Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+]>>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N+:14]=[N-:15]
Reactant: O=C(O)CCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCCCCCCCCC(=O)O

Procedure:
Reaction of 9-bromononanoic acid and NaN3, as described for the synthesis of 6, gave 5-azidobutanoic acid 12. Saponification was not necessary. Used without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:14]([CH2:13][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:15](=[O:16])[N:17]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: O=C(NCC1CCCCC1)NCC1CCCCC1
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
Cyanoacetic acid (Aldrich, 21.0 g) was dissolved in acetic anhydride (260 ml). This solution was added to 1,3-bis(cyclohexylmethyl)urea (from step (a), 54.5 g) and the solution maintained at 80° C. for 2 h under nitrogen. Volatiles were removed in vacuo and the residual oil dried by evaporation of portions of 10% water-ethanol (3×400 ml). The residual solids were dissolved in ethanol (600 ml)water(300 ml) at 80° C. with adjustment of the pH to 10 by addition of 10% aqueous sodium carbonate. The hot solution was diluted with water (75 ml) and cooled to ambient temperature. The colorless crystals which formed were filtered off, washed with water and dried at 0.5 Torr to give 6-amino-1,3-bis(cyclohexylmethyl)uracil (64.98 g, 94%), m.p. 138-141° C.; 1H-NMR (DMSO-d6) δ: 6.73 (br s, 2, NH2), 4.63 (s, 1, H-5), 3.67 (d, J=7.3 Hz, 2, NCH2), 3.57 (d, J=7.3 Hz, 2, NCH2), 1.55 and 1.09 (both m, 22, 2 cyclohexyl).
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]3[N:39]=[C:40]([NH:43]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:41][CH:42]=3)=[N:17]\[O:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:12](=[O:64])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].[C:66]([CH2:69][S:70][C:71]1[S:72][C:73]([SH:76])=[N:74][N:75]=1)(=[NH:68])[NH2:67]>CN(C=O)C>[C:66]([CH2:69][S:70][C:71]1[S:72][C:73]([S:76][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]4[N:39]=[C:40]([NH2:43])[S:41][CH:42]=4)=[N:17]\[OH:18])[C:12](=[O:64])[N:7]3[C:8]=2[C:9]([OH:11])=[O:10])=[N:74][N:75]=1)(=[NH:67])[NH2:68]
Reactant: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reactant: N=C(N)CSc1nnc(S)s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N=C(N)CSc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)s1
Yield: 27.2 %

Procedure:
To a solution containing 906 mg of sodium 3-hydroxymethyl-7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-trityloxyiminoacetamido]-3-cephem-4-carboxylate and 309 mg of 2-amidinomethylthio -5-mercapto-1,3,4-thiadiazole in 7 ml of DMF was added 1.01 g of ethyl o-phenylenephosphate under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 4 hours and subjected to a column chromatography on silica gel (100 g), being washed with acetone and eluted with acetone/water (9:1). The eluate was concentrated to dryness under reduced pressure, and there was added 20 ml of formic acid. The mixture was stirred at room temperature for 16 hours and then distilled to remove formic acid. To the residue was added a mixture of water and THF. The solution was washed with ethyl acetate, concentrated under reduced pressure and then subjected to a column chromatography on XAD-II (140 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated to 10 ml and the resultant precipitate was collected by filtration to give 160 mg of the title compound as pale yellow crystals.
Reaction SMILES: [H-].[Na+].I[CH3:4].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]2[C:19]([CH:20]=[CH:21][C:22]=1[CH2:23][OH:24])=[C:18]([C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32])[C:17](=[O:33])[CH:16]=[CH:15]2>C1COCC1>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]2[C:19]([CH:20]=[CH:21][C:22]=1[CH2:23][O:24][CH3:4])=[C:18]([C:25]1[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=1[F:31])[C:17](=[O:33])[CH:16]=[CH:15]2
Reactant: CI
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)c(CO)ccc2c1-c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
Oil free sodium hydride suspended in THF was added iodomethane (0.06 mL) and 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-7-(hydroxymethyl)-2H-quinolizin-2-one (Example 50, 40 mg) at 0° C. The mixture was warmed to room temperature and stirred for a couple of hours until reaction complete. The mixture was quenched with water, extracted with ethyl acetate, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (100% acetone) to give the title compound (22 mg).
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.CCN(C(C)C)C(C)C>CCO>[Br:15][C:16]1[C:17]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)C(C)(C)CNC1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C)(C)CN(c1nc(Cl)ncc1Br)C1CCCC1
Yield: 23.4 %

