Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[F:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH:22]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: COc1ccc(F)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(F)cc1-c1ccc(C#Cc2csc(C)n2)cn1
Temperature: 80 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-methoxy-5-fluorophenylboronic acid (2.0 mmol, 340 mg),dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 mg) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 18 h at 80° C., then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H—N-NMR (CD3OD, 500 MHz) δ 9.08 (s, 1H), 8.73 (d, 1H), 8.34 (d, 1H), 8.03 (s, 1H), 7.58 (dd, 1H), 7.45 (m, 1H), 7.33 (m, 1H), 3.97 (s, 3H), 2.77 (s, 3H). MS (ESI) 325.4 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:34]I.O>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([N:21]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH3:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C)c2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Sodium hydride (a 60% dispersion in liquid paraffin, 598.8 mg, 14.97 mmol) was washed twice with hexane and then suspended to N,N-dimethylformamide (10 ml). To this suspension was gradually added a solution of 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (998.9 mg, 2.25 mmol) in N,N-dimethylformamide (30 ml) and the reaction mixture was stirred at 60° C. for 30 minutes. To this mixture was added methyl iodide (2.19 g, 15.45 mmol) and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was cooled down to room temperature and water was added to the solution. The product was extracted with ethyl acetate. The extracts were dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain the title compound (69% yield) as an oily mixture of rotamers.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:28]([O:30][CH3:31])=[O:29].C([O-])([O-])=O.[K+].[K+]>COCCOC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([NH:1][C:28](=[O:29])[O:30][CH3:31])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:26][CH:25]=2)=[O:13])=[CH:16][CH:17]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)Nc1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
The product from Example 3 (500 mg, 1.45 mmol), methyl chloroformate (0.43 mL, 5.56 mmol), and K2CO3 (1.15 g, 8.33 mmol) were heated in DME (8 mL) at 65° C. for 24 hours. The mixture was allowed to cool to room temperature, concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 mL). The ethyl acetate was washed with H2O (3×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluant gradient from 99:1 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.15 (s, 1H), 8.53 (dd, J=4.5 Hz, 1.6 Hz 1H), 8.02–8.05 (m, 2H), 7.88 (dd, J=8.1 Hz, 1.4 Hz, 1H), 7.70–7.77 (m, 4H), 7.35–7.46 (m, 3H), 3.55 (s, 3H), 1.29 (s, 9H); MS (ESI+) m/z 404 (M+H)+.
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH3:13]>C(O)C.[Pt](=O)=O>[F:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([O:2][C:1]([O:14][CH3:15])=[O:16])=[CH:8][C:7]=1[NH2:9]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A mixture of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (3 g, 13 mmol), (EP 0307777 A2), and platinum(IV)oxide (300 mg) in ethanol (60 ml) was stirred under hydrogen at 0.3 atmosphere for 1 hour. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation to give 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.6 g, 100%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:11])[C:9]=2[CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:22](OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O)[C@@H:23]1[O:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:22][C@@H:23]1[CH2:24][O:25]1)[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(O)cccc2[nH]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Temperature: 25 °C

Procedure:
2-Methyl-1H-indol-4-ol (0.58 g, 3.9 mmol) and THF (20 mL) were placed in a round bottom flask and stirred at room temperature. Sodium bis(trimethylsilyl) amide (3.9 mL, [1M] in THF) was then slowly added to the reaction mixture. After fifteen minutes of stirring at room temperature (R)-glycidyl-3-nitrobenzenesulfonate was added and the reaction mixture was allowed to stir overnight. Work up of the reaction mixture was carried out with saturated sodium carbonate solution and ethyl acetate. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to yield a crude oil. The crude oil was purified by flash chromatography (20% Ethyl acetate/heptane) to yield the title compound as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([OH:23])=O)[NH:6]2.[N:24]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:24])=[O:23])[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (2.2 g), 1H-1,2,3-benzotriazol-1-ol (1.2 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.5 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 1 hr, and then at 60° C. for 1 hr. 28% Aqueous ammonia (2.0 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (1.84 g, yield 84%) as colorless prism crystals. melting point 221-222° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])C)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39](OB(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][C:25]([O:31][CH2:32][CH2:34][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:22])([F:23])[F:21])(=[O:18])=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: OB(O)Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)(OCCCc1ccccc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
329 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-isopropoxypropionate was dissolved in 4 ml toluene. 110 mg of 4-fluorophenylboric acid, 74 mg of tetrakistriphenyl phosphine palladium and 440 mg of potassium carbonate were added, followed by stirring overnight at 100° C. in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, filtered through Celite and the filtrate was evaporated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (6:1), 262 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-(4-fluorophenyl)phenylpropoxypropionate was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](=[NH:22])[NH:20][OH:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=O)=[CH:27][CH:26]=1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]([C:19]3[N:22]=[C:32]([CH2:31][C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[O:21][N:20]=3)=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=N)NO)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(-c3noc(Cc4ccc(OC)cc4)n3)cnc21

