Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH3:11])=[N:4][C:3]=1[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(OCC)(=O)C>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][C:3]1[N:4]=[C:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH3:11])[O:6][C:2]=1[CH3:1])(=[O:25])=[O:24]
Reactant: CCCC=Cc1nc(CCO)c(C)o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC/C=C/c1nc(CCOS(C)(=O)=O)c(C)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[5-Methyl-2-(1-penten-1-yl)oxazol-4-yl]ethanol (1.03 g) was dissolved in methylene chloride (10 ml), and triethylamine (1.03 ml) was added. Methanesulfonyl chloride (0.41 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 30 min. Ethyl acetate (100 ml) was added, and the mixture was washed with 10% aqueous citric acid solution (100 ml) and then with saturated brine (100 ml), and dried (Na2SO4). The solvent was evaporated under reduced pressure to give the title compound (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1.C(N(CC)CC)C>O1CCCC1>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cc(C)nn2C)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 70.9 %

Procedure:
Using N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (129 mg, 0.379 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (78.3 mg, 0.493 mmol), triethylamine (115 mg, 1.14 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (124 mg, 71%) was obtained as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:27][C:28]([NH:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41])=[O:29]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)NCC2
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)N(CC(=O)N[C@@H]1c3ccccc3C[C@@H]1O)CC2

Procedure:
prepared by reaction of 1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2C(=O)O)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of ethanol (728 ml) and 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester (337 g) was added 4N aqueous sodium hydroxide solution (728 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (17 g) was added and the mixture was stirred overnight. The activated carbon was filtered off, and washed with 50 v/v % ethanol-water (200 ml). The filtrate was acidified by dropwise addition of acetic acid (500 ml) at room temperature. To this mixture, water (414 ml) was added dropwise at room temperature, and the mixture was stirred for 2 hr. This suspension was filtered, and the obtained solid was washed with 40 v/v % ethanol-water (250 ml), and dried under reduced pressure at 80° C. to give the title compound (203 g, 2 steps 85%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Yield: 86 %

Procedure:
Using 6-bromonicotinic acid (2 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (2.5 g) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Preparation Example 119, the title compound (3.4 g) was obtained.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:10]=1.BrCCBr>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:19][O:18][C:16]([C:15]1([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1)=[O:17]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cccnc1
Agent: [Li+]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1(c2cccnc2)CC1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
To a cooled (−78° C.) solution of LDA (2.0M, 272 mL) in 500 mL anhydrous THF and 200 ml HMPA (dried with molecular sieves) was added gradually a solution of ethyl 3-pyridylacetate 7-1 (75.0 g, 454 mmol) in 50 mL THF. The mixture was stirred for 50 min at −78° C. and treated with neat 1,2-dibromoethane (117 mL, 1363 mmol) in one portion. The reaction mixture was stirred overnight while being allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4Cl and extracted three times with EtOAc. The combined organic layers were washed three times with H2O and then brine. After solvent removal, the residue was purified using silica gel chromatography (100% hexanes to EtOAc/hexane=7/3) to obtain the desired product 7-2 as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:22][O:23][CH2:24][CH2:25][CH3:26])[CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN.O>C(O)C>[CH2:24]([O:23][N:22]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:10][NH2:11])[CH2:25][CH3:26]
Reactant: CCCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCON=C(CN)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To 235 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(propoxyimino)ethyl]phthalimide in 5 ml of ethanol, 90 mg of hydrazine monohydrate was added and refluxed with heating for 3 hours with stirring. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 20 ml of water and extracted with ethyl acetate (35 ml×2). The resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 151 mg of the desired crude product as a brown oil. The oil was used in the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39]([NH:41][C@H:42]1[C@H:47]([OH:48])[CH2:46][CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[C:59](O)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O1CCCC1>[C:59]([O:48][C@H:47]1[CH2:46][CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43][C@H:42]1[NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:40])(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
To a solution of triphenylphosphine (5.83 g, 22.24 mmol) in tetrahydrofuran (THF) (60 mL) was added DIAD (4.38 mL, 22.24 mmol) and the mixture was stirred in an ice-water bath for 15 min and then allowed to warm to rt. To the suspension was added a suspension of trans-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (6.495 g, 18.54 mmol) in tetrahydrofuran (THF) (75 mL) followed by benzoic acid (2.72 g, 22.24 mmol). The reaction mixture cleared to a yellow solution and was stirred for 2 h. LCMS analysis showed product formation, however the SM peak was obscured by by-product so it was difficult to confirm reaction had gone to completion. The reaction was left to stir overnight (20 h). The reaction mixture was concentrated under vacuum. The residue was purified by silica chromotagraphy. The residue was loaded in DCM on a 340 g silica cartridge and purified using a 0-40% EtOAc/cyclohexane gradient. The appropriate fractions were combined and the evaporated in vacuo to give the crude product cis-benzyl 4-(benzoyloxy)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (8.11 g, 17.84 mmol, 96% yield) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH2:12][O:13][CH3:14].C(=O)(O)[O-].[Na+].[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1)#[N:21]>O1CCCC1.O>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=2[O:11][CH2:12][O:13][CH3:14])(=[O:30])=[O:29])[CH:27]=1)#[N:21]
Reactant: COCOc1cc(O)ccc1CCN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc(O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
4-(2-Aminoethyl)-3-methoxymethoxyphenol (12.3 g) and 7.9 g of sodium bicarbonate were suspended in a mixture of 133 mL of tetrahydrofuran and 14.4 mL of water, to the suspension was added 18 mL portions of a solution of 14.50 g of 5-cyano-2-methoxybenzensulfonyl chloride in 180 mL of tetrahydrofuran every 10 minutes while the internal temperature was kept at 10–20° C. After being stirred at room temperature for 8 hours, the reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate), and recrystallized from ethyl acetate-diisopropyl ether to give 21.87 g of 5-cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)ethyl]-2-methoxybenzenesulfonamide as a colorless crystal.
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:19]1([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]2[CH2:29][C@H:28]([NH2:30])[C@@H:27]2[CH2:31][CH3:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl.C(OCC)(=O)C>[C:4]([O:3][C:1]([NH:30][C@H:28]1[CH2:29][N:26]([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:27]1[CH2:31][CH3:32])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC[C@H]1[C@@H](N)CN1C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@H]1[C@@H](NC(=O)OC(C)(C)C)CN1C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 57.1 %