Procedure:
3-(cyclopentylamino)-N,2,2-trimethyl-propanamide (665 mg, 3.353 mmol) and 5-bromo-2,4-dichloro-pyrimidine (666 mg, 373.7 μL, 2.921 mmol) were dissolved in EtOH (10 mL) and DIPEA (511.4 mg, 691.9 μL, 3.957 mmol) was added. The reaction was allowed to stir at reflux temperature overnight. The solvent was removed in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc/Petrol) to give the sub-title product as a brown oil (266 mg, 23%); 1H NMR (400.0 MHz, DMSO) d 1.03 (s, 6H), 1.54-1.83 (m, 8H), 2.57 (s, 3H), 3.68 (s, 2H), 4.23 (quin, 1H), 7.53 (d, 1H), 8.63 (s, 1H); MS ES(+) 391.0, ES (−) 389.0.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C@@:6]([CH3:12])([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:8].C[C@]([N+]([O-])=O)([C@@H](O)C)CO>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C@@:6]([CH3:12])([C@@H:9]([OH:11])[CH3:10])[CH2:7][OH:8]
Reactant: C[C@@H](O)[C@](C)(N)CO
Agent: C[C@H](O)[C@@](C)(CO)[N+](=O)[O-]
Solvent: CC(=O)O
Product: C[C@H](O)[C@](C)(N)CO
Yield: 93.5 %

Procedure:
Using the procedure described for 32E, (±)-(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (32A, 41.1 g, 0.276 mol) gave 46.12 g (93.5%) of (±)-(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate, mp 163°-165°, (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CN1CCCC1=O>>[CH2:21]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1Cl
Temperature: 120 °C
Yield: 86 %

Procedure:
A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4.63 mmol), dibenzylamine (913 mg, 890 μL, 4.63 mmol), triethylamine (1.2 mL, 8.61 mmol) and 1-methyl-2-pyrrolidone (6 mL, 62.22 mmol) was heated at 120° C. for 9 h. The reaction mixture was cooled to the room temperature and poured into ice-water, extracted with EtOAc (20 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by silca gel column chromatography (2%-10% EtOAc in petroleum ether as eluant) to give N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (1.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.7 Hz, 1H), 7.37-7.21 (m, 10H), 6.32 (d, J=8.7 Hz, 1H), 4.80 (s, 4H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])OC.[BH4-].[Na+]>CO>[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH:27][CH2:1][C:3]2[S:7][C:6]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: NCCc1cccc(F)c1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)s2)cc1
Agent: COC([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccc(F)c3)s2)cc1
Reaction time: 3 h

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzamide (90 mg, 0.36 mmol) from Example 1, part B, method B, with 2-(3-fluoro-phenyl)-ethylamine (61 mg, 0.44 mmol), methyl orthoformate (0.48 mL) and methanol (0.7 mL). Stir the resulting mixture for 3 hours and then add sodium borohydride in portions. Stir the reactiom misture until the reaction is complete by TLC or HPLC analyses. Then, concentrate to remove the methanol. Partition the resulting residue between H2O (4 mL) and CH2Cl2 (6 ml). Dry the organic layer over sodium sulfate, filter and concentrate. Purify through flash chromatography [CH2Cl2/Ammonia (2.0 M in methanol) 20/1] to provide the title compound. 1H NMR (CDCl3): 7.72 (d, J=8.7 Hz, 2H), 7.21-7.13 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 6.92-6.80 (m, 3H), 6.56 (d, J=3.6 Hz, 1H), 6.36 (d, J=3.7 Hz, 1H), 5.82 (bs, 2H), 3.83 (s, 2H), 2.87 (t, J=6.5 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17]1)=[O:15])[CH3:12].Cl>C(O)C.O1CCOCC1>[CH2:11]([O:13][C:14]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CC(=O)c2cc(N)ccc21
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1CC(=O)c2cc(Nc3ncccc3[N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.48 g, 9.03 mmol), (R/S)-5-Amino-3-oxo-indan-1-carboxylic acid ethyl ester (1.98 g, 9.03 mmol) and 4M HCl in dioxane (2.3 mL, 9.0 mmol) in ethanol (15 mL) is refluxed for 9 h. The reaction mixture is left at rt overnight then a further equivalent of 4M HCl in dioxan is added. After 4 h refluxing, the solvent is evaporated and the crude mixture purified by MPLC eluting with EtOAc/Hexane to give (R/S)-5-(3-Nitro-pyridin-2-ylamino)-3-oxo-indan-1-carboxylic acid ethyl ester as a red solid. Title compound: ES-MS: 342.19 [M+H]+, tR=1.6 min (System 2)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O1CCCC1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:20]([O:19][C:17]([C:9]1[N:10]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c(Nc2ccncc2)c2ccccc21
Temperature: 0 °C
Yield: 50 %