Procedure:
Prepared from Intermediate 138 and 4-methoxyphenylacetic acid using a similar process to that described for Example 189 using similar or the same number of moles of reagents and/or volumes of solvents. LCMS showed MH+=435; TRET=3.26 min
Reaction SMILES: NC1C2C(C3C=CC(N[C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=C(OC)C=3)=CSC=2C(C#CCCCCN2C(=O)C3C(=CC=CC=3)C2=O)=CN=1.[OH2:49].NN>C(O)C>[CH3:29][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:20]1[C:18]([OH:19])=[O:49]
Reactant: O
Reactant: COc1cc(-c2csc3c(C#CCCCCN4C(=O)c5ccccc5C4=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: NN
Solvent: CCO
Product: Cn1c(C(=O)O)cc2ccccc21
Temperature: 50 °C
Reaction time: 15 h
Yield: 33.6 %

Procedure:
A solution of N-(4-{4-amino-7-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hex-1-ynyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.078 g, 0.119 mmol) in ethanol (5 mL) was treated with hydrazine monohydrate (0.048 g, 0.955 mmol). The reaction mixture was stirred for 15 hours at 50° C. The solvent was removed under reduced pressure. The compound was purified by preparative HPLC to afford 0.007 g (10%) the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.463 (s, 1H), 8.05-7.98 (m, 1H), 7.94 (s, 1H), 7.65-7.6 (m, 1H), 7.561-7.519 (m, 2H), 7.304-7.265 (m, 2H), 7.124 (s, 1H), 7.104-7.084 (m, 1H), 7.046-7.021 (m, 1H), 5.736 (brs, 2H), 3.99 (s, 3H), 3.867 (s, 3H), 2.7-2.6 (m, 2H), 2.58-2.5 (m, 2H), 1.6 (m, 4H); LCMS (Conditions a) 12, 3.45 min (95%), M+ 524.6.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH2:32][CH:28]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ncn(C2CCNC2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Nc1c(F)c(N2CCC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 95 °C
Yield: 60 %

Procedure:
To a suspension of 60 mg (0.2 mmol) of 5-amino -1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline -3-carboxylic acid and 80 mg of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 3 ml of dry pyridine under nitrogen was added 140 mg (0.9 mmol) of DBU, and the suspension was heated at 95° C. for 22 h. The resulting orange solution was then evaporated to dryness, water was added to the residue, and the orange solid was collected and washed with methanol to give 50 mg (60%) of yellowish solid after drying in vac-oven, m.p. 240.3°-242-3° C. 1H NMR (TFA) δ: 9.8 (s, 1H), 9.14 (s, 1H), 8.77 (s, 1H), 5.78-5.55 (m, 1H), 4.76-4.12 (m, 5H), 2.9-2.65 (m, 2H), 1.65-1.2 (m, 4H). Anal. calcd. for C19H18F 2 N6O3 : C, 54.81; H, 4.36; N, 20.17. Found: C, 54.52; H, 4.44; N, 20.00.
Reaction SMILES: [CH3:1][C:2]12[CH2:14][CH:6]3[C:7]([CH3:13])([CH3:12])[C:8]([CH3:11])([C:9]1=[O:10])[CH:5]3[CH2:4][CH2:3]2.[CH3:15][Mg]Cl>>[CH3:1][C:2]12[CH2:14][CH:6]3[C:7]([CH3:13])([CH3:12])[C:8]([CH3:11])([C:9]1([CH3:15])[OH:10])[CH:5]3[CH2:4][CH2:3]2
Reactant: C[Mg]Cl
Reactant: CC12CCC3C(C1)C(C)(C)C3(C)C2=O
Product: CC12CCC3C(C1)C(C)(C)C3(C)C2(C)O

Procedure:
Prepared from 5,7,8,8-tetramethyl-tricyclo[3.3.1.02,7]nonan-6-one by reaction with methyl magnesium chloride.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@@H:3]1[O:17][CH3:18].O=[CH:20][CH2:21][CH2:22][NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].C(O)(C(F)(F)F)=O>>[CH:26]1([C:24]([NH:23][CH2:22][CH2:21][CH2:20][NH:1][C@H:2]2[C:11]([CH3:13])([CH3:12])[C:10]3[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=3[CH2:4][C@@H:3]2[O:17][CH3:18])=[O:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=CCCNC(=O)C1CCCCC1
Reactant: CO[C@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@@H]1N
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@@H]1NCCCNC(=O)C1CCCCC1

