Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21]C)[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][C@H:6]1[CH3:24])[CH3:2].B(F)(F)F.N1C=CN=C1.[Si:34](Cl)([C:37](C)(C)C)([CH3:36])[CH3:35]>ClCCl.CN(C=O)C.CCCCCCC.C(OCC)(=O)C>[CH2:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][C@H:6]1[CH3:24])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)C[C@@H](C)[C@H]3[C@H]12
Agent: FB(F)F
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@@H]1Cc2cc(O[Si](C)(C)C)ccc2[C@H]2CC[C@]3(C)C(=O)C[C@@H](C)[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4 (270 mg) in dichloromethane (1 ml) was added BF3.DMS complex (800 μl). The mixture was stirred for 1.5 h and then poured into ice-water and extracted with ethyl acetate. The residue thus obtained was triturated with ether/heptane (1/1) to provide 5, (250 mg) as a light rose amorphous solid; Rf 0.27 (heptane/ethyl acetate 8/2). The material was dissolved in DMF (3 ml), imidazole (300 mg) was added followed by t-butyldimethylsilyl chloride. After stirring for 2 h at room temperature the silylation was completed. The reaction was quenched by addition of ice water, followed by extraction of the product with ethyl acetate. Chromatographic purification over a short silica column (heptane/ethyl acetate 9/1) gave 6 (220 mg) as a stiff colourless oil; Rf 0.60 (heptane/ethyl acetate 8/2). NMR (CDCl3) δ 7.12 (1H), 6.62 (1H), 6.18 (1H), 1.03 (s, 3H, 18-CH3), 0.98 (s, 9H, tert.butylsilyl), 0.97, 0.95 (2t, 6H, 7α and 15β ethyl), 0.20 (s, 6H, CH3-silylether).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C([O:9][CH:10](OCC)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.[CH3:23][N:24]([CH:26]=O)[CH3:25].[OH-].[Na+]>Cl.CCOCC>[CH2:13]([O:12][C:11](=[CH:23][N:24]([CH3:26])[CH3:25])[CH:10]=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: CCOC(COCc1ccccc1)OCC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: CN(C)C=C(C=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 96 h
Yield: 46.2 %

Procedure:
Prepared by a modification of the literature procedure reported in Croat. Chim. Acta, 1966, 235. Phosphorus pentachloride (0.13 mol) was added to benzyloxyacetaldehyde diethyl acetal (0.13 mol) at 20-30° C. The reaction mixture was heated at 60° C. for 75 min and then cooled to 0° C. The reaction mixture was treated with DMF (0.39 mol) and stirred at room temperature for four days. The reaction mixture was diluted with 1.0N HCl(aq) (200 ml) and ether (200 ml). The ether layer was discarded and the aqueous layer was basified with 8N NaOH(aq). The aqueous layer was extracted with ethyl acetate and ether and the combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The resulting black oil was purified by column chromatography to give the product as a brown solid (0.06 mol, 43%). δH (250 MHz; CDCl3) 8.62 (1H, s), 7.44-7.26 (5H, m), 6.18 (1H, s), 4.96 (2H, s), 3.04 (6H, s).
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1([OH:15])[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)#[CH:4].[CH2:16](Cl)[CH:17]=[CH2:18]>CO.CC(O)C.CC(OC)(C)C.Cl[Cu].C([O-])([O-])=O.[K+].[K+]>[C:3]([C:5]1([OH:15])[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)#[C:4][CH2:18][CH:17]=[CH2:16]
Reactant: C=CCCl
Reactant: C#CC1(O)CCCC2(CCCC2)C1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Solvent: COC(C)(C)C
Product: C=CCC#CC1(O)CCCC2(CCCC2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
To a mixture of KOH (7.93 g), K2CO3 (1.08 g) and CuCl (0.72 g) in MeOH (40 ml) cooled to 0° C. and kept under N2 was added dropwise a solution of 7-ethynyl-spiro[4.5]decan-7-ol (2) (16.80 g, 94.4 mmol) in iPrOH (40 ml). The resulting red-brown mixture was stirred another 20 minutes at 0° C., then was treated with allylchlorid (11.6 ml, 141.6 mmol, 1.5 equiv) added dropwise for 10 mn, warmed to room temperature and left under stirring at room temperature overnight. The mixture was diluted with MTBE (200 ml), washed with saturated NH4Cl (2×40 ml), H2O (3×30 ml) until neutral pH and dried over MgSO4. 18.52 g (90%) of crude product (3) was isolated as an orange oil that was used without further purification in the final step.
