Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 67.8 %

Procedure:
In the same manner as in Example 259 and using 1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (89 μL, 1.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (180 mg, 68%) was obtained as a white solid. melting point 253° C.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:60]=[CH:59][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1COCC1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:28]([OH:29])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:32][CH:31]=2)=[CH:59][CH:60]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To 4,4′-didocosoxy-benzophenone (28.3 g, 34.1 mmol) were added THF (300 mL) and methanol (15 mL), and the mixture was heated to 60° C. Sodium borohydride (6.10 g, 161 mmol) was added slowly, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was ice-cooled and 1N hydrochloric acid (80 mL) was added dropwise. THF was evaporated, water (450 mL) was added and 1N hydrochloric acid was added to pH 5 to 7. The slurry was filtered, and the obtained crystals were washed with water and methanol to give 4,4′-didocosoxybenzhydrol (28.5 g, 34.1 mmol, 99%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[F:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:59]=[CH:58][C:57]([CH2:60][CH2:61][CH:62]=[O:63])=[CH:56][CH:55]=2)[CH:50]=[C:51]([F:53])[CH:52]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([C@@H:62]([OH:63])[CH2:61][CH2:60][C:57]1[CH:58]=[CH:59][C:54]([C:49]2[CH:48]=[C:47]([F:46])[CH:52]=[C:51]([F:53])[CH:50]=2)=[CH:55][CH:56]=1)[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Reactant: O=CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: ClCCl
Product: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
In a flame-dried flask, 3-{3-[(45)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one (0.25 g) was taken up in dichloromethane (10 mL) and cooled to 0° C. Titanium tetrachloride (0.76 mL, 1 M solution) was added drop-wise and the reaction mixture was stirred for 10 to 15 minutes. (−)-Sparteine (0.36 mL) was added slowly to the reaction mixture and stirred at 0° C. for 20 minutes. A solution of the compound obtained from step e above (0.187 g) in dichloromethane (10 mL) was added slowly and stirring was continued at 0° C. After 3 hours, the reaction was quenched with the drop-wise addition of saturated ammonium chloride solution, and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as eluant to afford the title compound (0.24 g).
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1/[CH:11]=[CH:12]/[CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:28])[CH2:20][NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:15][CH2:14]1.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:48]C(Cl)C>C(Cl)(Cl)Cl.C(O)(=O)C>[ClH:48].[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1/[CH:11]=[CH:12]/[CH:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:28])[CH2:20][N:21]([CH3:29])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH2:17][CH2:18]1
Reactant: Cc1cccc(C)c1/C=C/C1CCN(C(=O)CNC2CCOCC2)CC1
Reactant: CC(Cl)Cl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc(C)c1/C=C/C1CCN(C(=O)CN(C)C2CCOCC2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
454 μl of 37% aqueous formaldehyde solution and 175 μl of acetic acid were added to a solution of 219 mg of (2-{4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidin-1-yl}-2-oxoethyl)tetrahydro-2H-pyran-4-ylamine in 5 ml of dichloroethane, followed by stirring at ambient temperature for 2 hours. Subsequently, 388 mg of sodium triacetoxyborohydride was added to the reaction mixture, followed by stirring at ambient temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate solution and chloroform were added to the mixture, then the organic layer was fractionated and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol-ammonia water). The resulting oil was dissolved in 5 ml of ethanol, and 172 μl of 4N hydrochloric acid-ethyl acetate was added to the mixture. The solvent was evaporated under reduced pressure. The residue was crystallized from 2-propanol-diisopropyl ether. The crystals were recrystallized from 2-propanol-diisopropyl ether to give 201 mg of (2-{4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidin-1-yl}-2-oxoethyl)methyl(tetrahydro-2H-pyran-4-yl)amine monohydrochloride.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([O-])=O>CO.CO.ClCCl.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:3][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: C[C@H](CCNC(=O)OCc1ccccc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: C[C@H](CCNC(=O)OCc1ccccc1)Nc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
Sodium borohydride (110 mg, 2.8 mmol) was added to a solution of nickel (II) chloride hexahydrate (330 mg, 1.4 mmol) in 10 mL of methanol. A solution of benzyl (3R)-3-[(3-nitroquinolin-4-yl)amino]butylcarbamate (1.11 g, 2.81 mmol) in 20 mL of 1:1 methanol/dichloromethane was added, and the resulting dark mixture was stirred for 5 minutes at room temperature. Additional sodium borohydride was added in small portions until the reaction solution become colorless. The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure. The resulting brown solid was triturated with dichloromethane, and the resulting mixture was filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to provide 0.96 g of benzyl (3R)-3-[(3-aminoquinolin-4-yl)amino]butylcarbamate as a brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]([CH2:22][CH3:23])[C:18]([O:20]C)=[O:19])[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:17]([CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C#CC(CC)N(C(CC)C(=O)OC)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(CC)N(C(CC)C(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 59 (584 mg, 163 mmol) was dissolved in THF (10 mL). Lithium hydroxide monohydrate (134 mg, 2.0 eq) was added followed by 10 mL of water. The mixture was stirred at room temperature overnight. The solvent was removed and the solution was adjusted to pH 3-4 using 3N HCl, The mixture was then extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine and dried (MgSO4). After removal of the solvent a white solid was obtained as the product 60. LCMS 366.0 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:39])[CH:14]([C:31]1[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH:23]([CH3:24])[CH2:22][CH:21]([CH2:25][CH2:26][C:27](=O)[CH3:28])[C:20]1=[O:30])[CH3:11].N1CCC[C@H]1C(O)=O.[H][H]>C(O)C.C(OCC)(=O)C.CO.[Pd]>[CH2:10]([O:12][C:13](=[O:39])[CH:14]([C:31]1[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH:23]([CH3:24])[CH2:22][C@H:21]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:8][C:7]3[CH2:6][CH2:5][CH2:4][NH:3][C:2]=3[N:1]=2)[C:20]1=[O:30])[CH3:11]
Reactant: CCOC(=O)C(CCCCN1C(=O)C(CCC(C)=O)CC1C)c1ccc(OC)nc1
Reactant: Nc1ncccc1C=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C(CCCCN1C(=O)[C@@H](CCc2ccc3c(n2)NCCC3)CC1C)c1ccc(OC)nc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-amino-3-formylpyridine (341 mg, 2.80 mmol), 3-5 (900 mg, 2.15 mmol) and proline (322 mg, 2.80 mmol) in ethanol (20 mL) was heated at reflux for 4 h, and the cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 3:0.3:0.3 to 8:0.8:0.8% ethanol/ammonium hydroxide/water in ethyl acetate) to give 3-6 as an inseparable mixture of diastereomers. To a stirred solution of the mixture of 3-6 in methanol (40 mL) was added a slurry of 10% palladium on carbon (150 mg) in ethanol (3 mL). The resulting suspension was stirred under a slight overpressure of hydrogen for 16 h. The reaction mixture was filtered through Celite and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 3:0.3:0.3 to 8:0.8:0.8% ethanol/ammonium hydroxide/water in ethyl acetate) to give 3-7 as a 2:1 mixture of diastereomers.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=1.O.[NH2:32][NH2:33]>C(O)C>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[CH:12]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[C:8]1[CH:7]=[C:6]([S:5][CH2:4][C:3]([NH:32][NH2:33])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CSc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1CCC(OC(c2cccc(SCC(=O)NN)c2)c2nc3ccccc3s2)CC1
Temperature: 80 °C

