Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)(=O)C>[C:1]1([CH:7]2[C:8]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:9]=3[CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CCC2
Temperature: 130 °C
Reaction time: 2 h
Yield: 19.62 %

Procedure:
A solution of 2-phenylcyclohexanone (1.500 g, 8.61 mmol) and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was stirred at 58° C. in a high-pressure vessel (75 mL) for 1 h. The temperature was raised to 130° C. and the reaction mixture was stirred for 2 h. After cooling to room temperature, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuum and the oily residue was purified by column chromatography on silica gel to provide 8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-phenyl-4-a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:22])[C@@H:14]([CH3:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[NH:68]([C:77]([O:79][CH2:80][C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)=[O:78])[C@H:69]([C:74]([OH:76])=O)[C@H:70]([CH2:72][CH3:73])[CH3:71].CN1CCOCC1.ClC(OCC(C)C)=O>CN(C=O)C.[Pd]>[C:40]1([O:39][C:37](=[O:38])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[NH:23][C:21](=[O:22])[C@H:13]([C@@H:14]([CH3:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[NH:12][C:10](=[O:11])[C@H:2]([C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[NH:1][C:74](=[O:76])[C@H:69]([C@H:70]([CH2:72][CH3:73])[CH3:71])[NH:68][C:77]([O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)=[O:78])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.08 h

Procedure:
A solution of Z-Thr(tBu)-Thr(tBu)-Lys(Boc)-OPh (346.9 g, 450 mmol) in 1 l DMF was hydrogenated in the presence of Tos-OH.H2O (85.6 g, 450 mmol) and 10% Pd-C. After the hydrogenation was completed the catalyst was filtered off. Z-Ile-OH (132.66, 500 mmol) was dissolved in 700 ml DMF and cooled to -35° C. While stirring at -35° C., N-methylmorpholine (55 ml, 500 mmol) was added, followed by the addition of isobutyl chloroformate (65 ml, 500 mmol). The reaction mixture was activated for 5 min. at -15° C. and quickly cooled to -20° C. The precooled DMF solution (-25° C.) from the hydrogenation step and N-methylmorpholine (50 ml, 450 mmol) were added simultaneously. The reaction mixture was stirred for 15 min. at -15° C. and 1 h at 25° C. and evaporated in vacuo. The residue was dissolved in 3 l ethyl acetate and washed with 10% Na2CO3 sol. (2×1.5 l), satd. NaCl-sol. (1×1 l), 5% KHSO4 /10% K2SO4 sol. (2×1.5 l) and satd. NaCl-sol., dried over Na2SO4, filtered and evaporated in vacuo. The residue was crystallized from ethyl acetate (2 l)/ether (2 l).
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[C:4]([OH:21])[CH:3]=1.C(OC([NH:29][C:30]1([C@@H:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH2:32][CH2:31]1)=O)(C)(C)C.CN1CCCCC1>CS(C)=O>[NH2:29][C:30]1([C@@H:33]2[CH2:37][CH2:36][N:35]([C:2]3[C:11]([CH3:12])=[C:10]4[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]4[C@@H:13]4[CH2:15][C@@H:14]4[F:16])=[C:4]([OH:21])[CH:3]=3)[CH2:34]2)[CH2:32][CH2:31]1
Reactant: Cc1c(F)cc(O)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CN1CCCCC1
Product: Cc1c(N2CC[C@@H](C3(N)CC3)C2)cc(O)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 66 h

