22H13BrF2NO5 requires 494.0409).