Reaction SMILES: [Si]([O:8][C:9]([C@@H:12]1[N:17]2[C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][C:19]=3[N:28]=[C:16]2[CH2:15][O:14][CH2:13]1)([CH3:11])[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]1[N:17]3[C@@H:12]([C:9]([OH:8])([CH3:10])[CH3:11])[CH2:13][O:14][CH2:15][C:16]3=[N:28][C:19]=1[CH:20]=[N:21]2
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)[C@H]1COCc2nc3cnc4ccccc4c3n21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)[C@H]1COCc2nc3cnc4ccccc4c3n21
Temperature: -50 °C
Yield: 91.6 %

Procedure:
(11R)-11-(1-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (1.14 g, 2.91 mmol) was dissolved in 30 mL of THF and the stirred solution was cooled to −50° C. Tetrabutylammonium fluoride (1.0 M solution in THF, 4.37 mL) was added slowly and the stirred reaction mixture was allowed top warm to ambient temperature over 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting material was partitioned between 50 mL of CH2Cl2 and saturated NaHCO3 solution. The layers were separated and the organic portion was washed with brine (4×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 8% MeOH/CHCl3) gave 2-[(11R)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (755 mg) as an off-white solid.
Reaction SMILES: [F-].[K+].[NH2:3][C:4]1[C:9]([F:10])=[C:8](Cl)[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH:16]=[CH2:17].CC1(C)C(C)(C)OB([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)O1.C(#N)C>C(Cl)Cl.O.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>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH:16]=[CH2:17]
Reactant: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Reactant: CC1(C)OB(c2ccc(C=O)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(C=O)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a 5-mL microwave safe vial was added potassium fluoride (0.378 g, 6.50 mmol), methyl 4-amino-6-chloro-5-fluoro-3-vinylpicolinate (0.5 g, 2.168 mmol), bis(triphenylphosphine)palladium(II) chloride (0.152 g, 0.217 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.528 g, 2.276 mmol). A mixture of water (1 mL) and acetonitrile (2 mL) was added and the reaction was capped and placed in a Biotage Initiator™ microwave reactor for 20 min at 115° C., with external IR-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (25 mL) and water (25 mL) and the organic layer was filtered through a cotton plug. An additional extraction using EtOAc (25 mL) was combined with the CH2Cl2 and dried over Na2SO4 (50 g). Following filtration of the combined organics through a cotton plug and concentration on a rotary evaporator, the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a white solid (635 mg): 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.13 (dd, J=8.3, 1.6 Hz, 2H), 8.03-7.93 (m, 2H), 6.91 (ddd, J=18.1, 11.6, 0.5 Hz, 1H), 5.73 (dd, J=11.5, 1.4 Hz, 1H), 5.60 (dd, J=18.1, 1.4 Hz, 1H), 4.77 (s, 2H), 3.94 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −143.49; ESIMS m/z 301 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:7]=1.CCN(C(C)C)C(C)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C1COCC1.CCOC(C)=O>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=2)=[CH:7][C:6]=1[C:8]1[C:9](=[O:18])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[CH:13][CH:12]=2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(-c2cc3cnccc3[nH]c2=O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(-c2cc3cnccc3[nH]c2=O)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-amino-2-chloro-phenyl)-1H-[1,6]-naphthyridin-2-one (60 mg, 0.23 mmol) and DIPEA (82 μl, 0.46 mmol) in anhydrous THF (2.5 mL), is added a solution of 3-trifluoromethyl-benzoyl chloride (44 μl). This mixture is stirred for 30 minutes at room temperature, diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, concentrated and purified by preparative HPLC, to give N-[4-chloro-3-(2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (18.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[O:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][N:15]3[C:16](=[O:18])[N:17]=2)=[CH:8][C:7]=1[F:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[O:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[NH:21][CH2:20][CH2:19][N:15]3[C:16](=[O:18])[N:17]=2)=[CH:8][C:7]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)c(F)c1)nc2=O
Solvent: CN(C)C=O