Procedure:
To a solution of {3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester (30 mg) in absolute ethanol (1 mL) is added hydrazine hydrate (0.1 mL). The reaction mixture is heated at 80° C. for 18 hours. Solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 95/5 to 80/20) to give {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid hydrazide.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18].CO>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH2:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Solvent: CO
Product: NC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate (50 g, 0.21 mol) was stirred in a solution of ammonia in methanol (7 M, 400 mL, 2.8 mol). After 2 days, the solution was concentrated with heating (50° C.) to about 300 mL at which point all solids remained dissolved. The reaction was then allowed to cool down and the resulting solid was filtered, washed with ether and dried to give 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid amide as colorless crystals (40 g).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:12]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni]>[NH2:25][C:12]1[CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:9]1=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 1 L round-bottom flask containing (R)-tert-butyl 2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylsulfonyl)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate (26.3 g, 0.0526 mol) in THF (200 mL) and methanol (200 mL) was added Raney Nickel (in H2O, 4 g). The mixture was stirred under H2 (30 psi) at rt overnight. The mixture was filtered and concentrated under vacuum to give (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (24.7 g, 100% yield) as a yellow solid. The residue was used directly for the next step without further purification. LC-MS MS (ESI) m/z 414.0 [M-56+H]+, 492.0 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 7.77 (brs, 1H), 7.04 (s, 1H), 4.68-4.45 (m, 1H), 4.45-4.38 (m, 2H), 3.92 (s, 3H), 3.70-3.58 (m, 1H), 3.58-3.41 (m, 1H), 3.30 (s, 3H), 2.49-2.25 (m, 1H), 1.50 (s, 9H), 1.12 (d, J=6.9 Hz, 3H), 1.05 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:37]1[N:38]=[C:39]([NH:42]C=O)[S:40][CH:41]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:12]([CH:15]=[C:16]([Cl:18])[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:19]([O:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:12]([CH:15]=[C:16]([Cl:18])[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate (syn isomer) (2.2 g) in methanol (11 ml) was added conc. hydrochloric acid (0.72 ml) and the resulting mixture was stirred at ambient temperature for 3 hours. To the reaction mixture were added water and ethyl acetate, the mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate, the separated organic layer was washed with brine, dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate (syn isomer) (1.98 g).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].O1CCCC1.[Cl:13][C:14]1[C:18]([F:20])([F:19])[C:17]([F:22])([F:21])[C:16]([F:24])([F:23])[C:15]=1Cl>CCOCC>[CH:1]1([O:6][C:15]2[C:16]([F:24])([F:23])[C:17]([F:21])([F:22])[C:18]([F:19])([F:20])[C:14]=2[Cl:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Reactant: OC1CCCC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: FC1(F)C(Cl)=C(OC2CCCC2)C(F)(F)C1(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Cyclopentanol (23 g, 0.27 mol) and sodium metal (5.6 g, 0.24 mol) were refluxed with 25 ml dry tetrahydrofuran (THF) overnight. The reaction mixture was diluted with 200 ml of dry ether and then added to 1,2-dichlorohexafluorocyclopentene (49 g, 0.2 mol) in 100 ml of dry ether at room temperature with stirring over 20 minutes. After the completion of the addition, the reaction mixture was heated to reflux for 2 hours. The reaction mixture was poured into ice water (150 ml) and the organic layer was separated. Then the aqueous layer was extracted with 4 portions of 100 ml of ether. Next, the organic layer and the ether extracts were combined and dried over CaCl2 overnight. Thereafter, the solvent was distilled out at atmospheric pressure. That which remained was distilled under reduced pressure to give the desired 2-chlorohexafluorocyclopentenyl cyclopentyl ether in 79% yield based on the 1,2-dichlorohexafluorocyclopentene used.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Cl[CH2:10][CH2:11][CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15]>>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][C:1]=1[CH2:10][CH2:11][CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: Cc1ccc(O)cc1
Product: CO[Si](CCCc1cc(C)ccc1O)(OC)OC
Yield: 99 %

