Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:16]([O:17][CH3:18])=[CH:15][C:13]([NH2:14])=[C:12]([Cl:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>ClCCl>[C:4]([Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([Cl:19])[C:13]([N:14]=[C:21]=[O:23])=[CH:15][C:16]=1[O:17][CH3:18])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N=C=O)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 263.5 %

Procedure:
A solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyaniline (intermediate 39; 300 mg, 1 mmol) in 4 ml of dichloromethane was cooled externally with an ice bath while dropping a solution of triphosgene (108 mg; 0.36 mmol) in 5 ml of dichloromethane. Triethylamine (0.28 ml; 2.01 mmol) was added slowly and the system stirred at room temperature for 3 hr. Half of the solvent is then evaporated in vacuo and 25 ml of pentane added. The white precipitate of ureas was filtered and the filtrate evaporated to dryness giving 311 mg of the title compound that were used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:20]([O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: OCc1cccc(F)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
To a solution of (2,3-difluoro-phenyl)-methanol (5.0 g, 35 mmol), imidazole (4.9 g, 72 mmol) and DMF (40 mL) was added tert-butyldimethylchlorosilane (5.4 g, 36 mmol). After stirring at ambient temperature for 24 hours, the mixture was partitioned between 400 mL of ether and 100 mL of water. The organic layer was washed twice with water, dried over MgSO4, filtered and concentrated in vacuo, affording 6.8 g of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane as a colorless oil. 1H NMR (400 MHz, CDCl3) δ7.22 (m, 1H), 7.04 (m, 2H), 4.79 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H) ppm.
Reaction SMILES: CN(C)C=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:16].[CH2:27](I)[CH3:28].[H-].[Na+]>O>[CH2:27]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:24])[F:25])=[O:16])[CH3:28]
Reactant: CC(CCCCOC(=O)c1cc2ccccc2[nH]1)=C(F)F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)OCCCCC(C)=C(F)F)cc2ccccc21
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.32 g (1.1 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-2-carboxylate and 0.34 g (2.2 mmol) of ethyl iodide, followed by the addition of 0.06 g (1.5 mmol) of sodium hydride at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 0.31 g (yield: 88%) of 6,6-difluoro-5-methyl-5-hexenyl 1-ethyl-1H-indole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH2:16])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1.[F:25][C:26]1([F:35])[CH2:30][CH2:29][C:28]([OH:34])([C:31](O)=[O:32])[CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH:16][C:31]([C:28]3([OH:34])[CH2:29][CH2:30][C:26]([F:35])([F:25])[CH2:27]3)=[O:32])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1
Reactant: O=C(O)C1(O)CCC(F)(F)C1
Reactant: C[C@@H](N)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)C1(O)CCC(F)(F)C1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Reference Example 4 (0.766 g, 2.18 mmol), (+)-3,3-difluoro-1-hydroxycyclopentanecarboxylic acid (0.454 g, 2.73 mmol), (1H-1,2,3-benzotriazol-1-yloxy)-[tris(dimethylamino)]phosphonium hexafluorophosphate (1.35 g, 3.06 mmol) in anhydrous dichloromethane (43 mL), was added triethylamine (0.553 g, 5.46 mmol). This reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc, washed with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution. The organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was subjected to silica gel chromatography eluting with 0-50% EtOAc in hexanes to provide the title compound as a foam, which gave proton NMR spectra consistent with theory and a mass ion (ES+) of 499.2 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.96 (bd, NH), 7.34 (d, J=8.8 Hz, 1H), 7.26 (m, 2H), 5.41 (m, 1H), 4.342 (s, 3H), 2.82 (m, 1H), 2.46-2.25 (m, 4H), 1.92 (m, 1H), 1.45 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:10]=12>C(#N)C>[CH:1]1([NH:7][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]3[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:10]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCCC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Cyclohexyl amine (9.07 ml, 0.7905 mole) was added to a mixture of ethyl 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (10 gm, 0.0395 mole) (example 3) in acetonitrile. After stirring for about 2 h at 110° C., acetonitrile was removed under reduced pressure. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo to give brownish solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[C:20]#[N:21].O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: OCCCCc1ccccc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Br)ccc1OCCCCc1ccccc1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
