Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z 511 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17]([CH2:19][NH2:20])[CH:16]=[CH:15][C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17]([CH2:19][NH:20][C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(CN)cc1S(=O)(=O)NC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(C)=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
0.63 g (8 mmol) of acetyl chloride dissolved in 10 ml of dichloromethane is added dropwise to a solution, cooled to 0° C., of 2.01 g (6.7 mmol) of N-tert-butyl-5-aminomethyl-2-methoxycarbonylbenzenesulfonamide and 0.93 ml (6.7 mmol) of triethylamine in 30 ml of dichloromethane, and the mixture is then stirred at room temperature for 2 h. The reaction solution is washed with water, dried and evaporated to dryness i.v. 2.1 g (91%) of N-tert-butyl-5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide are obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[CH:6]([CH2:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][C:5]2([CH3:14])[CH3:13]
Reactant: CC1=CC=C2C(C1)C(C)(C)CCC2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Temperature: 84 °C
Yield: 386.3 %

Procedure:
A solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene 1 (2.00 g, 9.88 mmol), N-bromosuccinimide (1.85 mmol, 10.37 mmol), benzoyl peroxide (91 mg, 0.28 mmol) in 35 mL of CCl4 was heated at reflux (84° C., oil bath) for 2.5 h. After cooling top room temperature, the solution was concentrated in vacuo. Diethyl ether (100 mL) was added and the solution was filtered (to remove the succinimide formed) and concentrated to give a crude oil. The crude oil was purified by silica gel column chromatography using as eluent petroleum ether. 6-(Bromomethyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene 8 (2.01 g, 72.5% yield) was obtained as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=2)=[CH:9][CH:8]=1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCCN3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.1 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-piperidin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (8) (0.023 g, 0.048 mmol) in anhydrous methanol (1.5 mL) were added a 37% aq. solution of formaldehyde (0.014 mL, 0.19 mmol) and sodium triacetoxyborohydride (0.050 g, 0.24 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2.5 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (9) (0.022 g, 91% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.66 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.27-7.13 (m, 6H), 6.92 (s, 1H), 3.49 (s, 2H), 3.15-2.98 (m, 4H), 2.97-2.90 (m, 1H), 2.75-2.69 (m, 1H), 2.07-1.97 (m, 1H), 1.90 (s, 3H), 1.73 (d, J=12.8 Hz, 1H), 1.66-1.54 (m, 3H), 1.50-1.38 (m, 1H), 1.36-1.27 (m, 1H). LCMS Method C: rt 4.88 min; m/z 498.3 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:21])[C:10]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH:12]=[CH2:13])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH3:20][C:10]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:11][CH2:12][CH3:13])[C:9]([OH:21])=[O:8]
Reactant: C=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(C)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 99.7 %

Procedure:
A solution of 2-methyl-2-phenyl-pent-4-enoic acid benzyl ester (2.31 g, 8.24 mmol) in ethyl acetate (20 mL) was treated with 10% palladium on carbon (0.24 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (1.58 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 0.91 (m, 3 H) 1.23 (m, 2 H) 1.57 (m, 3 H) 1.96 (m, 2 H) 7.36 (m, 5 H). MS (DCI/NH3+) m/z 210 (M+NH4)30.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([OH:19])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][CH:2]1[CH:3]([C:17]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:19])[CH2:4][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CC1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)C1CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a solution of 4-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrrolidinecarboxylic acid (available from Fluorochem, 59 mg, 0.22 mmol) in DMF (1 ml) was added HATU (85 mg, 0.22 mmol) and the mixture stirred for 10 mins. Then 6-(1H-indol-4-yl)-1H-indazol-4-amine (46 mg, 0.19 mmol) and DIPEA (0.065 ml, 0.37 mmol) were added and the mixture allowed to stand for 18 h at 20° C. The solvent was removed under a stream of nitrogen and the residue purified by Mass Directed Automated Preparative HPLC (Method E), to give the title compound (6 mg) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]#N)[CH:9]=[CH:8]2.[OH-:15].[K+].Cl.C(O)C.[OH2:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:21])=[O:15])[CH:9]=[CH:8]2
Reactant: COc1cccc2ccc(C#N)cc12
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1cccc2ccc(C(=O)O)cc12
Temperature: 70 °C
Yield: 99 %

