Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][O:16][C:17](=[O:48])[CH:18]([NH2:47])[CH2:19][S:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:39]4[O:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:38]=4[CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>O.C(Cl)Cl>[CH3:15][O:16][C:17](=[O:48])[CH:18]([NH:47][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=1[F:1])[CH2:19][S:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[C:39]4[O:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:38]=4[CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)C(N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Fluoro-5-trifluoromethylbenzoic acid (49 mg, 0.24 mmol) was added to a stirred solution of methyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate (92 mg, 0.2 mmol), EDCI (58 mg, 0.3 mmol) and triethylamine (404 mg, 0.56 mL, 0.4 mmol) in anhyd methylene chloride (5 mL). The reaction mixture was stirred at room temperature for 4-6 h (TLC control) and then diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined organic extract were washed with water, sat'd aq NaCl, dried over anhydrous MgSO41 filtered and concentrated in vacuo. Purification by flash column chromatography (30% ethyl acetate in heptane) afforded the title compound has a white solid (117 mg).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)C(C)C)C.[CH3:32][C@H:33]1[NH:38][CH2:37][CH2:36][N:35]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:42][C:41]=2[C:52]([F:55])([F:54])[F:53])[CH2:34]1>CN(C)C1C=CN=CC=1.O.ClCCl>[CH3:32][C@@H:33]1[CH2:34][N:35]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:42][C:41]=2[C:52]([F:55])([F:53])[F:54])[CH2:36][CH2:37][N:38]1[C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (121 mg, 0.410 mmol, 0.70 equiv), dichloromethane (15 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (196 mg, 1.17 mmol, 2.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (301 mg, 2.33 mmol, 4.00 equiv) were added at 0° C. The mixture was stirred for 2 h at room temperature. 4-(4-[[(3R)-3-Methylpiperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl) morpholine (200 mg, 0.580 mmol, 1.00 equiv) and 4-dimethylaminopyridine (71.0 mg, 0.580 mmol, 1.00 equiv) were added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (500 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 229 mg (73% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl(2R)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.57 (d, J=8.7 Hz, 1H), 7.13 (s, 1H), 7.01-7.05 (m, 1H), 5.71-5.83 (m, 1H), 4.26 (br, 1H), 3.87 (t, J=4.8 Hz, 5H), 3.55 (s, 2H), 3.26-3.30 (m, 1H), 3.20 (t, J=4.8 Hz, 4H), 2.79 (d, J=10.8 Hz, 1H), 2.63 (d, J=11.4 Hz, 1H), 2.25-2.33 (m, 1H), 2.07-2.16 (m, 1H), 1.30 (d, J=6.6 Hz, 3H). LCMS (ESI, m/z): 538 [M+H]+.
Reaction SMILES: C(N[CH2:4][CH3:5])C.[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:13][C:14](C)=[O:15]>>[CH3:13][C:14](=[O:15])[CH2:4][CH2:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:6]1=[O:12]
Reactant: O=C1CCCCC1
Reactant: CCNCC
Reactant: CC(C)=O
Product: CC(=O)CCC1CCCCC1=O

Procedure:
4-Diethylaminopropan-2-one prepared from acetone and diethylamine (J.C.S. 1937, 53) was reacted with cyclohexanone by the general method described in C.A. 72, 132478h to give 2-(3'-methyl-3'-oxopropyl) cyclohexanone as a colourless oil b.p. 150°/20 mm.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([Cl:24])=[CH:17][C:18]=3[Cl:23])[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[Cl:23][C:18]1[CH:17]=[C:16]([Cl:24])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:6]([CH3:25])[CH:7]=1)=[N:13]2
Reactant: C1CCNC1
Reactant: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCBr
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethylphenyl]-5,7-dichloro-3H-quinazolin-4-one (0.44 g, 1.00 mmol) in anhydrous DMF (10 mL) was added pyrrolidine (0.28 g, 4.00 mmol). The reaction mixture was stirred at room temperature for 6 hours under nitrogen. Solvent was evaporated under reduced pressure. Water (50 mL) was added. The separated solid was filtered, washed with water (20 mL), and dried under vacuum. The crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and 5% methanol (containing 7.0 M ammonia) in CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.31 g (72%). MP 209-210° C. 1H NMR (400 MHz, DMSO-d6): δ 12.39 (br s, 1H), 7.90 (s, 2H), 7.71 (d, J=1.95 Hz, 1H), 7.60 (d, J=1.95 Hz, 1H), 3.91 (t, J=5.85 Hz, 2H), 2.83 (t, J=6.05 Hz, 2H), 2.55 (m, 4H), 2.31 (s, 6H), 2.01 (m, 4H). MS (ES+) m/z 432.54 (100%), 434.49 (90%).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])#[N:4]
