Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1([F:25])[CH2:24][N:23]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:22]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(C(=O)N3CC(F)(F)C3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (490 mg, 2.0 mmol), 3,3-difluoroazetidine hydrochloride (260 mg, 2.00 mmol), DIPEA (0.686 mL, 3.93 mmol) and HATU (900 mg, 2.4 mmol) in DMF (4 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with EtOAc, the organic portion washed successively with water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0-100% EtOAc/hexane) to give Compound B166a (360 mg, 57% yield) as a white solid. HPLC: RT=1.9 min (LCMS Method Q). MS (ES): m/z=324.0 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (s, 2H), 7.62 (d, J=8.1 Hz, 2H), 4.53 (t, J=12.0 Hz, 4H), 1.36 (s, 12H).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[C:39](=[O:40])[NH:38][N:37]=[CH:36]2)[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[C:39](=[O:40])[N:38]([CH2:14][C:15]3[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:37]=[CH:36]2)[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)nc1C
Yield: 56 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 2-(bromomethyl)-5-(trifluoromethyl)furan to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 56% yield:
Reaction SMILES: Cl.[OH-:2].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11]>CC(C)=O.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:2])=[O:11]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)O
Reaction time: 1 h

Procedure:
2.5 g of hydrochloride were dissolved in 25 ml of acetone and 0.8 g of NaOH in 20 ml of water. To this solution, there were added 2 g of 5-chloro-2-methoxy-benzoyl chloride in 20 ml of acetone and the whole was stirred for 1 hour. Then, water and dilute hydrochloric acid were added and the product was recrystallized from methanol. The 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-5-chloro-2-methoxy-benzoic acid so obtained was found to melt at 171°-173° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[C:25]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:24][C:19]([C:20](OC)=[O:21])=[C:18]([O:31][CH3:32])[N:17]=1.O.[OH-].[Na+]>C(OCC)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[N:17]=[C:18]([O:31][CH3:32])[C:19]([CH2:20][OH:21])=[CH:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)nc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(F)c(-c2nc(OC)c(CO)cc2OCC(C)C)c1
Reaction time: 0.33 h
Yield: 661.3 %

Procedure:
To a suspension of lithium aluminum hydride (67 mg) in diethyl ether (2.0 mL) was added a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-isobutoxy-2-methoxynicotinate (213 mg) in diethyl ether (1.0 mL) at 0° C., and the mixture was stirred for 20 min. Water and aqueous sodium hydroxide solution were added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated to give a crude product of the title compound (1.30 g) as an orange oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH3:11][C:12]1[C:17]([CH:18]=O)=[CH:16][N:15]=[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[N:13]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(N(CC)CC)C>[OH-].[Na+].ClCCl.CN(C=O)C>[CH3:1][C:2]1[C:3]2[N:10]=[C:18]([C:17]3[C:12]([CH3:11])=[N:13][C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[N:15][CH:16]=3)[NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c2nc(-c3cnc(NCCCC4CCN(C)CC4)nc3C)[nH]c2c1

