Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(Sc2ccc(C(F)(F)F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Sc2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
Aldehyde 31.2 (162 mg, 0.574 mmol) was dissolved in MeOH (6 mL) and cooled to 0° C. Sodium borohydride (22.0 mg, 0.574 mmol) was added to the reaction. The solution was allowed to slowly warm to room temperature and was stirred for 1.5 hours. The reaction was quenched with dilute hydrochloric acid and then concentrated to dryness under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated to give 31.3 (151 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.38-7.43 (3H, m), 7.27-7.32 (3H, m), 7.20 (2H, d, J=8.2 Hz), 4.61 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:21]=[C:20]([CH:19]=[C:4]([CH:5]=[C:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:3]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 133.1 %

Procedure:
To a solution of tert-butyl 4-(3-fluoro-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (585 mg, 0.001 mol) in dry CH2Cl2 (7 mL) cooled to 0° C. was added trifluoroacetic acid (0.99 mL, 0.012 mol). The reaction mixture was stirred for 30 min at 0° C. and then for 1 h at RT. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (469 mg, 100%). 1H NMR (500 MHz, CDCl3): δ 9.82 (m, 1H), 8.43 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.07 (d, J=9 Hz, 1H), 6.83 (q, J=13.5 Hz, 2H), 6.43 (s, 1H), 3.29 (s, 1H), 3.17 (s, 1H), 2.85 (m, 1H), 2.72 (s, 1H).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(C(C)C)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-isopropylphenylboronic acid (164 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (59 mg, yield 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]#[CH:27])=[CH:21][CH:22]=3)[C:17]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[N:16][C:15]2=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1.C(OCC)(=O)C.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]#[CH:27])=[CH:21][CH:22]=3)[C:17]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[N:16][C:15]2=[S:47])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CCCc1ccc(OC)c(OC)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=S)n2CCCc1ccc(OC)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 130 mg (0.26 mmol) of the quinazolinone prepared in step D and 122 mg (0.30) mmol Lawesson reagent in 5 ml benzene is stirred for 2 h at 70° C. The solution turns slightly red. Equal amounts of Lawesson reagent are added after a total of 3 and 5 h, but the reaction remained incomplete. After extractive work-up with ethyl acetate and water, followed by chromatography of the crude material (hexane/ethyl acetate) the intermediate is obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[OH-].[K+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18]>O.C1COCC1.[OH-].[Na+]>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][C:17](=[S:18])[N:16]([CH3:20])[CH3:15])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)=O)ccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetovanillone (8.31 g, 50 mmol) and 2.81 g KOH (50 mmol) in H2O (34 mL), at 0°, is added a solution of dimethylthiocarbamoyl chloride (8.28 g, 67 mmol) in THF (14 mL), dropwise, at such a rate as to keep the reaction temperature below 12°. The reaction mixture is warmed to room temperature, and stirred for 30 minutes. It is then diluted with 1 N NaOH (100 mL) and extracted with EtOAc (3×80 mL). The combined organic phase is washed with H2O (1×100 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo to give dimethylthiocarbamic acid O-(4-acetyl-2-methoxy-phenyl) ester. To a thick walled pyrex tube is aded dimethylthiocarbamic acid O-(4-acetyl-2-methoxy-phenyl) ester (9.81 g, 38.77 mmol). The tube is flushed with nitrogen, sealed, and then heated to 250° for 1 hour. After cooling, the residue is chromatographed (silica gel, 1:1 EtOAc/hexane) to yield dimethylthiocarbamic acid S-(4-acetyl-2-methoxy-phenyl) ester.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1(C)C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=C1Cc2ccccc2C1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)Cc2ccccc21

Procedure:
A mixture of 2-indanone (2.0 g, 15.1 mmol) and pyrrolidine (1.6 mL, 19.7 mmol) in anhydrous toluene (61 mL) was refluxed under nitrogen with azeotropic removal of water (Dean-Stark apparatus) for 2 h. The mixture was then cooled and concentrated to dryness in vacuo to give the title compound. MS:m/z=186.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4].[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][C@@H:19]([CH3:23])[NH:18]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:16][C@H:17]1[NH:18][C@@H:19]([CH3:23])[CH2:20][N:21]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][CH:10]=[N:11]3)=[O:4])[CH2:22]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(CCl)Nc1cccc2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)C[C@H](C)N1

