Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[H-].[Na+].[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O.O.C(OCC)(=O)C.[I-].[K+]>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:39][CH:40]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (2.0 g, 6.8 mmol) in dry N,N-dimethylformamide (45 mL) was added sodium hydride (60% in mineral oil, 0.35 g, 8.8 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 1 h and 4-benzyloxybenzyl chloride (2.2 g, 9.4 mmol) was added in one portion, followed by potassium iodide (0.06 g, 0.34 mmol). The mixture was stirred at ambient temperature for 16 h and diluted with water (200 mL) and ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 25% to 35% gradient of ethyl acetate in hexanes to afford 1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (2.49 g, 75%) as a colorless solid: mp 87-89° C.; 1H NMR (300 MHz, CDCl3) δ 7.45-7.24 (m, 7H), 7.24-7.12 (m, 2H), 7.05-6.92 (m, 3H), 6.84-6.79 (m, 1H), 6.51 (s, 1H), 6.22 (s, 1H), 5.06-4.90 (m, 4H), 4.82-4.62 (m, 2H), 4.24-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.4, 158.4, 155.2, 144.6, 142.1, 138.3, 136.8, 132.3, 128.7 (2C), 128.6, 128.0 (2C), 127.5, 123.8, 123.3, 121.0, 115.2, 111.5, 109.3, 99.4, 80.2, 70.0, 64.5, 63.9, 58.0, 43.6; MS (ES+) m/z 492.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][OH:25])[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N(C)C(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C)C(=O)CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc1

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-(4-methoxyphenyl)-benzene propanamide (2.0 g) in CH2Cl2 (50 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.911 mL), and methanesulfonyl chloride (0.64 mL). After two hours the reaction mixture was washed with water (100 mL), brine (100 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.56 g).
Reaction SMILES: [S:1](=[O:3])=[O:2].[C:4]1([S:10][C:11]([Si](C)(C)C)([F:13])[F:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F-].[Cs+].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[S:1](=[O:3])=[O:2].[F:12][C:11]([F:13])([S:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[S:1]([F:21])(=[O:3])=[O:2]
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(C)C(F)(F)Sc1ccccc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S=O
Agent: [Cs+]
Solvent: CC#N
Product: O=S(=O)(F)C(F)(F)Sc1ccccc1
Temperature: 25 °C

Procedure:
A solution of sulfur dioxide was prepared by bubbling sulfur dioxide (3.9 g, 61 mmol) in a solution of anhydrous acetonitrile (20 ml) at ambient temperature. This solution was added to PhSCF2SiMe3 (4.3 g, 18.4 mmol, obtained according to the procedure from example 6) and stirred at ambient temperature under an inert atmosphere. Anhydrous CsF (2.8 g, 18.5 mmol) was then added to the reaction mixture, which was stirred at ambient temperature overnight. The reaction was monitored by TLC and by 19F NMR (CDCl3) until the disappearance of PhSCF2SiMe3. F-TEDA (7.15 g, 20 mmol) was added to the mixture, at −20° C., which was then stirred for 1 h at ambient temperature. The mixture was concentrated and the solid residue washed with ethyl ether (10×50 ml). The filtrate was evaporated and the product purified by bulb-to-bulb distillation. The product difluoro(phenylsulfanyl)methanesulfonyl fluoride was obtained in the form of a colorless liquid (2.5 g, 57%).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[C:18]([CH:23]3[O:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:17]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:17][C:18]=1[CH:23]1[O:24][CH2:25][CH2:26][CH2:27][O:28]1
Reactant: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(C3OCCCO3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(Oc1ccc(Br)c(C2OCCCO2)c1)c1ccc(C(=O)O)cc1
Reaction time: 4 h
Yield: 96.9 %

Procedure:
To the solution of 4-[1-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic acid methyl ester (1000 mg) in methanol (20 mL) is added sodium hydroxide (5 N aqueous, 2 mL) and stirred for 4 h. The reaction mixture is concentrated and acidified by 5 N HCl (2 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (940 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(C)=NC=2C2C=CC(Cl)=CC=2Cl)CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])[C:11]([CH3:30])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:32][CH2:16]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.75–1.13, 1.53–1.59, 2.31, 2.98–3.09, 3.35–3.40, 3.57–3.65, 4.23–4.25, 5.37, 5.62, 7.12–7.42; MS (ESI+) for C25H25Cl2N3O m/z 454 (M+H)+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[OH:16])[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[N:6]=[CH:7][CH:8]=[CH:9]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc2cccnc12
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc2cccnc12
Temperature: 25 °C
Yield: 54 %