Procedure:
A mixture of 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (205 mg, 0.694 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (314 mg, 1.388 mmol), N-methyl piperidine (0.243 ml, 1.388 mmol), and dimethyl sulfoxide (1.5 ml) was stirred for 66 hours while heating in an oil bath at 80° C. under a nitrogen-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (50 ml) and 10% aqueous citric acid solution (30 ml), and after separating the organic layer, the aqueous layer was further subject to extraction into chloroform (30 ml). The combined organic layer was then dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure to thereby obtain a crude 7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]([C:24]3[CH:29]=[C:28]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)[CH:27]=[CH:26][C:25]=3[Cl:35])[OH:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:23])[C:24]3[CH:29]=[C:28]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)[CH:27]=[CH:26][C:25]=3[Cl:35])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1cc(-n2cccn2)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)c1cc(-n2cccn2)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A mixture of 4-chloro-N-{5-chloro-2-[(2-chloro-5-pyrazol-1-yl-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (400 mg, 0.64 mol), Dess-Martin periodinane (409 mg, 0.96 mmol), in DCM was stirred at RT for 2 hours and then purified by flash column to give 4-chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:64])([F:63])[C:15]([O:24][CH2:25][C:26]([CH2:48][O:49][C:50]([C:59]([F:62])([F:61])[F:60])([C:55]([F:58])([F:57])[F:56])[C:51]([F:54])([F:53])[F:52])([CH2:33][O:34][C:35]([C:44]([F:47])([F:46])[F:45])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][OH:32])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17].C(Cl)Cl>C1COCC1>[CH3:8][S:9]([O:32][CH2:31][CH2:30][CH2:29][O:28][CH2:27][C:26]([CH2:33][O:34][C:35]([C:36]([F:39])([F:38])[F:37])([C:40]([F:41])([F:42])[F:43])[C:44]([F:47])([F:46])[F:45])([CH2:48][O:49][C:50]([C:51]([F:52])([F:53])[F:54])([C:55]([F:56])([F:57])[F:58])[C:59]([F:60])([F:61])[F:62])[CH2:25][O:24][C:15]([C:16]([F:19])([F:18])[F:17])([C:20]([F:23])([F:22])[F:21])[C:14]([F:63])([F:64])[F:13])(=[O:11])=[O:10]
Reactant: OCCCOCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Triethylamine (Et3N, 9.6 mL) and methanesulfonyl chloride (5.4 mL, 68.4 mmol) were added to a solution of compound 5 (20.2 g, 23.8 mmol) dissolved in THF (100 mL) and anhydrous CH2Cl2 (200 mL) mixed solvent at 0° C. The reaction mixture was then stirred at room temperature overnight. The reaction was quenched with water and extracted with CH2Cl2. Evaporation through rotary evaporation followed by flash chromatography on silica gel using hexane/EtOAc as the eluent afforded product mesylate 6 (20.8 g, 22.5 mmol, 95% yield) as a colorless oil: 1H NMR (500 MHz, CD3COCD3) δ 4.21 (t, J=7.5 Hz, 2H), 4.11 (s, 6H), 3.48 (t, J=5.0 Hz, 2H), 3.42 (s, 2H), 2.94 (s, 3H), 1.94-1.90 (m, 2H); 13C NMR (126 MHz, CD3COCD3) δ 122.9 (q, J=293.0 Hz), 81.2-81.0 (m), 68.6, 68.5, 67.1, 67.0, 47.7, 37.6, 30.7; 19F NMR (470 MHz, CD3COCD3) δ −71.19 (s); MS (APCI) m/z 927 (M+H)+, 831 (M−OMs)+; HRMS (ESI) calcd for C21H18F27O7S, 927.0342 (M+H)+, 944.0608 [M+NH4]+. found 927.0357, 944.0553, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:37])=[C:9]([N:11]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.[OH-].[Na+:39]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:37])=[C:9]([N:11]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=3)[S:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.[Na+:39]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc3ccc(F)cn3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)nc2ccc(F)cn12

Procedure:
A solution of Compound 118 (0.200 g, 0.372 mmol) in MeOH (10 mL) was treated with 1N NaOH (0.383 mL, 0.383 mmol) and heated at reflux for 1 day. The solvent was evaporated in vacuo to give the Compound 120, as a colorless solid (0.184 g, 91%). 1H-NMR (DMSO-d6): δ 8.46-8.51 (m, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.56 (dd, J=9.9, 5.3 Hz, 1H), 7.21-7.41 (m, 5H), 4.75 (s, 2H), 2.25 (s, 3H); MS: m/z 524 (MH+ of carboxylic acid).
Reaction SMILES: [Li]C(C)(C)C.I[C:7]1[C:15]2[C:10](=[CH:11][C:12](C(C3C=CC=CC=3)=C)=[CH:13][CH:14]=2)[N:9](COCC[Si](C)(C)C)[N:8]=1.C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: C=C(c1ccccc1)c1ccc2c(I)nn(COCC[Si](C)(C)C)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc2[nH]ncc2c1
Temperature: 42 °C
Reaction time: 0.33 h
Yield: 197 %