Procedure:
A mixture of 2-chloro-N-(quinolin-5-yl)acetamide (7.76 g) (J. Indian Chem Soc, 1940, 17, 619-621), cis-2,6-dimethylpiperazine (4.42 g), sodium bicarbonate (8.9 g) in ethanol (100 ml) was heated at reflux for 4 h. The solvent was removed under reduced pressure. The residue was partitioned between chloroform and brine. The organic phase collected and the aqeuous phase further extracted (×6) with chloroform. The combined extracts dried (MgSO4) and solvent removed under reduced pressure. Yield: 6.8 g
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6]1)[CH3:3].CO.[C:24]([OH:27])(=[O:26])[CH3:25]>[Pd]>[C:24]([OH:27])(=[O:26])[CH3:25].[C:24]([OH:27])(=[O:26])[CH3:25].[CH3:3][N:2]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)C[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a flask containing Pd/C (1.5 g, Degussa type E101) was added methanol/acetic acid (100 mL, 3:1). Benzyl 4-((dimethylamino)methyl)cyclohexylcarbamate (15.8 g, 54 mmol) in methanol/acetic acid (300 mL, 3:1) was added. A balloon of H2 was added and the reaction stirred at rt for 6 h. The reaction was filtered through celite, the filtrate concentrated, and azeotroped with toluene. The thick oil was dried under vacuum to give desired product (17.9 g, crude) as a waxy solid. 1H NMR (300 MHz, MeOD) δ 3.11-2.98 (m, 1H), 2.78 (d, J=7.0 Hz, 2H), 2.69 (s, 6H), 2.07 (br d, J=13.9 Hz, 4H), 2.02-1.86 (m, 2H), 1.92 (s, 6H), 1.79-1.67 (m, 1H), 1.53-1.35 (m, 2H), 1.20-1.05 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10]CC)=[O:9].O.[OH-].[Li+]>O1CCCC1.O.C(O)C>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn(C)c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (8.00 g, 34.3 mmol) in tetrahydrofuran (60 mL), water (20 mL) and ethanol (20 mL) was treated with lithium hydroxide monohydrate (3.17 g, 75.5 mmol) and stirred for 4 hours at room temperature. Removal of solvents under reduced pressure provided a white solid residue, which was diluted with water (50 mL), washed with diethyl ether (50 mL) and adjusted to pH 2.5 with aqueous 6 N hydrochloric acid. The thick suspension was extracted with 2-methyltetrahydrofuran (2×125 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the product as an off-white solid. Yield: 6.49 g, 31.7 mmol, 92%. LCMS m/z 205.2 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.91 (s, 1H), 12.64 (br s, 1H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[SiH](C)O[SiH](C)C.C(OC(=O)C)(=O)C.FC(F)(F)S(O[Si](C(C)C)(C(C)C)C(C)C)(=O)=O.[CH2:41]([Si:49]([CH3:55])([CH3:54])[O:50][SiH:51]([CH3:53])[CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:51]([CH3:52])([CH3:53])[O:50][Si:49]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:55])[CH3:54])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](C)O[Si](C)(C)CCc1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: C[SiH](C)O[SiH](C)C
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(CCc1ccccc1)O[Si](C)(C)CCc1ccccc1
Yield: 58 %

