Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[NH:19]1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH3:17][CH:18]1[NH:19][CH:20]([CH3:24])[CH2:21][N:22]([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:23]1
Reactant: CC1CNCC(C)N1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC1CN(C2=Nc3ccccc3Oc3ccccc32)CC(C)N1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a stirred solution of 10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one (0.4 g; 1.9 mmol; Aldrich) in dry toluene (20 mL) at room temperature was added 2,6-dimethyl piperazine (0.99 g; 8.7 mmol; Aldrich) followed by the dropwise addition of TiCl4 (1M in toluene, 2.27 mL; 2.27 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution (30%, 50 mL). The resulting mixture was extracted with dichloromethane (4×75 mL), and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using CHCl3 :MeOH (94:6) eluant to give 0.353 g (60%) of 11-(3,5-dimethyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine as a pale yellow solid; m.p. 112°-114° C.
Reaction SMILES: C[O-].[Na+].CO.[Br:6][C:7]1[S:11][C:10]([C:12](=O)[CH2:13][O:14][C:15]2[C:24]([I:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1.[Br-].[CH3:32]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Br:6][C:7]1[S:11][C:10]([C:12]([CH2:13][O:14][C:15]2[C:24]([I:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:29])[C:17]=3[CH:16]=2)=[CH2:32])=[CH:9][CH:8]=1
Reactant: CC1(C)CCC(C)(C)c2cc(OCC(=O)c3ccc(Br)s3)c(I)cc21
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 30% sodium methoxide in methanol (1.65 ml, 8.66 mmol) was added over 8 hours to a mixture of 5-bromo-2-[(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)acetyl]thiophene (4.3 g, 7.9 mmol) and methyltriphenylphosphine bromide (3.8 g, 10.7 mmol) in THF (45 ml). The mixture was stirred for 12 h at room temperature. The mixture was concentrated in a rotary evaporator under vacuum at 40° C. It was extracted with ethyl ether and washed with water. The organic phase was then dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:42])[C@@H:17]([O:20][C:21]1[CH:22]=[C:23]([CH:39]=[CH:40][CH:41]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[C:27]([CH3:37])=[C:26]1[CH3:38])[CH2:18][CH3:19]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:22]=[C:21]([CH:41]=[CH:40][CH:39]=2)[O:20][C@@H:17]([CH2:18][CH3:19])[C:16]([O:15][CH3:14])=[O:42])[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: CC[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(=O)OC
Agent: Cl
Product: CC[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(Cl)Cl.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C1COCC1>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:33](=[O:35])[CH3:34])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of trans-N1-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (example 85) (14 mg, 0.034 mmol), DCM (0.5 ml), THF (0.500 ml), TEA (0.014 ml, 0.101 mmol) and acetic anhydride (3.48 μl, 0.037 mmol) was stirred at ambient temperature for 1 hour, and the reaction progress was followed by LCMS. The solvent was concentrated off, added 1.0 ml of DMSO, filtered and purified by prep LC. After lypohilization 6.3 mg of title compound was obtained as a TFA salt. LCMS (m/z): 445.2 (MH+), retention time=0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.21-1.55 (m, 6H) 1.70 (d, J=12.89 Hz, 2H) 1.92 (s, 3H) 1.93-2.06 (m, 3H) 2.10 (br. s., 2H) 3.28-3.32 (dMeOH, 2H App.) 3.34-3.47 (m, 2H) 3.55-3.73 (m, 2H) 3.94 (dd, J=11.28, 3.08 Hz, 2H) 7.00 (s, 1H) 7.94 (s, 2H) 8.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(O)c1F
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(F)c(O)c1F
Yield: 86.7 %

