Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:11]([C:17]([O:19]CC)=O)[C:12]([O:14]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-]CC.[Na+].[NH2:26][C:27]([NH2:29])=[O:28]>C(O)C>[CH2:1]([CH:11]1[C:12](=[O:14])[NH:29][C:27](=[O:28])[NH:26][C:17]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NC(N)=O
Reactant: CCCCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCC1C(=O)NC(=O)NC1=O

Procedure:
To a solution of diethyl decylmalonate of step a) in 40 ml of ethanol are added 2.72 g of sodium ethoxide and then 1.8 g of urea. The reaction mixture is refluxed for 2 hours, then the precipitate is filtered and redissolved in 40 ml of water. The resulting aqueous solution is acidified with 6 N hydrochloric acid. The solid which separates is recovered by filtration and dried under vacuum at 40° C. overnight, to give 2.152 g of the product, m.p. 190° C.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: Nc1cccs1
Product: CCOC(=O)C(=CNc1cccs1)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)3-ethoxyacrylate (5.0 g)and 2-aminothiophene (2.22 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2-thienyl)aminoacrylate, which is then treated with 60% sodium hydride as in Reference Example 22 to give ethyl 1-(2-thienyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.05 g), as white powder (recrystallized from ethyl acetate - n-hexane), m.p. 198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1>COCCOCCOC.[Pd]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:41][CH:42]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2ccc3c(c2)-c2c(nc(C)[nH]c2=O)CC3)cc1)C(=O)OCC
Agent: [Pd]
Solvent: COCCOCCOC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A solution of diethyl N-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxo-benzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate (0.50 g, 0.84 mmol) in diglyme (10 ml) was stirred with 10% palladium on carbon (0.25 g) (Aldrich) under nitrogen at reflux for 3 hours. The solution was diluted with diglyme (20 ml), filtered hot through celite, and concentrated under high vacuum. The resulting solid was suspended in hot methanol (50 ml), stirred overnight at room temperature, filtered, and dried under high vacuum to give diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate as a white solid (0.25 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, J=7 Hz, 3H, esterCH3), 1.12 (t, J=7 Hz, 3H, esterCH3), 1.78-2.15 (m, 2H, gluCH2), 2.35 (t, J=7 Hz, 2H, gluCH2), 2.4 3 (s, 3H, C3—CH3), 3.98 (q, J=7 Hz, 2H, esterCH2), 4.04 (q, J=7 Hz, 2H, esterCH2), 2.35-4.39 (m, 1H, gluCH), 7.21 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 7.76 (d, J=9 Hz, 1H, Ar), 7.91 (dd, J=9, 2 Hz, 1H, Ar), 8.19 (d, J=9 Hz, 1H, Ar), 8.29 (d, J=9 Hz, 1H, Ar), 8.51 (d, J=7 Hz, 1H, gluNH), 10.44 (d, J=2 Hz, 1H, Ar), 10.88 (br s, 1H, SO2NH), 12.75 (br s, 1H, N H). Mass spectrum (CI-CH4): 595 (M+1, 24.1%). Anal. Calculated for C29H30N4O8S: C, 58.58; H, 5.08; N, 9.42; S. 5.39. Found: C, 58.46; H, 5.10; N, 9.34; S. 5.41.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:31])([F:32])[F:30])=[CH:28][C:3]=3[C:2]([F:1])([F:34])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [ClH:1].C(O/[CH:5]=[C:6]1\[C:7](=O)[C:8]2[C:13]([O:14][C:15]3\1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2)C.[CH3:22][NH:23][NH2:24]>C(O)C>[ClH:1].[CH3:22][N:23]1[CH:5]=[C:6]2[C:15]3([O:14][C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:7]2=[N:24]1)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3
Reactant: CCO/C=C1\C(=O)c2ccccc2OC12CCNCC2
Reactant: CNN
Agent: Cl
Solvent: CCO
Product: Cn1cc2c(n1)-c1ccccc1OC21CCNCC1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
(Z)-3-(Ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (2.46 g, 7.94 mmol) in ethanol (24.6 mL) was treated with methylhydrazine (423 μL, 7.94 mmol). The reaction mixture was heated at 70° C. for 1 h and then at 100° C. for 10 min. The mixture was allowed to cool to room temperature overnight. The yellow solid was filtered off and was washed with ethanol to give 2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] hydrochloride (1.20 g, 74%). ESI-MS m/z calc. 255.1, found 256.3 (M+1)+; Retention time: 0.65 minutes. 1H NMR (400 MHz, DMSO) δ 9.01 (s, 2H), 7.75 (s, 1H), 7.61 (dd, J=7.5, 1.2 Hz, 1H), 7.28-7.20 (m, 1H), 7.10-6.99 (m, 2H), 3.89 (s, 3H), 3.28-3.18 (m, 4H), 2.18-2.02 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([CH3:17])=[N:11][N:12]([CH2:15][CH3:16])[C:13]=2[OH:14])=[O:8])=[C:5]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]#N>O>[S:20]([C:32]1[CH:33]=[CH:2][C:3]([CH3:19])=[CH:4][CH:5]=1)([O:14][C:13]1[N:12]([CH2:15][CH3:16])[N:11]=[C:10]([CH3:17])[C:9]=1[C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:4][C:5]=1[S:20]([CH3:23])(=[O:22])=[O:21])(=[O:22])=[O:21]
Reactant: CC#N
Reactant: CCn1nc(C)c(C(=O)c2ccc(C(F)(F)F)cc2S(C)(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1nc(C)c(C(=O)c2ccc(C(F)(F)F)cc2S(C)(=O)=O)c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.37 g (1 mmol) of 4-(4-Trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy-1-ethyl-3-methylpyrazole and 0.20 g (1.1 mmol) of p-Tos-Cl were dissolved in 20 ml of CH3CN. 0.26 g (1.8 mmol) of potassium carbonate was then added, and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried with MgSO4 and concentrated. This gave 4-(4-Trifluoromethyl-2-methylsulfonylbenzoyl)-l-ethyl-3-methyl-5-pyrazolyl tosylate as a wax.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([NH:11][NH2:12])[N:8]=[N+:9]([O-:10])[C:4]=2[CH:3]=1.[CH2:15](OC(OCC)OCC)C>C(O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]3[CH:15]=[N:12][N:11]=[C:7]3[N:8]=[N+:9]([O-:10])[C:4]=2[CH:3]=1
Reactant: NNc1nc2ccc(Br)cc2[n+]([O-])n1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: [O-][n+]1nc2nncn2c2ccc(Br)cc21
Temperature: 145 °C
Yield: 65.4 %

