Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[CH3:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][NH2:23])=[N:18][CH:17]=[CH:16][N:15]=1>C(O)(C)C>[CH3:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][NH:23][CH2:7][CH:6]([OH:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1nccnc1OCCN
Reactant: Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: Cc1ccccc1OCC(O)CNCCOc1nccnc1C
Reaction time: 24 h

Procedure:
A solution of 4.92 g of 1-(o-methyl-phenoxy)-2,3-epoxypropane and 4.59 g of 2-methyl-3-(2-amino-ethoxy)-pyrazine in 150 ml of isopropanol is stirred for 24 hours at about 20° C. and thereafter a further 1.47 g of 1-(o-methyl-phenoxy)-2,3-epoxy-propane are added. After standing for a further 24 hours at about 20° C., the reaction mixture is evaporated under a waterpump vacuum, the residue is dissolved in ether, the ether solution is extracted by shaking with 2 N hydrochloric acid and the combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution and extracted by shaking with ether. The combined ether extracts are washed with water, dried over sodium sulphate and evaporated under a waterpump vacuum. The residue crystallises from methylene chloride/petroleum ether, giving 1-[2-(2-methyl-3-pyrazinyloxy)-ethyl-amino]-3-(2-methylphenoxy)-2-propanol; melting point 82°-84° C. The acid fumarate prepared with the calculated amount of fumaric acid crystallises from isopropanol, melting point 140°-141° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: Brc1cncnc1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(Oc2cncnc2)c1
Yield: 47.5 %

Procedure:
NaH (166 mg, 6.92 mmol, 1.10 eq) in DMF (15 mL) in a flame-dried microwave vial was cooled to 0° C. and 3-bromophenol (982 μL, 6.29 mmol, 1.00 eq) was added dropwise. The reaction was stirred for 30 min. at 0° C. at which point 5-bromopyrimidine (1.0 g, 6.3 mmol, 1.0 eq) was added and the reaction microwaved at 200° C. for 60 minutes. The reaction was diluted with ethyl acetate (50 mL) and was with water (3×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 750 mg (52%) of the title compound as an orange oil: 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.67 (s, 2H), 7.43-7.36 (m, 3H), 7.16 (dt, J=7.7, 1.9 Hz, 1H); ES-MS [M+1]+: 251.0.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:28](=[O:29])[N:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18](=[O:27])[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH:11](C(O)=O)[S:12][C@H:7]12)=[O:4].[C:30]1([C:36]2[O:37][C:38]([SH:41])=[N:39][N:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C)C=O.[C:47](=O)([O-:49])[O-:48].[K+].[K+]>CCOCC>[C:30]1([C:36]2[O:37][C:38]([S:41][CH2:2][C:3]([NH:5][CH:6]3[C:28](=[O:29])[N:8]4[C:9]([C:47]([OH:49])=[O:48])=[C:10]([CH2:16][NH:17][C:18](=[O:27])[C:19]5[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=5[Cl:25])[CH2:11][S:12][C@H:7]34)=[O:4])=[N:39][N:40]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CBr)NC1C(=O)N2C=C(CNC(=O)c3c(Cl)cccc3Cl)C(C(=O)O)S[C@H]12
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(CSc1nnc(-c2ccccc2)o1)NC1C(=O)N2C(C(=O)O)=C(CNC(=O)c3c(Cl)cccc3Cl)CS[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
1.0 g. of 7-bromoacetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-carboxylic acid and 0.36 g. of 2-phenyl-5-mercapto-1,3,4-oxadiazole were dissolved in 10 ml. of dimethyl formamide and 0.28 g. of calcinated potassium carbonate were added. The reaction mixture was stirred at room temperature for 8 hours, 30 ml. of ether were added, the precipitate was filtered off and dissolved in 30 ml. of water. The solution was adjusted to pH 5 by adding dilute sulphuric acid and extracted with 20 ml. of ethyl acetate. The aqueous layer was adjusted to pH 2 by adding dilute sulphuric acid and extracted with 60 ml. of ethyl acetate. The organic extract was dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue was treated with ether and dried. 0.72 g. of 7-(2-phenyl-1,3,4-oxadiazole-5-ylthio)acetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][S:11][CH2:12][C@H:13]([O:29][C:30](=[O:42])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:14][O:15][C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CCN(C(C)C)C(C)C.[C:52](Cl)(=[O:68])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>C(Cl)Cl>[CH2:32]([NH:31][C:30]([O:29][C@H:13]([CH2:14][O:15][C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][S:11][CH2:10][C@H:2]([NH:1][C:52](=[O:68])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-tert-butyl 2-amino-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoate in dry DCM (0.1 M) at 0° C. was added DIEA (1.2 eq) and palmitoyl chloride (1.1 eq). The reaction was allowed to warm to room temperature then stirred for 16 hours. The crude reaction was then concentrated and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient 0-60% EtOAc/Hex to afford the title compound as a white solid.
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].CC(C)=O.[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH:1]([CH3:3])[CH3:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)O
Reactant: c1ccccc1
Solvent: CC(C)=O
Product: CC(C)c1ccccc1

