Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]4)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C1COCC1>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:19][CH2:18][N+:17]([O-:33])([CH2:22][CH2:21]3)[CH2:16]4)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(-c2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)s2)cc1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3ncc(-c4ccccc4)s3)O1)C2
Yield: 27.6 %

Procedure:
(R)—N-(5-Phenylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.101 g, 0.297 mmol) was dissolved in THF (15 mL) and treated with m-CPBA (0.061 g, 0.356 mmol) for 30 min. at room temperature. The reaction was concentrated in vacuo to afford the crude product. The crude product was purified by reverse phase HPLC to yield pure fractions. The fractions were concentrated via vacuo and dried in a vac. oven for 18 hours to yield (S)-2-(5-phenylthiazol-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.03 g, 0.082 mmol, 27.8% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.86-8.12 (m, 1H), 7.64 (br. s., 2H), 7.44 (s, 3H), 4.13-4.31 (m, 3H), 3.97-4.07 (m, 1H), 3.90 (d, J=10.7 Hz, 4H), 3.54-3.74 (m, 1H), 2.28-2.42 (m, 1H), 1.95-2.24 (m, 3H). LC/MS: retention time 1.04 (M+1=357.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=3)=[CH:23]2)=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccc(NC(=O)c5ccc(Cl)cc5)cc4c3)c2cc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.110 g, 0.31 mmol) in 10 ml of CH2Cl2 was added K2CO3 (0.086 g, 0.62 mmol). The mixture was cooled to 0° C. and 4-chlorobenzoyl chloride (44 mL, 0.34 mmol) was added. The solution was stirred for 16 h and allowed to gradually warm up to RT. The reaction was diluted with water and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 485.0 (M+1). Mass Calc'd for C29H21ClN2O4: 484.937.
Reaction SMILES: [CH2:1]([Cl:6])[C:2]([F:5])([F:4])[F:3].[CH2:7]([F:12])[C:8]([F:11])([F:10])[F:9]>>[CH3:1][C:2]([F:5])([F:4])[F:3].[CH:7]([F:3])([F:12])[C:8]([F:11])([F:10])[F:9].[CH2:1]([Cl:6])[C:2]([F:5])([F:4])[F:3]
Reactant: FCC(F)(F)F
Agent: FC(F)(F)CCl
Product: CC(F)(F)F
Product: FC(F)C(F)(F)F

Procedure:
From the above results, it is believed that the reaction of HCFC-133a into HFC-134a occurs predominantly and HFC-143a and HFC-125 are produced from a side reaction in the first reactor, whereas the reaction of TCE into HCFC-133a is predominant but production of HFC-134a from HFC-134a is little in the second reactor.
Reaction SMILES: N1[C:10]2[C:5](=[C:6]([S:11]([N:14]3[CH2:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][O:17][CH2:16][C@H:15]3[CH2:26][OH:27])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=CC=1.[H-].[Na+].[CH3:30]I.C[N:33]([CH:35]=O)[CH3:34]>>[CH3:30][O:27][CH2:26][C@H:15]1[N:14]([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:34]=2[N:33]=[CH:35][CH:4]=[CH:5]3)(=[O:13])=[O:12])[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH2:18][O:17][CH2:16]1
Reactant: O=S(=O)(c1cccc2ncccc12)N1Cc2ccccc2COC[C@H]1CO
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of compound 15 (40 mg, 0.1 mmol) in DMF (3 mL) at 0° C. was added NaH (168 mg, 0.4 mmol). The mixture was stirred at rt for 0.5 h and to it was added MeI (22 mg, 0.16 mmol). The reaction was stirred at rt for 2.5 h, quenched with H2O and extracted with EA (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give compound 16 (22 mg, 53% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.51 (d, 1H, J=8.0 Hz), 8.16 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=8.0 Hz), 7.60 (t, 1H, J=8.0 Hz), 7.46-7.43 (m, 1H), 7.18 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=7.6 Hz), 6.91-6.82 (m, 2H), 5.12 (d, 1H, J=8.0 Hz), 4.99-4.90 (m, 2H), 4.72 (s, 1H), 4.62-4.59 (d, 1H), 4.23 (d, 1H, J=8.0 Hz), 3.76 (d, 1H, J=8.8 Hz), 3.60 (t, 1H, J=8.0 Hz), 3.33-3.29 (m, 1H), 3.17 (s, 3H). MS (ESI) calcd for [C21H22N2O4S+H]+ (m/z): 399.48. found: 399.2.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].[C:21]([NH:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30][C:31](=O)[C:26]=12)=[O:29])(=[O:23])[CH3:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:31](=[O:30])[C:26]3[C:27](=[CH:33][CH:34]=[CH:35][C:25]=3[NH:24][C:21](=[O:23])[CH3:22])[C:28]2=[O:29])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 402.8 %

Procedure:
