Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:12]([C:14]1[C:15]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1)=[O:13])[C:4]([NH:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:5])#[N:2]>[OH-].[K+].C(O)C>[C:1]([CH:3]([C:12]([C:14]1[C:15]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1)=[O:13])[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])#[N:2]
Reactant: COC(=O)CNC(=O)C(C#N)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(C(=O)NCC(=O)O)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
N-[2-Cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl) -3-oxo-propanoyl]-glycine, methyl ester (1.7 g), is suspended in 1% KOH solution in 95% ethanol (60 ml) and heated under stirring at the reflux temperature for 30 minutes. After cooling the precipitate is filtered and washed with ethanol, then dissolved in water. The aqueous basic solution is extracted with ethyl acetate and then acidified to pH 3 with 2N HCl. The precipitate is extracted with ethyl acetate and the organic solution washed with N HCl and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is crumbled with ethanol to yield 1.2 g of N-[2-cyano-3-(1,4-dihydro 1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanoyl]-glycine, m.p. 247°-249° C. dec.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([N:32]3[C:36](=[O:37])[CH:35]=[CH:34][C:33]3=[O:38])=[CH:20][N:19]=2)[CH:11]=[CH:10][C:9]=1[N+:39]([O-:41])=[O:40]>>[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([N:32]3[C:36](=[O:37])[CH2:35][CH:34]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:33]3=[O:38])=[CH:20][N:19]=2)[CH:11]=[CH:10][C:9]=1[N+:39]([O-:41])=[O:40]
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)C=CC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Product: Nc1nc(NCCNc2ncc(N3C(=O)CC(N4CCOCC4)C3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
Large excess of morpholine was added to clean fractions of 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-pyrroline-2,5-dione concentrated in vacuo, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-morpholin-4-ylpyrrolidine-2,5-dione.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Reaction time: 0.5 h

Procedure:
3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10° C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15° C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutralized by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling. The mixture was extracted with dicbloromethane (2×150 ml), then dried (Na2SO4) and evaporated to give the crude product (2.69 g) as a yellow solid. Flash column chromatography using as eluant 5% methanol in dicbloromethane gave a pure sample of the title compound (660 mg) and a further sample (1.95 g) containing ca. 10% of the isomer 3-methyl-8-nitroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[N:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[N:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nncs2)=NC1c1ccc(F)cc1Br
Yield: 72.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.76 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.6 g, 72%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: ClC(Cl)C.[CH:5]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[C:20]([C@@H:23]3[CH:28]4[O:29][C@@H:25]([CH2:26][CH2:27]4)[C@@H:24]3[CH2:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH2:38][CH2:39][C:40]([OH:42])=O)[O:21][CH:22]=2)=[O:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:56]([CH2:58][NH2:59])[OH:57]>>[CH:5]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[C:20]([CH:23]3[CH:24]([CH2:30][C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[CH2:38][CH2:39][C:40](=[O:42])[NH:59][CH2:58][CH2:56][OH:57])[CH:25]4[O:29][CH:28]3[CH2:27][CH2:26]4)[O:21][CH:22]=2)=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)CCc1ccc(F)cc1C[C@H]1[C@@H]2CCC(O2)[C@H]1c1nc(C(=O)NCCCCC2CCCCC2)co1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C(CCc1ccc(F)cc1CC1C2CCC(O2)C1c1nc(C(=O)NCCCCC2CCCCC2)co1)NCCO
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A dichloroethane (0.3 mL) solution of 3-(2-{(1S,2R,3S)-3-[4-(4-Cyclohexyl-butylcarbamoy)-oxazol-2-yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4fluoro-phenyl)-propionic acid (1) (30 mg, 0.057 mmol) was treated with triethylamine (12 μL, 0.086 mmol) and ethyl chloroformate (7 μL, 0.073 mmol). After 30 min., ethanolamine (10 μL, 0.17 mmol) was added and the solution stirred for 18 h. The resulting mixture was partitioned between 10 mL 1 M NaOH and 15 mL dichloromethane. The dichloromethane solution was washed with 1 M NaOH (6×10 mL). A small amount of brine was added to avoid an emulsion. The dichloromethane solution was then washed with brine (15 mL) and then was dried (Na2SO4), filtered and evaporated. Purification by preparative thin layer chromatography (4% methanol/dichloromethane) gave 12 mg (0.021 mmol, 37%) of the title compound. 1H NMR (300 MHz, ppm) δ 8.11 (s, 1 H) 7.3–7.2 (m, 1 H) 7.11–7.06 (m, 1 H) 6.84–6.78 (m, 2 H) 6.2–6.1 (m, 1 H) 5.00 (d, J=4.0 Hz, 1 H) 4.81 (d, J=4.4 Hz, 1 H) 3.7–3.6 (br m, 2 H) 3.5–3.3 (m, 6 H) 2.84–2.79 (m, 2 H) 2.66–2.57 (m, 1 H) 2.4–2.0 (m, 4 H) 1.9–0.8 (overlapping m, 21 H).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].[CH3:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20]>>[CH2:1]([S:13][CH2:20][CH:19]([CH3:21])[C:18]([O:17][CH3:16])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: C=C(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCSCC(C)C(=O)OC
Temperature: 122 °C
Reaction time: 0.17 h