Procedure:
A solution of 8-methoxy-2-naphthonitrile (263 mg, 1.44 mmol) and KOH (242 mg, 4.3 mmol) in 95% ethanol (5 mL) is heated to reflux for 72 hours. The solvent boiled off during heating leaving a solid. The reaction mixture is allowed to cool, dissolved in 1:1 ethanol-water then acidified to pH<2 with concentrated HCl. The resulting precipitate is collected by filtration, washed with water and dried by heating at 70° C. under vacuum to give 8-methoxy-2-naphthoic acid as a white solid (288 mg, 99%). HRMS (EI) calculated for C12H10O3: 202.0630, found 202.0629.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C@H:37]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH:36][C@H:37]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Boc-D-Trp(CHO)-OH (2.99 g), TsOH.H-Phe-OBzl (3.85 g, and HOBT (1.22 g) were dissolved in a mixed solvent of methylene chloride (60 ml) and DMF (15 ml). To this solution was added WSC (1.53 g) under ice cooling, and the reaction mixture was stirred for 3 hours at the same temperature. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed successively with diluted sodium hydrogencarbonate solution (twice), water, 0.5N hydrochloric acid, and saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether (1:1), which was filtered, washed with diisopropyl ether, and dried to give Boc-D-Trp(CHO)-Phe-OBzl (4.95 g).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(O)(C(F)(F)F)=[O:28].FC(F)(F)C(OO)=O.[OH-:42].[Na+]>C(Cl)Cl>[O:42]=[S:23]1(=[O:28])[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:4]3([CH2:3][N:2]([CH3:1])[CH3:26])[CH2:5][CH2:6][O:7][CH2:8][CH2:9]3)=[CH:15][CH:14]=2)[CH2:25][CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: [OH-]
Reactant: CN(C)CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Agent: O=C(OO)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC1(c2ccc(OCCCN3CCS(=O)(=O)CC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 46 %

Procedure:
Dimethyl-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine (300 mg, 0.792 mmol) and TFA (0.99 ml) were cooled to 0 to 5° C. and trifluoro-peracetic acid (4M, 0.77 ml) was added and the reaction allowed to warm to ambient temperature overnight. The mixture was diluted with DCM (6 ml), basified with NaOH (2M, 8 ml) and extracted with DCM (2×20 ml). The DCM extracts were dried over MgSO4, filtered and concentrated in vacuo at 35° C. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (151 mg, 46%) as a white solid. 1H NMR (400 MHz, CDCl3) δ7.22 (d, 2H), 6.85 (d, 2H), 4.01 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.10-2.97 (m, 8H), 2.72 (t, 2H), 2.40 (s, 2H), 2.14-1.82 (m, 6H), 1.97 (s, 6H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17](=[O:27])[N:18]3[C:23]=2[C:22]2[S:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19]3)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[O:27]=[C:17]1[C:16]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:15][C:14]([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])=[C:23]2[N:18]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][S:24][C:22]=12
Reactant: CCOC(=O)C1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2sccc2CC3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2sccc2CC3)CC1

Procedure:
A solution of 0.1 g of ethyl-1-[[4,5-dihydro-7-oxo-8-phenyl-7H -thieno[2,3-a]quinolizin-10-yl]carbonyl]-4-piperidinecarboxylate and 0.016 g of sodium hydroxide in 2 ml of methanol was heated under reflux for 3 hours. The mixture was then evaporated in vacuo, the residue was taken up in water and extracted with chloroform. The aqueous phase was made acid with 3N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated in vacuo, and there was obtained crude 1-[[4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]-quinolizin-10-yl]carbonyl-4-piperidine-carboxylic acid.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.B(F)(F)F.[CH2:32]([O:34][C:35](=O)[CH3:36])C.P([O-])([O-])(O)=O.[K+].[K+]>C1(OC)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:32][O:34][C:35]1[CH:36]=[CH:12][C:11]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Agent: FB(F)F
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: COc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)cc1
Temperature: 0 °C

Procedure:
0.1 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid are dissolved in a solution of 0.056 g of anisole in 5 ml of chloroform, and the solution is cooled to 0°C and saturated with boron trifluoride gas for 15 minutes. The temperature of the reaction mixture is thereafter brought to room temperature over the course of 2 hours; 50 ml of acetic acid ethyl ester are added, and the mixture is again cooled to 0°C and slowly poured into 50 ml of a 10% strength aqueous dipotassium hydrogen phosphate solution. The pH value is adjusted to 7.5 and the mixture is thoroughly shaken. The aqueous phase is twice washed with 50 ml portions of acetic acid ethyl ester, the pH value is adjusted to 2 by means of 20% strength aqueous phosphoric acid, and three extractions with 50 ml portions of acetic acid ethyl ester are carried out. The oroganic extracts are repeatedly washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. 3-(4-Methoxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid containing a small amount of the corresponding 2-methoxy-benzyl compound are thus obtained as the residue; in a thin layer chromatogram, this acid does not differ from the product of the process of example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].B(F)(F)F.[CH3:39][CH2:40][O:41]CC>C(O)CO>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4([C:29]([CH3:31])([CH3:30])[CH3:32])[O:41][CH2:40][CH2:39][O:33]4)=[C:22]([CH3:34])[CH:21]=3)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2s1
Reactant: CCOCC
Agent: FB(F)F
Solvent: OCCO
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC4(C(C)(C)C)OCCO4)c(C)c3)ccc2s1
Temperature: 90 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
A solution of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid ethyl ester (170 mg, 0.354 mmol)) in ethylene glycol (3.0 mL) is treated with BF3-Et2O (2.0 mL). The mixture is stirred at 90° C. for 6 h, cooled to RT, and quenched with water (50 mL). The mixture is extracted with EtOAc (2×20 mL), and the organic layer is concentrated and purified using silica gel column chromatography (10% EtOAc/Hex) to afford the product as an oil (94 mg, 51%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][NH:13][C:14](=[O:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[CH:17]=1.O>N1C=CC=CC=1>[CH3:12][NH:13][C:14](=[O:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[C:18]([CH3:23])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)Oc1ccc(NS(=O)(=O)c2ccc(C)cc2)c(C)c1