Procedure:
A mixture of 7-bromo-3-hydrazino-1,2,4-benzotriazine 1-oxide (1 g, 3.91 mmol) and 1,1,1-triethoxymethane (6.24 g, 42.08 mmol) was heated to 145° C. for 3 h, and the ethanol formed during the reaction was continuously distilled off. After cooling in a refrigerator for 12 h, the solid filtered off and washed with ether to give 7-bromo[1,2,4]triazolo[3,4-c][1,2,4]benzotriazine-5-oxide, (Compound Number 5, 0.68 g, 63% yield), 1H-NMR (300 MHz; DMSO): 9.95 ppm (s,1H, H-1); 8.60 ppm (d,1H, H-6); 8.47 ppm (d, 1H, H-9) and 8.38 ppm (dd,1H, H-8).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][C:12]1([F:15])[F:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][C:12]2([F:15])[F:14])=[CH:4][N:3]=1
Reactant: FC1(F)CC1CBr
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC1(F)CC1COc1ccc(Br)nc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
The mixture of 5.00 g (28.7 mmol) of 2-bromo-5-hydroxypyridine, 6.14 g (35.9 mmol) of 1-bromomethyl-2,2-difluorocyclopropane and 9.93 g (71.8 mmol) of K2CO3 in 100 ml ACN is stirred at 70° C. for 14 h. The reaction mixture is diluted with EtOAc, washed with water and 1N aq. NaOH, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(C)=O)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and acetyl chloride, there is obtained ethyl N-acetyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 308 (2), 279 (25), 194 (100);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:19]=[C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:18])[C:12]2=[N:11]1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:19]=[C:13]2[CH:14]=[N+:15]([O-:28])[CH:16]=[C:17]([F:18])[C:12]2=[N:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(F)cc3Cl)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichloro-4-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (3.37 g, 11.2 mmol) in DCM (50 mL) under nitrogen, was added mCPBA (2.9 g, 16.8 mmol). The reaction mixture was stirred at 0° C. for 2 hours, warmed to room temperature, and stirred for a further 5 hours. The reaction was washed with sodium thiosulfate (sat. aq.), sodium hydrogen carbonate (sat. aq.), and brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to afford the title compound as an off-white solid (2.98 g, 84% yield). LCMS (Method D): RT=2.48 min, m/z: 316 [M+H+].
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([OH:36])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([OH:36])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH2:14].[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: NCCCc1c(Br)ccc2c1CCO2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCCc1c(Br)ccc2c1CCO2
Reaction time: 8 h

