Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([NH:30][NH2:31])=[O:28])[C:11]=1[NH:10][C:9]([C:12]1[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=1)=[O:8]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)cccc12
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cccc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.27 g of 8-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-4H-3,1-benzoxazine-4-one, 0.025 ml of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of chloroform and methyl t-butyl ether to obtain 0.21 g of N-[2-chloro-6-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].Cl[C:27]([O:29][CH3:30])=[O:28]>>[CH3:30][O:29][C:27]([NH:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5])=[O:28]
Reactant: COC(=O)Cl
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Product: COC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C)cc(C)c1

Procedure:
Following the method of Example 18, 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride and methyl chloroformate gave the title compound after recrystallisation from ethyl acetate/petroleum ether, m.p. 128°-129° C. 1H NMR (360 MHz, CDCl3) δ8.04 (1H, s), 7.52 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8 Hz), 7.18 (1H, t, J=8 Hz), 7.09 (1H, t, J=8 Hz), 6.95 (1H, s), 6.83 (2H, s), 5.25 (1H, d, J=7.5 Hz), 5.00 (2H, dd, J=12 Hz), 4.73 (1H, m), 3.65 (3H, s), 3.29 (2H, d, J=5 Hz), 2.29 (6H, s).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].F[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1>>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2nc[nH]c12
Reactant: O=[N+]([O-])c1cccc(F)c1
Product: O=[N+]([O-])c1cccc(-n2cnc3c([N+](=O)[O-])cccc32)c1

Procedure:
4-Nitro-1-(3-nitrophenyl)benzimidazole was prepared analogueously to 3 g from 4-nitrobenzimidazole and 1-fluoro-3-nitrobenzene. Mp 260°-262° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([C:30]2[S:31][C:32]([CH2:36]O)=[C:33]([CH3:35])[N:34]=2)[CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:36][C:32]3[S:31][C:30]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([F:29])([F:27])[F:28])=[C:20]([F:19])[CH:21]=4)=[N:34][C:33]=3[CH3:35])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2)sc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2)sc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with [2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 0228434 A2] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain {6-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as light yellow gum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:11]([NH2:25])=[N:12][CH:13]=[C:14]([B:16]4[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]4)[CH:15]=3)=[CH:7][C:6]=2[CH:26]=1.[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>C1COCC1>[NH2:25][C:11]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([CH3:36])[CH:28]=4)=[O:35])=[CH:26][C:6]=3[CH:7]=2)=[CH:15][C:14]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:13][N:12]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4cc(N)ccc4s3)c2)OC1(C)C
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(B5OC(C)(C)C(C)(C)O5)cnc4N)cc3c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (734.6 mg, 2 mmol. 1 eq) in anhydrous THF (10 mL) at room temperature was added dropwise m-tolylisocyanate (0.251 mL, 1 eq). After the reaction was stirred at room temperature for 4 hours, it was partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper solution layer was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (DCM to MeOH-DCM 1:5). The products' fractions were collected, concentrated, the solid was triturated with EtOAc-Hex (1:7) yielding 1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-methylphenyl)urea as a white powder upon filtration in amount of 407 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Cl:25][C:26]1[CH:37]=[CH:36][C:29]([C:30](N(OC)C)=[O:31])=[CH:28][C:27]=1[S:38](=[O:41])(=[O:40])[NH2:39]>O1CCCC1>[Cl:25][C:26]1[CH:37]=[CH:36][C:29]([C:30](=[O:31])[C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:28][C:27]=1[S:38]([NH2:39])(=[O:41])=[O:40]
Reactant: Brc1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(N3CCC(c4ccccc4)CC3)cc2)ccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.227 g of 1-(4-bromo-phenyl)-4-phenyl-piperidine in tetrahydrofuran (5 mL) is cooled to −78° C. and treated with 2 portions of 0.29 mL each of tert-butyllithium (1.5 M in pentane). After 20 min at −78° C. the reaction mixture is treated with 0.1 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (5 mL) and stirred for another 1.5 h. The temperature is then increased slowly to 0° C. and after completion the reaction is quenched by addition of 2 mL of saturated aqueous ammonium chloride and extracted with diethyl ether. The organics are washed with water, dried over magnesium sulfate, concentrated to 0.27 g of crude product which is purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-chloro-5-[4-(4-phenyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide as a powder. MS (m/z): (M−1) 453; Rf 0.65 (1:1 hexanes/ethyl acetate)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:16]1[C:11]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCc1cccc(O)c1
Reactant: Cc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cccnc1Oc1cccc(CO)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
3-Hydroxymethyl-phenol (3.69 g, 29.7 mmol), 2-fluoro-3-methyl-pyridine (3.00 g, 27 mmol) and cesium carbonate (9.68 g, 29.7 mmol) were suspended in dimethylsulfoxide (25 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (250 mL) and ethyl acetate (250 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-50%, EtOAc:heptane) to afford the title compound (3.33 g, 57% yield) as a thick oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17](B5OC(C)(C)C(C)(C)O5)[CH:16]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1.Br[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([C:31]5[CH:35]=[CH:34][S:33][C:32]=5[C:36]#[N:37])[CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1
Reactant: CC1(C)OB(c2cccc(-n3cnc4cc(-c5ccoc5)cnc43)c2)OC1(C)C
Reactant: N#Cc1sccc1Br
Product: N#Cc1sccc1-c1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1