Procedure:
tert-Butyl dicarbonate (202 mg, 0.93 mmol) and triethylamine (0.27 mL, 1.93 mmol) were added to a solution of cis(±)-1-(diphenylmethyl)-2-ethylazetidin-3-amine obtained in Example (235d) (206 mg, 0.77 mmol) in dichloromethane (4 mL), followed by stirring for two hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1) to obtain 161 mg of the title compound as a colorless oily substance (57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])(C)(C)C.CN(C)[CH:29]=[O:30].[NH4+].[Cl-]>CCOCC>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH:29]=[O:30])=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C#Cc3ccc(Br)cn3)cc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)CCSc2ccc(C#Cc3ccc(C=O)cn3)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (-78° C.) solution of 358 mg (1.0 mmol) of 2-(4,4-dimethylthiochroman-6-yl)ethynyl-5-bromopyridine in 5 ml of anhydrous ether was added slowly under nitrogen 1.3 ml of 1.7M (2.21 mmol) tert-butyl lithium in pentune. The mixture was stirred at -78° C. for 1 h and then treated with 95 mg (1.3 mmol) of anhydrous dimethylformamide. The mixture was stirred at -78° C. for a further 0.5 hours, then warmed to 0° C. and treated with 5 ml of saturated NH4Cl solution followed by 5 ml of ether. The organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined, washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexanes) followed by high pressure liquid chromatography (Whatman M-9 Partisil 10/50 column, 15% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].[H-].[Na+].[CH3:12]I>CS(C)=O>[CH3:12][O:9][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8]
Reactant: CC(O)c1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(C)c1ccccn1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 223 g. of 1-(2-pyridyl)-ethanol in 1500 ml. of dry dimethylsulfoxide is added 2.3 moles of sodium hydride in portions, under nitrogen, maintaining the temperature at 20°C. After two hours, 331 g. of methyl iodide is added at 20°C. After stirring for another 3 hours, the mixture is poured onto ice-water and extracted three times with ether. The organic phase is washed with water, dried over magnesium sulfate, concentrated in vacuo, and the residue is distilled to give 2-(1-methoxyethyl)pyridine.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH3:11])=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:13]>C(Cl)Cl>[CH:1]([C:4]1[C:5]([CH2:11][OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C(C)C)ccc[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cccnc1CO
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of 3-isopropyl-2-methyl-pyridine 1-oxide (26.05 g, 173 mmol) in CH2Cl2 (690 mL) was added dropwise TFAA (51.83 mL) over 30 min. under N2 then stirred for an additional 3 h. Caution: exothermic reaction on addition of TFAA. The mixture was concentrated in vacuo to a minimum volume. Brine (200 mL) was added, basified to pH 9 with solid K2CO3 slowly, then the aqueous mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford (3-isopropyl-pyridin-2-yl)-methanol (26 g, 99%) as an orange oil. 1H NMR(CDCl3) δ 1.24 (d, 6H, 7.0 Hz), 2.92 (sep, 1H, J=6.6 Hz), 4.79 (s, 2H), 7.02-7.25 (m, 1H), 7.61 (d, 1H, J=7.9 Hz), 8.41 (d, 1H, J=4.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCCC>C(OC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10][Br:15])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: COC(C)=O
Product: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 80.4 %