Reactant: CN
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Solvent: CCO
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of methylamine in ethanol (33%, 75 ml.) was added to a solution of N-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.1 g.) in ethanol (30 ml.). The reaction mixture was set aside at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was recrystallized twice from isopropyl alcohol/petroleum ether, affording N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, m.p. 141°-143°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])O[CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:21].C(O)(=O)C>C(O)C.O>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[C:11]([OH:12])=[CH:10][C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:21][CH:7]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc(C(C)(C)C)cc1=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(C(C)(C)C)cc1O
Temperature: 95 °C
Yield: 76 %

Procedure:
6-tert-Butyl-4-oxo-4H-pyran-3-carboxylic acid ethyl ester (300 mg, 1.34 mmol, prepared according to the literature procedure by McCombie, S. W. et al. J. Org. Chem. 1991, 56, 4963-4967) and ammonium acetate (300 mg, 4.16 mmol) were combined in ethanol/water (8 mL/3 ml). Acetic acid was added and reaction mixture was heated at 95° C. for 30 min. It was concentrated and basified with aqueous sodium hydroxide and extracted with methylene chloride (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6-tert-butyl-4-hydroxy-nicotinic acid ethyl ester as a white solid (230 mg, 76%). LR-MS: 224 [(M+H)+]
Reaction SMILES: S(Cl)([Cl:3])=O.COC1C=CC(COC([NH:15][CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[OH:18])=O)=CC=1.[CH2:24](O)[CH3:25]>>[ClH:3].[CH2:24]([O:21][C:19](=[O:20])[C@@H:17]([OH:18])[CH2:16][NH2:15])[CH3:25]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(COC(=O)NC[C@H](O)C(=O)O)cc1
Reactant: CCO
Product: CCOC(=O)[C@@H](O)CN
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
At 0°-5°, add thionyl chloride (2.80 ml) dropwise to N-(4-methoxybenzyloxycarbonyl)-(S)-isoserine (5.0 g) in absolute ethanol (100 ml). Heat the mixture under reflux for 1 hour and stir for 20 hours at room temperature. Concentrate the reaction mixture in vacuo and pour the reaction mixture into diethyl ether (300 ml), and filter the solid. Wash the solid with diethyl ether and dry in vacuo to give the title compound, an amber oil, [α]D26 =-19.8° (MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Br:25][C:26]1[C:27]([C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:29])=[C:31]([O:35][CH3:36])[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cccc(Br)c1C(=O)Cl
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(Br)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 76 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-bromo-6-methoxybenzoyl chloride, the title compound (yield 76%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:45][CH2:46][N:48]([CH3:47])[CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methyl-3-(R)-amino pyrrolidine dihydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.90 (m, 12 H) 2.18 (m, 1 H) 2.26 (s, 3 H) 2.32-2.56 (m, 2 H) 2.60-2.68 (m, 2 H) 3.34 (s, 3 H) 3.95 (s, 3 H) 4.07 (t, J=13.52 Hz, 2 H) 4.34-4.54 (m, 2 H) 7.51 (d, J=8.0 Hz, 1 H), 7.54 (br. s., 1 H) 7.90 (s, 1 H), 8.21 (s, 1 H) 8.27 (d, J=8.0 Hz, 1 H) 8.40 (br. s., 1 H). Melting point: 98-99° C. [M+H] calculated for C27H35F2N7O3, 544; found 544.
Reaction SMILES: CC1CCC(C)C(C)(C)C=1C=O.CC(C)=O.O(C)[Na].[CH3:20][CH:21]1[C:26]([CH3:28])([CH3:27])[C@@H:25](/[CH:29]=[CH:30]/[C:31]([CH3:33])=[O:32])[C:24]([CH3:34])=[CH:23][CH2:22]1.CC1C(C)(C)[C@H](/C=C\C(C)=O)C(C)=CC1>C(O)C.CO>[CH3:20][CH:21]1[C:26]([CH3:27])([CH3:28])[C:25](/[CH:29]=[CH:30]/[C:31]([CH3:33])=[O:32])=[C:24]([CH3:34])[CH2:23][CH2:22]1
Reactant: CC(=O)/C=C/[C@H]1C(C)=CCC(C)C1(C)C
Agent: CC(=O)/C=C\[C@@H]1C(C)=CCC(C)C1(C)C
Agent: CC1=C(C=O)C(C)(C)C(C)CC1
Agent: CO[Na]
Solvent: CCO
Solvent: CO
Solvent: CC(C)=O
Product: CC(=O)/C=C/C1=C(C)CCC(C)C1(C)C
Yield: 76 %

Procedure:
On the other hand, addition of a solution of 3.0 g (19.74 mmol) of pure 2,5,6,6-tetramethyl-1-cyclohexen-1-carbaldehyde in 3 ml of ethanol and of 3 ml of acetone (41 mmol) to 4 ml (~22 mmol) of a 30% solution of NaOCH3 in methanol, the reaction having proceeded for 18 h at room temperature, provided, after the usual treatment and bulb-to-bulb distillation, a mixture (3.29 g) containing 34% of trans-α-irone, 6% of cis-α-irone and 50% of β-irone (yield 76%).