Procedure:
To a 4 mL vial were added 3,5-dimethyl-benzene-1,2-diamine.2HCl (69 mg, 0.33 mmol), 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (92 mg, 0.33 mmol), 2,3-dichloro-5,6-dicyano-p-benzoquinone (75 mg, 0.33 mmol), and DMF (2 mL). After addition of triethylamine (0.09 mL, 0.66 mmol), the resultant mixture was stirred for 5 hours at room temperature. The resultant mixture was then diluted with 1N NaOH (7.5 mL) and dichloromethane (7.5 mL). The organic layer was concentrated and purified by flash chromatography to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][NH:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]4[CH2:49][CH2:50][C:51]5[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=5)[CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: c1ccc2c(c1)CCNC2
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCc3ccccc3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 1,2,3,4-tetrahydroisoquinoline (Aldrich) to give the title product. LC-MS (ES+) 780 [(M+H)+].
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[NH:10][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:4].C([O-])(=O)C.[Na+].Cl>O.C(O)(=O)C.CO.CS(C)=O>[Br:1][C:7]1[C:8]([OH:19])=[C:9]([CH:18]=[C:5]([C:3]#[N:4])[CH:6]=1)[NH:10][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)ccc1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(=O)Nc1cc(C#N)cc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A mixture of 1.1 g of bromine and 5 ml of acetic acid was added dropwise to a solution of 1.5 g of ethyl 5-cyano-2-hydroxyoxanilate and 1 g of sodium acetate in a mixed solution of 10 ml of dimethyl sulfoxide, 10 ml of methanol and 20 ml of acetic acid. After stirring the mixture for 30 minutes at room temperature, 6 ml of 2 normal hydrochloric acid and 200 ml of water were added to the reaction mixture and the product was extracted with a mixture of 30 ml of toluene and 40 ml of ethyl acetate. The extract was washed with water, dried, and then concentrated under reduced pressure. Crystals formed were washed with a mixture of ether and n-hexane to provide 1.5 g of ethyl 3-bromo-5-cyano-2-hydroxyoxanilate.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:22]([O-:24])=[O:23])=[C:14]([N:17]3[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:25])[C:8]1=[O:26])=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:22]([O-:24])=[O:23])=[C:14]([N:17]3[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:25])[C:8]1=[O:26])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
24.5 g (68 mmol) of 1-(ethoxycarbonylmethyl)-6-nitro-7-(1-pyrrolyl)-2,3(1H,4H)-quinoxalinedione (Example 52) were dissolved in 500 ml of tetrahydrofuran, and a solution of 6.6 g (270 mmol) of lithium hydroxide in 100 ml of water was added. The mixture was stirred at room temperature for 16 h and then the tetrahydrofuran was removed under reduced pressure, and the aqueous phase was filtered. The filtrate was acidified with 1M hydrochloric acid, and the precipitate was filtered off with suction to yield 17.5 g (77%) of the product.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:13](=[O:15])[CH3:14].C(O)C.[OH-].[Na+]>Cl.O>[OH:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:13](=[O:15])[CH3:14]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)C(C)=O)OC1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O
Reaction time: 4.5 h

Procedure:
A solution is prepared from ethyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]acetamido}heptanoate (4.5 g., 0.01 mole), ethanol (50 ml.) and 4 drops of concentrated hydrochloric acid, and kept at ambient temperature for 4.5 hours. Then to the reaction mixture is added a solution of sodium hydroxide (0.72 g., 0.018 mole) in water (8 ml.) and the mixture is kept at ambient temperature for an additional twenty hours. Most of the ethanol is removed by evaportion in vacuo and the resulting solution is diluted with water (100 ml.). This solution is extracted, once with ether, then acidified with hydrochloric acid. The oil that separates is extracted into ether, the ethereal extract is dried over sodium sulfate, then the solvent is removed under vacuum to give 7-[N-(4-hydroxynonyl)acetamido]heptanoic acid as a yellow oil; pmr (CDCl3) δ 0.93 (3H,m CH3), 2.10 (3H,s CH3CO), 3.38 (4H,m NCH), 7.03 (2H,s COOH, OH).
Reaction SMILES: [C:1](OCC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].Cl.[N:17]1([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[C:1]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:18][CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Yield: 6.8 %