Procedure:
Into the same type equipment used in Example 1 202 grams of 98% 1-dodecanthiol was added to 1.0 grams of KOH and 112 grams methylmethacrylate with stirring over a 10 minute period. The reaction mixture went from 70° C. to 98° C. The reaction mixture was stirred an extra hour at 98° C. to 93° C. and slowly heated up to 122° C. over a 5 hour period. The reaction mixture was stripped at 125° C. and 20 mm pressure. GC analysis indicated a purity of 93.2% product. 300 grams filtered product was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of maleic acid (0.066 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 4 h and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then a sample (1 mL) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give Nilotinib maleate form II.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>>[F:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)s1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)s4)nc23)CC1
Yield: 17 %

Procedure:
Beginning with 0.414 gm (1.8 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 2.73 mMol 5-fluoro-2-thiophenecarbonyl chloride, 0.11 gm (17%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:17])[CH2:10][C:11](N(OC)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][Mg]Br.C(OCC)C.Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]([CH3:17])[CH2:10][C:11](=[O:12])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C[C@H](C)OCc1ccccc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C[C@H](C)OCc1ccccc1
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of the above (3S)-3-(benzyloxy)-N-methoxy-N-methylbutanamide (196 g) in THF (1.5 L), a 3M methyl magnesium bromide/diethyl ether solution (0.38 mL, 1.1 mol) was gradually added under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. After the reaction, the reaction mixture was poured to 2N hydrochloric acid, and after THF was distilled off under reduced pressure, it was extracted with diethyl ether. After it was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure to give a crude product. This was purified by reduced pressure distillation to give a title compound (44 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7]C1C=C(C2C=CC(C(NCC3CC3)=O)=CC=2)C(C)=CC=1)=[O:6]>C1(N)CC1>[C:5]([NH2:7])(=[O:6])[C:4]1[CH:28]=[CH:29][N:30]=[CH:2][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: NC1CC1
Product: NC(=O)c1ccncc1
Yield: 40.9 %

Procedure:
A solution of 2-chloro-N-(4′{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in cyclopropylamine (2 ml) was heated at 85° C. for 48 h and then at 110° C. for 72 h in a sealed tube.The reaction was concentrated under vacuum, the residue triturated with water and purified by preparative HPLC. The solvent was evaporated under vacuum to give 2-(cyclopropylamino)-N-4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (6 mg). NMR; δH [2H6]—DMSO 10.32,(1H, s), 8.62,(1H, t), 8.14,(1H, d), 7.93,(2H, d), 7.71-7.67,(2H, m), 7.44,(2H, d), 7.29,(1H, d), 7.05,(1H, d), 7.00-6.98,(2H, m), 3.16,(2H, t), 2.55,(1H, m), 2.20,(3H, s), 1.05,(1H, m), 0.71,(2H, m), 0.43,(4H, m), 0.24,(2H, m). LCMS: retention time 2.74 min, MH+441.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH3:25])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1cccc(-c2csc3cnc(Cl)nc23)c1)S(C)(=O)=O
Yield: 93.4 %