Procedure:
The title compound was prepared from 6-(furan-3-yl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3H-imidazo[4,5-b]pyridine and 3-bromothiophene-2-carbonitrile as described in Example 8 to afford the free base as a tan sold; δH (400 MHz, d6-DMSO) 7.17 (1H, s), 7.70 (1H, d, J 5), 7.78-7.86 (3H, m), 8.15 (1H, d, J 8), 8.20 (1H, d, J 5), 8.36-8.37 (2H, m), 8.50 (1H, d, J 2), 8.78 (1H, d, J 2), 9.02 (1H, s); m/z (ES+) 369 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]([CH3:9])[CH:7]=[CH2:8])[CH3:2].[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:32]=[CH:31][C:27]([CH:28]=[N:29][OH:30])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]([CH:7]1[O:30][N:29]=[C:28]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([CH3:11])[CH:21]=3)=[CH:32][CH:31]=2)[CH2:8]1)[CH3:9])[CH3:2]
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=CC(C)=CC(=O)OCC
Product: CCOC(=O)C=C(C)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 84 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 3-methyl-penta-2,4-dienoic acid ethyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting ethyl acetate:hexane (gradient) to give 3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-but-2-enoic acid ethyl ester (0.93 g, 84%) as a mixture of diasteromers. MS found: (M+H)+=431.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:22]([O:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1)[CH3:23]
Reactant: CCO
Reactant: COC(=O)c1ccc2c(c1C)SCCC2O
Agent: O=S(=O)(O)O
Product: CCOC1CCSc2c1ccc(C(=O)OC)c2C

Procedure:
13.8 g (0.058 mol) of methyl 4-hydroxy-8-methylthiochroman-7-carboxylate are heated at boiling point for 4 hours in 60 ml of ethanol with addition of 1 g of sulfuric acid. The solvent is then distilled off and the residue is taken up with water. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with sodium hydrogen carbonate solution, dried and concentrated. The product is purified by chromatography.
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([CH3:18])=[C:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClS([N:38]=[C:39]=O)(=O)=O.CN(C)C=O>>[C:39]([C:8]1[C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)(=[O:27])=[O:28])=[C:10]([CH3:18])[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:38]
Reactant: CCOC(=O)Cn1c(C2CCCCC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CCCCC1
Yield: 71.7 %

Procedure:
General procedure II was followed using ethyl 2-(5-cyclohexyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (642 mg, 1.36 mmol), chlorosulfonyl isocyanate (0.147 mL, 1.70 mmol) and N,N-dimethylformamide (0.105 mL, 1.36 mmol) to afford ethyl 2-(3-cyano-2-cyclohexyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (485 mg, 0.975 mmol, 72% yield) as a white sticky foam.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:25])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1

Procedure:
According to Preparation 2: Tert-butyl 4-[2-fluoro-3-(trifluoro-methyl)phenyl]-4-hydroxypiperi-dine-1-carboxylate (3.1 g, 8.5 mmol, methylen chloride (20 ml), trifluoroacetic acid (2 ml). Yield: 0.62 g. MS m/z (rel. intensity, 70 eV) 263 (M+, 22), 245 (96), 244 (44), 191 (25), 56 (bp).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])[CH:3]=1.C(N(CC)CC)C>C1COCC1>[OH:17][C@H:13]([CH2:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)[C:14]([OH:16])=[O:15]
Reactant: Cc1cc(CC(=O)C(=O)O)cc2c1OCCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](O)C(=O)O)cc2c1OCCO2
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a solution of 15.1 g (47.0 mmol) (1R)—B-chlorodiisopinocampheylborane in 50 mL THF was added dropwise within 15 min to a solution of 9.2 g (38.9 mmol) 3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxo-propionic acid and 5.4 mL (39.0 mmol) triethylamine in 100 mL THF cooled to −35° C. and the reaction mixture was stirred for 1 h at RT. After the end of the reaction the reaction solution was evaporated down i.vac., combined with 200 mL 1 M NaOH and 150 mL TBME, stirred, the aqueous phase was separated off, acidified with 2 M HCl and extracted twice with 250 mL EtOAc. The combined organic phases were dried, filtered through activated charcoal and evaporated down i.vac.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Si]([I:28])(C)(C)C>C(Cl)Cl>[I:28][N:6]1[C:7](=[O:16])[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: C[Si](C)(C)I
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 7-A) and Et3N (2.66 ml, 19.12 mmol) were stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 ml, 9.54 mmol). After stirring for 15 minutes 12 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 ml and diluted with an additional 20 ml of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].C(O)(=O)C>C(O)C.[Zn]>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C@@H:9]2[C@H:10]([NH2:15])[CH2:11][CH:12]=[CH:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc([C@H]2CC=CC[C@H]2N)cc1OC
Yield: 32.4 %