Procedure:
Phosphorus oxychloride (0.58 mL, 1 equiv) and quinolin-8-ol (Aldrich, 900 mg, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (0.86 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min. The triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow syrup (870 mg, 54%). This crude product was used for next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[B:17]1(B2OC(C)(C)C(C)(C)O2)[O:21]C(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:16][S:13]([NH:12][C:4]1[CH:3]=[C:2]([B:17]([OH:21])[OH:18])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)(=[O:15])=[O:14]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(B(O)O)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 556.1 %

Procedure:
N-(3-Bromo-5-(trifluoromethyl)phenyl)methanesulfonamide (1.33 g, 4.06 mmol), bis(pinacolato)diboron (4.12 g, 16.22 mmol), potassium acetate (2 g, 20.38 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (500 mg, 0.61 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (340 mg, 0.61 mmol) were suspended in dioxane (35 ml) and stirred at 90° C. for 48 h. After evaporation of the solvent under reduced pressure, ethyl acetate (100 ml) was added to the residue and the precipitated salts were eliminated by filtration. The solvent was evaporated under reduced pressure to give 6.39 g (100% yield) of the title compound as a mixture of (3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)boronic acid and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide that was used in next step without further purification. (1:1). Estimated Purity: 24%
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C@@H:16]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1)[CH2:17][N:18]([CH:31]([CH3:33])[CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:16]([NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:17][NH:18][CH:31]([CH3:33])[CH3:32])=[CH:35][C:36]=1[C:41]([F:42])([F:43])[F:44]
Reactant: CC(C)N(C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Product: CC(C)NC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 55 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-isopropyl-4-nitro-benzenesulfonamide to give the title compound as a white solid. LC/MS [454 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (s, 1H), 9.01 (d, 1H), 8.55 (s, 1H), 8.38 (d, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 5.47 (s, 1H), 3.15 (d, 1H), 3.02 (s, 1H), 2.80-2.69 (m, 1H), 0.96 (dd, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)(=O)C.[CH2:20](I)[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:11][C:9](=[O:10])[C:8]1[CH:14]=[CH:15][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([CH2:22][CH:21]=[CH2:20])[CH:7]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(NC(C)=O)cc1
Reactant: C=CCI
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCc1cc(C(=O)OCC)ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A solution of ethyl-4-acetylaminobenzoate (Coneglio, L. Rend. Acad. Sci. Napoli [3] 1931, 36, 56-60) (2.07 g, 0.01 mol) and palladium acetate (1.12 g, 0.005 mol) in dry toluene (17 mL) was heated at reflux for 0.75 h under nitrogen. The solution was cooled to 60° C., the toluene was decanted, and the residue was washed with fresh toluene. The combined filtrates were heated at reflux for 3 h, the precipitate was collected by filtration, and mixed with the previous residue. The combined greenish residues were dried under vacuum for 3 h. To this residue, glacial acetic acid (40 mL) and allyl iodide (8.40 g, 0.05 mol) were added and the mixture was stirred at room temperature for 16 h. The palladium was removed by filtration through Celite and the filtrate was concentrated. The residue was passed through a column of silica gel using 1:1 ethyl acetate:hexane as eluent to give 0.85 g (69%) of ethyl-4-acetylamino-3-allylbenzoate as a white powder, mp 127°-128° C.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1O>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH:20]1[CH2:19][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: OC1Cc2ccccc2C1
Product: C=CCOC(=O)NC1CC(=O)OC1OC1Cc2ccccc2C1
Yield: 64.6 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester (5.2 gram, 20 mmol) as described for 40 using 2-indanol (8.05 gram, 60 mmol) to afford 4.10 grams (65% yield) of the title compound as a mixture of epimers. Purification provided 1.76 gram (28% yield ) of the 4(S), 5(R) epimer as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 2.42 (dd, J=17.2, 10.5 Hz, 1H), 2.79 (dd, J=17.2, 8.4 Hz, 1H), 2.99 (dd, J=16.7, 4.1 Hz, 1H), 3.04 (dd, J=16.7, 4.1 Hz, 1H), 3.22 (dd, J=17.2, 6.6 Hz, 1H), 3.26 (dd, J=17.2, 6.6 Hz, 1H), 4.53 (m, 3H), 4.70 (m, 1H), 5.20 (m, 2H), 5.60 (d, J=5.3 Hz, 1H), 5.87 (m, 1H), 7.17 (m, 4H) ppm. LC-MS (ES+): m/e=318 (M+H). Analytical HPLC (C18 column): 17.094 min.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)nc2)C2CCCCC2)sc2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of methyl 5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridine-2-carboxylate (460 mg) synthesized above, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (5.00 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (452 mg, quantitative) as a pale-brown solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)[CH:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1.O>[C:3]([C:2]([C:1]#[N:5])=[C:15]([CH:16]([CH3:18])[CH3:17])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:4]
Reactant: N#CCC#N
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=C(C#N)C#N)C(C)C