Procedure:
Patent Literatures 4 to 6 disclose methods in which isopropanol from the hydrogenation of acetone is directly reacted with benzene to give cumene. In particular, Patent Literature 6 discloses a process in which by-product acetone is hydrogenated to isopropanol, the isopropanol is reacted with benzene, and the resultant cumene is reacted to give phenol. In this process, however, the hydrogenation adds a step to the cumene process.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Br[CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)ccc1Cl
Reactant: CCCBr
Product: CCCN1CCN(c2ccc(Cl)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-Chloro-3-nitro-phenyl)-piperazine and 1-bromopropane, the title compound was recovered by the procedure described in Example 2. m.p. 249° C. (HCl); MS m/z (rel. intensity, 70 eV) 283 (M+, 27), 254 (87), 165 (bp), 153 (78), 56 (90).
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:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH:52][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[CH3:23])=[O:41])[CH3:51])[CH:47]=[CH:48][CH:49]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: C[C@@H](N)c1cccc(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (82 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (17 mg, yield 12%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH3:25][C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.42 g, 5.88 mmol), as prepared in step 3 of Example 1, and N-methylmorpholine (1.29 mL, 11.76 mmol) in methylene chloride (40 mL) was added 3-methylbenzenesulfonyl chloride (1.12 g, 5.88 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. Additional methylene chloride (60 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (5 to 10% ethyl acetate in methylene chloride) to give the title compound as a white solid (2.1 g, 91%). 1H-NMR (300 MHz, CDCl3) 8 7.63 (m, 2H), 7.55 (br s, 1H), 7.42 (d, 1H, J=8 Hz), 7.32 (m, 2H), 6.01 (d, 1H, J=8 Hz), 4.64 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:1][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of benzyl 4-formylpiperidine-1-carboxylate (3 g) and tert-butyl piperazine-1-carboxylate (2.2 g) in dichloromethane (100 ml) was added sodium triacetoxyborohydride ((2.6 g). The resulting solution was stirred at room temperature for 18 hours and then washed with 2M sodium hydroxide (2×50 ml) and 2M hydrochloric acid (2×50 ml), dried over Magnesium sulphate, filtered and evaporated to afford tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (4.9 g) as an oil. Tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (4.9 g) was dissolved in ethanol and purged with argon. 20% Palladium hydroxide on carbon (500 mg) was added. The reaction mixture was purged with argon, evacuated and filled with hydrogen from a balloon. The reaction mixture was stirred at room temperature for 2 hours. A white solid precipitate formed. The reaction mixture was warmed to 40° C. and stirred at this temperature for a further 1 hour until the precipitate dissolved. The reaction mixture was allowed to cool to room temperature and stirred for a further 18 hours. The reaction mixture was purged with argon, filtered through celite and evaporated to afford tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (3.2 g) as a solid. Mass spectrum: M+H+ 284
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1C=CN=C1.[N+:18]([CH:21]=[C:22]1[NH:27][CH2:26][CH2:25][CH2:24][S:23]1)([O-:20])=[O:19].C(COC)[O:29]C>C(Cl)Cl>[N+:18]([C:21](=[C:22]1[NH:27][CH2:26][CH2:25][CH2:24][S:23]1)[C:8]([C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:29])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: COCCOC
Reactant: O=[N+]([O-])C=C1NCCCS1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: O=C(C(=C1NCCCS1)[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution/suspension of 20.4 g of p-nitrobenzyl chloride in 25 ml of monoglyme was added dropwise at 5°-10° to a solution of 9.09 g of N-methylimidazole in 75 ml of monoglyme and the mixture was stirred for an additional 30 minutes at 5°-10°, after which was added dropwise (same temperature) a solution/suspension of 16.0 g of tetrahydro-2-(nitromethylene)-2H-1,3-thiazine in 25 ml of monoglyme, after which the stirred mixture was allowed to warm to room temperature and stirred for 96 hours. The mixture then was taken up in methylene chloride, washed with water and saturated sodium chloride solution, dried (Na2SO4) and the solvent evaporated under reduced pressure to give an oil which was chromatographed on florosil using methylene chloride as eluent to give a gum, which was washed with ether to give 17, as a yellow solid, m.p.: 158°-160.5°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2F)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
Lithium diisopropylamide (10.9 mmol, 2M tetrahydrofuran) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.36 mmol) in tetrahydrofuran (25 mL) at 0° C. After 1.5 h 2-fluorobenzyl bromide (0.788 mL, 6.54 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with the addition of water (10 mL) followed by 1M hydrochloric acid (10 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), the organic layers collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.330 g, (22 %) of 4-(2-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CD3Cl3, 300 MHz) δ 7.11-7.00 (m, 5H), 4.00 (br., 2H), 2.92 (s, 2H), 2.90 (br., 2H), 2.05 (br., 2H), 1.46 (br., 2H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]([CH3:14])=[O:13])[C:9]([OH:11])=[O:10].C(O[C:19](=O)[CH3:20])(=O)C.S(=O)(=O)(O)O.[C:27](=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:11])[O:10][C:19]([CH3:20])([CH3:27])[O:13][C:12]=1[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)C(C(=O)O)c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1=C(c2ccccc2Cl)C(=O)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(2-chlorophenyl)acetoacetic acid (9.6 g), acetone (6.8 ml), and acetic anhydride (8.8 ml) was kept at -15° and concentrated sulfuric acid (0.53 ml) was added thereto. This was kept at -15° C. and the reaction was carried out for 24 hours. The reaction mixture was added to an aqueous 10 % sodium carbonate solution (250 ml) which was ice-cooled, and the mixture was stirred for a short time at room temperature. White crystals which formed were collected by filtration, and washed well with water and then with hexane. The crystals obtained were dried well under reduced pressure to obtain the captioned compound (9.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2ccc(OCc3ccccc3)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
A mixture of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (10.0 g, 19.5 mmol), triethylsilane (15.6 mL, 97.5 mmol) and trifluoroacetic acid (15.0 mL, 195 mmol) was mixed and stirred at 0° C. for 20 min. The mixture was concentrated under vacuum. The residue was triturated with diethyl ether to afford 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (7.40 g, 76%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.44-7.25 (m, 14H), 7.23-7.17 (m 2H), 7.11-7.02 (m, 2H), 6.95 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.55-6.49 (m, 1H), 6.46 (dd, J=8.6, 2.6 Hz, 1H), 5.09 (s, 1H), 4.99 (s, 2H); MS (ES+) m/z 498.3 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH2:16])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].C(#N)C.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(N(CC)CC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH:16][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2]
Reactant: Brc1cccnc1
Reactant: C=CCC(CCCC#N)CCC(=O)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(CC=Cc1cccnc1)CCCC#N