Product: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(Cl)c3)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E71 using tert-butyl 7-((4-(3,4-dichlorophenoxy)-3-fluorobenzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (30 mg, 0.057 mmol) in DMF (2 mL) and silica gel (150 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]([OH:25])[CH3:24])[C:11]1=[O:26])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:26])[C@@H:12]([CH2:22][C@@H:23]([OH:25])[CH3:24])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](CC(C)O)OC[C@H]1C1CCCCC1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)C[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a solution of 3-[(2R,5R)-5-cyclohexyl-2-(2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (420 mg, 0.91 mmol, 1.0 equiv) in THF (8 mL), MeOH (4 mL) and water (4 mL) was added LiOH.H2O (115 mg, 2.73 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for one hour. The volatile solvent was removed under vacuum and the residue was acidified by addition of 3.0 N HCl aqueous solution until pH=1. The mixture was extracted with EtOAc (50 mL). The separated organic layer was washed with brine (10 mL), dried (over Na2SO4) and concentrated. The residue was purified by HPLC (0.1% NH4OH) to give product (68 mg, 16.7%). MS: 448.2 [M−H+]. 1H NMR (400 MHz, CD3OD) δ 1.07-1.31 (m, 8H) 1.32 (s, 9H) 1.45-1.60 (m, 2H) 1.63-1.85 (m, 4H) 1.87-1.98 (m, 1H) 2.02-2.11 (m, 1H) 3.60-3.66 (m, 1H) 3.93-4.03 (m, 2H) 4.15 (d, 1H) 4.26-4.35 (m, 1H) 6.94 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1ccsc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1sccc1C(=O)O
Temperature: 0 °C
Yield: 0.1 %

Procedure:
Ethyl 2-methyl-3-thiophenecarboxylate (3.42 g, 20.09 mmol; see step (ii) above) was dissolved in ethanol (5 mL) to which was added a solution of sodium hydroxide (3.2145 mg, 80.362 mmol) in water (10 mL). The reaction mixture was heated under reflux for 2 h. The volume was reduced to half under reduced pressure at 40° C. and the residue was cooled with ice water. Dilute HCl was added dropwise with stirring until pH 2. The white solid material was filtered off, washed with water and dried under reduced pressure at 50° C. to give the required material (2.1850 mg, 77% yield), m.p. 115-117° C., lit. m.p. 116-117° C. (see D. W. Knight, A. P. Nott J. Chem. Soc., Perkin Trans. 1 791-794 (1983)).
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1.[Li+].[OH-]>C1COCC1.CO.O>[I:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1
Reactant: CCOC(=O)c1cn(C2CCCCO2)nc1I
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carboxylate (85 g, 242.75 mmol, 1.00 equiv) in THF (300 mL) and methanol (300 mL) was added a solution of LiOH (17.5 g, 730.69 mmol, 3.01 equiv) in water (400 mL). The resulting solution was stirred at room temperature overnight and then concentrated under vacuum to remove the organic solvent. The resulting solution was diluted with 400 mL of H2O and then acidified to pH 6.0 with 1M hydrochloric acid. The mixture was extracted with 3×800 mL of dichloromethane. The combined organic layers was washed with 3×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 75 g (96%) of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carboxylic acid as an off-white solid. LCMS (method D, ESI): RT=1.23 min, m/z=323.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:34]=[CH:33][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc4ccccc4c3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (150 mg, 0.35 mmol, see step (b) Example 1) and 2-naphthyl-boronic acid (91 mg, 0.53 mmol). Yield 66 mg, (34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:21](=[O:22])[CH2:20][C:19](=[O:23])[CH3:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: C=C1CC(=O)O1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 50 °C
Yield: 43.8 %

Procedure:
The product of Step (d) (0.5 g, 2.2 mmol) was dissolved in acetonitrile (1 ml). In a separate flask, diketene (0.17 ml, 2.2 mmol, stabilized with copper sulfate) was dissolved in acetonitrile (1 ml). The diketene solution was added to the amine suspension In three portions, the reaction mixture was sealed and heated to 50° C. for 18 hours. The solvent was evaporated to dryness and purified by silica gel chromatography (5% MeOH/CH2Cl2) to afford the title compound, (0.3 g, 44%); MS (ES+) m/e 313 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8](=O)[CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O=P(Cl)(Cl)[Cl:20].CCN(CC)CC>C(Cl)(Cl)Cl>[Cl:20][C:8]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[Cl:1])=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C#N)C(=O)c1scc(C)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C#N)=C(Cl)c1scc(C)c1Cl
Temperature: 5 °C
Yield: 66.9 %

Procedure:
To a solution of ethyl 3-(3-chloro-4-methyl-2-thienyl)-2-cyano-3-oxopropanoate (15.40 g, 56.67 mmol, 1 eq.) in 200 ml of CHCl3 was added POCl3 (86.9 g, 566 mmol, 10 eq.). Et3N (14.33 g, 141.6 mmol, 2.5 eq.) was added dropwise with stirring at 5° C., and the mixture was refluxed for 4 h. The mixture was evaporated. After evaporation, the mixture was diluted with DCM (CH2Cl2) and with ice water and was extracted with DCM (CH2Cl2) and washed with brine. The organic layers were combined and dried over MgSO4 before concentration under reduced pressure. The residue was subjected to column chromatography on silica gel to give ethyl 3-chloro-3-(3-chloro-4-methyl-2-thienyl)-2-cyanoacrylate (11 g, 66% yield) as a mixture of 2 isomers
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 15 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 4-aminobenzonitrile (2.36 g (20.0 mmol))in pyridine (10 ml), 4-chlorobenzenesulfonyl chloride (4.35 g (20.6 mmol)) was added under cooling in a water bath (15° C.). After 18 hours' stirring at room temperature, water (100 ml) was added to the reaction mixture and the stirring was continued to bring about separation of crystals, which were then collected by filtration and washed with water to give 4.45 g (76%) of 4-chloro-4′-cyanobenzenesulfonanilide as pale orange crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.O>O1CCCC1>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([OH:16])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC1CC2CCC(C1)N2Cc1ccccc1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
In tetrahydrofuran (16 ml) was dissolved 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (1.0 g, 4.64 mmol), and a 1M-diisobutylaluminum hydride/toluene solution (11.6 ml, 11.6 mmol) was added dropwise thereto at −78° C. over a period of 10 minutes and stirred for another 1 hour. Water was added dropwise thereto to quench the excess reactants, and the resulting mixture was separated by the addition of a 2N-aqueous hydrochloric acid solution and ethyl acetate. The aqueous layer was adjusted to pH 10 or lower with a 2N-aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-ol (886 mg, 88%).
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[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([C:39]([F:42])([F:41])[F:40])[C:32]3[N:36]=[C:35]([CH3:37])[NH:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>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:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[C:32]6[N:36]=[C:35]([CH3:37])[NH:34][C:33]=6[CH:38]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C(F)(F)F)c5nc(C)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
140 mg (0.510 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([OH:16])=O)[N:11]=[C:10]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([NH:25][C:26]([NH:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:27])[C:22]=4[C:23](=[O:24])[C:9]=23)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][C:48]([CH2:50][CH2:51][C@H:52]([NH:60][C:61]([C:63]1[CH:68]=[CH:67][C:66]([N:69](C(OCC2C=CC=CC=2)=O)[CH3:70])=[CH:65][CH:64]=1)=[O:62])[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][C:48]([CH2:50][CH2:51][C@H:52]([NH:60][C:61]([C:63]3[CH:64]=[CH:65][C:66]([NH:69][CH3:70])=[CH:67][CH:68]=3)=[O:62])[C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[O:49])=[O:16])[N:11]=[C:10]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([NH:25][C:26](=[O:27])[NH:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[C:22]=4[C:23](=[O:24])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCN)C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)Cn1nc2c(c1-c1ccc(O)cc1)C(=O)c1c(NC(=O)NN3CCOCC3)cccc1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCNC(=O)Cn2nc3c(c2-c2ccc(O)cc2)C(=O)c2c(NC(=O)NN4CCOCC4)cccc2-3)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 38 (0.52 g, 1.1 mmol) and compound 12 (0.55 g, 1.1 mmol) were dissolved in DMF and HBTU (0.8 g, 2.1 mmol) was added as a solid followed by DIEA (0.52 ml, 3 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc and the organic phase washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to an oil. This oil was purified by flash silica chromatography (1 to 2 to 3 to 4 to 5% MeOH/CH2Cl2) to give a yellow foam (0.45 g, 0.47 mmol, 43%, compound 39).
Reaction SMILES: CO[C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C:5](=[O:11])[CH:4]=1.[NH3:12]>>[NH2:12][C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C:5](=[O:11])[CH:4]=1
Reactant: N
Reactant: COC1=CC(=O)CCC1(C)C
Product: CC1(C)CCC(=O)C=C1N
Temperature: 100 °C

Procedure:
3-Methoxy-4,4-dimethyl-2-cyclohexen-I -one in condensed anhydrous ammonia (50 mL) was heated at 100 ° C. (850 psi) for 34 hours. Ammonia was removed by evaporation, the residue dissolved in ethyl acetate (5 mL) and filtered through Florisil to provide 1,14 g of the title compound as a pale tan oil.