Procedure:
As shown in Scheme 2, a new 3-arylpropyl trimethoxysilane compound, 3-(2-hydroxy-5-methylphenyl)-propyltrimethoxysilane (abbreviated PholTMS) was synthesized. 60 g of p-cresol and 100 g of 3-chloropropyltrimethoxysilane were mixed under reflux for 24 hours. The product was confirmed by NMR spectrum, and the yield was more than 99%. 1H NMR of PholTMS (400 MHz, CD3OD): δ0.65 (t, 2H), 1.56 (p, 2H), 2.34 (s, 3H), 2.63 (t, 2H), 3.58 (s, 9H), 6.5-7 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.[H][H]>O>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Reactant: [H][H]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C=NO)cc1
Temperature: 25 °C

Procedure:
8.3 g of 4-nitrobenzaldoxime together with 100 ml of tetrahydrofuran are initially introduced into a stirred autoclave. 50 mg of FeCl2.4 H2O and 0.2 g of the catalyst from Example A1 are added to the solution. Hydrogenation is carried out at 120° C. and a hydrogen pressure of 20×105 pascals. When hydrogenation is complete, the mixture is cooled to room temperature, the reactor is rendered inert with nitrogen and the catalyst is filtered off. The solvent is distilled off to give, after chromatographic purification, 3.5 g (51% of theory) of 4-aminobenzaldoxime.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:29])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:5].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:15]([C:12]2[CH:13]=[C:14]3[C:6]([C:4](=[O:5])[C:3]4[C:18]([F:29])=[CH:19][CH:20]=[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[C:2]=4[F:1])=[CH:7][NH:8][C:9]3=[N:10][CH:11]=2)=[O:16])[CH:31]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)O)cc23)c1F
Reactant: Nc1cccnc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)Nc4cccnc4)cc23)c1F

Procedure:
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid pyridin-3-ylamide P-1801 is prepared in one step from 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 41 and pyridin-3-ylamine 42 as shown in Scheme 6.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C([OH:31])(C)C>O1CCCC1.O.OOS([O-])=O.[K+]>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:26])=[O:31])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Reactant: CC(C)O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(cis-4-Hydroxymethyl-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (120 mg, 0.307 mmol) was dissolved in a solvent mixture of isopropyl alcohol (4 ml), tetrahydrofuran (1 ml) and water (0.5 ml) and oxone™ (132 mg, 0.215 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2 increasing to 97:3, by volume). The resulting foam was triturated with diethylether (5 ml) to give the product (108 mg) as a white solid.