Procedure:
A mixture of 1300 g of ethyl 4-(3-cyanopropyl)-6-heptenoate, 6397 ml of acetonitrile, 3190 mL of triethylamine and 920.9 g of 3-bromopyridine is degassed and then heated to reflux. Palladium II acetate catalyst (13 g) and 36.42 g of tri-o-tolylphosphine are added and the mixture is heated under reflux overnight. Additional catalyst (13 g) is added and the mixture is again heated under reflux for 7 hours. Further catalyst (6.5 g) is again added and the reaction is again heated under reflux overnight. The reaction mixture is cooled, diluted with 6 L of methylene chloride, and evaporated to dryness. The residue is partitioned between ether and water. The ether layer is separated and the aqueous layer is extracted two more times with ether. The combined ether extracts are extracted with 2×8 L of 1 N hydrochloric acid. The acid extract is cooled and made basic with 1200 ml of conc. ammonium hydroxide to pH 10, and extracted with ether (3×8 L). The ether extract is dried over sodium sulfate and evaporated to dryness to yield ethyl 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoate.
Reaction SMILES: [C:1](OCC)(=[O:7])[C:2](OCC)=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1.CC[O-].[Na+].C(O)(=O)C>O>[OH:3][C:2]1[C:1]([OH:7])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ccc(OC)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Diethyl oxalate (83 ml, 0.61 mol) was added dropwise to a stirred solution of diethyl 2,2′4-(4-methoxyphenyl)azanediyl)diacetate (4) (180 g, 0.61 mol) in NaOEt (21% by wt in EtOH) (506 ml, 1.3 mol), the mixture was stirred at 100° C. for 1 h. The reaction was quenched with acetic acid (210 ml, 3.7 mol) and the resulting suspension was poured into iced water (1 L), the resulting off-white solid collected by vacuum filtration. The crude product was recrystallised from hot EtOH (3.5 L) to give diethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-001) (152 g, 71%) as a white solid: m/z 350 (M+H)+ (ES+); 348 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 7.13-7.01 (m, 2H), 6.92-6.81 (m, 2H), 3.99 (q, J=7.1 Hz, 4H), 3.78 (s, 3H), 0.99 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:11]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O:29]CC)C>>[CH2:1]([N:8]1[C:9](=[O:29])[S:10][N:24]([C:21]2[CH:22]=[CH:23][C:18]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:19][CH:20]=2)[C:25]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOCC
Reactant: S=C=NCc1ccccc1
Product: O=c1sn(-c2ccc(Oc3ccccc3)cc2)c(=O)n1Cc1ccccc1

