Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][C:3]=1[C:29]#[N:30].[CH3:31][O:32][CH2:33][C:34]#[C:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]2[O:43][CH2:44][O:45][C:37]=12.[ClH:46].CN(C)C(=N)N(C)C>C(O)CC.C(OCC)C>[ClH:1].[ClH:46].[C:29]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:40][C:39]1[CH:41]=[CH:42][C:36]([C:35]#[C:34][CH2:33][O:32][CH3:31])=[C:37]3[O:45][CH2:44][O:43][C:38]=13)=[C:10]([O:12][CH:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH:9]=[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:7]=2)#[N:30]
Reactant: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1Cl
Reactant: COCC#Cc1ccc(N)c2c1OCO2
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCCO
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2

Procedure:
A mixture of 4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (125 mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (179 mg) in 1-propanol (8 ml) was treated with a 11.0M solution of hydrogen chloride in diethyl ether (0.30 ml) then stirred and heated at reflux for 1 hour. The mixture was allowed to cool and neutralised by the addition of tetramethylguanidine (0.10 ml). The resulting solution was evaporated to dryness and the residue was purified by chromatography on a Biotage silica cartridge (20 g) eluting with a gradient of methanol in dichloromethane (1–10%). The fractions containing the product were combined and evaporated. The residue was dissolved in ethanol (8 ml) and treated with 2 equivalents of hydrogen chloride (1.0M in diethyl ether). The title compound was thus obtained as a white solid (130 mg); NMR Spectrum: (DMSOd6, 300K) 1.87 (m, 2H), 2.10 (m, 2H), 2.31 (m, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 3.36 (s, 3H), 3.50 (m, 4H), 3.87 (m, 4H), 3.97 (m, 2H), 4.32 (m, 2H), 4.37 (s, 2H), 5.10 (m, 1H), 6.18 (s, 2H), 1.05 (m, 3H), 7.13 (s, 1H), 8.87 (s, 1H), 10.43 (s, 1H), 11.34 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH3:23]>O.CC#N.CO>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14])[CH3:23]
Reactant: COc1cc2nc[nH]c(=O)c2cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CCOc1cc2c(=O)[nH]cnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 6-hydroxy-7-methoxyquinazoline-4(3H)-one (1.0 g, 5.2 mmol) and Cs2CO3 (1.69 g, 5.2 mmol) in H2O:MeCN:MeOH (10:5:1, 20 mL) was stirred at room temperature for 30 minutes and to it was added bromoethane (0.567 g, 5.2 mmol). Then, it was stirred at 60° C. two days. It was filtered to afford 6-ethoxy-7-methoxyquinazolin-4(3H)-one as a solid (0.550 g, 48%). 1H NMR (300 MHz, DMSO-d6) δ 8.0 (s, 1H), 7.91 (s, 1H), 7.4 (d, 1H), 7.1 (d, 1H), 4.15 (t, 2H), 3.9 (s, 3H), 1.4 (t, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[O:13][C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[O:16][C:17]=2[C:18]([NH2:20])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[C:6]1([C:12]2[O:13][C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[O:16][C:17]=2[C:18]#[N:20])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C1=C(c2ccccc2)Oc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1=C(c2ccccc2)Oc2ccccc2O1

Procedure:
3.59 ml (30 mmol) of phosphorus oxychloride are slowly added to a solution of 1.52 g (6 mmol) of the amide obtained in Step A in 15 ml of anhydrous pyridine. The medium is then heated at reflux for 2 hours under argon and then allowed to cool. After evaporation of the solvent in vacuo, the residue obtained is diluted with dichloromethane; the organic phase is then hydrolysed with a saturated solution of sodium hydrogen carbonate. The aqueous phase is extracted with dichloromethane; the organic phase is then dried over magnesium sulphate. The solvent is then evaporated under reduced pressure. Chromatography on a silica column (eluant: AcOEt/PE: 40/60) allows the title nitrile to be obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=2)[CH:16]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OC2CCCCO2)ccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-(4-{[2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propanoate (0.599 g, 1.30 mmol) in methanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.436 g, yield 75%) as colorless needle crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[O:33]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1COc1ccc(C[C@H](NC2=NS(=O)(=O)c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
The crude product from Step A was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2/ethyl acetate/hexane). The yield was 35%. MS (ES) 455 (M+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH:33]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:36])=[O:35])=[CH2:32]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 15 h