N-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of example 4 from 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.6 g, 0.2 mmol), 3-acetamido-phthalic anhydride (0.4 g, 0.2 mmol) and sodium acetate (0.16 g, 0.2 mmol) in acetic acid (15 ml) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as white solid (0.4 g, 40%): mp 118-120° C.; 1H NMR (CDCl3) δ1.45 (t, J=7.0 Hz, 3H, CH3), 2.27 (s, 3H, CH3CO), 2.92 (s, 3H, SO2CH3), 3.66 (dd, J=3.8, 14 Hz, 1H, CH2), 4.11 (q, J=6.8 Hz, 2H, OCH2), 5.88-5.94 (m, 1H, NCH), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.12-7.16 (m, 3H, Ar), 7.49 (d, J=7.5 Hz, 1H, Ar), 7.66 (t, J=7.5 Hz, 1H, Ar), 8.77 (d, J=8.5 Hz, 1H, Ar), 9.44 (s, 1H, NH); 13C NMR (CDCl3) δ 14.5, 24.9, 41.7, 48.3, 54.1, 64.9, 11.5, 113.6, 115.0, 115.8, 118.3, 120.0, 120.2, 123.1, 125.1, 130.9, 135.4, 136.2, 137.7, 140.4, 150.9, 167.4, 169.1, 169.4; Anal Calcd for C22H22F2N2O7S: C, 53.22; H, 4.47; N, 5.64. Found: C, 53.18; H, 4.20; N, 5.64.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:39])=[C:19]([C:21]2([CH:36]([F:38])[F:37])[CH2:23][N:22]2[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:20]=1>CN(C=O)C.C1COCC1>[C:6]([O:5][C:3](=[O:4])[C:2]([O:1][CH2:23][C:21]([C:19]1[CH:20]=[C:15]([Br:14])[CH:16]=[CH:17][C:18]=1[F:39])([NH:22][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:36]([F:38])[F:37])([CH3:11])[CH3:10])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1(c1cc(Br)ccc1F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)OCC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])(c1cc(Br)ccc1F)C(F)F
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of tert-butyl α-hydroxyisobutyrate (533 mg, 3.32 mmol) in 4.5 mL DMF and 0.75 mL THF was added portion wise (133 mg, 3.32 mmol) sodium hydride at room temperature. After the reaction mixture had been stirring for 15 minutes, a solution of 2-(5-bromo-2-fluoro-phenyl)-2-difluoromethyl-1-(2-nitro-benzenesulfonyl)-aziridine (1 g, 2.22 mmol) was added. The reaction mixture was stirred at rt for 150 minutes and quenched with aqueous NH4Cl solution. TBME was added, the layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 6/1→5/1 to give 1.10 g of the title compound as a pale yellow resin.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[CH:22]([C:25]1[S:26][CH:27]=[C:28]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[N:29]=1)([CH3:24])[CH3:23].[Si]([O:50][CH2:51][C:52]([C:55]1[C:56]([F:63])=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH:58]=O)([CH3:54])[CH3:53])(C(C)(C)C)(C)C.C(O)(=O)C>CN1C(=O)CCC1>[F:63][C:56]1[C:55]([C:52]([CH3:54])([CH3:53])[CH2:51][OH:50])=[CH:62][CH:61]=[CH:60][C:57]=1[CH2:58][N:40]1[CH2:39][CH2:38][C:36]2([O:35][CH2:34][CH2:33][N:32]([C:30]([C:28]3[N:29]=[C:25]([CH:22]([CH3:24])[CH3:23])[S:26][CH:27]=3)=[O:31])[CH2:37]2)[CH2:42][CH2:41]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cccc(C=O)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(C)(C)CO)c4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (0.502 g) was added to a stirred solution at 0° C. of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.668 g) and 3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluorobenzaldehyde (example 90, step f) (0.49 g) and acetic acid (0.090 mL) in NMP (20 mL). The reaction mixture was then stirred at 20° C. for 18 hours. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The resultant gum was dissolved in THF (20 mL) and treated with tetrabutylammonium fluoride (1M in THF, 3.16 mL). The solution was allowed to stand at 20° C. for 8 hours. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 0 to 1% methanol in dichloromethane with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.63 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][S:10]C.[Na]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10][CH3:9])[N:3]=1
Reactant: CSC
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,6-dibromopyridine. (1.0 eq.) in DMSO (0.3M) was added sodium methylsulfide (1.1 eq.). The mixture was stirred for 2 d at rt then poured in water. The resulting precipitate was filtered off and the filtrate was extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[O-:16]C1C=C2C(C=CC(S([O-])(=O)=O)=C2)=CC=1.[Na+].[Na+]>>[OH:16][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Reactant: NS(=O)(=O)c1ccc2ccc(I)cc2c1
Agent: [Na+]
Product: NS(=O)(=O)c1ccc2ccc(O)cc2c1