Procedure:
Following the process of Example 11(c) using (6S,7S)-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide and cyclohexanecarboxylic acid (3-oxo-propyl)-amide the TFA salt of the title compound was prepared. (m/z): [M+H]+ calcd for C24H37N3O3, 416.28; found, 416.6.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:22]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]O)=[CH:26][CH:25]=1)#[N:23]>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Sc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(C#N)cc2)cc1)Sc1ccccc1

Procedure:
3-(4-Hydroxyphenyl)-2-phenylsulfanylpropanoic acid ethyl ester was reacted with p-cyanophenethyl alcohol using the same method as in Example 38(c) to give 3-{4-[2-(4-cyanophenyl)ethoxy]phenyl}-2-phenylsulfanylpropionic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=O)[CH2:23][CH:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25]1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:22]([CH2:23][CH:24]2[CH2:25][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27]2)=[N:21][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (1.0 g, 1.99 mmol) in DCM (20 mL) was added pyridine (1.5 mL). (CF3SO2)2O (1.4 g, 4.97 mmol) was added slowly at −10° C. The reaction mixture was stirred at 0° C. for 1 h. Sat. NaHCO3 was added at 0° C. very slowly. The organic layer was separated and the water layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10˜50% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutylcarbamate (0.7 g, 48%) as a slight yellow solid. ESI-MS (EI+, m/z): 484.0 [M-+H]+.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=[O:18]>C1C=CC=CC=1.CO>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([O:19][CH3:1])=[O:18]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyldiazomethane (2M in hexanes, 5.0 mL, 10.0 mmol) was added to a solution of 3-(2-bromophenyl)propionic acid (1.376 g, 6.00 mmol) in anhydrous benzene (28 mL) and anhydrous methanol (8 mL). The reaction mixture was stirred at room temperature for 2 h, and then the volatiles were removed in vacuo, to yield crude methyl 3-(2-bromophenyl)propionate which was carried forward without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#N.[OH2:13]>C(O)=O>[CH3:12][NH:11][C:4]1[C:3]([CH:1]=[O:13])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: CNc1nc(SC)ncc1C#N
Reactant: O
Solvent: O=CO
Product: CNc1nc(SC)ncc1C=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4.00 g (0.022 mol) of 5-cyano-4-methylamino-2-methylsulfanyl-pyrimidine (from Example 3) in 150 mL of 50% aqueous formic acid was reacted with 6.0 g of water-wet Raney Nickel. The mixture was stirred at 25° C. for 12 hours. The solids were filtered and washed with 40 mL of 50% aqueous formic acid. With ice bath cooling, a cold saturated solution of potassium carbonate was added slowly to the green filtrate until complete precipitation of a solid was achieved (pH is still acidic; pH about 5). The solid was extracted into 200 mL of ethyl acetate, and the solution was dried (potassium carbonate), filtered, and concentrated; wt 2.30 g (57%), mp 98°-100° C.; tlc (1:1 hexane:ethyl acetate) one spot Rf 0.5;
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[C:13]([Cu])#N.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)c1cccnn1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 168.4 %

Procedure:
To a solution of compound 2 (100 mg, 0.22 mmol) in DMF (10 mL) was added CuCN (40 mg, 0.44 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) under N2 at room temperature. The resulting mixture was stirred 30 min at 180° C. in a microwave reactor. Water (15 mL) was added and the mixture was extracted with EtOAc (3×20 mL), and the combined organic layers were dried over Na2SO4 and concentrated to give the residue which was purified by preparative TLC on silica gel (petroleum ether:ethyl acetate=5:1) to give compound 3 (46 mg, 52%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2cnccn2)co1

Procedure:
The title compound was prepared by a method analog to that described in Example 14 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyrazine. The title compound (2 mg) was obtained as a pale solid, m/z 327 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH2:9])=[O:5].[N+:11]([O-])([OH:13])=[O:12]>C(OCC)C>[O:1]([CH:2]([CH3:10])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH2:9])=[O:5])[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC(O)CC(=O)NCCN
Solvent: CCOCC
Product: CC(CC(=O)NCCN)O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
30 g. 2-(3-Hydroxybutanoylamino)-ethylamine are slowly introduced, with stirring at 5° to 10° C., into 100% nitric acid. After stirring for 2 hours at 0° to 5° C., the reaction solution is stirred into 1 liter of ice-cooled anhydrous diethyl ether, the supernatant ethereal layer is decanted off, the separated oil is covered with methylene chloride and the base is liberated with sodium carbonate. After suction filtration and evaporation in a vacuum at a maximum bath temperature of 20° C., there are obtained 33 g. (84% of theory) of base in the form of an oil.