Procedure:
380 mg Of styrene and 240 mg of 1,1,3,3-tetramethyldisiloxane were placed in a glass tube to which 20 μL (21.6 mg) of acetic anhydride and 2 μL (2.3 mg) of triisopropylsilyl trifluoromethanesulfonate (i-Pr3SiOSO2CF3) were added by microsyringe. 5 μL (platinum weight: 0.0017 mg) Of a toluene solution (platinum content: 0.04 wt %) of zero-valent platinum complexed with divinylsiloxane were added to this. The tube was put in a 60° C. oil bath and heated for 8 hours. After cooling, the tube contents were analyzed by gas chromatography, which revealed that the styrene conversion rate was 55%, 1-phenethyl-1,1,3,3-tetramethyldisiloxane had been produced at a yield of 58% (based on 1,1,3,3-tetramethyldisiloxane) and 1,3-bis(phenethyl)-1,1,3,3-tetramethyldisiloxane at a yield of 21%, and the ratio of alpha addition to beta addition of phenethyl groups was 1:49.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][NH:7][CH:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:5])[N:7]([CH3:6])[CH:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:2]
Reactant: CCN=C=O
Reactant: CNC1c2ccccc2Oc2ccccc21
Solvent: ClCCl
Product: CCNC(=O)N(C)C1c2ccccc2Oc2ccccc21

Procedure:
Ethyl isocyanate (1 ml.) was added to a solution of 9-methylaminoxanthen (2.02 g.) in methylene chloride (10 ml.). There was an exothermic reaction and after 20 minutes at room temperature the solvent was evaporated. The residue was recrystallised from benzene to give N'-ethyl-N-methyl-N-9-xanthenylurea, m.p. 139°-141°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:17][S:18][C:14]=2[CH:13]=1)[CH2:4][CH2:5]O)[CH3:2].CCN(S(F)(F)[F:37])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH2:5][F:37])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:17][S:18][C:14]=2[CH:13]=1)[CH3:2]
Reactant: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CCF)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 10.6 %

Procedure:
To 540 mg (11.37 mmol) 2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol in 6 ml CH2Cl2 were added 0.22 ml (1.7 mmol) DAST at −78° C. After stirring at that temperature for 3.5 h, additional 0.2 ml (1.6 mmol) DAST were added and the mixture was slowly warmed to RT over night. The solution was added to a cooled aqueous solution of Na2CO3 and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. Column chromatography CH2Cl2:MeOH 95:5 yielded 79.3 mg (16%) Ethyl-(2-fluoro-ethyl)-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine as brown oil, MS: 441 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](CC3C=CC(OC)=CC=3)[N:10]=2)=[N:7][CH:8]=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>ClCCCl>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:6]2[N:5]=[C:4]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:3]([O:2][CH3:1])=[CH:8][N:7]=2)=[N:10]1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cnc(-c2n[nH]c3ccccc23)nc1Nc1ccncc1
Reaction time: 72 h

Procedure:
13.4 g of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (1-5-1, 30.6 mmol, 1 eq.) was suspended in 121 ml of 1,2-dichloroethan. First 71 ml of trifluoroacetic acid (918 mmol, 30 eq.) were added dropwise, followed by 27 ml of trifluoromethanesulfonic acid (306 mmol, 10 eq.). The reaction mixture was stirred for three days under nitrogen atmosphere. The mixture was cooled with an ice bath to +3° C., upon which 2M aq. sodium hydroxide solution was added until pH=12. The resulting brown suspension was stirred for 18 hours at room temperature and then the precipitate was filtered off and dried under vacuo at 70° C. to yield 9.74 g (27.7 mmol, 90.3%) of the analytically pure target compound as a light brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](O)[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2.O=P(Cl)(Cl)[Cl:27].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[Cl:27][C:6]1[C:7]2[C:8](=[N:9][C:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:11][N:12]=2)[N:23]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COCc1cc(Cl)c2ncc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
6-Methoxymethyl-3-(3-trifluoromethyl-pyridin-2-yl)-pyrido-[2,3-b]pyrazin-8-ol (146 mg, 0.436 mmol) is dissolved in a solution of CHCl3 (20 mL), POCl3 (0.12 ml, 1.31 mmol) and 2,6-lutidine (0.2 mL, 1.31 mmol). The mixture is heated at reflux overnight. The reaction is concentrated under reduced pressure. EtOAc (30 mL) is added and the mixture is extracted with NaHCO3 (aq) (30 mL) and brine (30 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by silica gel preparatory TLC eluting with hexanes/EtOAc (1:1) to yield the title compound as a light yellow oil that solidifies upon standing.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:19][C:20]1[C:25]([CH3:26])=[C:24]([NH2:27])[N:23]([CH3:28])[C:22](=[S:29])[N:21]=1.CO.N>C(#N)C.O1CCOCC1>[NH2:17][CH:16]1[C:15](=[O:18])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][S:29][C:22]3[N:21]=[C:20]([NH2:19])[C:25]([CH3:26])=[C:24]([NH2:27])[N+:23]=3[CH3:28])[CH2:7][S:8][C@H:9]12
Reactant: Cc1c(N)nc(=S)n(C)c1N
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: N
Solvent: CC#N
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(N)nc(SCC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)[n+](C)c1N
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.1 %