Procedure:
Under nitrogen, stir and cool to 0° C. a mixture of ethyl 3-(4-pyridinylamino)indole-2-carboxylate (see U.S. Pat. No. 5,328,920; 0.20 g, 0.711 mmol) in dimethylformamide (5 mL). Add a 1M solution of potassium tert-butoxide in tetrahydrofuran (0.75 mL, 0.75 mmol) in one portion, stir for 10 min, and then add ethyl bromoacetate (0.12 g, 0.72 mmol) in one portion. Stir at 0° C. for 50 min and quench the reaction into water (30 mL). Extract the aqueous mixture with ethyl acetate (2×20 mL), combine the extracts, wash with water (25 mL), brine (25 mL) and dry over MgSO4. Concentrate under vacuum, chromatograph the residue on a Redisep silica gel cartridge (10 g) eluting with 5% methanol/dichloromethane to 20% methanol/dichloromethane. Combine non-homogeneous fractions concentrate and chromatograph again as above. Combine all homogenous fractions and concentrate to obtain 0.13 g (50%) of the title compound as a white solid: MS 368(M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCOCC1
Solvent: CO
Solvent: O
Product: COC(=O)C1CCOCC1
Yield: 15 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (50 g, 385 mmol) in anhydrous methanol (500 mL) was added 4-methylbenzenesulfonic acid hydrate (72.5 g, 385 mmol). The mixture was refluxed for 2 hr. The solvent was removed in vacuo. Ethyl ether and water was added. The organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (8.3 g, 75%) which was used in next step without purification.
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=CC=1C)C.[CH2:19]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]1[O:30]C(C)=C(CCO)N=1)[CH3:20].C(I)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH:29]=[O:30])[CH3:20]
Reactant: CCOc1cc(F)ccc1-c1nc(CCO)c(C)o1
Agent: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1C=O

Procedure:
In analogy to the procedure described in example 7 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared from 4-fluoro-2-hydroxy-benzaldehyde [J. Chem. Soc., Perkin Trans. 1 (1994), (13), 1823-31] by i) treatment with ethyl iodide, potassium carbonate in N,N-dimethylformamide to give 2-ethoxy-4-fluoro-benzaldehyde; ii) conversion of 2-ethoxy-4-fluoro-benzaldehyde into 4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole in analogy to the procedures described in examples 2 a] and b]; iii) conversion of 4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole into 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol by treatment with sodium cyanide in DMSO followed by hydrolysis of the nitrile function with sodium hydroxide in ethanol/water at reflux and reduction of the acid formed with BH3×THF in tetrahydrofuran at room temperature) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester as light yellow liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]CC)=O.CC(C)([O-])C.[K+].[C:17](#[N:19])[CH3:18].O>C(Cl)Cl>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][C:17]#[N:19]
Reactant: CC#N
Reactant: CCOC(=O)c1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CCC(=O)c1cccs1