Procedure:
Reagents: Benzylisothiocyanate (13 mmol, 1.6 mL), 4-phenoxyphenyl-isocyanate (13 mmol, 2.3 mL) and SO2Cl2 (13 mmol, 1 mL) in diethyl ether (50 mL). Isolation: filtration of reaction mixture. Purification: recrystallization from EtOH.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([OH:11])=O)=[O:7])=[CH:2]1.[NH2:12][CH:13]1[C:30](=[O:31])[N:15]2[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[NH:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[NH:26][N:25]=[N:24][CH:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[O:7])=[CH:2]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Reactant: O=C(O)CS(=O)c1ccsc1
Product: O=C(CS(=O)c1ccsc1)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12

Procedure:
380 mg. of 3-thienylsulfinylacetic acid of the R form and 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 369 mg. of 7-(3-thienylsulfinylacetamido)-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][NH:29][CH3:30].C(C1C=CC(S(N)(=O)=O)=CC=1)(=O)C>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]([CH3:30])[CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1

Procedure:
From the damp 4-acetylbenzenesulfonyl chloride from 200 g. of sodium 4-acetylbenzenesulfonate, and 1 l. of 20% aqueous dimethylamine, following the procedure of (c) above, there is obtained 4-acetyl-N,N-dimethylbenzenesulfonamide; m.p. 97°-99° C. after crystallization from aqueous ethanol.