Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:37][C:38](=[O:56])[CH2:39][C@@H:40]([OH:55])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])C1C=CC=CC=1.O>O1CCOCC1.CO.[Pd]>[C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:37][C:38](=[O:56])[CH2:39][C@@H:40]([OH:55])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])([OH:10])=[O:8]
Reactant: CC(C)CCCCCCCCCCC[C@H](O)CC(=O)N[C@@H](CCCC(=O)OCc1ccccc1)C(=O)O[C@@H](CCCCCCCCCCCC(C)C)CC(N)=O
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CCCCCCCCCCC[C@H](O)CC(=O)N[C@@H](CCCC(=O)O)C(=O)O[C@@H](CCCCCCCCCCCC(C)C)CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-{(3S)-3-hydroxy-15-methylhexadecanoylamino}pentanoyl]oxy-15-methylhexadecanamide (80 mg) in a mixture of 1,4-dioxane (10 ml) and methanol (10 ml) were added 10% palladium on active carbon (50 mg) and water (1 ml). The mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was filtered off and the solvent was removed under reduced pressure to give (3S)-3-[(2S)-5-carboxy-2-{(3S)-3-hydroxy-15-methylhexadecanoylamino}-pentanoyl]oxy-15-methylhexadecanamide as white powder (56 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a suspension of 4′-chloro-4-ethylbenzenesulfonanilide (4.70 g (15.9 mmol)) in 15 ml of acetic acid, 97% fuming nitric acid (0.69 ml (16.1 mmol)) was added dropwise with stirring at room temperature. The resulting mixture was stirred at 50° C. for 30 minutes and then allowed to cool to room temperature. Water (100.0 ml) was added to the reaction mixture and the resulting crystals were filtered and washed with waterto give 5.35 g (99%) of 4′-chloro-4-ethyl-2′-nitrobenzenesulfonanilide as pale yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:52])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:44](=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:72][C:73]([CH3:78])([CH3:77])[CH2:74][CH2:75][OH:76].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:44]([N:24]1[C@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=3[CH3:19])=[CH:8][CH:7]=2)[C:3]([OH:52])=[O:2])=[O:22])[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:76][CH2:75][CH2:74][C:73]([CH3:78])([CH3:77])[CH3:72])=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25]1)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)CCO
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(O)cc1)CO3
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCCC(C)(C)C)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-{[(3S,8S)-7-Benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (18 mg) was dissolved in DCM, triphenyl phosphine (5.9 eq.). 3,3-Dimethyl-butan-1-ol (excess) added and mixture cooled on ice. DIAD (5.1 eq.) was added and the reaction mixture stirred on ice for 10 minutes and rt for 16 hours. The reaction mixture was directly purified over silica (DCM-EtOAc 8:2 to DCM-EtOAc 6:4). The resulting residue was hydrolyzed according to General Procedure B and purified over silica (DCM to DCM+1% MeOH to DCM+7% MeOH) to give the title compound (11 mg). LCMS (m/z): 769.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12]C(=O)C2C=CC=CC=2)[CH2:9][C@H:8]1[CH:21]=[C:22]([CH3:26])[C:23](=[O:25])[CH3:24])=[O:6])[CH:2]=[CH2:3].C[O-].[Na+].C(O)(=O)C.C(OCC)(=O)C>CO.[Cl-].[Na+].O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[CH:21]=[C:22]([CH3:26])[C:23](=[O:25])[CH3:24])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](OC(=O)c2ccccc2)C[C@H]1C=C(C)C(C)=O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C=C(C)C(C)=O
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-benzoyloxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.23 g) in methanol (5 ml) was added 28% solution of sodium methoxide in methanol (0.13 ml) at 0° C. and the resulting mixture was stirred at the same temperature for 1 hour. To this solution was added acetic acid (0.04 ml), and the mixture was poured into a mixture of brine and ethyl acetate. The organic layer was separated, washed three times with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (20 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])CCC.[Br:16]Br>C1COCC1>[Br:16][C:8]1[C:7]([O:9][CH3:10])=[CH:6][N:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1cncc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cncc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
To a stirred solution of 3,5-dimethoxypyridine (2.7 g, 19.4 mmol) in dry THF at −78° C. was added n-butyllithium (23.3 mmol, 2 M solution in cyclohexanes). During this addition a precipitate formed and the reaction was allowed to warm to room temperature for 5 minutes. The precipitate separated into an oily phase and the reaction was re-cooled and treated with bromine (1.5 ml, 29.1 mmol) and again allowed to warm to room temperature. After stirring for 10 minutes the solution became homogeneous and was quenched with 10% Na2S2O3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated onto silica-gel under reduced pressure. The solid residue was purified by flash chromatography (silica-gel, eluted sequentially with hexanes:EtOAc, 2:1, 1:1, 1:2) to give the product as a white solid (2.4 g, 57%). 1H-NMR (300 MHz, CDCl3) δ 7.95 (s, 2H), 3.99 (s, 6H).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4]>CO>[OH:11][CH:10]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)[C:9]1[CH:21]=[CH:22][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(C(O)c2cc3ccccc3o2)cc1
Reaction time: 1 h

