Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[Si]([C:16]#[CH:17])(C)(C)C.N#N>C(Cl)Cl.CCN(CC)CC.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:16]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2)#[CH:17]
Reactant: C#C[Si](C)(C)C
Reactant: Cn1ccc2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(ccn2C)c1
Temperature: 25 °C

Procedure:
5-iodo-1-methyl-1H-indole (1.5 g, 5.84 mmol) were dissolved in mixture of CH2Cl2 (10 ml) and NEt3 (5 ml) and the system was evacuated-back filled by N2 thrice. Pd(PPh3)2Cl2 (122 mg, 3% mol) and TMS-acetylene (0.858 g, 8.7 mmol) were added to it and again flushed N2 into the system. CuI (89 mg, 8% mol) was added and flushed N2 very quickly and reaction was stirred under positive pressure of N2 until reaction completed by TLC (ca. 3 hours). The reaction mixture was diluted with 10 ml of hexane and filtered through celite plug, purified by passing through small column and then suspended in MeOH (20 ml) containing 10 ml of THF. NaOH was added to reaction mixture and stirred at room temp until starting material consumed completely. The reaction mixture was concentrated to 10 ml and extracted with EtOAc from aqueous NH4Cl solution, which was purified by column chromatography; Yield (60%); 1H NMR (300 MHz, CDCl3) δ: 3.03 (s, 1H), 3.73 (s, 3H, NMe), 6.45 (d, J=3.0 Hz, 1H), 7.05 (d, J=3.0 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 7.33 (dd, J=9.0, 1.2 Hz, 1H), 7.80 (bs, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C@@H:27]3[C:32](=[O:33])[N:31]([CH3:34])[CH2:30][CH2:29][N:28]3[CH3:35])=[CH:23][CH:22]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[CH3:35][N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C@H:27]1[C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:36]4[CH2:48][CH2:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[C:6]=3[CH2:5][OH:4])[N:13]=2)=[CH:22][CH:23]=1
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc([C@@H]4C(=O)N(C)CCN4C)cc3)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCN(C)[C@H](c2ccc(Nc3nc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2)C1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
A mixture of 114b (360 mg, 0.54 mmol) and LiOH.H2O (138 mg, 2.76 mmol) in iPrOH/THF (1:1, 3 mL) and H2O (1 mL) was stirred at 30° C. for 2 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 114 (72 mg, 21%) as a white solid. LCMS: [M+H]+ 623. 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J=4.5, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.83-7.78 (m, 3H), 7.36 (d, J=8.0, 2H), 6.89 (s, 1H), 5.12-5.14 (m, 1H), 4.68-4.70 (m, 1H), 4.49-4.53 (m, 1H), 4.38-4.43 (m, 1H), 4.15-4.06 (m, 2H), 3.89-3.90 (m, 1H), 3.72-3.73 (m, 2H), 3.65 (s, 3H), 3.21-3.22 (m, 1H), 3.01-3.03 (m, 4H), 2.71-2.56 (m, 5H), 2.20 (s, 3H), 1.90-1.92 (m, 2H), 1.79-1.80 (m, 2H)
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[C:10]([CH:13]=2)[CH:11]=O)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23].CO.O(C)[Li]>CCCCCCC.O.CN(C=O)C>[S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[C:10](/[CH:11]=[CH:23]/[C:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:24])[CH:13]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [Li]OC
Solvent: CO
Solvent: O
Solvent: CCCCCCC
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Reaction time: 2 h
Yield: 87 %

Procedure:
An alternative procedure: 5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A (42.3 g), 4-acetylbenzoic acid (22.1 g), MeOH (250 mL) and DMF (600 mL) were sequentially charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter. After complete dissolution, LiOMe (10.5 g) was added in one portion and the resulting solution was aged at 40° C. for 2 h. Upon completion, as determined by HPLC, the reaction mixture was transferred to a separatory funnel containing cold H2O (800 mL, precooled to 10 deg C.). An additional 400 mL cold H2O was used to rinse the reaction vessel and this rinse was also added to the seperatory funnel. The combined aqueous was washed with iPrOAc (500 mL) and then acidified to a pH of 3 with 6 N HCl (ca. 60 mL). The resulting heterogeneous solution was aged for 30 min and then the precipitate was filtered, washed with 70% EtOH (100 mL) and dried on the filter funnel under a stream of N2 affording desired acid 5 as a crude yellow solid. The crude dry product and THF (260 mL) were charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter. Heptane (30 mL) was slowly added to the resulting solution over 30 min and then aged resulting in crystallization. Additional heptane (270 mL) was added over 1 h, aged for an additional 1 h and then filtered. The reaction vessel was then rinsed with 70% EtOH (100 mL) and this rinse was added to the filter cake. The wet cake was then transferred to a clean reaction vessel containing 70% EtOH (750 mL) and the resulting heterogeneous mixture was stirred overnight. The product was then filtered, rinsed with fresh 70% EtOH (100 mL) and then dried on the filter funnel under a stream of N2. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40° C., 20 inHg) affording 52.05 g (87% yield) of desired 4-[3-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-E-acryloyl]-benzoic acid 5 as a yellow crystalline solid, m.p. 231–232° C. (dec.). HPLC assay of this solid indicated >99.9 LCAP. 1H-NMR identical as above.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]\[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.I[CH3:25]>CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]\[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:25])[CH:19]=[CH:18]3)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(/C=C\c2ccc3[nH]ccc3c2)cc(OC)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(/C=C\c2ccc3c(ccn3C)c2)cc(OC)c1
Reaction time: 0.08 h

Procedure:
A suspension of KOH (2 mmol, 112 mg) in DMSO (5 mL) is stirred for 5 min. Then, compound 12a (1 mmol, 279 mg) and iodomethane (1.2 mmol, 75 μL) are added to the solution. The mixture is stirred at room temperature for 30 min, poured into water/ice, and extracted with ethyl acetate. The combined organic extracts are washed with brine (5 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure affords a residue, which is chromatographed on silica gel (20% ethyl acetate/light petroleum).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[C:28]2=[N:29][CH:30]=[CH:31][N:27]2[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[C:28]4=[N:29][CH:30]=[CH:31][N:27]4[N:26]=[CH:25][N:24]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnn2ccnc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnn2ccnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Yield: 78.7 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.106 g, 0.32 mmol), 4-chloroimidazo[2,1-f][1,2,4]triazine (WO2010/014930) (0.050 g, 0.32 mmol) and diisopropylethylamine (0.222 mL, 1.28 mmol) in isopropanol (2 mL) was heated to 60° C. in a sealed tube for 0.5 h. The reaction mixture was cooled and diluted with EtOAc (20 mL) and washed with water (2 mL) The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 321 as a pale pink solid, (94 mg, 78%). LCMS (Method C): RT 4.31 min [M+H]+ 374.01. 1H NMR δ (ppm) (DMSO-d): 9.15 (1H, d, J=7.24 Hz), 8.02 (1H, d, J=1.09 Hz), 7.95 (1H, s), 7.71 (1H, dd, J=8.81, 4.85 Hz), 7.57-7.54 (3H, m), 7.48-7.39 (3H, m), 7.10 (1H, td, J=9.33, 2.51 Hz), 6.83 (1H, dd, J=8.91, 2.52 Hz), 5.57 (1H, dq, J=7.00 Hz), 1.61 (3H, d, J=6.88 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl.[NH2-].[Na+].CO.C(Cl)(Cl)Cl>O>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH:17]=[CH:16][CH:15]=[CH:14][C:6]1=2
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: CN(C)CCCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC1=Cc2ccccc2N(CCCN(C)C)c2ccccc21
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A 500 ml round bottom flask containing 9.87 g (0.044 moles) of 10-methoxy-5H-dibenz[b,f]azepine prepared in Example 3 and 13.9 g (0.088 moles) of 3-dimethylaminopropylchloride was evacuated for several days. Anhydrous toluene (250 ml) was added followed by 7.04 g (0.176 moles) of sodium amide. The heterogeneous solution was stirred at ambient temperature for a few minutes and then refluxed for 16 hours. After 16 hours of refluxing, tlc analysis of the reaction mixture (silica gel GF plates, methanol:chloroform 1:9; visualized under UV lamp and sulfuric acid-ceric sulfate spray) revealed that the reaction was complete and that no starting material remained. Enough water was added to slowly decompose the excess sodium amide. The dark-brown solution was placed in a 1 liter separatory funnel and extracted with four 250 ml portions of water. The organic phase was dried over anhydrous magnesium sulfate, charcoal was added and the mixture was filtered through a Celite pad. The filtrate was concentrated leaving a brown oil (12.6 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=1)=[CH:15]2)(=[O:8])=[O:7].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(O)C>[OH:25][CH2:24][C:22]1[N:23]=[C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[S:20][CH:21]=1
Reactant: CCOC(=O)c1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=S(=O)(Nc1cccc2cc(-c3nc(CO)cs3)[nH]c12)c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a mixture of ethyl 2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-4-carboxylate (0.35 g) and tetrahydrofuran (15 mL) was added lithium aluminum hydride (0.11 g) at 0° C., and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added ethanol (5 mL) and then saturated aqueous ammonium chloride solution (5 mL) was added. The resulting inorganic salt was removed by filtration, and the filtrate was concentrated. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated. Ethyl acetate was added to the obtained residue, and the resulting crystals were collected by filtration and dried to give the title compound (0.10 g, yield 32%) as yellow crystals. melting point>233° C. (decomposition).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([OH:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([O:1][CH2:2][C:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([OH:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cccc2c1CCc1ccccc1C2O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCc1cccc2c1CCc1ccccc1C2O