Procedure:
To ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (60 mg, 0.21 mmol) was added DCM (1.1 mL) and DIPEA (45 μL, 0.26 mmol) at 0° C. Then 2-chloroethanesulfonyl chloride (68 mg, 0.42 mmol) was added and the reaction was stirred vigorously for 15 hours before being quenched by pouring into a separatory funnel containing aqueous sodium hydrogen carbonate (20%). The aqueous layer was then extracted with ethyl acetate (×3) and the organic layers were combined, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified using a silica column, eluting with DCM with a 10-80% of a 2% methanol/EtOAc modifying co-solvents. The product was collected and concentrated in vacuo to afford the desired product as a yellow solid. LRMS (ESI) calc'd for C17H17N4O4S [M+H]+: 373, found 373. 1H NMR (600 MHz, CDCl3) δ 10.74 (bs, 1H), 9.04 (s, 1H), 8.12 (s, 1H), 7.38-7.54 (m, 5H), 6.61 (dd, 1H, J=17.4, 10.8 Hz), 6.33 (d, 1H, J=16.2 Hz), 5.96 (d, 1H, J=10.2 Hz), 4.04 (q, 2H, J=7.2 Hz), 1.01 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=S)[NH2:2].NC1C=CC(C(C)C(OC)=[O:26])=CC=1>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:26])[NH2:2]
Reactant: COC(=O)[C@@H](C)c1ccc(NC(N)=S)cc1
Reactant: COC(=O)C(C)c1ccc(N)cc1
Product: COC(=O)C(C)c1ccc(NC(N)=O)cc1

Procedure:
Following the same procedure described for (S)-methyl 2-[4-(carbamothioylamino)phenyl]propanoate and starting from methyl 2-(4-aminophenyl)propanoate (98 mmol), after workup methyl 2-[4-(carbamoylamino)phenyl]propanoate was isolated as white solid (74%). 1H-NMR (CDCl3): δ 8.25 (bs, 1H, CSNH), 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.20 (bs, 2H, CSNH2), 3.75 (m, 1H), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:16][CH2:17]OS(C)(=O)=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].I.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[N:44]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:31].C(N(CC)C(C)C)(C)C>C(#N)C>[NH3:11].[C:1]([N:11]1[CH2:15][CH2:14][C:13]([CH2:16][CH2:17][N:47]2[CH2:48][CH2:49][CH2:50][N:44]([C:36]3[N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:45][CH2:46]2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)OCc4ccccc4)C3)CC2)nc2ccccc21
Product: N
Reaction time: 18 h
Yield: 1 %

Procedure:
Combine 1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (10.2 g, 25.3 mmol), (1.34 g, 2.5 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (16.5 g, 30.4 mmol), and N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/6 containing 1% concentrated aqueous ammonia to give 1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl) ethyl)-3-phenylpyrrolidine.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[NH2:21][C:22]1[C:23]([CH3:29])=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:23]([CH3:29])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13]
Reactant: Cc1c(N)cccc1O
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1Oc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
3.6 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 9.2 mmol, 1 eq.), 1.1 g 3-amino-2-methyl phenol (9.2 mmol, 1 eq.) and 4.5 g caesium carbonate (13.8 mmol, 1.5 eq.) were suspended in 35 mL DMF and stirred at rt for 16 h. LCMS analysis showed complete turnover. The reaction mixture was diluted with ethyl acetate, quenched with saturated sodium chloride solution, the layers were separated and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 1.18 of the desired product (26% yield).
Reaction SMILES: [BrH:1].N[C:3]1[S:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][N:7]=1.N([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:3]1[S:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][N:7]=1
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1nnc(Br)s1
Temperature: 65 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
48% Aqueous hydrobromic acid (67.5 ml) was added to a solution of 2-amino-5-t-butyl-1,3,4-thiadiazole (43 g) in glacial acetic acid (300 ml) the mixture was warmed to 65° C. and a solution of sodium nitrite (56 g) in water (80 ml) was added dropwise with stirring over 60 minutes at 65°-75° C. The mixture was cooled to 20° C. and was poured into water. The organic layer was extracted into ether (2×300 ml) and the extracts were combined, washed with sodium bicarbonate solution until neutral and dried over magnesium sulphate. The drying agent was filtered off and the solvent was evaporated to give a yellow oil which was distilled under reduced pressure to give 2-bromo-5-t-butyl-1,3,4-thiadiazole (47 g, 78%) as a colourless liquid, bp 134°-136° C. at 23 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[CH2:19](N(CC)CC)[CH3:20].BrCC>C(#N)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: CCN(CC)CC
Reactant: COC(=O)N1CC2CCC(=O)CC2CC1C(=O)O
Solvent: CC#N
Solvent: CCBr
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 50 °C