Procedure:
N-(3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (200 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) and sodium hydride (36 mg, 0.89 mmol) was slowly added at 0° C. 10 minutes later, after adding iodomethane (100 mg, 0.71 mmol), the reaction mixture was stirred for an hour, diluted with ethyl acetate, and washed with brine. The organic layer was dried with magnesium sulfate, filtered, and then concentrated. The target compound (195 mg, 94% yield) was obtained without purification.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(OC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)(C)(C)C>>[CH2:13]([O:11][C:10](=[O:12])[C@H:3]([CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)[NH:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: OCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CN[C@@H](Cc1c[nH]cn1)C(=O)OCc1ccccc1

Procedure:
N-Methyl-L-histidine was converted with benzyl alcohol in the presence of hydrochloric acid at room temperature into the corresponding benzyl ester and this was reacted according to the procedure described by D. H. Rich et al. in Proc. 9thAmerican Pept. Symp.. Toronto 1985. page 217, with t-butoxycarbonyl-L-phenylalanine in the usual manner. Thereafter, the N-[N-t-butoxycarbonyl)-3-phenyl L-alanyl]-N-methyl-L-histidine benzyl ester obtained was hydrogenated for one hour in the presence of 5% palladium on carbon, to obtain N-[N-(t-butoxy-carbonyl)-3-phenyl L-alanyl]-N-methyl-L-histidine, Rf: 0.2 in a 80:20:3:3 mixture of chloroform, methanol, water and acetic acid. This compound was then reacted in the usual manner with (αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol. The crude product obtained was then chromatographed on silica gel with a 20:1:0.1 mixture of methylene chloride, methanol and ammonia, upon which the two epimeric compounds were separated. Recrystallization of the crude product obtained from the first fraction from ether/ methylene chloride/hexane yielded t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl] carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoyl]-phenylethyl] carbamate as white crystals of melting point 95°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:22][O:23][CH2:24][CH2:25]Br>O1CCCC1>[CH3:22][O:23][CH2:24][CH2:25][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1CCCC1
Reactant: COCCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC)CCCC1
Temperature: -70 °C
Yield: 65 %

