Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[C:15]([O:17]COC)[CH:14]=[C:13]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:12]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:12]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(OCOC)cc(C(=O)OC)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(C(=O)OC)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
After adding 30.0 ml of trifluoroacetic acid to a solution of 11.8 g (30.9 mmol) of the obtained ester compound in methylene chloride (50.0 ml), the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester =2:1) to obtain 8.86 g of 3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-hydroxybenzoic acid methyl ester (yield: 85%) as a colorless oil.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[C:29]1([Si:35]2(CCCCC)[CH2:40][CH2:39][CH:38]([CH:41]3[CH2:46][CH2:45][CH:44]([CH:47]=O)[CH2:43][CH2:42]3)[CH2:37][CH2:36]2)C=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:47][C@H:44]2[CH2:43][CH2:42][C@H:41]([C@H:38]3[CH2:39][CH2:40][Si@H:35]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:36][CH2:37]3)[CH2:46][CH2:45]2)=[CH:27][CH:28]=1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2CCC(C=O)CC2)CC1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)cc3)CC2)CC1

Procedure:
The general procedure of Example 4 was repeated using 4-fluorobenzyltriphenylphosphonium bromide and 4-(4-phenyl-4-n-pentyl-4-silacyclohexyl)cyclohexane carbaldehyde, thereby obtaining trans-4-(trans-4-(2-(4-fiuorophenyl)ethyl)cyclohexyl)- 1-n-pentyl-1-silacyclohexane with the following results of IR and 13C-NMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH2:11])=[CH:9][N:10]=2.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH:11][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[CH:9][N:10]=2
Reactant: CCN=C=O
Reactant: Nc1cnc2ccc(Cl)nc2n1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cnc2ccc(Cl)nc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A total of 5.0 g 6-Chloro-pyrido[2,3-b]pyrazin-3-ylamine (27.7 mmol; 1 eq) was suspended in 150 mL of dry 1,4-dioxane. 2.63 g (33.2 mmol; 1.2 eq) ethyl isocyanate was added and the reaction mixture was stirred at 100° C. for 4 hours. Additional 1.97 g (27.7 mmol; 1 eq) of ethyl isocyanate were added and the resulting solution was stirred at 100° C. for further 4 hours. After cooling to room temperature, the precipitate was filtered of and dried in vacuo to afford 6.5 g (93.3% yield) of 1-(6-Chloro-pyrido[2,3-b]pyrazin-3-yl)-3-ethyl-urea.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:5]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:4][N:3]=1.Cl>C(O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:5]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:4][N:3]=1
Reactant: CCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nc(C)ncc1C(=O)OCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(C)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
The product of example 1B (3.5 g, 4.91 mmoles) was suspended in 50 ml of ethanol. Concentrated hydrochloric acid (2.1 ml) was added and the mixture was stirred for 11/2 hours at room temperature. The solution was concentrated under vacuum and the resulting residue was diluted with water. Potassium acetate was added in portions until the pH was neutral. Ether (5 ml) was added and the mixture was stirred. The sticky solid which formed was dissolved in chloroform. The chloroform solution was dried over sodium sulfate and then concentrated. The resulting residue was crystallized from ether to provide 2.08 g of the desired product. M.p. 164°-166° C. 1H NMR (CDCl3) δ0.85 (t, 3H, J=7 Hz), 1.25 (m, 2H), 1.32 (t, 3H, J=7 Hz), 1.50 (m, 2H), 2.24 (s, 3H), 3.38 (t, 2H, J=7 Hz), 4.30 (q, 2H, J=7 Hz), 4.73 (s, 2H), 7.00 (m, 4H), 7.42 (dd, 1H, J=8 Hz, J=1Hz), 7.50-7.62 (m, 2H), 7.75 (dd, 1H, J=8 Hz, J= 1Hz), 8.02 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:22][C:23]([C@@H:25]3[CH:40]=[C:39]4[C@@H:28]([CH2:29][C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][C:37]=64)[NH:32][CH:31]=5)[N:27]([CH3:41])[CH2:26]3)=[O:24])([CH:19]([CH3:21])[CH3:20])[O:18][C@@:13]2([OH:42])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:3].OP(O)(O)=O.C[Si](C)(C)[Br:50]>ClCCl>[CH3:3][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:22][C:23]([C@@H:25]3[CH:40]=[C:39]4[C@@H:28]([CH2:29][C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][C:37]=64)[NH:32][C:31]=5[Br:50])[N:27]([CH3:41])[CH2:26]3)=[O:24])([CH:19]([CH3:20])[CH3:21])[O:18][C@@:13]2([OH:42])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:1]
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Reactant: C[Si](C)(C)Br
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]c(Br)c(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12