4-Phenylbutanol (0.834 g) was dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (60%, 0.638 g) was added. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (0.640 g) was added, and the mixture was further stirred at 40-50° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (1.04 g) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:34][OH:35])(=[O:15])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>ClCCl>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:34]=[O:35])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)c1cnc2c(CO)cccc2c1Nc1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Oxalyl chloride (18.22 g, 0.144 mol) in dichloromethane (180 ml, dried over molecular sieves) was cooled to -70° C., and a solution of dimethylsulphoxide (13.08 g, 0.168 mol) in dry dichloromethane (20 ml) added dropwise under nitrogen with stirring, keeping the temperature below -60° C. After 30 minutes, a solution of 3-butyryl-4-(2-methylphenylamino)-8-hydroxymethylquinoline (40 g, 0.12 mol) in dry dichloromethane (700 ml) was added dropwise below -60° C. After a further 30 minutes, triethylamine (102 ml) was added dropwise, and the mixture allowed to warm to room temperature, washed with water and dried (Na2SO4). The filtered solution was evaporated to a yellow oil, which crystallised on trituration with ether to give the title compound (33.02 g), m.p. 142°-4°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(-c2ccc(Br)cc2)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromothiobenzamide (7.62 g, 35.2 mmole), ethyl 4-chloroacetoacetate (5.82 g, 35.2 mmole) and dimethylformamide (23 ml) was stirred under nitrogen and heated in an oil-bath at 115°-120° C. for 11/2 hours. Thin layer chromatography showed the presence of unreacted thioamide. More ethyl chloroacetoacetate (2.91 g, 17.6 mmole) was added and heating was continued for 11/2 hours, by which time no unreacted thioamide remained. The mixture was cooled and poured into ice-water (125 ml) and extracted with ether (2×100 ml). The extract was washed with water (2×100 ml), dried (MgSO4) and evaporated to a semi-solid which contained the desired ester and the corresponding acid. The mixture was dissolved in ethanol (100 ml) saturated with hydrogen chloride and the solution was allowed to stand at room temperature for 1 day. The solution was evaporated to dryness and the ester was used without further purification for preparing the amide.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[NH:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:13]([C:24](ON1C(=O)CCC1=O)=[O:25])[C@@H:14]([CH3:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1COCC1.CN(C=O)C>C(N(CC)CC)C>[NH:12]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@H:13]([C:24]([NH:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:4](=[O:5])[OH:6])=[O:25])[C@@H:14]([CH3:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@@H](N)CC(=O)O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension consisting of 2.3 g of H-Asp-OEt, 5.8 g of Boc-Thr(Bzl)-OSu, 20 ml of THF and 20 ml of DMF was added 2 ml of triethylamine under ice-cooling condition, and the mixture was stirred for 1 hour, then the pH of the reaction mixture was controlling to about pH 7, and the reaction was continued for 36 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the thus obtained residue was acidified by adding 1N-hydrochloric acid, then was extracted with ethyl acetate (80 ml×3 times). The organic layer was washed with water, then with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. Crystallized and recrystallized from diethyl ether-petroleum ether to obtain 5.59 g (yield: 86.6%) of the above-mentioned objective product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6].[H][H]>[Pd].C(OCC)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH:19]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To 26.6 g of 2-methoxy-5-nitro-N-(4-trifluoromethylbenzyl)benzamide were added 270 ml of ethyl acetate and 2.6 g of 10% palladium on carbon under an atmosphere of argon, then argon was replaced with hydrogen gas, and the mixture was stirred for 8 hours at room temperature under an atmosphere of hydrogen gas. Catalyst was filtered through Celite(Hyflo Super-cel) and, after washed the collected material well with ethyl acetate, the filtrate was concentrated under reduced pressure. The residue obtained was purified by means of column chromatography (silica gel, ethyl acetate) to obtain 24.5 g of 5-amino-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:30]([OH:33])[CH2:31][OH:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH2:21]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:30]([OH:33])[CH2:31][O:32][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](OCCC[C@@H](OCc1ccccc1)[C@H](O)CO)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC[C@@H](OCc1ccccc1)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
18.33 g of triphenylmethyl chloride were added to a solution of 26.22 g of (2R, 3R)-3-benzyloxy-6-(t-butyldiphenylsilyloxy)hexane-1,2-diol (prepared as described in Preparation 17) and 18.40 ml of triethylamine in 500 ml of toluene. The resulting mixture was heated under reflux for 3 hours. At the end of this time, it was cooled and then diluted with water. It was then extracted three times with ethyl acetate. The combined extracts were washed, in turn, with water, with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, after which they were dried over anhydrous magnesium sulfate, and the solvent was stripped off by evaporation under reduced pressure. The resulting oily residue was dissolved in 270 ml of tetrahydrofuran, and then 90 ml of a saturated aqueous solution of sodium bicarbonate were added, and the resulting mixture was stirred at room temperature for 1 hour. After this work-up, 40 g of the oily product were subjected to column chromatography through 500 g of silica gel, 37.01 g of the title compound were obtained, as a colorless oil, from those fractions eluted with mixtures of hexane and ethyl acetate ranging from 95:5 to 9:1 by volume.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22]OC)=[CH:18][CH:17]=[C:16]([C:25]#[N:26])[CH:15]=2.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH:21]=[CH2:22])=[CH:18][CH:17]=[C:16]([C:25]#[N:26])[CH:15]=2