Procedure:
1.2 30 g of malononitrile, 3.3 g of ammonium acetate and 4 ml of acetic acid are added to a solution of 55 g of ethyl 2-(isobutyryl)acetate (“AA”) in 210 ml of toluene, and the mixture is boiled at 130° for 1 hour on a water separator. Conventional work-up gives 41.0 g of ethyl 4,4-di-cyano-3-isopropylbut-3-enoate (“AB”), boiling point 95-99° at 0.4 mbar.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29](I)=[CH:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]3=[N:25][CH:26]=2)[CH:16]=[N:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46](B2OC(C)(C)C(C)(C)O2)[C:45]([CH3:58])=[N:44]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[CH:16]=[N:17][C:18]([O:19][CH3:20])=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:14]=4)[CH:22]=3)[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]=2)[C:45]([CH3:58])=[N:44]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ncc(-c2cnc3c(c2)c(I)cn3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Yield: 63.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 5-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-6-methoxypyridin-3-yl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 66) (100 mg, 0.155 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (61 mg, 0.186 mmol) using Pd(PPh3)2Cl2 (5 mg, 0.0077 mol) and sodium carbonate (49 mg, 0.465 mmol) in DME/water (10/1 ml) to afford 61 mg (54.5% yield) of the titled compound. MS: m/z=621.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1ccc(Br)cc1I
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 4-Bromo-2-Iodophenol [207115-22-8] (0.9 g, 3.0 mmol), 4-Methoxyphenylacetylene (0.43 g, 3.3 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.4 g, 45%): Mp=192-194° C.; 1H NMR (CDCl3) δ 7.77 (d, 2 H, J=9.1 Hz), 7.66 (s, 1 H), 7.37-7.32 (m, 2 H), 6.98 (d, 2 H, J=9.1 Hz), 6.82 (d, 1 H, J=0.8 Hz), 3.87 (s, 3 H).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:66][O:67][CH:68]([F:70])[F:69])[C:27]([NH:29][CH:30]2[C:64](=[O:65])[N:32]3[C:33]([C:48]([O:50]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:49])=[C:34]([CH2:37][S:38][C:39]4[N:44]([CH3:45])[C:43](=[O:46])[C:42]([OH:47])=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:66][O:67][CH:68]([F:69])[F:70])[C:27]([NH:29][CH:30]2[C:64](=[O:65])[N:32]3[C:33]([C:48]([OH:50])=[O:49])=[C:34]([CH2:37][S:38][C:39]4[N:44]([CH3:45])[C:43](=[O:46])[C:42]([OH:47])=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)nnc(O)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: Cn1c(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(N)n4)[C@H]3SC2)nnc(O)c1=O
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.20 g) and anisole (2.5 ml) in methylene chloride (2.5 ml) was added trifluoroacetic acid (5 ml) under ice-cooling. After being stirred for 30 minutes, the mixture was poured into diisopropyl ether (50 ml). The resultant mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The separated aqueous layer was washed with ethyl acetate, acidified with 6N hydrochloric acid and extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and evaporated under reduced pressure. The residue was triturated in diethyl ether and collected by filtration to give 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:36]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:41]=1>>[CH2:36]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:33][CH3:34])(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:41]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1F

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 505.18 (M+H+.), was prepared in analogy to example 9, steps 1 to 5. Step 4 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][OH:6].[C:13](Cl)([Cl:15])=[O:14]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][O:6][C:13]([Cl:15])=[O:14]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(OC)c(COC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50% solution of 2,5-dimethoxybenzyl alcohol and dry benzene was added dropwise to an ice-cold stirring solution of 12.5 wt. % phosgene in benzene (1 mole of alcohol per 2 moles phosgene). The resulting solution was maintained at 0° for 1 hour and then stirred an additional 2 hours at room temperature. Excess phosgene, byproduct hydrogen chloride and a small amount of benzene was removed in vacuo at room temperature to provide crude 2,5-dimethoxybenzyloxycarbonyl chloride solution. The crude product was added dropwise to a 50 wt. % solution of p-aminobenzoic acid in dry tetrahydrofuran containing 2 moles of pyridine per mole of acid. An additional two equivalents of pyridine was added dropwise simultaneously with the carbonyl chloride addition. Upon completion of the addition (25-40 mins.), the resulting mixture was added dropwise with stirring to ice-cold 5% aqueous hydrochloric acid (10 volumes of acid per final volume of reaction solution). The product was collected by filtration, dried and purified by recrystallization from acetone. m.p. 124-25.