Procedure:
p-Toluenesulfonyl chloride (2.1g., 0.011 mole) was added portionwise to a solution of 3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole) in pyridine (15 ml.). An exotherm to about 45° C. resulted and warming was continued at 48° C. for a short time. An excess of water was added and upon stirring and cooling, the product crystallized. The filtered product (3.1g.) was recrystallized from ethanol/water to give material with m.p. 181°-83.5° C.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[CH3:14][NH2:15]>C(OCC)(=O)C>[Cl:13][C:6]1[C:3]([C:4]#[N:5])=[C:2]([NH:15][CH3:14])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CN
Solvent: CCOC(C)=O
Product: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Temperature: 5 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a 1 L two-neck round bottom flask was added 2,6-dichloro-3-nitrobenzonitrile (11.1 g, 51.1 mmol) followed by ethyl acetate (102 mL). The flask was equipped with an internal thermometer and magnetic stir bar and cooled to 5° C. by immersion into an ice bath. Methylamine was added dropwise to the cooled reaction mixture as a 40% aqueous solution (8.9 mL, 115 mmol) with vigorous stirring. The reaction mixture was stirred for an additional 3 hours with cooling, after which more methylamine (1.8 mL, 23 mmol) was added. The reaction vessel was removed from the ice bath and stirred for an additional 1.5 hours. To the reaction mixture was added water (30 mL) followed immediately by hexane (45 mL) and the resulting slurry was stirred for 15 minutes. The solid was recovered by filtration and washed with water followed by methanol to provide 6-chloro-2-methylamino-3-nitro-benzonitrile (10.49 g, 96%) as a bright yellow solid, which was used directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.55-8.53 (m, 1H), 8.28 (d, 1H, J=9.0 Hz), 6.95 (d, 1H), J=9.0 Hz), 3.30 (d, 1H, J=5.5 Hz).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.O1CCCC1.[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[S:39])([CH3:30])[CH3:29]>ClCCl>[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:11]2[N:12]=[CH:13][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)[N:10]=2)=[CH:15][CH:16]=1)=[S:39])([CH3:30])[CH3:29]
Reactant: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 65 °C

Procedure:
To 4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.496 g, 1.63 mmol) in a 25 mL vial equipped with a stir bar, Vigreux column, and nitrogen inlet was added tetrahydrofuran (4.08 mL) followed by 1-isopropyl-2-isothiocyanatobenzene (0.826 ml, 4.89 mmol). The reaction was heated to 65° C. overnight. The reaction was cooled to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted with dichloromethane (2×). The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography using 0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent provided a white solid. The solid was dried at 55° C. at about 25 in. Hg providing the title compound as a white solid (0.361 g, 46%).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:13])[CH3:12])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([O:31]C)=[O:30])[CH:27]=3)[C:22]([S:33][CH3:34])=[CH:21]2)=[N:18][CH:19]=1>C1COCC1.O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:13])[CH3:12])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([OH:31])=[O:30])[CH:27]=3)[C:22]([S:33][CH3:34])=[CH:21]2)=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C(C)O)ccc4F)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)O)ccc12
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.30 g, 7.07 mmol) was added at room temperature to a solution of 300a) (1.0 g, 2.36 mmol) in THF/water (1:1, 40 mL). The reaction mixture was stirred at this temperature for 16 h and then concentrated. The residue was diluted with water (20 mL) and washed with ethyl acetate (2×30 mL). The aqueous phase was adjusted with sodium hydrogen sulfate to a pH value of 2. The precipitating solid was filtered off through a sintered funnel and residual water was removed by azeotropic distillation with toluene. Light brown solid. Yield: 0.75 g (75% of theory)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 20 mmol) in methylene chloride (100 ml) containing TFA (25 ml) was stirred for 1 hour at ambient temperature. Water (50 ml) and methylene chloride (100 ml) were added and the pH of the aqueous layer was adjusted to 8 with solid sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether and the solid was filtered and dried under vacuum to give 7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (8.3 g, 100%).