Procedure:
40 g of (±)-cis-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound H1) are dissolved in 400 ml of ethanol and 40 g of zinc powder are added. After heating to boiling temperature, 65 ml of glacial acetic acid are added dropwise. Afterwards, the reaction mixture is filtrated and concentrated. The residue is redissolved in diluted hydrochloric acid and extracted with toluene. The aqueous layer is alkalized using 6 N solution of sodium hydroxide and extracted several times with toluene. The combined organic phases of the alkalic extraction are dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 6/3/1. 11.5 g of the title compound are obtained.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[S:32][CH3:33])=[O:11])=CC=1)([O-])=O.O1CCCC1.CO>[Pd].O1CCCC1.CO>[CH3:33][S:32][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:17]2[C:12]=1[C:10]([OH:11])=[O:9]
Reactant: CSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CSC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 4 h

Procedure:
A solution of 53 mg of 3-methylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 5 ml of a warm 2:1 mixture of tetrahydrofurane and methanol is added to a mixture, which has been prehydrogenated for 30 minutes in a hydrogenation apparatus, of 51 mg of 5% strength palladium-on-charcoal catalyst in 1 ml of tetrahydrofurane/methanol, 1:1, and the mixture is hydrogenated for 4 hours whilst stirring. The solution is filtered, the catalyst is washed with 4 times 6 ml of ethyl acetate and the filtrate and the washing liquid are evaporated in vacuo. The residue is dissolved in methylene chloride and extracted with dilute aqueous sodium bicarbonate solution. The aqueous phase is extracted by shaking three times with methylene chloride and the yellow oil of the intermediate layer is discarded. The aqueous bicarbonate solution is cooled in an ice bath, covered with ethyl acetate and acidified to about pH 2 with 2 N hydrochloric acid. The organic phase is separated off, the yellow oil of the intermediate layer is again discarded and the aqueous phase is extracted with methylene chloride. The combined ethyl acetate and methylene chloride phases are washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is recrystallised from methylene chloride/diethyl ether and gives 3-methylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid of melting point 122°-125° C.; IR spectrum (KBr): characteristic bands at 5.64; 5.95; 6.25; 6.55; 6.70; 8.20; 8.58; 8.94 and 13.25μ.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14]CC#N)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:21]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:12](=[O:14])[C:11]1[CH:18]=[CH:19][CH:20]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCC#N)c1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(=O)OCc2ccccc2)c1
Temperature: 80 °C
Yield: 18.8 %

Procedure:
Cyanomethyl 3-(t-butyloxycarbonylamino)-benzoate [compound of Example 61-(2)] (27.6 g), glycine benzyl ester·p-toluenesulfonate (33.7 g), triethylamine (20.2 g) and 4-dimethylaminopyridine (0.2 g) are mixed. The mixture is stirred at 80° C. two nights. The reaction mixture is extracted with ethyl acetate (200 ml). The extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a silica gel column chromatography (eluant, chloroform-ethyl acetate). The fractions containing the desired compound are collected, and the solvent is distilled off under reduced pressure. The residue is recrystallized from 70% aqueous acetonitrile to give N-[3-(t-butyloxycarbonylamino)benzoyl]glycine benzyl ester (7.2 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1COCC1.[CH3:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[OH:19][C:12]1[CH:11]=[C:10]([CH3:20])[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:26])[CH:32]=3)=[N:7][CH:6]=2)=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1O
Temperature: 85 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.35 g) in a mixed solvent of THF (8.40 mL)-water (2.80 mL) were added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.53 g), potassium carbonate (0.66 g) and tetrakis(triphenylphosphine)palladium(0) (0.14 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.35 g).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>C(OCC)C>[CH2:5]([N:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:1]([Cl:4])=[S:2])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCNCCCC
Reactant: S=C(Cl)Cl
Solvent: CCOCC
Product: CCCCN(CCCC)C(=S)Cl
Reaction time: 1 h

Procedure:
To a solution of 29.9g (0.26 mole) thiophosgene in 600 ml ethyl ether at 0° was added a solution of 25.8g (0.20 mole) dibutylamine 20.2g (0.20 mole) triethylamine and 250 ml ethyl ether over a period of 35 minutes during which time solids formed. After stirring an additional 1 hour, the mixture was filtered and the resulting filtrate was removed of volatiles under reduced pressures to yield 35g of crude dibutylthiocarbamoyl chloride.