Procedure:
A mixture of 2,4-difluoro-3-hydroxybenzaldehyde (0.255 g, 1.613 mmol) and malonic acid (0.168 g, 1.613 mmol) in pyridine (6 ml) and piperidine (0.06 ml) was heated to reflux for 1 h. All the volatile were removed and the residue was partitioned between NaHCO3 sat. and Et2O. The aqueous phase was acidified with 37% HCl until pH<3 and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to give (E)-3-(2,4-difluoro-3-hydroxyphenyl)acrylic acid (280 mg) as pale a brown solid. The compound was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13].C1C=CC=CC=1>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(Cl)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
To p-chlorophenylacetic acid (85.30 g, 0.50 mole) was added ethanol (92 g, 2.0 mole), benzene (78.11 g) and conc. sulfuric acid (2.5 g, 0.025 mole) and the azeotropic dehydration reaction was performed for 6 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, while it was cool and the solution was extracted with diethyl ether. The ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off under reduced pressure and the resulting residue was distilled under reduced pressure to give 96.30 g (96.9%) of the title compound as a colorless liquid, b.p. 105°-106° C./2.5 mmHg (lit. 130° C./13 mmHg).
Reaction SMILES: C1([NH:7]N)C=CC=CC=1.[Cl:9][C:10]1[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[C:13]([Cl:19])[C:11]=1[NH2:12]>>[Cl:9][C:10]1[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[C:13]([Cl:19])[C:11]=1[NH:12][NH2:7]
Reactant: NNc1ccccc1
Reactant: CCc1cc(Cl)c(N)c(Cl)c1
Product: CCc1cc(Cl)c(NN)c(Cl)c1

Procedure:
The phenylhydrazine used as starting material in Reference Example 10 was prepared by proceeding in a similar manner to that hereinbefore described in Reference Example 5 but replacing the 2-chloro-4-ethylaniline by 2,6-dichloro-4-ethylaniline. 2,6-Dichloro-4-ethylphenylhydrazine, m.p. 48°-50° C., was obtained in the form of a cream-coloured solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[NH:4][N:3]=1.[H-].[Na+].[CH3:19][CH:20]([CH3:23])[CH2:21]Br>CN(C=O)C.O>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:12])=[O:13])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH2:19][CH:20]([CH3:23])[CH3:21])[N:3]=1
Reactant: CC1=NNS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=NN(CC(C)C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
The product from step B (0.9 g, 2.85 mmol) was dissolved in DMF (10 mL). Sodium hydride (0.17 g, 4.28 mmol of a 60% suspension in mineral oil) was added slowly at room temperature. The mixture was stirred for 15 min and then 2-methyl bromopropane (0.47 mL, 4.28 mmol) was added. The mixture was warmed to 80° C. and stirred for 2h. And then cooled to 0° C. and stirred for 12h. DMF was evaporated under high vacuum. The residue obtained was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over MgSO4 and evaporated to provide an oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to give the desired compound as a white solid (0.54 g, 50%). mp: 140°-142° C. 1H NMR (DMSO-d6): δ:0.89 (6H, d, 2CH3); 2.03 (1H, m, CH); 2.49 (3H, s, CH3); 3.64 (2H, δ, CH2); 7.94 (1H, s, CH); 8.21 (2H, s, NH2 exchangeable). Analysis calculated for C9H13N3O4S3 : C, 35.59; H, 4.78; N, 12.45 Found: C, 35.56; H, 4.44; N, 12.36.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[O:9]=[C:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[Cl-].[NH4+]>O1CCCC1>[OH:9][C:10]1([CH3:5])[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 1.5 h
Yield: 41 %

Procedure:
Methylmagnesium bromide-tetrahydrofuran solution (1.12 M, 3.90 mL, 4.38 mmol) was added dropwise to tert-butyl 3-oxoazetidine-1-carboxylate (500 mg, 2.92 mmol) in tetrahydrofuran (5 mL) under cooling with ice and stirred for 90 minutes. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→1/1 (v/v)) to give the title compound as a colorless solid (224 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[CH2:25][CH2:24][N:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][C:21]=4[C:20]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[N:19]3)[CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C[Si]([N:45]=[C:46]=[O:47])(C)C.CO.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[CH2:25][CH2:24][N:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:22][C:21]=4[C:20]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=4)=[N:19]3)[CH2:11][CH2:10]2)=[C:4]([NH:8][C:46]([NH2:45])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3NC(N)=O)CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.5 %