Procedure:
In Scheme VI, Step A, 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as herein defined above) is esterified by reaction with a compound of formula R5-Br (where R5 is as herein defined) to provide the 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate of compound (2). For example 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction is heated at 50° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1N HCL. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compound of structure (2). This crude material may then be purified under standard conditions well known in the art. For example, the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are combined and concentrated under vacuum to provide the purified compound of structure (2).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[S:14][C@@H:15]2[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27](=[O:39])[N:16]2[CH:17]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH:18]=1>ClCCl>[CH3:12][CH:13]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[N:16]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:15]2[S:14]1=[O:9]
Reactant: CC1=CC(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A solution of 3-chloroperbenzoic acid (0.40 g.) in dichloromethane (10 ml.) was dropwise added to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (0.92 g.) in dichloromethane (10 ml.) and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was filtered and the filtrate was washed in turn with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide (0.56 g.), mp 173° to 175° C.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[OH:14][CH2:15][C:16]1[N:17]=[CH:18][S:19][C:20]=1/[CH:21]=[CH:22]\[S:23][C:24]1[C@H:25]([CH3:55])[C@@H:26]2[C@@H:43]([C@H:44]([O:46][Si:47]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:45])[C:42](=[O:54])[N:27]2[C:28]=1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>C1COCC1>[C:7]([O:14][CH2:15][C:16]1[N:17]=[CH:18][S:19][C:20]=1/[CH:21]=[CH:22]\[S:23][C:24]1[C@H:25]([CH3:55])[C@@H:26]2[C@@H:43]([C@H:44]([O:46][Si:47]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:52][CH3:53])[CH3:45])[C:42](=[O:54])[N:27]2[C:28]=1[C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)=[O:30])(=[O:9])[CH3:8]
Reactant: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C\c3scnc3COC(C)=O)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N-Dimethylaminopyridine (37 mg), 0.133 ml of pyridine, and 0.114 ml of acetic anhydride were added to 3 ml of a solution of 695 mg of 4-nitrobenzyl (1R,5S,6S)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-6-((1R)-1-triethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate in THF, and the mixture was stirred at room temperature for 1.5 hr. Ethyl acetate was added to the reaction solution, and the mixture was washed with brine, was dried over anhydrous magnesium sulfate, and was filtered. Silica gel (5 g) was added to the filtrate, the mixture was filtered, and the filtrate was concentrated under the reduced pressure to give 730 mg of 4-nitrobenzyl (1R,5S,6S)-2-[[(Z)-2-(4-acetoxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-6-((1R)-1-triethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O.[C:38]([O-])([O-])=[O:39].[K+].[K+]>[Pd].CCO.COCCOC>[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:34]4[O:30][C:31]([CH:38]=[O:39])=[CH:32][CH:33]=4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Reactant: OB(O)c1ccco1
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 75 °C

Procedure:
A mixture of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride salt (5.05 g, 10 mmol), 2-furylboronic acid (1.85 g, 12 mmol) and palladium catalyst (730 mg, 1.0 mmol) in 10 mL of K2CO3(2.0M), 10 mL of EtOH and 40 mL of DME was heated at 75° C. under nitrogen atmosphere for 4 hr. LS-MS showed the reaction completed. Concentrated the mixture under reduced pressure and washed the residue with water (2×50 mL) then with cool ether (100 mL) to get a gray solid (4.5 g), which was used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH2:12][OH:13])[CH:9]([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:9]([F:11])[F:10])[NH:14][C:15](=[O:18])[CH2:16][O:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)NC(CO)(c1cccc(Br)c1)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1COCC(c2cccc(Br)c2)(C(F)F)N1

Procedure:
N-[1-(3-Bromo-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide (8.10 g, 23.65 mmol) and potassium tert-butoxide (5.31 g, 47.3 mmol) were heated to 95° C. in 118 ml tert-butanol for 30 minutes. After completion water was added and the reaction was evaporated. The residue was put between ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 9.13 (s, 1H, NH), 7.78 (s, 1H), 7.59 (m, 2H), 7.42 (t, 1H), 6.48 (t, 1H, CHF2), 4.28 (d, 1H), 4.10 (m, 2H), 3.92 (m, 1H); MS: 306 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:21]([I:22])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:24][C:25]1([OH:29])[CH2:28][NH:27][CH2:26]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([I:22])[C:2]([N:27]3[CH2:28][C:25]([OH:29])([CH3:24])[CH2:26]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Reactant: CC1(O)CNC1
Agent: Cl
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2I)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 88.1 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3) and 3-methylazetidine-3-ol hydrochloride to afford a beige foam. HPLC (Condition 7) tR=6.84 min, UPLC-MS (Condition 8) tR=1.14 min, m/z=510.0/512.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(#N)C>[N:1]1([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCCn1cncn1)OCc1ccccc1
Yield: 81.1 %

Procedure:
4.7 g of 1,2,4-triazole and 9.5 g of potassium carbonate were added to a solution of 15 g of benzyl 4-bromobutyrate in 150 ml of acetonitrile. The mixture was refluxed by heating, for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added 30 ml of methylene chloride. The insolubles were collected by filtration and washed. The filtrate and the washings were combined and purified by silica gel column chromatography (eluant: methylene chloride/methanol=50/1) to obtain 11.6 g of benzyl 4-(1,2,4-triazol-1-yl)butyrate as a colorless oily substance.