Procedure:
Sodium borohydride (7.4 g., 0.2 mol.) is added portionwise to a rapidly stirred solution of 26.7 g. (0.1 mol.) of 2-(4'-nitrobenzoyl)benzofuran in methanol. The reaction mixture stirred at 25° for one hour then quenched by addition of water. The aqueous slurry is extracted with chloroform, the extracts are dried (MgSO4) and the solvent is removed in vacuo to give 2-(α-hydroxy-4'-nitrobenzyl)benzofuran which is immediately converted to the corresponding α-chloride by reaction with 14.3 g. (0.12 mol.) of thionyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[C:11]=2[O:13][CH3:14])[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[C:11]=2[O:13][CH3:14])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(OC)c(F)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(F)c(OC)c21
Temperature: 25 °C

Procedure:
Ethyl 1-ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylate (1.37 g, 4.7 mmol) is suspended in a mixture of acetic acid:water:sulfuric acid (8:6:1). The mixture is refluxed for 3 hours, and then cooled to room temperature. The crystals are filtered and rinsed with cold water.
Reaction SMILES: Cl[C:2]1N(C2C=CC(C(OC)=O)=CC=2)N=C[C:3]=1C(=O)NC1CCCCC1.[CH:26]1([NH:32][C:33]([C:35]2[CH:36]=[N:37][N:38]([C:46]3[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=3)[C:39]=2[S:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:41]1([S:40][C:39]2[N:38]([C:46]3[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=3)[N:37]=[CH:36][C:35]=2[C:33](=[O:34])[NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:42][CH2:43][CH2:3][CH2:2][CH2:44][CH2:45]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCC2)cc1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCCCC2)cc1

Procedure:
Methyl 4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate was prepared from cycloheptylthiol and methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate #15) by the same process used for Intermediate #96.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([N+:28]([O-])=O)[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl>O>[C:19]([C:18]1[C:17](=[O:27])[NH:16][C:13]2[C:12]([N:28]=1)=[CH:11][C:10]([CH:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH:7]([CH3:9])[CH3:8])=[CH:15][CH:14]=2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C(c1ccc(NC(=O)CC(=O)c2ccccc2)c([N+](=O)[O-])c1)n1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)C(c1ccc2[nH]c(=O)c(C(=O)c3ccccc3)nc2c1)n1ccnc1
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A mixture of 7 parts of N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]-β-oxobenzenepropanamide, 7.03 parts of potassium carbonate and 70 parts of water was stirred for 1.5 hours at reflux temperature. After cooling, the whole was treated with a hydrochloric acid solution 3N to pH 7. The product was extracted with dichloromethane (3×104 parts). The combined extracts were dried, filtered and evaporated. The residue was taken up in ethanol. The product was filtered off and dried, yielding 5.1 parts (73.0%) of 3-benzoyl-6-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2(1H)-quinoxalinone, N4 -oxide monohydrate; mp. 210.0° C. (comp. 154).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([NH:17][CH:3]([CH2:4][N+:5]([O-:7])=[O:6])[C:2]([F:9])([F:8])[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])C=CC(F)(F)F
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CC(NCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 3,3,3-trifluoro-1-nitroprop-1-ene (4 g, 28.4 mmol) and benzylamine (3.2 g, 30.0 mmol) in toluene (50 mL) was stirred for RT or 1 h. The mixture was concentrated and the residue was purified by column chromatography (EtOAc/PE=1/10) to give the title compound (5.5 g, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 3.91-3.95 (m, 1H), 4.06-4.14 (m, 1H), 4.45-4.51 (m, 1H), 4.63-4.67 (m, 1H), 7.30-7.39 (m, 5H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>ClCCl.O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 12 h

Procedure:
1.3 g tert-butyl 1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylate are dissolved in 20 ml dichloromethane, combined with 1.04 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hours. A further 2 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane is added and the mixture is stirred for a further 24 hours. The solvents are eliminated in vacuo and the residue is taken up twice in dichloromethane and this is then eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH2:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[N:5][N:4]=[N:3]1.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[NH:28][N:27]=[N:26][CH:25]=3)[CH2:20][S:21][C@H:16]12>>[CH3:1][N:2]1[C:6]([S:7]([CH2:9][CH2:10][C:11]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]4[NH:28][N:27]=[N:26][CH:25]=4)[CH2:20][S:21][C@H:16]23)=[O:13])=[O:8])=[N:5][N:4]=[N:3]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Reactant: Cn1nnnc1S(=O)CCC(=O)O
Product: Cn1nnnc1S(=O)CCC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12