Procedure:
To a stirred solution of 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine (0.062 g, 0.104 mmol) in CH2Cl2 (0.52 mL) was added trimethylsilyl isocyanate (0.017 mL, 0.125 mmol). The reaction mixture was allowed to stir for 48 h at room temperature. The reaction had not gone to completion, so an additional 0.017 mL (0.125 mmol) of trimethylsilyl isocyanate was added and the reaction was heated to 45° C. for 10 h. Column chromatography (silica, 3-10% MeOH/CH2Cl2) afforded 1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-urea (0.015 g, 22%). MS (electrospray): exact mass calculated for C28H33CIF3N7O3S, 639.2; m/z found, 640.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.26 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.09 (t, J=8.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 4.65 (s, 2H), 4.55 (s, 2H), 4.15 (t, J=6.7 Hz, 2H), 3.65-3.73 (m, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.87-2.92 (m, 2H), 2.91 (s, 3H), 2.70 (d, J=11.4 Hz, 2H), 2.40 (t, J=6.7 Hz, 2H), 2.09-2.22 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH2:3][Cl:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)c1ccc(Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(C)(CCl)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 56.5 %

Procedure:
To 25 g of 4-tert-butylchlorobenzene synthesized in (1) above were added 20 g of sulfuryl chloride and a catalytic amount of benzoyl peroxide, and the temperature was elevated and the mixture was maintained at 100° C. for 1 hour. Then, the mixture was distilled under reduced pressure to give 17.0 g of 2-(4-chlorophenyl)-2-methyl-1-chloropropane (bp.: 121°-123° C./10 mmHg).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Product: Cc1cccc([N+](=O)[O-])c1-c1cccs1
Yield: 62 %

Procedure:
2-Bromo-3-nitrotoluene (3.35 g, 15.5 mmol) and 2-(tributylstannyl)-thiophene (5.7 g, 15.3 mmol, 1.0 eq) were coupled as in Example 75 to give 2.08 g of 2-(2-methyl-6-nitrophenyl)thiophene, which was reduced under conditions similar to Example 64 to give 1.4 g of 3-methyl-2-(2-thienyl)aniline.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=2[CH:28]=1>COCCOC.Cl>[CH3:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=2[CH:28]=1
Reactant: CCCCSc1ccccc1-c1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: Cl
Solvent: COCCOC
Product: CCCCSc1ccccc1-c1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
In 1,2-dimethoxyethane (20 ml) and 6N hydrochloric acid (6.7 ml) was dissolved methyl 7-[(4-butylthio)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (670 mg), and the mixture was stirred at 100° C. for 16 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7-[(4-butylthio)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (620 mg).
Reaction SMILES: [O-]CC.[K+:4].[CH:5]([O:7][CH2:8][CH3:9])=[O:6].C([O:12][C:13](=O)[CH2:14][N:15]=[C:16]([O:18][CH2:19][CH3:20])[CH3:17])C>C(OCC)C.CCO>[CH2:8]([O:7][C:5]([C:14]([N:15]=[C:16]([O:18][CH2:19][CH3:20])[CH3:17])=[CH:13][O-:12])=[O:6])[CH3:9].[K+:4]
Reactant: CCOC=O
Reactant: CCOC(=O)CN=C(C)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=C[O-])N=C(C)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a stirred suspension of 3.222 g (36 mmol, 1.05 eq) of potassium ethoxide in 30 mL diethyl ether and 5 mL EtOH at 0° C., a solution of 3.849 g (52 mmol, 1.5 eq) ethyl formate and 6 g (35 mmol) (1-ethoxy-ethylideneamino)-acetic acid ethyl ester in 30 mL diethyl ether and 5 mL EtOH is then slowly added. The reaction mixture is stirred for one hour at 0° C. After addition of 40 mL diethyl ether, the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the obtained solid was washed with diethyl ether and dried under vaccum to yielded 5 g (60%) of potassium 2-ethoxycarbonyl-2-(1-ethoxy-ethylideneamino)-ethenolate as an orange solids.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>[OH:10][C:8]1[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=[C:2]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(O)cc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dihydroxybenzaldehyde (14.4 mmol) and pyridine (114 mmol) in methylene chloride (20 ml) was slowly added trifluoromethanesulfonic anhydride (36.2 mmol) keeping the temperature below 5° C. After 10 min the mixture was washed with water and the organic phase was concentrated under reduced pressure. The crude brown crystals (6.4 g—product and pyridine −1:1), phenylboronic acid (13.2 mmol), sodium carbonate (39.6 mmol) and dichlorobis(triphenylphosphine)-palladium (II). (3 mol %) was dissolved in DME (40 ml) and water (20 ml). The mixture was refluxed for 17 h under Argon, cooled to room temperature and extracted with ethyl acetate. Purification by chromatography yielded 5-Hydroxy-biphenyl-3-carbaldehyde
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([C:14]3=O)[CH2:12]1)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([C:14]3=[S:32])[CH2:12]1)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC12CC3CC(C1)C(=O)C(C3)C2)OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC12CC3CC(C1)C(=S)C(C3)C2)OCc1ccccc1
Temperature: 70 °C
Yield: 85.9 %