Procedure:
A 67 ml. portion of ethyl 2-thiophenecarboxylate is added to 56 g. of potassium t-butoxide (exothermic). After cooling, 33 ml. of acetonitrile is added and the mixture is stirred and heated on a steam bath for 1.5 hours. A 250 ml. portion of water is added followed by 200 ml. of methylene chloride. The mixture is stirred overnight. The aqueous layer is separated and combined with 42 ml. of concentrated hydrochloric acid. This mixture is extracted with 300 ml. of methylene chloride followed by two 100 ml. portions of methylene chloride. The combined extracts are then washed with 200 ml. followed by 100 ml. of 10% sodium bicarbonate. The extracts are dried over sodium sulfate and passed through magnesol. The filtrate is combined with hexanes and evaporated giving crystals of β-oxo-2-thiophenepropionitrile.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:4][CH2:5][C:6]1([CH2:7][CH2:8][CH:9]=[CH2:10])[O:14][CH2:13][CH2:12][O:11]1)(=[O:3])[CH3:2]
Reactant: C=CCCC(=O)COC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCCC1(COC(C)=O)OCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 15.6 g. (0.1 mole) of 1-acetoxy-5-hexen-2-one, 18.6 g. (0.3 mole) of ethylene glycol in 250 ml. of benzene containing 1.56 g. of p-toluene sulfonic acid monohydrate is heated to reflux using a Dean-Stark water separator. After 2 hours, the reaction mixture is shaken well with 250 ml. of cold water. The aqueous layer is washed with 3×25 ml. of ether. The combined organic layers are dried over anhydrous magnesium sulfate. Evaporation of the solvent gives 2-acetoxymethyl-2-(3-buten-1-yl)-1,3-dioxolane in 90% yield as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[C:28](N=C(N(C)C)N(C)C)([CH3:31])([CH3:30])[CH3:29].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)[CH2:29][CH:28]([CH3:31])[CH3:30])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)n1
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1cc(C)nc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (100 mg, 0.257 mmol) in acetonitrile (5 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.054 mL, 0.257 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.056 mL, 0.515 mmol) added. The reaction was then heated by microwaves to 150° C., for 25 minutes. After cooling the solvent was removed under a stream of nitrogen and the crude sample purified by mass directed autoprep (formic acid modifier). The solvent was removed under a stream of nitrogen to give the title product (11.7 mg) as a yellow oil which solidified. LCMS (2 min, formic) Rt 1.31 min, m/z (ES+) 445 (M+H).
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:12][CH:11]=1)C.[NH3:29]>>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][NH:6][CH2:5][C:4](=[O:28])[NH2:29])=[CH:15][CH:14]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: N
Reactant: CCOC(=O)CNCCOc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2 (0.27 g, 0.685 mmol) dissolved in 7 N methanolic ammonia (25 mL) was stirred in a sealed tube at room temperature overnight. After this time, TLC analysis indicated that the reaction was complete. The reaction mixture was concentrated and further dried under vacuum to afford the desired product 3 (0.25 g, quantitative yield) as a yellow viscous oil which was used directly without further purification. m/z (ESI) 366.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:26](O)[CH2:27][CH2:28][CH:29]=[CH2:30]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:10])[C:11]([O:13][CH2:30][CH2:29][CH2:28][CH:27]=[CH2:26])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C=CCCCOC(=O)C(C)NC(=O)OC(C)(C)C

Procedure:
N-(t-Butoxycarbonyl)alanine (3.1 g, 1 eq) and DCM (50 mL) were added to a vessel with stirring followed by the addition of CDI (3.1 g, 1.15 eq). The mixture was stirred at ambient temperature for 18 h after which time 4-penten-1-ol (1.8 g, 1.25 eq) was added. The mixture was stirred a further 18 h at ambient temperature at which point the reaction was quenched with 1N HCl. A biphasic mixture was formed and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 solution and then concentrated to give pent-4-en-1-yl 2-((tert-butoxycarbonyl)amino)propanoate as an oil. The oil was dissolved in DCM (50 mL) and methanesulfonic acid (2.2 g, 1.4 eq) was added. The mixture was stirred at ambient temperature for ˜22 h then cooled in an ice/water bath. Ethyl 2-chloro-2-oxoacetate (3.4 g, 1.5 eq) was added followed by drop-wise addition of triethylamine (5.0 g, 3 eq). The mixture was stirred for 7 h after which time the reaction was quenched by 1N HCl to form a biphasic mixture. The layers were separated and the organic layer was washed with a saturated aqueous NaHCO3 solution. The organic layer was then concentrated under reduced pressure to provide pent-4-en-1-yl 2-(2-ethoxy-2-oxoacetamido)propanoate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.64 (d, J=6.94 Hz, 1H), 5.66-5.83 (m, 1H), 4.90-5.05 (m, 2H), 4.49-4.62 (m, 1H), 4.31 (qd, J=7.17, 2.26 Hz, 2H), 4.13 (td, J=6.59, 2.13 Hz, 2H), 2.02-2.14 (m, 2H), 1.67-1.78 (m, 2H), 1.44 (d, J=7.19 Hz, 3H), 1.34 (t, J=7.15 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 171.64, 159.94, 155.83, 136.94, 115.40, 64.98, 63.10, 48.40, 29.71, 27.44, 17.88, 13.80; HRMS (M+Na) m/z, calcd for C12H19NO5Na, 280.1161; found, 280.1166.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:29][C:26]2[CH:25]=[CH:24][C:23]([C@H:22]3[C:15]4=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]4[CH2:19][CH2:20][CH2:21]3)=[CH:28][CH:27]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: CCc1ccc(B(O)O)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1ccc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of (4-ethylphenyl)boronic acid (802 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg), and powdered 4A MS (5.00 g) in MeCN (18 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (132 mg) as a white solid.