Procedure:
To a 3 L 3-necked round-bottomed flask equipped with a thermometer and dropping funnel were added diisopropylamine (136 mL, 0.98 mol) and tetrahydrofuran (750 mL). The solution was stirred under nitrogen and cooled in an ice-bath. Through the dropping funnel was added n-butyllithium (2.5 M in hexanes; 376 mL, 0.94 mol), and the solution was allowed to stir at 0° C. for 30 min and then cooled to −70° C. Through the dropping tunnel was added a solution of cyclopentanecarboxylic acid, methyl ester (83.04 g, 0.65 mol) in tetrahydrofuran (135 mL). The solution was stirred at −70° C. for 1 h and then a solution of 2-bromoethyl methyl ether (55.5 mL, 0.59 mol) in tetrahydrofuran (135 mL) was added. The solution was stirred at −70° C. for 1 h and then the cooling bath was removed. The solution was stirred at room temperature overnight, then poured into saturated ammonium chloride solution (2 L) and extracted with ether (3×500 mL). The combined ether layers were washed with saturated brine (6×400 mL), dried (Na2SO4), filtered, evaporated, and distilled under vacuum to give 1-(2-methoxyethyl)cyclopentanecarboxylic acid, methyl ester (71.39 g, 59%) as a pale yellow liquid (bp 94–102° C. at 8 mm). This was dissolved in a mixture of tetrahydrofuran (340 mL), methanol (340 mL) and 1 M sodium hydroxide solution (425 mL). The mixture was stirred and heated at 55–60° C. for 24 h and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. Water (400 mL) was added and the solution was extracted with ether (2×200 mL). The aqueous layer was acidified to pH 1 with 1 N HCl (500 mL), and extracted with ether (300 mL, then 2×200 mL). The combined ether layers were washed with saturated brine (2×200 mL), dried (Na2SO4), filtered, and evaporated to give 1-(2-methoxyethyl)cyclopentanecarboxylic acid (63.68 g, 97%) as a yellow liquid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:38]([C:40]1([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)#[CH:39]>C1(C)C=CC=CC=1.[Cu]I.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>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:39]#[C:38][C:40]3([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CC1(O)CCOCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC3(O)CCOCC3)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 4-ethynyl-tetrahydropyran-4-ol (prepared as in Example 46, 252 mg, 2.0 mmol), copper(I) iodide (20 mg), and dichlorobis(triphenylphosphine)palladium(II) (40 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-tetrahydropyran-4-yl-ethynyl)-pyrazin-2-yl]-propionamide (474 mg, 89.30%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H30ClN3O4S (M+H)+ 532.1668, found 532.1675.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:41](=[O:42])[N:18]3[CH:19]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH:20]([CH:23]=O)[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C.O>[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:41](=[O:42])[N:18]3[CH:19]([C:25]([O:27][CH:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:26])[C:20](=[CH:23][O:3][C:1](=[O:4])[CH3:2])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
Sodium acetate (0.23 g.) was added to a solution of diphenylmethyl 7-(2-phenylacetamido)-3-formylcepham-4-carboxylate (0.5 g.) in acetic anhydride (2 ml.), and stirred at 50° C. for 1.5 hours. The resultant solution was added to ethyl acetate (60 ml.) and water (50 ml.) and adjusted to pH 7.2 with sodium bicarbonate. The organic layer was separated, washed with aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was evaporated in vacuo to give diphenylmethyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (0.4 g.).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.COCCOC>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nc(C)cc3c2c(=O)cc(Nc2ccccc2)n3-c2ccccc2)cc1
Temperature: 90 °C
Yield: 62.3 %

Procedure:
An 8-mL amber vial was charged with 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (72 mg, 0.20 mmol), 4-methoxyphenylboronic acid (3-6 mg, 0.24 mmol), Pd(OAc)2 (1 mg, 0.02 mmol), Ph3P (5 mg, 0.02 mmol), K2CO3 (110 mg, 0.8 mmol, 2 M), and DME (2 mL). The mixture was heated to 90° C. 2 d. Water was added to the reaction mixture and it was extracted with CH2Cl2. The organic layer was dried over Na2SO4. The residue after concentration in vacuo was triturated with Et2O to provide 2-anilino-5-(4-methoxyphenyl)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (54 mg, 63%): LCMS RT: 1.92 min, MH+: 434.5.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C1(P(=[CH:29][CH:30]=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:29][CH:30]=[O:31])=[CH:4][CH:3]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: ClCCl
Product: O=CC=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
Part A. 4-bromobenzaldehyde (9.11 gm, 49.28 mmol) and (triphenylphosphoranylidene) acetaldehyde (15.00 gm, 49.28 mmol) were combined in 250 mL of methylene chloride and stirred overnight at room temperature. The volatiles were removed under vacuum and the residue dissolved in 200 mL of EtOAc, filtered through a pad of silica gel and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel eluting hexane:ethyl acetate (3:1, v:v) to give 3-(4-bromophenyl) acrolein as a pale yellow solid 3.67 gm, (35%). MS m/e 211 (M+H)+ 1 H NMR (CDCl3) 6.70 (dd, 1H), 7.43 (m, 3H), 7.54 (d, 2H), 9.69 (d, 1H).