Procedure:
Under an anhydrous condition, a solution containing 2.72 g of 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid and 1.70 g of 4,6-diamino-1,5-dimethyl-2-(1H)-pyrimidinethione suspended in a mixture of 10 ml of dry acetonitrile and 10 ml of dioxane was cooled to 0° C.; and 4.8 ml of boron trifluoride diethylether was added. The temperature of the reaction solution was increased to 50° C.; the solution was stirred for five hours; and then 10 ml of methyl alcohol was added. The resultant solution was stirred for 10 minutes and was added with 30 ml of ice water. The pH of the solution was adjusted to 7.1 by adding aqueous ammonia solution After concentration under a reduced pressure, e.g., about 20 mmHg, the solution was adjusted to pH 3.7 with 2N-aqueous hydrochloric acid; and allowed to stand at a room temperature for 24 hrs. The precipitates resulted from the reaction solution were filtered, washed with 10 ml of distilled water and with 10 ml of methyl alcohol, and dried to give 3.02 g of the title compound as a solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].O[N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:3][C:2]([C:1]([O:6][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])=[O:5])=[CH2:4]
Reactant: O=C1CCC(=O)N1O
Reactant: C=C(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: C=C(C)C(=O)ON1C(=O)CCC1=O
Reaction time: 3 h
Yield: 71.7 %

Procedure:
In 20 ml of acetonitrile were dissolved methacrylic acid (1.72 g, 20 m mols) and N-hydroxysuccinimide (2.19 g, 19 m mols), and under ice-cooling, N,N'-dicyclohexylcarbodiimide (4.33 g, 21 m mols) was added. The reaction was conducted in the dark, at 0° C. for one hour and at room temperature for 3 hours. The precipitate was separated by filtration and the filtrate was distilled under reduced pressure. To the residue was added petroleum ether and, after cooling, the crystals were collected by filtration. By the above procedure there was obtained 2.5 g of methacrylic acid N-hydroxysuccinimide ester as crystals melting at 100°-102° C.
Reaction SMILES: O[C@H:2]([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=[O:7])[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:4][C@@H:3]1[C@H:2]([CH3:36])[O:7][C:6]([C:8]2[NH:9][C:10]([C:13]3[CH:18]=[C:17]([CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=3)[O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[N:22][CH:21]=3)=[CH:11][CH:12]=2)=[N:5]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
N-[(1R,2R)-2-Hydroxy-1-methylpropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.33 g, 2.57 mmol) synthesized in Example (88b) was dissolved in tetrahydrofuran (25 mL), and anhydrous methanesulfonic acid (0.92 g, 5.14 mmol) and triethylamine (1.43 mL, 10.28 mmol) were added, followed by stirring at 50° C. for 5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (40 mL) was added, and the solution was separated with ethyl acetate (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-70%) to afford the desired compound (0.95 g, yield 74%) as a white solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:17][CH2:16]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:19][CH2:20]1)([OH:10])=[O:8]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Yield: 77.3 %

Procedure:
To a solution of 700 mg (1.32 mmol) of 3-[1-(3-benzyloxycarbonylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in acetic acid was added 50 mg 10 % palladium-carbon, and the mixture was stirred for 5 hours in a hydrogen atmosphere at ambient temperature. The reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. The resulting crude crystals were recrystallized from ethanol to give 450 mg (1.02 mmol) of the title compound.