Procedure:
E-2-Bromostyrene (23 μL, 0.174 mmol, 2.5 equiv) was dissolved in THF (1.0 mL) and was cooled to −78° C. t-BuLi (205 μL, 0.348 mmol, 5.00 equiv) was added and the mixture was warmed to 42° C. for 7 min to give a deep red mixture. The solution was added to freshly dried zinc chloride (29 mg, 0.209 mmol, 3.00 equiv) via cannula and the mix was allowed to warm to 23° C. with stirring for 20 min. This solution was added to a neat mixture of 3-Iodo-6-(1-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (33.1 mg, 0.0696 mmol, 1.0 equiv) and Pd(PPh3)4 (4 mg, 0.0035 mmol, 0.05 equiv) at 23° C. via cannula. This solution was allowed to stir for 15 min and was treated with saturated sodium bicarbonate and extracted with ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography using two columns (5:95 ethyl acetate-hexane; 12 mL silica: and 1:99 ethyl acetate-benzene; 12 mL silica) gave 6-(1-Phenyl-vinyl)-3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazole (16.2 mg, 51%): Rf sm 0.38, p 0.29 (ethyl acetate-hexane 1:9); 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H, J=8.4 Hz), 7.62-7.22 (m, 14H), 5.71 (s, 2H), 5.57 (s, 2H), 3.60 (t, 2H, J=8.2 Hz), 0.90 (t, 2H, J=8.2 Hz), −0.08 (s, 9H); HRMS (FAB) [m+H]/z Calc'd 453.2362, Found 453.2354.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6]([CH3:9])([CH3:8])[CH2:5][NH:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:8][C:6]1([CH3:9])[CH2:5][NH:4][CH2:3][C@@H:2]([CH3:1])[NH:7]1
Reactant: C[C@H]1NC(C)(C)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CNCC(C)(C)N1
Reaction time: 1 h

Procedure:
3(R),5,5-Trimethylpiperazin-2-one (XXX, Step III, 0.91 g) is added portionwise to a mixture of lithium aluminum hydride (0.45 g) in THF (40 ml). The reaction is allowed to stir at 20-25° for 1 hr and at reflux for an additional 2 hr. After cooling to 20-25° the reaction is quenched by the successive addition of water (0.5 ml), sodium hydroxide (15%, 0.5 ml) and water (1.5 ml). After stirring for 0.5 hr the solids are filtered off and the filtrate is dried over magnesium sulfate. The mixture is filtered and methanolic hydrochloric acid (5 ml) is added. After stirring for 1 hr the methanol is removed under reduced pressure and the remaining solid is triturated with ether to provide the title compound, mp >250°; IR (mineral oil) 2994, 2986, 2978, 2923, 1580, 1390 and 990 cm-1 ; NMR (CD3OD) 3.80-3.93, 3.52-3.65, 3.15-3.30, 1.59, 1.56 and 1.45 δ; MS (m/e) 128, 113 and 84; [α]25D -9° (methanol).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1)([O-])=O>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([N:7]2[CH:8]=[C:4]([NH2:1])[N:5]=[CH:6]2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cn(-c2cccc(C(F)(F)F)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Nc1cn(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 4-nitro-1-(3-(trifluoromethyl)phenyl)-1H-imidazole (1.5 g, 5.54 mmol, 1.00 equiv, 95%) in methanol (30 mL). The mixture was treated with Pd/C (1.5 g) and stirred under a hydrogen atmosphere for 4 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.2 g (88%) of 1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-amine as a brown oil.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][Si:2]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (1.9 ml, 15 mmol) was added dropwise to a stirred solution of 4-bromobenzyl alcohol (2.0 g, 11 mmol) in toluene (25 ml) and pyridine (2 ml) at 0° C. The stirred mixture was heated to ambient temperature during 3 hours. The reaction mixture was filtered and the organic solution evaporated to yield pure 4-bromobenzyl trimethylsilyl ether. The silyl ether can be further purified by distillation (b.p. 73° C., 0.1 mm Hg). Yield after distillation: 1.49 g (50%).
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][C:7]([O:9]C)=O)[CH2:2][CH3:3].C[O-].[Na+].[CH2:17]([CH2:19][NH2:20])[OH:18]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[OH:18][CH2:17][CH2:19][NH:20][C:7](=[O:9])[CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:11][CH2:12][CH3:13]
Reactant: CCCN(CCC)CCC(=O)OC
Reactant: NCCO
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCCN(CCC)CCC(=O)NCCO
Yield: 99.6 %