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(C#N)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1c(-c2ccc(O)cc2O)c(=O)oc2cc(C#N)ccc12
Temperature: -30 °C
Reaction time: 4 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile (380 mg, 1.04 mmol) was dissolved in CH2Cl2 (12 mL) at room temperature in a 200 ml round bottom flask. The reaction mixture was then cooled to −30° C., and BBr3 (1.8 ml) was added, then the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and water (40 mL) was added, followed by ethyl acetate (50 mL). The reaction mixture was then poured into a separation funnel. The organic layer separated and washed with water (1×40 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 50%-100% ethyl acetate in hexanes to yield the title compounds as a foam and a yellow solid, respectively.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1>CC#N>[CH3:6][O:5][C:3](=[O:4])[C:2](=[N+:26]=[N-:27])[C:1]([O:8][CH3:9])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 39 °C
Reaction time: 0.25 h

Procedure:
9.9 g. (0.075 mole) of dimethyl malonate, 50 ml of anhydrous acetonitrile, and 7.6 g (0.075 mole) of triethylamine (b.p. 88.5-90.5° C.) were added to a 300 ml double-jacketed flask with a dropping funnel, reflux condenser and mechanical stirrer (Rushton). The temperature of the mixture was adjusted to 20° C., and 14.8 g (0.075 mole) of p-toluenesulfonyl azide in 50 ml of CH3CN is added dropwise with vigorous stirring over 15 minutes. The addition caused the reaction mixture to warm to 38-40° C. and assume a yellow colour. After the mixture had been stirred at room temperature for 2.5 hours, the solvent was evaporated at 35° C. (12 mm). The partially crystalline residue was triturated with 100 ml of ether, and the mixture, including the insoluble residue, was placed in a 500 ml separatory funnel. The mixture was washed successively with a 50 ml solution of potassium hydroxide (2N) and a 50 ml solution of potassium hydroxide (0.5N) solution. The yellow-orange ethereal phase was dried over anhydrous sodium sulfate, and the solvent evaporated at 35° (15 mm) until the residue had attained a constant weight. The yellow-orange diazo ester weighed 5 g. The product was checked by 1HNMR spectroscopy and found to be ca. 90% pure.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:26]1(C)C=CC=CC=1>>[Cl-:1].[C:4]([CH2:3][CH2:2][CH2:26][P+:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([OH:6])=[O:5]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1
Reactant: O=C(O)CCCl
Product: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 95 %

Procedure:
A solution of 1 g (9.2 mmol) of 3-chloropropanoic acid and 2.4 g (9.2 mmol) of triphenylphosphine was refluxed in 10 mL of toluene overnight. After cooling, the mixture was concentrated to give 3.25 g (95%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[NH:19][N:20]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.CC1C=CC(S(O[CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)(=O)=O)=CC=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[N:20]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: CC1(C)C(=O)NN=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C3) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B3*HCl)
Reaction SMILES: [CH3:1][C:2]1[C:11]([S:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[C:11]([S:12][CH3:13])[C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CSc1cccc(NCC=O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CSc1cccc(N(CC=O)C(=O)CCl)c1C
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-3-methylthioanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-3-methylthioanilino)acetaldehyde.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18]OC(=O)C4C=CC=CC=4S(=O)(=O)NC(OCC)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:42][C:43]1[N:47]([CH3:48])[N:46]=[N:45][N:44]=1.C(=O)([O-])O.[Na+].P(=O)(O)(O)O>O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18][S:42][C:43]4[N:47]([CH3:48])[N:46]=[N:45][N:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1nnnc1S
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 81.1 %

Procedure:
In water (50 ml) is suspended 7β-phenylacetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (3.0 g) together with 5-mercapto-1-methyl-1H-tetrazole (1.0 g). The mixture is adjusted to pH 5.5 with sodium hydrogen carbonate and the resultant solution is heated at 60° C. for 50 minutes. The solution is brought to pH 2.0 with dilute phosphoric acid and extracted with ethyl acetate (100 ml). The extract is rinsed with a saturated aqueous solution of sodium chloride, dried and concentrated. Then, following the addition of ether, the precipitate is recovered by filtration. By the above procedure is obtained 7β-phenylacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:17][CH3:16])=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: CNCc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and methylamine.