Procedure:
A solution of 3-(5-bromo-2,3-dihydro-benzofuran-4-yl)-propylamine (256 mg) in pyridine (3 ml) at 40 was treated with acetic anhydride (0.11 ml) and the solution stored overnight at 4°. The cold solution was acidified with 2N hydrochloric acid and the mixture extracted with ethyl acetate. The extracts were dried and evaporated and the residue chromatographed on silica (20 g) using dichloromethane:methanol:ammonia (100:8:1) to give the title compound as an oil which slowly solidified (175 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[I:23]I.O>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:16])=[CH:14][C:15]=1[I:23])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: II
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(F)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
Add a solution of [1-(6-fluoro-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (9.3 g, 38.8 mmol) in dry THF (90 mL) into tert-butyllithium (68.4 mL, 116.3 mmol, 1.7 M solution in pentane) in dry THF (70 mL) over 15 min under N2 at −78° C. Stir at −78° C. for 1 hour. Add a solution of iodine (14.8 g, 58.2 mmol) in dry THF (90 mL) over 15 min. Stir at −78° C. for 2 hours. Warm up to 0° C. Add water. Warm up to room temperature. Extract with ethyl acetate. Wash the organic layer with Na2CO3 solution, water and saturated aqueous sodium chloride, and dry over MgSO4. After filtration, concentrate and purify the crude by flash chromatography (5% to 20% ethyl acetate/hexane). Afford the desired product [1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (2.8 g, 20%), MS (ES) m/z 367 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]1([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:20][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
An equimolar mixture of 25.0 g (0.18 mol) 4-methoxybenzaldehyde and 28.3 g (0.18 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. The reaction mixture was cooled first to room temperature and then in a refrigerator to 10° C. The precipitated solid was then filtered off and dried under vacuum. Yield: 37.6 g (74.3%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.13 (d, 2H); 7.69 (m, 2H); 7.77 (d, 1H); 7.96 (d, 2H); 8.04 (d, 2H); 9.11 (s, 1H); 13C-NMR (400 MHz, DMSO-d6): δ [ppm]=55.6; 114.7; 124.9; 127.5; 129.6; 133.8; 134.0; 138.8; 165.0; 170.8.
Reaction SMILES: [C:1]([O:7][CH:8]([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>>[CH2:13]([O:12][CH:11]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:14]
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(=O)OC(C)C

