Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC)=O.[C:14]([CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([NH:28][C:29]([C:31]2[NH:35][C:34]3[S:36][C:37]([Cl:39])=[CH:38][C:33]=3[CH:32]=2)=[O:30])[C:19]1=[O:40])([OH:16])=O.N>C1COCC1.CCOC(C)=O.O>[Cl:39][C:37]1[S:36][C:34]2[NH:35][C:31]([C:29]([NH:28][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]([CH2:17][C:14](=[O:16])[NH2:3])[C:19]3=[O:40])=[O:30])=[CH:32][C:33]=2[CH:38]=1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 1 h
Yield: 55.6 %

Procedure:
Triethylamine (38 μL, 0.27 mmol) then ethyl chloroformate (26.1 μL, 0.27 mmol) were added to N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 100 mg, 0.25 mmol) in anhydrous THF (2 mL) at 0° C. followed by stirring for 1 h. Concentrated aqueous NH3 (1 mL) was added and the reaction was stirred for a further 1 h. Water (20 mL) and EtOAc (40 mL) were added and the organic layer was separated, washed with 1M HCl (20 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (MeOH:DCM 1:19) to afford the title compound (56 mg, 56%) as a white solid.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13][C:14]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>C(Cl)Cl>[CH:13]([C:14]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)=[O:12]
Reactant: CCOC(=O)C1(CO)CCCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1(C=O)CCCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Neat PCC was added to a stirred suspension of powdered 4 Å molecular sieve (˜0.5 g) in a solution of ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (165 mg, 0.877 mmol) in DCM (6 mL) and the mixture was stirred at rt 5 h. The suspension was filtered through a plug of silica gel and eluted with (0-2% EtOAc in DCM) afford ethyl 2-formyltetrahydro-2H-pyran-2-carboxylate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.53 (s, 1H), 4.35-4.20 (m, 2H), 3.97-3.77 (m, 2H), 2.23-2.12 (m, 1H), 1.90-1.77 (m, 1H), 1.77-1.69 (m, 1H), 1.64-1.56 (m, 3H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[N:21]=[CH:20]2)[NH:12][N:11]=1)([CH3:9])[CH3:8].[CH2:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1F)[C:35]#[N:36])[CH3:31].O>CS(C)=O>[CH2:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:12]1[C:13]2[C:18](=[C:17]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[N:21]=[CH:20]3)[CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]([CH3:9])[CH3:8])=[N:11]1)[C:35]#[N:36])[CH3:31]
Reactant: CC(C)c1n[nH]c2cccc(-n3cnc(-c4cnn(C)c4)c3)c12
Reactant: CCc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cnn(C)c4)c3)cccc21
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
Cesium carbonate (850 mg) was added to a solution of compound (5a) (200 mg) in DMSO (2.2 mL), and the mixture was heated to 130° C. The mixture was stirred for 10 minutes and 3-ethyl-4-fluorobenzonitrile (292 mg) was added thereto. The resulting mixture was stirred at the same temperature for 1.5 hours. After completion of the reaction, the reaction solution was allowed to standing still for cooling, and water was poured thereto. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (chloroform/ethyl acetate/methanol) to obtain compound (6a) (151.8 mg, yield 54%) as a white foamy substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CNC(=O)c1cc(OC)ccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide of Example 607 was reacted with 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-5-methoxy-N-methyl-benzamide as a lyophylate (22%); 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.39 (s, 1H), 8.77 (bs, 1H), 8.55 (bs, 1H) 8.17 (s, 1H), 7.63 (d, J=8.17 Hz, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 7.03 (d, J=8.89 Hz, 1H), 6.87 (d, J=8.68 Hz, 1H), 3.82 (s, 3H), 2.80 (d, J=3.80 Hz, 3H), 2.50 (m, 2H), 2.16 (m, 2H), 1.27 (s, 6H); MS (m/e) 495.45 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:30](=[O:31])[C:29]3[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CNCCO1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
5.60 g (20.3 mmol) of 2-[(2R)-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (specification of U.S. Pat. No. 6,159,967, EXAMPLE 51(d)) was dissolved in methylene chloride (60 mL) and 2.83 mL (24.3 mmol) of triethylamine was added thereto. 5.60 g (20.3 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride and 248 mg (2.03 mmol) of 4-dimethylaminopyridine were added to the mixture under ice-cooling and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture and the methylene chloride layer was washed with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1) to obtain 5.68 g (yield: 54%) of 2-{(2R)-2-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)benzoyl]morpholin-2-yl}ethanol.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][S:19]([O-])(=O)=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C[S-].[Na+].[C:26](OCC)(=O)C.O>CN(C=O)C>[CH3:26][S:19][CH2:18][C:16]1[N:17]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(C)=O
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methanesulfonate (0.55 g, 1.58 mmol) was dissolved in DMF (30 ml), and sodium thiomethoxide (0.13 g, 1.74 mmol) was added thereto. The mixture was stirred at 70° C. for 3 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was recrystallized from ethanol to give the titled compound (0.35 g, 75%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]3[N:13]=[C:14]([NH2:16])[N:15]=[C:11]3[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[N:4][N:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.[CH2:40]([N:42]=[C:43]=[O:44])[CH3:41]>C1(C)C=CC=CC=1>[CH2:40]([NH:42][C:43]([NH:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[N:12]2[N:13]=1)=[O:44])[CH3:41]
Reactant: Cc1nnc(-c2cc(-c3cccnc3)cc3nc(N)nn23)o1
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3nnc(C)o3)n2n1
Temperature: 110 °C