Reaction time: 72 h

Procedure:
4.0 g of 1-(hydroxymethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol prepared in Example 1-c was dissolved in 20 ml of tetrahydrofuran, and 1.2 ml of pyridine and 1.4 ml of acetic anhydride were added at room temperature, followed by stirring for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:9), to give 3.5 g of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]2[CH2:16][C:17]([CH2:19][CH:12]1[CH2:13][CH2:14]2)=O.[BH3-]C#N.[Na+].[OH-].[Na+]>CO.ClCCl.O.C(O)(=O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:16]2[C@H:15]3[N:11]([CH3:10])[C@H:12]([CH2:13][CH2:14]3)[CH2:19][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CNC2CC[C@H]3CC[C@@H]2N3C)cc1

Procedure:
4-Methylbenzylamine (607 mg, 5.0 mmol) was dissolved in 10 ml methanol and placed in 100 ml flask. Tropinone (697 mg, 5.0 mmol) in 10 ml methanol was added. Acetic acid (0.75 ml) was added until pH˜5. NaCNBH3 (628 mg, 10 mmol) was slowly added. Gas evolution observed. After 20 hrs magnetic stirring dichloromethane, 2M NaOH and water were added until pH˜10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40° C.) yielded 1.14 g crude 47AKU-17. TLC (10% methanol in dichloromethane): Rf=0.4. HPLC-MS (Method A): M+=245.2 (UV/MS(%)=65/96).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:31])[C:4](=[O:30])[C:5]([C:20]2[CH:21]=[C:22]([CH:28]=O)[N:23]([CH2:25][CH2:26][F:27])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].[BH3-]C#N.[Na+]>[Cl-].[Cl-].[Zn+2].CO>[NH2:1][C:2]1[N:3]([CH3:31])[C:4](=[O:30])[C:5]([C:20]2[CH:21]=[C:22]([CH2:28][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])[N:23]([CH2:25][CH2:26][F:27])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCNCC
Reactant: CN1C(=O)C(c2cccc(-c3cccnc3F)c2)(c2cc(C=O)n(CCF)c2)N=C1N
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)Cc1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cn1CCF
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
To a glass tube was added methanol (0.5 mL), 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde (0.05 g; 0.12 mmol), diethylamine (43 μL; 0.41 mmol), and 1.8 mL of a methanolic solution of ZnCl2 (0.1 M), and NaBH3CN (0.2 M). The mixture was stirred 24 hours at room temperature. The solvent was evaporated and the residue was dissolved in chloroform, washed with 0.1 N NaOH solution, dried over MgSO4, and evaporated to give the title compound as an amorphous white solid, 0.021 g (37% yield), mp 121-140° C.; MS (ES) m/z 479.2, [M−H]−.
Reaction SMILES: FC(F)(F)C(O)=O.ClC(Cl)C([O:12][N:13]=[C:14]([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)[C:15]([NH:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:16])=O.CCOCC.CS(C)=O>C1(OC)C=CC=CC=1>[OH:12][N:13]=[C:14]([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)[C:15]([NH:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:16]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c4cccs4)[C@H]3SC2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: COc1ccccc1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NO)c4cccs4)[C@H]3SC2)s1

Procedure:
Trifluoroacetic acid (8 ml.) was added to a solution of the above ester (1.387 g.) in anisole (2 ml). at 20°. After 5 minutes the solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solvent was evaporated and again the residue was dissolved in ethyl acetate. The solution was washed with water and then extracted with sodium bicarbonate solution. The combined extracts were washed with ethyl acetate, then taken to ph 1.9 with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated under reduced pressure to give a foam. Trituration with ether gave the title compound as a buff solid (0.50 g.), [α]D - 84° (c 1, DMSO), λmax. (pH 6 buffer) 271.5 nm (ε 17,600), νmax. (Nujol) include 3250 (NH), 1780 (β-lactam), 2600 + 1710 (CO2H), and 1674 + 1548 cm.-1 (CONH), τ values (DMSO-d6) 0.24 (doublet, J 8 Hz; NH) 2.37 and 2.82 (thienyl protons) 4.12 (double doublet, J 5 and 8 Hz; C-7H), 4.76 (doublet, J 5 Hz; C-6H), 5.40 and 5.75 (2 doublets, branches of quartet, J 13 Hz; C-3 Ch2), 6.13 + 6.40 (2 doublets, branches of quartet, J 18 Hz; C-2 CH2) and 7.29 (singlet; CH3).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[N:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27](I)[CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[N:21]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCCI
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1Cc1nc(/C=C/C(=O)O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)/C=C/c1csc(CN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound 72 (980 mg) in dimethylformamide (3.00 mL) was added n-butyl iodide (570 μL) at room temperature and then thereto was added potassium carbonate (691 mg) at 0° C. The solution was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed water and brine, dried over anhydrous sodium sulfate and concentrated. The organic residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=78:22→50:50) to give the title compound (960 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]3[NH:35][CH2:34][C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[N:31][CH:32]=2)[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:19][C:14]1[CH:13]=[C:12]([C:4]2[C:3]([CH3:20])=[C:2]([N:35]3[C:29]4[C:30](=[N:31][CH:32]=[C:27]([N:24]5[CH2:25][CH2:26][O:21][CH2:22][CH2:23]5)[CH:28]=4)[C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:34]3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: Cc1c(-c2cc(F)cc(F)c2)nc2ncccc2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2ncccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,8-naphthyridine (60 mg, 0.206 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (56.8 mg, 0.206 mmol), sodium tert-butoxide (39.7 mg, 0.413 mmol) and XPhos precatalyst (15 mg, 0.021 mmol). Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(2-(3,5-difluorophenyl)-3-methyl-1,8-naphthyridin-4-yl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 9.14 (1H, dd, J=4.1, 2.0 Hz), 8.13 (1H, dd, J=8.4, 2.0 Hz), 7.67 (1H, d, J=2.3 Hz), 7.46 (1H, dd, J=8.3, 4.2 Hz), 7.21-7.33 (2H, m), 6.88-7.00 (1H, m), 5.78 (1H, d, J=2.3 Hz), 4.14-4.21 (2H, m), 3.93-4.07 (2H, m), 3.70-3.80 (4H, m), 3.52-3.66 (2H, m, J=11.3, 11.3, 2.5, 2.2 Hz), 2.91-3.07 (4H, m), 2.27-2.43 (5H, m), 1.70-1.89 (2H, m). Mass Spectrum (ESI) m/e=530.2 (M+1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][CH3:15].[CH2:19]([C:23]1[N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[C:25](C=O)=[C:26]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[N:27]=1)[CH2:20][CH2:21][CH3:22].CN(C1C=CC=CN=1)C.C(OC(=O)C)(=O)C.N12CCCN=C1CCCCC2>O1CCCC1.C(Cl)Cl.C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C.O>[CH2:19]([C:23]1[N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[C:25](/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16])=[C:26]([CH2:28][O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])[N:27]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(C=O)n1Cc1ccccc1Cl
Reactant: CCC(=O)OC
Agent: CN(C)c1ccccn1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(/C=C/C(=O)OC)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To tetrahydrofuran (80 mL) is added n butyl lithium (15.5 mmol in hexane) and at -78° C. under argon is then added diisopropylamine (2.4 mL, 17.1 mmol). Methyl propanoate (15.3 mmol) is added neat over 5-6 minutes, and the mixture was stirred an additional 30 minutes at -78° C. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-4-(t-butyldimethylsilyloxy)methyl-1H-imidazol-5-carboxaldehyde (10.2 mmol) in tetrahydrofuran (10 mL) is added via a cannula, and the reaction mixture is stirred for 15 minutes. The reaction is partitioned between saturated ammonium chloride and ether, and the ether layer is washed with water, dried and concentrated to give crude product. This is chromatographed over silica gel with 20-50% of ethyl acetate in hexane to afford a mixture of isomeric β-hydroxyester products. A solution of this mixture (8.54 mmol) in methylene dichloride (100 mL) is treated with 4 dimethylaminopyridine (3 mmol) followed by acetic anhydride (84 mmol), and the solution is stirred at room temperature for 5 hours. The reaction is poured into water, stirred for 20 minutes and the product is extracted into ether. The ether extracts are washed with dilute hydrochloric acid solution, water, sodium bicarbonate solution and brine. The dried, concentrated mixture of β-acetoxyester products is used directly in the elimination reaction. To a solution of the β-acetoxyester product (4.5 mmol) in toluene (60 mL) is added of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.9 mmol), and the mixture is heated at 90° C. for 24 hours. The reaction is concentrated to 10 mL, diluted with ether and flash filtered through a 14×3 cm plug of silica gel with ether rinses to afford the crude olefinic product. Chromatography over silica gel with an ethyl acetate in hexane gradient gives homogeneous methyl (E) 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-(t-butyldimethylsilyloxy)methyl-1H-imidazol-5-yl]-2-propenoate. The elimination of the acetate with DBU produces predominantly the trans (E) isomer.