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.CN(C)C=O.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>O>[Cl:1][C:2]1[C:3]([C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Oc1ccc2ccncc2c1Cl
Reactant: CN(C)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=S)c1ccc2ccncc2c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (122 g., 0.68 m.) 8-chloro-7-hydroxyisoquinoline in 180 ml. of dimethylformamide was added (450 g., 4.5 m.) triethylamine followed by (140 g., 0.87 m) dimethylthiocarbamoyl chloride. The mixture was stirred for four hours at room temperature and then poured into 5400 ml. of water. The resulting solid was collected by filtration, dried, dissolved in chloroform, dried with sodium sulfate and evaporated to yield 8-chloro-7-dimethylthiocarbamoylisoquinoline.
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][NH:13][CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=2)[NH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>C1COCC1>[C:6]1([CH2:5][O:4][C:2](=[O:3])[N:13]([CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=3)[NH:18][CH:17]=2)[CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCc1c[nH]c2ccc(CNS(C)(=O)=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1c[nH]c2ccc(CNS(C)(=O)=O)cc12)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Benzyl chloroformate (1.1 ml) was added to a stirred, ice-cooled solution of N-[[3-[2-(methylamino)ethyl]-1H-indol-5-yl]methyl]methanesulphonamide (1.3 g) and diisopropylethylamine (1.5 ml) in dry THF (40 ml). After 1/2 h, water (3 ml) was added and the stirring was continued for 1 h.
Reaction SMILES: O1CCOCC1.[C:7](O)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[N:17]1([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:7]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:18][CH2:19]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Yield: 23 %

Procedure:
To a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride were added 1.2 g of benzoic acid and 3.0 g of 5-(1-piperazinylcarbonyl)oxindol hydrochloride. To this mixture, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide dissolved in 5 ml of methylene chloride was added dropwise at 10° to 20° C. under ice-cooling externally with stirring. Then, the mixture was stirred for 3.5 hours at the same temperature. Crystals which precipitated were filtered off, and the filtrate was concentrated to dryness under reduced pressure. The resultant residue was dissolved in 100 ml of methylene chloride, and the organic layer was washed, in turn, with 5% aqueous hydrochloric acid solution, 5% aqueous sodium hydrogen carbonate solution, and water, and dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was distilled off and the residue was recrystallized from methanol to give 0.79 g of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [CH:1]1([S:4][CH2:5][CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:27])([CH3:26])[C:9]2=[O:28])[CH2:3][CH2:2]1.[OH:29]OS([O-])=O.[K+].[OH2:35]>CO>[CH:1]1([S:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:26])([CH3:27])[C:9]2=[O:28])(=[O:29])=[O:35])[CH2:3][CH2:2]1
Reactant: CC1(C)C(=O)N(CCCSC2CC2)c2cc(NC(=O)c3ccncc3)ccc21
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CC1(C)C(=O)N(CCCS(=O)(=O)C2CC2)c2cc(NC(=O)c3ccncc3)ccc21

Procedure:
To a solution of N-(1-(3-(cyclopropylthio)propyl)-3,3-dimethyl-2-oxoindolin-6-yl)isonicotinamide (130 mg, 329 μmol) in methanol (1 ml) was added dropwise a solution of oxone (303 mg, 493 μmol) in water (1.00 ml). After 2 hours at room temperature the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent. The title compound was obtained as white foam (91 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>CO.O1CCOCC1>[ClH:21].[CH2:14]([CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(CC2CCCNC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(t-butoxycarbonyl)-3-benzylpiperidine (400 mg, 1.45 mmol) in methanol (5 mL) was added hydrogen chloride in dioxane (4M, 15 mL). The resulting yellow solution was stirred for 1 hr, at which time the reaction was concentrated in vacuo to provide 3-benzylpiperidine hydrochloride (308 mg, 100%) as an amorphous solid. 1H NMR (300 MHz, CD3OD), δ: 7.27 (m, 2H,), 7.19 (m, 3H), 3.29 (br. d, 1H, J=12Hz), 3.20 (br. d, 1H, J=12 Hz), 2.87 (br. t, 1H, J=12 Hz), 2.67 (m, 1H), 2.60 (d, 2H, J=7Hz), 2.08 (m, 1H) 1.70-1.87 (m, 3H), 1.26 (m, 1H). MS (CI), m+/z: (M+H)+=176.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CON(C)C(C)=O