Procedure:
A suspension of the product of Step 3 in toluene (20 mL) containing dibutyltin diacetate (0.1 mL) and ethyl isocyanate (0.2 mL) was heated to 110° C. for 48 h. The suspension was cooled and the precipitate was filtered and washed with toluene to give the tile compound as a solid; m.p. 318-321°. ACPI-MS Found: [M+H]+=365.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[F:11][C:12]([F:35])([C:16]([F:34])([F:33])[C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:13](Cl)=[O:14].[SiH4]>[Pd]>[C:12]([CH:13]=[O:14])([C:16]([C:17]([C:18]([C:19]([C:20]([C:21]([F:22])([F:23])[F:24])([F:25])[F:26])([F:28])[F:27])([F:30])[F:29])([F:32])[F:31])([F:34])[F:33])([F:35])[F:11]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: [SiH4]
Product: O=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
Catalyst 10% Pd/C (200 mg) was placed in a 3-necked round bottom flask and cooled at 0° C. Triisopropylsilane (3.32 g, 21 mmol) was added, followed by perflurooctanoyl chloride (7.9 g, 18.2 mmol). The mixture was allowed to warm to room temperature and was then controlled at 25°-27° C. during the exothermic reaction. After 3 hr, GC analysis showed aldehyde/acid chloride ratio=94/6. Another 0.26 mL of silane was added and stirring was continued for 1 hr. Vacuum transfer gave liquid which was chilled at -25° C. The resulting solid was shaken with petroleum ether, chilled at -25° C., and separated again. In this way, 6.48 g of product was obtained, mp ca. -5° C. NMR spectra were as described in Example 1.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([O:31][C:32]5[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:50])[CH2:43][C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)=[S:40])=[CH:34][C:33]=5[F:51])=[N:26][CH:27]=[N:28]4)=[CH:23][C:22]=3[O:52][CH3:53])[CH2:18][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1.[BrH:54]>CC(O)=O.CCOCC>[BrH:54].[BrH:54].[F:51][C:33]1[CH:34]=[C:35]([NH:38][C:39]([NH:41][C:42](=[O:50])[CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[S:40])[CH:36]=[CH:37][C:32]=1[O:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH:17]3[CH2:18][CH:13]4[CH2:12][NH:11][CH2:15][CH:14]4[CH2:16]3)=[C:22]([O:52][CH3:53])[CH:23]=2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (3.3 g, 4.5 mmol) was dissolved in AcOH (70 ml) to which was added 33% HBr in AcOH (12 ml). The reaction mixture was stirred at room temperature for 1 hr, diluted with Et2O (1000 ml) and the resulting solids filtered, washed with Et2O, and dried under high vacuum to give the 1-{3-fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea, dihydrobromide salt (3.4 g, 100%). 1H-NMR (400 MHz, DMSO): 12.42 (s, 1H), 11.80 (s, 1H), 8.84 (br s, 2H), 8.64 (s, 1H), 7.92 (m, 1H), 7.59 (s, 1H), 7.49 (m, 2H), 7.41 (s, 1H), 7.33 (m, 4H), 7.27 (m, 1H), 4.17 (d, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.17 (m, 2H), 3.10 (m, 2H), 2.83 (m, 2H), 2.45 (m, 1H), 2.15 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 602.2, found 602.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([N:16]3[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]3)=[C:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[N:10]=[N:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCN(c3nnc(-c4ccc(F)cc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 110 °C
Yield: 63.6 %