Procedure:
To 746 g of methyl beta-dipropylaminopropionate which was prepared in the same manner as in Example 4 were added 15.4 g of 28% methanolic solution of sodium methoxide, then 293 g (4.8 moles) of ethanolamine were added dropwise thereinto and the mixture was made to react at 70° C. for one hour. After completion of the reaction, the mixture was neutralized, desalted, 0.3 g of phenothiazine were added thereto and the low-boiling-point substances were removed by distillation to give 858 grams of N-hydroxyethyl-beta-dipropylaminopropionamide. The purity as checked by gas chromatography was 98% and the yield was 97.3%.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.C(Cl)(Cl)Cl.CO>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:47]4[CH:48]=[CH:49][C:44]([C:43](=[O:50])[NH2:51])=[CH:45][CH:46]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: NC(=O)c1ccncc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Yield: 8.1 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E isomer, 4.1 g, 5.7 mmoles) and isonicotinamide (1.4 g, 11 mmoles) in dry DMSO (6 ml) was stirred for 2 hours at room temperature while monitoring by TLC (silica gel plate, CHCl3 :CH3OH=3:1). The reaction mixture was diluted with ethyl acetate (100 ml) to separate a yellow gum, which was treated with formic acid (40 ml) and sodium bisulfite (390 mg) at 45° C. for 30 minutes. The resulting solution was concentrated to dryness. The residue was dissolved in H2O (100 ml) and insolubles were removed by filtration. The combined filtrate and water wash was applied to the top of a column containing reverse phase packing (PrepPAK-500/C18, 120 ml). The column was eluted with H2O. The eluate was collected in 300 ml fractions and monitored by uv (254 nm) and HPLC (Lichrosorb RP-18, 4×300 mm, 0.01M ammonium phosphate buffer, pH 7.2 containing 20% CH3OH). Fraction Nos. 4 and 5 were combined and concentrated to a small volume. Lyophilization gave 250 mg (8.1%) of the title compound I-1H, melting at >180° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4](/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.O>[CH3:1][C:2]1[S:3][C:4](/[CH:17]=[CH:18]/[CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1
Reactant: CCCCCC(O)/C=C/c1sc(C)nc1CCCCCCC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC(/C=C/c1sc(C)nc1CCCCCCC(=O)OC)OC(C)=O
Reaction time: 24 h

Procedure:
To the solution of 367 mg of 2-methyl-4-(6-carbomethoxy-hexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Ic, R1 = CH3) in 4 ml of anhydrous pyridine, 1 ml of acetic anhydride was added. The reaction mixture was allowed to stand for 24 hours at room temperature, diluted with 50 ml of water and extracted with 3 × 15 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated in vacuo. The obtained 403 mg of evaporation residue was purified by preparative thin layer chromatography, using a silica gel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. Thus, 290 mg of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-acetoxy-1-trans-octenyl)-thiazole (Ie, R1 = CH3) of chromatographic purity were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:9][CH:8]=1.[ClH:30]>ClCCl.O1CCOCC1>[ClH:30].[ClH:30].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12]([N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][NH2:22])[CH2:19][CH2:20]2)(=[O:13])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the compound prepared in Example 243 (0.088 g) in dichloromethane (1 mL) was treated with 4N hydrogen chloride in dioxane (0.151 mL) at room temperature. The mixture was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo to provide the title compound (0.072 g) having the following physical data.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 82 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (86 mg, 82%) which was obtained as a white solid. MS: m/e=365.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1)[CH3:2].[CH3:10][C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[N:4][CH:5]=2)[C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: CCc1ccc(N)cn1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1ccc(-n2c(C)ccc2C)cn1
Yield: 45.7 %

Procedure:
A mixture of 2-ethylpyridin-5-amine (3.2 g, 26 mmol), 2,5-hexanedione (3.0 g, 26 mmol) and acetic acid (1 ml) in toluene (50 ml) was heated under reflux for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (20 ml). The aqueous phase was basified with aqueous sodium hydroxide (2M) and then extracted with dichloromethane (50 ml). The extract was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica by elution with dichloromethane/methanol (95:5) to give the title compound (2.38 g, 46%) as a colourless oil, which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][O:16][C:14]([C:13]1[CH:12]=[C:11]([CH:20]=[CH:19][CH:18]=1)[O:10][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:15]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1

Procedure:
A solution of t-butyl bromoacetate (506 g, 2.59 mol), methyl 3-hydroxybenzoate (395 g, 2.60 mol) and potassium carbonate (789 g, 5.71 mol) in DMF (2 L) was stirred at room temperature for two hours. The reaction mixture was concentrated and then water (1 L) was added, followed by extraction with ethyl acetate (2 L). The organic layer was washed with water (1 L) twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain t-butyl [3-(methoxycarbonyl)phenoxy]acetate as a colorless oil.