Procedure:
From isopropyl acetoacetate (28.8 g, 0.20 mol) which can be made by the process described by Lawesson etal., Organic Synthesis, Coll. Vol. V, 155-157 (1973), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 14.3 g, 35.7%; bp=85°-90° C. at 0.20 mm Hg; NMR (CDCl3) δ 1.3-1.6 (m, 9H), 2.3-2.6 (d, 3H), 4.1-4.5 (m, 2H), 5.0-5.4 (m, 1H), 7.6-7.8 (d, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=[CH:47][C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: OB(O)c1c(F)cccc1C(F)(F)F
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4C(F)(F)F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-(trifluoromethyl)phenyl)boronic acid gave 279. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.90 (s, 1H), 7.84-7.68 (m, 3H), 7.47 (s, 2H), 5.03 (t, J=5.2 Hz, 1H), 3.71-3.52 (m, 5H), 3.29-3.13 (m, 2H), 2.72 (s, 3H), 2.48-2.40 (m, 1H), 1.63-1.47 (m, 5H). LCMS (ES+) m/z 529 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].[CH3:25][S:26][CH2:27][CH2:28]Cl>CN(C=O)C.C(OCC)C.Cl>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:28][CH2:27][S:26][CH3:25])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Reactant: CSCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSCCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 100 °C
Reaction time: 144 h

Procedure:
26.7 g of 5-{[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone (i.e., the compound of Example 2) was dissolved in 418 ml of DMF to which was added 3.34 g of a 60% sodium hydride dispersion. The resultant mixture was stirred at 100° C. under an argon atmosphere. To this was added 8.33 ml of methylthioethyl chloride and the resulting black solution was stirred at 100° C. for 6 days. The material was allowed to cool to 30° C. after which insoluble material was filtered off. The solid was washed with DMF until its color was gone leaving a white solid which was discarded. The pH of the filtrate and washings was adjusted to 1.5 by the addition of 1N hydrochloric acid with stirring. The mixture was then diluted with a mixture of 1000 ml of diethyl ether and 500 ml of 1N hydrochloric acid which was then shaken and separated. The organic layer was washed with two portions of water and one portion of brine and subsequently dried over sodium sulfate, filtered, evaporated and chased with chloroform to give a black foam/oil. This material was triturated with about 75 ml of chloroform and then filtered and the insoluble solid was washed with additional chloroform until its brown color was gone. The filtrate was then loaded onto a silica gel column which was eluted with 8000 ml of a gradient of 10-30% ethyl acetate in hexane. The various fractions containing the desired product were combined and again loaded onto a silica gel column and eluted with 8000 ml of a gradient of 10-35% acetone in hexane. The fractions containing the desired product were recrystalled with hexane/ethyl acetate to give 1.2 g of the title compound as a tan/orange solid, m.p. 165.5°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[Br:13].Br[CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17])=[CH:7][C:6]=2[Br:13]
Reactant: Oc1cc(Br)c2ncc(Br)cc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cc(Br)c2ncc(Br)cc2c1

Procedure:
In a similar procedure, 3,8-dibromo-6-hydroxyquinoline was reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide to give 2-(3,8-dibromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide as a colourless gum, 1H NMR (CDCl3) δ: 1.07(3H, t);1.59 (3H, s); 1.60(3H, s); 1.78(3H, s); 1.99-2.06(2H, m); 4.52(1H, t); 6.30(1H, s); 7.00(1H, m); 7.82(1H, dd); 8.21(1H, d); 8.88(1H, m).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([C:27]([SH:30])([CH3:29])[CH3:28])[NH2:26]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([C:18]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:31])[C:27]([SH:30])([CH3:29])[CH3:28])=[O:20])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: Cl
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C)C(C)(C)S

Procedure:
The title compound was synthesized by coupling Nα -Boc-(p-chloro) phenylalanine (4.96 g, 16.5 mmol) to 3.6 g (18.2 mmol) of D-penicillamine methylester hydrochloride using the procedure described above in Example 19. The title compound was obtained as a white solid (6.2 g, 84.5%).