Procedure:
To 100 ml of ethanol were added 1.36 g of ethyl benzoate, 0.5 g of sodium ethylate and 2.6 g of 5-(piperazinylcarbonyl)oxindol hydrochloride and the mixture was reacted in an autocrave at 140° to 150° C. under 110 atm for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 200 ml of chloroform. After washing, in turn, with 1% aqueous potassium carbonate solution, dilute hydrochloric acid, and water, the chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The resultant residue was purified by silica-gel column chromatography [silica-gel: WAKO C-200, eluent: chloroform:methanol (V/V)=20:1], and the crude crystal was recrystallized from methanol to give 215 mg of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]([F:15])([F:14])[F:13])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.CN(C=O)C>[F:15][C:12]([F:13])([F:14])[C:6]1[C:5]2[C:9](=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(C(F)(F)F)c[nH]c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in anhydrous THF (0.5 mL) at 0° C. was added BH3.THF complex (1M in THF) (1 mL, 0.95 mmol, 4 eq) dropwise. The mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% ACN in water) to give 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: [NH2:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([NH:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][CH:12]([C:20]([NH:22][S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])=[O:21])[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=[O:5].[CH2:42](O)C.C(O)(=O)C>C([O-])([O-])OCC>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13](=[O:14])[CH:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:1]=[CH:42]2)=[CH:37][CH:36]=1)[C:20]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])=[O:21])[CH3:17]
Reactant: CCN(CC)C(=O)C(Cc1ccc(NC(=O)c2ccccc2N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCO
Agent: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)C(Cc1ccc(-n2cnc3ccccc3c2=O)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
The compound (429 mg) obtained in Example 43 was dissolve in a mixed solution (1.5 mL) of ethanol/acetic acid (10/1), ethyl ortho-formate (187 μL) was added, and the mixture was heated under reflux for 7 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (175 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][CH3:18])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[N:7][C:6]=1[CH2:16][O:17][CH3:18])=[O:4]
Reactant: COCc1nc(C2=CCCCC2)oc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COCc1nc(C2CCCCC2)oc1C(=O)OC
Reaction time: 8 h
Yield: 88 %

Procedure:
5.30 g 2-Cyclohex-1-enyl-4-methoxymethyl-oxazole-5-carboxylic acid methyl ester were dissolved in 40 ml methanol. 500 mg palladium on charcoal (10%) were added and the reaction mixture was stirred under an atmosphere of hydrogen overnight. The catalyst was filtered off through a pad of celite, the filtrate was evaporated in vacuo to obtain 4.70 g 2-Cyclohexyl-4-methoxymethyl-oxazole-5-carboxylic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9](/[C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][CH:32]=1)[O:14][CH2:15][C:16]1[CH:17]=[C:18]([C:26](OC)=[O:27])[C:19](=[CH:24][CH:25]=1)[C:20](OC)=[O:21])\[CH3:10])[CH3:2].[BH4-].[Li+]>>[OH:27][CH2:26][C:18]1[CH:17]=[C:16]([CH:25]=[CH:24][C:19]=1[CH2:20][OH:21])[CH2:15][O:14][C:13]1[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]/[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([OH:35])[CH2:33][CH3:34])[CH:32]=[CH:31][CH:30]=1
Reactant: CCC(O)(CC)CCCC/C=C(\C)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(CC)CCCC/C=C(\C)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 397 mg (0.85 mmol) of dimethyl 4-[3-((E)-7-ethyl-7-hydroxy-1-methylnon-1-enyl)phenoxymethyl]phthalate (prepared in a manner similar to Examples 72(a-c)) with 55 mg (2.5 mmol) of lithium borohydride, a colourless oil is obtained (m=323 mg; Y=92%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-])=O>CO.[Pd]>[NH2:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[NH:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.6 %