Procedure:
Combine 3-(4-fluoro-phenyl)-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (522 mg, 1.73 mmol), 5-chloro-pyrazine-2-carboxylic acid methyl ester (360 mg, 2.07 mmol), diisopropylethylamine (900 μl, 5.19 mmol) and dioxane (3 mL) in a round bottom flask. Heat to 110° C. for 18 h. Concentrate reaction mixture and purify by column chromatography (0-100% ethylacetate/heptane gradient). Triturate product with acetonitrile to give 480 mg of (R)-4-[6-(4-fluoro-phenyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (63%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:18](=[O:19])[CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)n1nnc(N)n1
Product: CC(C)(C)n1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 191-192° and MS: (neg. ions): m/e=334.3 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-tert-butyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([CH:9]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10]1=[O:15])=[O:8].[C:17]([C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C(Cl)Cl>C1(C)C=CC=CC=1.O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:17]([C:20]1[S:24][C:23]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=2)[C:7]([CH:9]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10]2=[O:15])=[O:8])=[CH:22][CH:21]=1)(=[O:19])[CH3:18]
Reactant: CN1CCC(C(=O)c2cncc(Br)c2)C1=O
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cncc(C(=O)C3CCN(C)C3=O)c2)s1
Temperature: 85 °C
Yield: 50 %

Procedure:
A mixture of 3-(5-bromonicotinoyl)-1-methylpyrrolidin-2-one 3 (1 equiv), 5-Acetyl-2-thiopheneboronic acid (1.2 equiv), 1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complex with DCM (0.1 equiv) and 2M Na2CO3(4 equiv) in toluene/1,4-dioxane(4:1, 15 volumes) was degassed and filled with nitrogen. Then the reaction mixture was heated to 85° C. and maintained for 2 h. After completion of the reaction filtered through Celite bed and washed with ethyl acetate. The combined organic layer was dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude residue which was purified by silica-gel column chromatography using 2% MeOH/DCM as an eluent to afford 50% yield of titled compound.
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]([CH2:7][OH:8])[CH2:5][OH:6].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C1COCC1>[Si:9]([O:6][CH2:5][C:4](=[CH2:3])[CH2:7][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To a dry flask containing sodium hydride (2.270 g, 56.75 mmol) in THF (150 mL) under N2 at 0° C. was added slowly 2-methylenepropane-1,3-diol (5 g, 56.75 mmol). The reaction was warmed to room temperature and stirred 45 min. TBS-Cl (8.55 g, 56.75 mmol) was added in one batch and stirring was continued for another 45 min, until complete by TLC. To the reaction was added water and the mixture was extracted three times with EtOAc and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated at −10-15° C. Silica gel chromatography (20%-50% EtOAc/Hex) afforded the title compound (11.36 g, 99%) as a clear oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].[CH3:18][C:19](=[O:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:32][C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH2:18]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCCCCCCCC(C)=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(CCCCCCCCCCCC)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.1 h