Procedure:
Following the process of Example 30, 1 g of α-ergocryptine phosphate is brominated with 2.0 ml of trimethylbromosilane. After isolating, the title base is obtained in a yield of 0.9 g (0.001359 mole, 91.5%), m.p.: 218° C., [α]D20 =-195° (c=1, dichloromethane).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31]Cl)[C:26]=1[CH3:33])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO.C(OCC)(=O)C>[CH2:14]([O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:26]=1[CH3:33])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 99.9 %

Procedure:
To a liquid prepared by dissolving with stirring 6.8 g (0.045 mol, 0.9 eq.) of 2-mercaptobenzimidazole and 11.6 g (0.06 mol, 1.2 eq.) of a 28% sodium methoxide solution in 150 mL of methanol, a liquid containing 15.0 g of 4-decyloxy-2-chloromethyl-3-methylpyridine dissolved in 75 mL of methanol was added at 30° C. Subsequently, the mixture was heated to reflux for 0.5 hours and cooled, and then methanol was solid dried under reduced pressure. An orange-colored oily residue resulting therefrom was dissolved in 300 mL of ethyl acetate, and then the organic layer was washed with 150 mL of water. 45 g of silica gel was added with stirring to the organic layer, subsequently the silica gel was removed by filtration, and then the filtrate was concentrated to dryness under reduced pressure, to obtain 18.5 g of pale orange crystals. The pale orange crystals were recrystallized from ethyl acetate (10 vol.), to obtain 9.7 g of pale orange crystals (HPLC: 99.6 Area %, yield 47.1%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].C([Mg]Cl)(C)C.[CH:12]([C:15]1[NH:19][N:18]=[C:17]([NH:20][C:21]2[C:22]3[CH2:38][CH2:37][CH2:36][C:23]=3[N:24]=[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32](OC)=[O:33])[N:26]=2)[CH:16]=1)([CH3:14])[CH3:13]>C1COCC1>[CH:12]([C:15]1[NH:19][N:18]=[C:17]([NH:20][C:21]2[C:22]3[CH2:38][CH2:37][CH2:36][C:23]=3[N:24]=[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:33])[N:26]=2)[CH:16]=1)([CH3:14])[CH3:13]
Reactant: Nc1nccs1
Reactant: COC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3nccs3)nc3c2CCC3)n[nH]1
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
To a solution of thiazol-2-amine (1.08 g, 10.8 mmol) in THF (12 mL) was added isopropyl magnesium chloride (5.4 mL, 10.8 mmol) dropwise at 0° C. The reaction mixture was stirred at the same temperature for 20 min., followed by dropwise addition of solution of methyl (2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate (1 g, 2.702 mmol) in THF (5 mL). The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was quenched with a saturated solution of ammonium chloride (200 mL) and extracted with EtOAc (2×200 mL). The organic layer was washed with water (2×200 mL) followed by brine (200 mL) and dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was recrystallized in diethyl ether (50 mL) to afford (2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-N-thiazol-2-yl-pyrrolidine-2-carboxamide (600 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.30 (d, 6H), 2.00-2.22 (m, 5H), 2.50-2.70 (m, 3H), 2.80-3.05 (m, 3H), 3.61-3.80 (m, 2H), 4.85 (d, 1H), 6.28 (brs, 1H), 6.93 (d, 1H), 6.99 (brs, 1H), 7.40 (d, 1H). The other enantiomer is prepared using chiral (R) starting material.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1>CCO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Temperature: 64 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Excess NaOH (11 ml, 11.00 mmol, 1M aq) was added to a stirring solution of ethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (1.9 g, 5.50 mmol) in EtOH (55 ml) and THF (55 ml) and was allowed to stir at 64° C. overnight. The mixture was concentrated and diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (1.7 g, quant.). 1H NMR (300 MHz, DMSO-D6) δ ppm 7.31-7.48 (m, 2 H) 7.71 (s, 1 H) 8.00-8.14 (m, 2 H) 8.29 (s, 1 H) 10.80 (s, 1 H) 13.35 (s, 1 H). LC-MS retention time: 0.99 min; m/z (MH−): 416. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:45]([O:52][CH2:53]Cl)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.C1COCC1>[CH2:45]([O:52][CH2:53][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]1=[O:34])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: ClCOCc1ccccc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(COCc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
To a stirring solution of 1.0 g (2.18 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL of DMF at -5° C. is added 2.40 mL (2.40 mmol, 1.1 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and then 530 μL (3.05 mmol, 1.4 equiv) of chloromethyl benzyl ether (80%, tech.) is added neat. The resulting solution is stirred for 1 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with H2O (2×80 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 4/1 to hexane/EtOAc 1/2 as eluent afforded 500 mg of the title compound as a white solid, along with 320 mg of recovered starting benzodiazepine: mp. 203°-204° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-7.18 (m, 13H), 7.10 (m, 2H), 6.92 (m, 3H), 4.98 (m, 1H), 4.56 (dd, 2H, J=11.8, 22.7), 4.25 (m, 3H), 4.08 (dd, 1H, J=5.0, 9.8), 3.83 (s, 3H), 3.67 (dd, 1H, J=5.0, 7.5), 1.06 (2×d, 6H, J=6.2); low resolution MS (FAB)m/e 578 (MH+), 443, 413, 277, 223; Anal. (C35H35N3O5) Calcd. C, 72.77; H, 6.11; N, 7.27 Found C, 71.62; H, 6.06; N, 7.10.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]=[N:15]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(C1N=[C:22]([C:32]2[C:33]([O:39][CH3:40])=[N:34][CH:35]=[CH:36][C:37]=2[I:38])[N:23]([OH:31])C=1C1C=CC=CC=1)C>>[I:38][C:37]1[CH:36]=[CH:35][N:34]=[C:33]([O:39][CH3:40])[C:32]=1[C:22]1[N:23]([OH:31])[C:13]([C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:12][CH:11]=2)=[CH:14][N:15]=1
Reactant: O=C(C=NO)c1ccc(N2CCOCC2)cc1
Reactant: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1
Product: COc1nccc(I)c1-c1ncc(-c2ccc(N3CCOCC3)cc2)n1O
Yield: 22 %