Procedure:
A mixture of ketone 10A (240 mg, 0.8 mmol) and Lawesson reagent (200 mg, 0.48 mmol) in anhydrous toluene was heated at 70° C. for overnight. The solvent was removed under vacuum and the residue was purified by silica gel chromatography [Hexane:EtOAc 4:1(v/v)] to give the title compounds 10B (130 mg, 54%). LC-MS (ESR): m/z=316 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[C:16]([OH:18])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si](CC(N)=O)(C)C.[NH2:33][CH:34]1[C:55](=[O:56])[N:36]2[C:37]([C:52]([OH:54])=[O:53])=[C:38]([CH2:41][S:42][C:43]3[N:47]([CH2:48][C:49]([OH:51])=[O:50])[N:46]=[N:45][N:44]=3)[CH2:39][S:40][C@H:35]12.C(=O)(O)[O-].[Na+].Cl>O.C(O)(C)C.CC(C)=O.CN(C)C=O.O1CCCC1>[CH2:6]([O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[C:16]([NH:33][CH:34]1[C:55](=[O:56])[N:36]2[C:37]([C:52]([OH:54])=[O:53])=[C:38]([CH2:41][S:42][C:43]3[N:47]([CH2:48][C:49]([OH:51])=[O:50])[N:46]=[N:45][N:44]=3)[CH2:39][S:40][C@H:35]12)=[O:18])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Reactant: Nc1nc(C(=NOCc2ccccc2)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(C(=NOCc2ccccc2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=O)O)CS[C@H]23)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
Phosphorus oxychloride (0.8 g) was added at 0° C. to a mixture of 2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (1.1 g) and dry tetrahydrofuran (11.0 ml), and the mixture was stirred for 15 minutes at 0° C. Trimethylsilylacetamide (0.7 g) was added thereto and it was stirred for 15 minutes. Phosphorus oxychloride (0.8 g) was added thereto and it was stirred for 15 minutes. To the resulting mixture was added dry dimethylformamide (0.4 g) and it was stirred for 30 minutes at 0°-3° C. to give clear solution. On the other hand, acetone (9.0 ml) was added to a solution of 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.5 g) and sodium bicarbonate (1.0 g) in water (9.0 ml) and thereto was added the clear solution as obtained above at -3° to 3° C. and pH 7.5 to 8.5. The mixture was stirred for 1 hour at the same temperature and pH. An aqueous layer was separated and washed with ethyl acetate. After distilling off the remaining ethyl acetate, the aqueous layer was adjusted to pH 5.0 with 10% hydrochloric acid and subjected to column chromatography on Diaion HP-20 resin (Trademark: prepared by Mitsubishi Chemical Industries Ltd.) using 10% isopropyl alcohol as an eluent. The eluate was adjusted to pH 2.7 with 10% hydrochloric acid and precipitates were collected by filtration, washed with water and dried to give 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.78 g).
Reaction SMILES: [O:1]=[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(C(C=C)=O)=C.[N+](NC(N)=O)([O-])=O>C(O)C>[OH:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCCCCC(NCCC(=O)c1ccccc1-c1ccccc1)C(=O)OCC
Agent: C=CC(=O)C=C
Agent: NC(=O)N[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)CCCCCCC(NCCC(O)c1ccccc1-c1ccccc1)C(=O)OCC

Procedure:
A solution of diethyl 2-(3-hydroxy-3-(p-biphenylyl)-propylamino)nonanedioate (5 g), which was prepared via diethyl 2-(3-oxo-3-(p-biphenylyl)propylamino)nonanedioate from the appropriate vinyl ketone using the procedure of Example 2, in absolute ethanol (20 ml) was heated at 60° while nitrourea (1.12 g) was added portion-by-portion.