Procedure:
A mixture of 4-(methylamino)-3-nitrobenzoic acid (29 g, 1.0 eq) and Pd/C (5 g, 10%) in 300 mL MeOH was stirred at rt under hydrogen for 48 h and filtered. The filtrate was concentrated in vacuo to give the product (9 g, 36.5%). 1H NMR (400 MHz, DMSO-d6) δ 7.21 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 6.37 (d, J=8.4 Hz, 1H), 5.28 (brs, 1H), 4.60 (brs, 2H), 2.76 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[CH:6][C:7]1[S:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:28].[CH3:29][N:30]([CH2:32][CH2:33][Cl:34])[CH3:31].O>CN(C)C=O>[ClH:34].[ClH:28].[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[CH:6][C:7]1[S:8][C:9]2[N:10]([CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH2:11][CH2:12][CH2:13][C:14]=2[N:15]=1
Reactant: CN(C)CCCl
Reactant: COc1cccc(C=Cc2nc3c(s2)NCCC3)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C=Cc2nc3c(s2)N(CCN(C)C)CCC3)c1OC
Temperature: 90 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
2-(2,3-Dimethoxystyryl)-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridine (1.0 g, 3.3 mmole) and powdery potassium carbonate (1.37 g, 9.92 mmole) were suspended in dimethylformamide (20 ml). To the suspension was added N,N-dimethylaminoethyl chloride hydrochloride (0.57 g, 3.97 mmole) and the mixture was heated with stirring at 90° C. for 4 hours. Water was added to the mixture and an organic substance was extracted with a chloroform-methanol mixed solvent. The extract was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. The resulting oily compound was neutralized with hydrochloric acid and recrystallized from diethyl ether-ethanol to obtain the title compound (870 mg, yield: 54.4%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:12][C@@H:13]2[C:42](=[O:43])[N:15]3[C:16]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:27])=[C:17]([C:20]4[S:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:12][C@@H:13]2[C:42](=[O:43])[N:15]3[C:16]([C:26]([OH:28])=[S:27])=[C:17]([C:20]4[S:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: Cc1nnc(C2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4csc(NC=O)n4)[C@H]3SC2)s1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4csc(NC=O)n4)[C@H]3SC2)s1
Reaction time: 0.75 h
Yield: 54.9 %

Procedure:
To a solution of benzhydryl 7β-[2-(2-formylaminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate (1.2 g) in a mixture of dichloromethane (3.6 ml) and anisole (1.2 ml) was added trifluoroacetic acid (2.4 ml) under ice-cooling. The mixture was stirred at the same temperature for 45 minutes. The reaction mixture was poured into diisopropyl ether (80 ml) and the resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (40 ml), tetrahydrofuran (20 ml) and ethyl acetate (40 ml). To the separated aqueous solution were added ethyl acetate (40 ml) and tetrahydrofuran (20 ml). The mixture was adjusted to pH 1.8 with 1N-hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β-[2-(2-formylaminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (490 mg).
Reaction SMILES: N([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]NC(C)=O)=[CH:9][CH:8]=1)C(C)=O.O1CCOCCOCCOCCOCCOCC1>CCOCC.C(C1C=CC=C(O)C=1O)(C)(C)C.C1C(N)=CC=C(N)C=1>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][CH:8]=1)=[CH2:5]
Reactant: CC(=O)NCCc1ccc(CCNC(C)=O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)c1cccc(O)c1O
Agent: Nc1ccc(N)cc1
Solvent: CCOCC
Product: C=Cc1ccc(C=C)cc1
Temperature: 210 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
Under N2, 248.3 g (1 mol) of 1,4-bis(2-acetaminoethyl)benzene, 11.2 g (100 mmol) of potassium tert.-butylate, 95% pure, 26.4 g (100 mmol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6), 250 g of a mixture of isomeric phenoxydiphenyl ethers, 250 mg of tert.-butylcatechol and 250 mg of p-phenylenediamine are initially introduced into a distillation apparatus analogous to Example 1. An additional 250 mg of tert.-butylcatechol are placed in the distillation receiver. After a vacuum of 10 mbar has been applied, the temperature of the bottom is increased. The cleavage reaction starts at about 175° C. and is detectable by the appearance of the products in the still head. The reaction is completed in 1-2 h by slowly increasing the bottom temperature to 210° C. Finally, the vacuum is increased to 5 mbar for a short time. The distillate is taken up in 300 ml of ether and 200 ml of water, the aqueous phase is separated off, and the organic phase is washed once more with 200 ml of water, dried with sodium sulfate and the solvent is removed by distillation in vacuo. 213.2 g of residue contains 58.4% of p-divinylbenzene (96% of theory), 2.6% of 4-(2-acetaminoethyl)styrene and 37.3% of isomeric phenoxydiphenyl ethers. 111.0 g of p-divinylbenzene are obtained with a boiling point of 40°-41° C. at about 0.5 mbar after renewed distillation over a 20 cm Vigreux column. Yield 85% of theory. Purity 99.9%.