Reactant: Cc1cc(Br)ccc1C(C)(C)C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(C(C)(C)C#N)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a stirred solution of 2-(4-bromo-2-methylphenyl)-2-methylpropanenitrile (3.1 g, 13.0 mmol) in anhydrous THF (75 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (7.16 mL, 14.3 mmol). This reaction mixture is stirred at that temperature 10 min., then N-methoxy-N-methyl-acetamide (2.77 mL, 26.0 mmol) is added and the solution is then warmed up to room temperature over 1 h. Acidic brine (30 mL of brine, 15 mL of 3% HCl aq) is then slowly added and the solution extracted with EtOAc (3×100 mL). The organic layer is dried with MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash-chromatography using a 5 to 20% EtOAc in hexane gradient to provide the expected product 2-(4-acetyl-2-methylphenyl)-2-methylpropanenitrile (1.77 g, 68%) as a yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.84-7.74 (2H, m), 7.43-7.40 (1H, m), 2.70 (3H, s), 2.60 (3H, s), 1.81 (6H, s).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Cl-].[NH4+]>C(O)C.C(Cl)Cl.[Fe]>[NH2:30][C:17]1[C:18]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: N#CCC[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A suspension of trans 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyl]-propionitrile (3.83 g, 8.50 mmol) in ethanol (28.5 mL, IMS grade) was treated with water (9.5 mL) followed by ammonium chloride (2.71 g, 50.7 mmol) and iron powder (1.89 g, 33.8 mmol) and the mixture was heated to 80° C. for 45 minutes. The solid was filtered and washed with ethanol (IMS grade). The filter cake was extracted repeatedly with DCM. The DCM extracts were washed with water and the aqueous layer was back-extracted with DCM (×2). The combined DCM extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum to give 2.08 g of crude product. The filtered cake, from above, was extracted repeatedly with 2M NH3 in MeOH. The washings were concentrated under vacuum and worked up to provide a further 190 mg of crude product. The remaining filter cake was stirred with DCM (35 mL) and the DCM decanted off, and then 20% [2N NH3 in MeOH] in DCM. The combined chlorinated extracts were filtered through Celite® to remove traces of iron residue and concentrated under vacuum to give a third batch of crude product (0.66 g). The three batches of crude product were dissolved in DCM, combined and concentrated under vacuum to give 2.97 g (83%) of trans 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyl]-propionitrile as a pale brown solid that was used in the next step without further purification. 1H NMR (400 MHz, DMSO) δ: 8.01 (d, 2H), 7.66 (t, 1H), 7.57 (t, 2H), 7.54 (s, 1H), 7.46 (d, 1H), 6.66 (d, 1H), 5.10 (d, 1H), 4.33 (s, 2H), 3.68-3.56 (m, 1H), 2.01-1.91 (m, 2H), 1.81-1.72 (m, 2H), 1.50 (q, 2H), 1.38-1.19 (m, 3H), 1.17-1.04 (m, 2H) plus 2H obscured by solvent peak.
Reaction SMILES: CN(C=O)C.[C:6]1([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][NH:22][C:23]4[CH:24]=[CH:25][N:26]=[C:27]5[C:32]=4[N:31]=[CH:30][C:29]([OH:33])=[CH:28]5)=[N:19][N:20]=3)[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:35]([F:40])([F:39])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[F:39][CH:35]([F:40])[O:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:22][CH2:21][C:18]3[N:16]4[N:17]=[C:12]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=5)[CH:13]=[CH:14][C:15]4=[N:20][N:19]=3)=[CH:24][CH:25]=[N:26]2)=[N:31][CH:30]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
DMF (0.5 mL) and water (0.1 mL) were added to a pressure vessel containing 8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (50 mg, 135 μmol), sodium 2-chloro-2,2-difluoroacetate (47 mg, 311 μmol), cesium carbonate (62 mg, 190 μmol). The reaction mixture was stirred at 100° C. for 18 h, cooled to RT and concentrated in vacuo. Purification by MPLC (DCM/MeOH+1% NH4OH: 100/0 to 90/10) afforded the title compound (10 mg, 17% yield). MS m/z=420.1 [M+H]+. Calc'd for C21H15F2N7O: 419.40.