Procedure:
408 mg. of 3-(1-methyl-1H-tetrazol-5-ylsulfinyl)propionic acid and 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 120 mg. of 7-[3-(1-methyl-1H-tetrazol-5-ylsulfinyl)propionamido]-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20](OC)=[O:21])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.ClC1C=CC(SC2OC(C3C=CC(F)=CC=3)=NC=2CO)=NC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:11][C:10]=2[CH2:20][OH:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Product: OCc1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1

Procedure:
To a solution of 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylic acid (45 mg, 0.132 mmol) in MeOH (2649 μl) was added TMS-diazomethane (132 μl, 0.265 mmol, 2M in Et2O). Additional TMS-diazomethane aliquots were added until no more gas evolution was observed. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 12 g, 0 to 50% EtOAc in hexane), to give methyl 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylate (30 mg). methyl 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylate was reduced using DIBAL, using a similar procedure as described in the preparation of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (INTERMEDIATE B1.1), to provide {5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl}methanol. MS: M+H=326.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:31](=[O:32])[CH2:30][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: CN1CCN(CC(=O)Nc2ccc3nc(NC4CCc5cc(F)ccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:26][O:27]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O1CCCC1>[CH3:1][O:2][CH:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][CH:11]=1)[CH2:26][OH:27]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCc1ccc(OCC(CO)OC)cc1
Yield: 53.2 %

Procedure:
A mixture of about 527 mg of 1-[2-methoxy-3-(triphenylmethoxy)propoxy]-4-tetradecylbenzene, about 10 mg of p-toluenesulfonic acid and about 5 ml of methanol:tetrahydrofuran (about 1:1) was stirred under argon for about 16 hours and the solvents removed under reduced pressure. The residue was dissolved in ether:hexane (about 1:1), washed with aqueous sodium bicarbonate, brine, dried and evaporated, giving about 171 mg of the desired title compound, mp 43°-45° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])CO)[CH3:19]>C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCC(CC)CO
Reactant: COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Temperature: 140 °C
Reaction time: 10 h
Yield: 94.6 %

Procedure:
A mixture of 45 g of methyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate, 24.7 g of 2-ethylhexylalcohol, 0.5 g of dibutyltin oxide and 50 ml of toluene was heated to 140° C., whereto toluene was further added while the solvent was being distilled off. After the mixture was stirred for 10 hours, toluene was distilled off. The obtained residue was purified by silica gel column chromatography to give 60 g of 2-ethylhexyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate as a pale yellow oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[CH:3][N:2]([CH3:5])[CH3:1])[CH:19]=[O:20]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C=C(C=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
73 g of dimethylformamide are cooled to -50° C. 92 g of phosphorus oxychloride are added dropwise, followed by 34.2 g of 2-chlorophenylacetic acid, and the reaction mixture is stirred at room temperature for 30 minutes. It is then heated at 70°-80° C. for 5 hours 30 minutes. The reaction mixture is rendered alkaline with potassium carbonate, 200 ml of toluene are added and the mixture is heated in a water bath for 1 hour.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[C:28](=[O:35])[CH2:27]1.[Na].CC1CCNC(=O)C1.C(Cl)(Cl)=O>O.CC(C)=O>[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:33])[C:28](=[O:35])[CH2:27]1
Reactant: NCCc1ccc(S(=O)(=O)NC(=O)NC2CCCCC2)cc1
Reactant: CC1CCN(C(=O)Cl)C(=O)C1
Agent: CC1CCNC(=O)C1
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1CCN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2)C(=O)C1
Reaction time: 2 h

Procedure:
1.6 g of N-(4-[2-amino-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea and 0.2 g of sodium hydroxide are dissolved in 10 ml of water and 50 ml of acetone. With agitation and ice cooling, a solution of 0.85 g of 4-methyl-2-oxo-piperidine-1-carboxylic acid chloride (prepared by reaction of the sodium compound of 4-methyl-2-oxo-piperidine with phosgene) in 20 ml of acetone is added dropwise to this solution, and agitation is continued for 2 hours at room temperature. Subsequently, the acetone is evaporated under reduced pressure, the batch is acidified, suction-filtered, the product is reprecipitated from dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea obtained has a melting point of 177°-178° C. and is identical with the product obtained according to Example 8.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:26]1([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[CH:26]1([O:31][C:32](=[O:37])[C:33]([NH:34][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)([CH3:35])[CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(N)C(=O)OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NC(C)(C)C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.3 %

Procedure:
To a solution of N-Boc-piperidinone (2.00 g, 10.0 mmol) in dichloroethane (25 mL) was added α,α-dimethylglycine cyclopentyl ester tosylate (3.97 g, 11.6 mmol) and sodium triacetoxyborohydride (4.248 g, 20.0 mmol). The mixture was stirred at room temperature for 22 hours then poured into ethyl acetate (300 mL). The organic layer was washed with water (3 times 100 mL), dried (MgSO4) and concentrated to yield the desired product (3.556 g, 84% yield) which was carried forward without further purification. LC/MS: m/z 355.25 [M+H]+