Yield: 5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 11, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 1.00 g, 3.73 mmol) was converted to the title compound (40 mg, 5%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 8.17 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.62 (dd, J=8.6, 1.8 Hz, 1H), 7.35 (s, 2H), 7.28 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.9, 2.3 Hz, 1H); MS(ESI−) m/z 236.3 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[CH2:20]([SH:22])[CH3:21].[H-].[Na+].O>O1CCCC1>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:4]=[C:3]([CH2:2][S:22][CH2:20][CH3:21])[CH:7]=[N:6]1
Reactant: CCS
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl) 2H-1,2,3-triazole (2.9 g) was added portionwise to a stirred mixture of ethanethiol (0.5 g) and sodium hydride (0.25 g) in tetrahydrofuran (30 ml) and the mixture stirred at room temperature for 3 hours. The mixture was added to water and extracted with ether. The extract was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(ethylthiomethyl)-2H-1,2,3-triazole, m.p. 53°-54°. (Compound 19)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:24]1N=NC2C=[CH:28][CH:29]=[CH:30][C:25]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38]N1CCOCC1.N1CCCC1>CN(C=O)C>[CH3:14][C:13]([CH3:15])([CH3:38])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[N:24]1[CH2:25][CH2:30][CH2:29][CH2:28]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN1CCOCC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCCC1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (7.00 g, 30.3 mmol) and TBTU (9.72 g, 30.27 mmol) was mixed in DMF (70 mL). The mixture was cooled to 0° C. and NMM (3.99 mL, 36.3 mmol) was added. After 10 min was pyrrolidine (3.00 mL, 36.32 mmol) added. The resultant mixture was stirred at 0° C. for 30 min. and at rt over night. The mixture was concentrated and the residue dissolved in DCM (250 mL). The organic phase was washed with NaHCO3 (saturated, 2×200 mL) and brine (200 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1 to 90:10, KP-SIL 340 g column). The solvent was removed under reduced pressure to give the title compound (6.4 g, 74%). 1H NMR (400 MHz, CDCl3) δ 0.99, 1.43, 1.80-2.01, 3.31-3.45, 3.47-3.59, 3.67-3.79, 4.29, 5.28. Total no of protons: 27. LCMS (M+H)+: 285.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[C:8]1([CH3:40])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1N[C:17]2[CH:23]=[C:22]([CH2:24][C:25]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([CH:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37])=[N:32][CH:33]=3)=[O:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.F[P-](F)(F)(F)(F)F.N1([O:57]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.NC1C=CC(C(C)CC(OCC)=O)=NC=1>CN(C)C=O>[CH2:2]([O:38][C:36](=[O:37])[CH2:35][CH:34]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25](=[O:26])[CH2:24][C:22]2[CH:21]=[CH:20][C:18]3[N:19]=[C:15]([NH:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH3:40])[O:57][C:17]=3[CH:23]=2)=[CH:33][N:32]=1)[CH3:39])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C(C)CC(=O)O)nc3)cc2[nH]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCOC(=O)CC(C)c1ccc(N)cn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 140.5 %

Procedure:
A stirred solution of 2-o-tolylamino-benzoxazol-6-acetic acid (0.42 g, Reference Example 2) in dimethylformamide (15 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.57 g), then with diisopropylethylamine (0.4 g) and then with a solution of ethyl (3RS)-3-(5-aminopyrid-2-yl)butyrate (0.3 g, Reference Example 5) in dimethylformamide (5 mL). The mixture was stirred at room temperature for 5 hours then left to stand over night and then evaporated to low bulk. The residue was partitioned between water and ethyl acetate. The organic phase was washed with dilute acetic acid, then with water, then with aqueous bicarbonate solution (5%), then with water, then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give the title compound (0.5 g) as a colourless glass. TLC: RF=0.36 (eluting with ethyl acetate). MS: 473 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[CH3:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22]/[CH:23]=[CH:24]/[CH2:25][CH3:26]>CN(C)C=O>[CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH2:22]/[CH:23]=[CH:24]/[CH2:25][CH3:26])[CH:8]=[CH:7][C:6]=2[CH3:13]
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Reactant: CC/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC/C=C/COc1ccc(C)c2[nH]c(=O)c(C)cc12
Yield: 25.6 %

Procedure:
3,8-Dimethyl-5-hydroxycarbostyril (1.72 g, 9.1 mmol), potassium carbonate (2.51 g, 18.1 mmol), E-1-Bromo-2-pentene (2.0 g, 13.4 mmol) and dimethylformamide (30 ml) were allowed to react at 60° C. for 1 hour. After the completion of the reaction, the procedure described in Reference Example 31 was followed to obtain 0.60 g of the title compound as a colorless solid (25.6%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>ClCCl>[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])=[O:18])=[CH:15][CH:14]=1
Reactant: CO[Si](CCCN)(OC)OC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClCCl
Product: CO[Si](CCCNC(=O)c1ccc(I)cc1)(OC)OC
Reaction time: 1 h

Procedure:
4-Iodo-N-[3-(trimethoxysilyl)propyl]-benzamide (1) was prepared, as illustrated in FIG. 5, where a solution of 3-aminopropyltrimethoxysilane (1.78 mL, 10 mmol) in 10 mL of dichloromethane was added dropwise to a suspension of 4-iodobenzoyl chloride (1.33 g, 5 mmol) in 20 mL of dichloromethane at 0° C. The mixture was stirred for 1 hour and solvent was evaporated in vacuo. The residue was purified by column chromatography on silica using 2% methanol in chloroform. The solvent was removed by rotary evaporation to give a viscous oil. 1H NMR (300 MHz, CDCl3): δ 0.70 (t, J=8.1 Hz, 2H), 1.73 (m, 2H), 3.42 (m, 2H), 6.64 (br, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 6.81, 22.78, 42.54, 50.89, 98.41, 128.78, 134.44, 137.91, 167.03. HRMS calculated for C13H20INO4Si 409.0206, found 410.0295 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[I:35])=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[I:35][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]1[C:10]2[N:9]=[CH:8][N:7]([C:1]3[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=3)[C:12](=[O:13])[C:11]=2[S:14][CH:15]=1
Reactant: CCOC(OCC)OCC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2I)c1N
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccccc4I)csc3c2=O)cc1
Yield: 51 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-iodophenyl)thiophene-2-carboxylate (700 mg, 1.95 mmol), triethyl orthoformate (3 ml), p-anisidine (231 mg, 2.12 mmol), and acetic acid (0.3 ml) were used to give 460 mg (1.00 mmol, 51% yield) of the title compound.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([S:20][C:21]2[N:25]([CH3:26])[N:24]=[N:23][N:22]=2)[C:8]=1[CH2:27][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:35](N(CC)CC)C.CI>C(#N)C>[C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:18])(=[O:19])[C:9]([CH3:35])([S:20][C:21]2[N:25]([CH3:26])[N:24]=[N:23][N:22]=2)[C:8]=1[CH2:27][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(Sc3nnnn3C)S(=O)(=O)[C@H]12
Solvent: CC#N
Solvent: CI
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(C)(Sc3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-(1-methyl-1,2,3,4-tetrazol -5-yl)thiomethyl-3-cephem 1,1-dioxide (100 mg), prepared as described in PTC EP 90/02189 in acetonitrile (2 ml) was treated at room temperature with triethylamine (0.040 ml) and methyl iodide (0.060 ml). The reaction mixture was stirred for 30 minutes and the organic solvent completely removed in vacuo. The resulting crude residue was eventually taken up in dichloromethane and purified by flash chromatography affording the title compound as a yellowish solid (40 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:11]1([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:19][C:18]([CH3:21])([C:17]([O:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:22])[CH3:20]
Reactant: CC(C)(N)C(=O)OC1CCCC1
Reactant: O=Cc1cccc(CBr)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(NCc1cccc(CBr)c1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
To a solution of 3-(bromomethyl)-benzaldehyde (0.503 g, 2.52 mmol) in dichloroethane (20 mL) was added α,α-dimethylglycine cyclopentyl ester (0.893 g, 5.2 mmol) and sodium triacetoxyborohydride (1.47 g, 6.9 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (3 times 50 mL). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, 7:3 heptane:ethyl acetate) to yield the desired product (0.350 g, 39% yield). LC/MS: m/z 354/356 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:17]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[N:17][C:6]=1[CH3:7]
Reactant: Cc1cccc(C(=O)c2cc(C)c(C)o2)n1
Reactant: N
Solvent: CO
Product: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Temperature: 160 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (810 mg), methanol (7 ml), and a 28% aqueous ammonia solution (7 ml) were placed in a sealed tube, and the mixture was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6,6′-trimethyl-[2,2′]bipyridin-3-ol (753 mg, yield 93%).