Procedure:
(4-Morpholin-4-yl-phenyl)-oxo-acetaldehyde oxime (0.111 g, 0.474 mmol) was reacted as described for the synthesis of 4-ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol and afforded the title material (0.049 g, 22%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([S:44]([CH:41]4[CH2:43][CH2:42]4)(=[O:46])=[O:45])[CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(N3CCNCC3)ccn2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(piperazin-1-yl)-pyridin-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 182, triethylamine (42.0 uL, 0.30 mmol) and cyclopropanesulfonyl chloride (9.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7](Cl)=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cscc1Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)c1cscc1Cl
Reaction time: 12 h

Procedure:
4-Chlorothiophene-3-carbonyl chloride (13.5 g, 0.075 mol) are dissolved in 30 ml of dioxane and the solution is added dropwise at room temperature to a solution of aniline (7.7 g, 0.083 mol) in pyridine (160 ml). Stirring is carried out for 12 hours at room temperature, after which the mixture is evaporated to dryness and the residue is taken up in dichloromethane. The organic phase is extracted with aqueous citric acid solution, sodium bicarbonate solution and water, dried and evaporated to dryness. Yield: 16.7 g, 94%; mp. 119° to 121° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20]
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (102 mg, 0.31 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (80 mg, 0.34 mmol) and DIPEA (104 μL, 0.61 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (128 mg, 78%). LCMS (Method C): RT 3.57 min [M+H]+ 536.3/538.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[C:15]=2[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[C:15]=3[CH:26]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1=O
Temperature: 80 °C
Yield: 54.1 %

Procedure:
To a mixture of 2,4,5-Trichloro-pyrimidine (0.315 g, 0.00172 mol), 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.40 g, 0.0017 mol) in anhydrous N,N-Dimethylformamide (10 mL, 0.1 mol) was added Potassium carbonate (0.35 g, 0.0025 mol) and heated at 80° C. for 17 hours. The reaction was evaporated, water added and tan solid collected. This was chromatographed on a SiO2 prep plates with hexane/acetonitrile (1-1) giving 8-(2,5-Dichloro-pyrimidin-4-ylamino)-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a cream colored solid (0.35 g, 54%); Mp 71-74° C.; LCMS (m/e) 380 (M); 1H-NMR (DMSO, 400 MHz) 9.50 (s, 1H), 8.42 (s, 1H), 7.45-7.43 (d, 1H, J=7.83 Hz), 7.35 (s, 1H), 7.21-7.19 (d, 1H, J=8.34 Hz), 3.54-3.48 (q, 2H, J=7.08 Hz), 3.43-3.41 (t, 2H, J=5.31 Hz), 3.32-3.28 (t, 2H, J=4.04 Hz), 3.21-3.16 (q, 2H, J=6.32 Hz), 1.16-1.11 (t, 3H, J=7.07 Hz), 1.20-1.18 (t, 3H, J=6.82 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[C:25]([CH3:41])=[CH:24][N:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[C:26]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[C:25]([CH3:41])=[CH:24][N:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2[nH]c(=O)oc2c1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(C)cn3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
688 mg (2.50 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 378 mg (1.25 mmol) 6-(2-chloro-5-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one (mixture) were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]=2[CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:38][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:13])=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]=2[CH:18]=1
Reactant: COc1ccc2oc(C(=O)O)c(OC(C)C)c2c1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)NCc3ccccc3)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-methoxy-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 1.00 mmol) [Connor, et al., J. Med. Chem. 35, 935(1992)] and 1,1'-carbonyldiimidazole (211 mg, 1.30 mmol) in 7 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.66 mL, 6.00 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:3 to 1:1) provides 5-methoxy-3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 79% yield; mp=68°-69° C.