Procedure:
To a stirred, room temperature solution of diisopropylamine (49 mL, 0.35 mol) in dry THF (500 mL) was added a 2.06M solution (170 mL, 0.35 mol) of n-butyl lithium in hexanes in one portion. The solution was cooled to -78° C. To the stirred solution was added neat trimethylsilylchloride (213 mL, 1.68 mol) over 6 minutes. Stirred for 6 minutes. To this solution was added a solution of 2-tetradecanone (71.40 g, 0.3362 mol) in dry THF (710 mL) over 33 minutes. Stirred 5 minutes. To the mixture was added triethylamine (375 mL, 2.7 mol) over 6 minutes followed by a saturated sodium bicarbonate solution (780 mL). The mixture was allowed to warm. When the temperature reached 0° C., petroleum ether (1.7 L) was added, and the organic layer was washed with chilled H2O (2×1.4 L), chilled 0.1M citric acid (3×2 L) and saturated NaCl. The organic layer was dried (Na2SO4) and rotoevaporated and dried in vacuo to give a yellow oil; yield 97.6 g (102%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.S(Cl)([Cl:17])=O>>[CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11]([Cl:17])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)COc2ccc(C(=O)O)cc21
Product: CC1(C)COc2ccc(C(=O)Cl)cc21
Yield: 127.7 %

Procedure:
The product of stage (a) (3 g) was boiled under reflux in thionyl chloride (3.6 g) for 3 hours. Removal of the thionyl chloride under vacuum gave crude title product (4.2 g).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][NH2:4].[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=O)[CH3:25])=[CH:18][CH:17]=1.O>C1C=CC=CC=1.CO.ClCCl>[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[CH3:25])=[CH:18][CH:17]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)CCc1ccc(OCCO)cc1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccccc1
Product: CC(CCc1ccc(OCCO)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
A mixture of 2-hydroxy-2(3-chlorophenyl)ethanamine (2.87 g) and 4-[4-(2-hydroxyethoxy)phenyl]butan-2-one (3.48 g) in benzene (250 ml) was treated under reflux in a Dean and Stark apparatus until water evolution was complete. The solvent was evaporated, the residue dissolved in methanol (200 ml) and cooled in ice. Sodium borohydride (5.3 g) was added in portions over 30 minutes. After a further hour at ambient temperature, the solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was dried (MgSO4) and evaporated to give an oil. Chromatography on silica gel in 5% methanol in dichloromethane gave the title compound as a white solid, mp 103°-5° C., as a 39:61 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[BrH:17]>O>[Br:17][CH2:12][CH2:11][CH2:10][N:6]1[C:5]2[CH:14]=[C:15]([Cl:16])[C:2]([Cl:1])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Reactant: Br
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCBr
Yield: 81 %

Procedure:
A mixture of 57.5 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one and 450 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 2.50 hours. The reaction mixture is cooled and water is added. The precipitated product is filtered off, stirred in 700 parts of water, filtered off again and dried in vacuo, yielding 59 parts (81%) of 1-(3-bromopropyl)-5,6-dichloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 198.1° C.
Reaction SMILES: [NH2:1][OH:2].C[O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=O>CO>[OH:2][NH:1][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:4]
Reactant: COC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12
Reactant: NO
Solvent: CO
Product: O=C(CCCCc1cn(-c2cccnc2)c2ccccc12)NO
Reaction time: 20 h

Procedure:
A solution of hydroxylamine (from 2.06 g of hydroxylamine hydrochloride and 2.02 g of sodium hydroxide) and 7.6 g of 3-(4-methoxycarbonylbutyl)-N-(3-pyridyl)indole in 25 ml of methanol is allowed to stand at room temperature for 20 hours. The methanol is evaporated and the residue is taken up in 5 ml of water and adjusted to pH=7. The mixture is extracted with methylene chloride, the extract is washed with water, dried and evaporated to dryness yielding 3-[4-(hydroxycarbamoyl)butyl]-N-(3-pyridyl)indole.