Procedure:
A mixture of 5-methyl-2-nitro-benzoic acid methyl ester (93.95 g, 481.35 mmol), 1,3-dibromo-5,5-dimethylhydantoin (75.70 g, 264.74 mmol), in methyl acetate (550 mL) was heated at 78° C. for 40 minutes while stirred with a mechanical stirrer. Then a solution of 2,2′-azobisisobutyro-nitrile (3.95 g, 24.07 mmol) in methyl acetate (80 mL) was added, and the mixture was heated at about 75° C. for 13 hours. The mixture was allowed to cooled to 15° C. and stirred for 2 hours to age the precipitate. The suspension was filtered, washed with 10° C. methyl acetate (2×50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL). The organic layer was washed with 2% brine (2×500 mL) and water (2×500 mL), and concentrated to about 2 volumes. To the mixture, was added t-butyl methyl ether (or MTBE, 300 mL). The mixture was heated at about 70° C. for 15 minutes, cooled to about 53° C. over one hour, seeded with the product (about 250 mg, or simply re-crystallized) at 45° C., then at 20˜25° C., while blowing nitrogen with a glass pipette overnight. The resulting solid was filtered via a medium pore-sized funnel, washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 5-bromomethyl-2-nitro-benzoic acid methyl ester as an off-white solid (58.3 g, 44.0% yield). The solid was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:11]1=[S:12])[CH3:14]
Reactant: Cc1cc(C)c(N=C=S)cc1C
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(C)c(C)cc2C)C1=S
Yield: 58.4 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 17.7 g of 2,4,5-trimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (15.3 g) as an off-white solid, m.p. 162°-164° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.21; H, 6.93; N, 10.80. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:32][CH:28]1[CH2:29][CH2:30][CH2:31][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: NC1CCCN(Cc2ccccc2)C1
Product: O=C(NC1CCCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 1-benzyl-3-piperidinylamine [see J. Med. Chem. (1980), 23(8), 848-851]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 40:60, by volume, hexane:ethyl acetate in 10% increments, to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-(1-benzyl-3-piperidinyl)hexahydro-2-pyridinecarboxamide as a yellow gum.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19](=[N:26][OH:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[C:30]1([C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N+]=[N-])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19](=[N:26][OH:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O:14][CH:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid (syn-isomer)(2.0 g) in tetrahydrofuran (50 ml.) maintained at 37° was added portionwise a solution of diphenyldiazomethane in petroleum (b.p. 60°-80°) until the purple colour persisted for one hour. After addition of acetic acid to destroy excess diphenyldiazomethane, the solution was evaporated to dryness, taken up in ethyl acetate, then washed with sodium bicarbonate, and brine, dried and evaporated. The residue was triturated with petroleum spirit, and the resulting solid filtered and dried to give diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (syn-isomer) (1.93 g 69%), [α]D +24° (c 1, DMSO), λmax. (EtOH) 253 nm (ε 16,150), νmax. (CHBr3) 3610 (OH), 1796 cm.-1 (β-lactam), τ (DMSO-d6) values include 0.27 (doublet, J 9 Hz; NH), 8.03 (singlet; OCOCH 3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:26]([CH3:29])=[C:27]=[O:28]>C(Cl)(Cl)Cl>[CH3:29][NH:26][C:27]([N:15]1[CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13][CH2:14]1)=[O:28]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCNCC1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-4-yl-1,3-dihydro-indol-2-one (30 mg, 0.08 mmol) (from Example 15a supra) in chloroform (2 mL) was added isocyanatomethane (5.4 mg, 0.096 mmol) (Chem. Service). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and resulting material was recrystallized from dichloromethane-hexanes to give rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid methylamide as a white solid. (Yield 5 mg, 14.5%).
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10])=[N+:2]=[N-:3].S(=O)(=O)([OH:13])N.Cl([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:13])=[O:10])=[N+:2]=[N-:3]
Reactant: NS(=O)(=O)O
Reactant: [N-]=[N+]=Nc1ccsc1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccsc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
3-Azidothiophene-2-carbaldehyde (1.22 g, 8.0 mmol) was dissolved in 30 mL of acetone:H2O (2:1) and treated with sulfamic acid (1.16 g, 12.0 mmol). Sodium chlorite (1.27 g, 17.1 mmol) was added and stirred at 0° C. for 30 min. The mixture was alkalinized to pH 9 with sodium carbonate, and the product was washed with diethyl ether (10 mL). The aqueous layer was carefully treated with aqueous concentrated HCl to pH 1. The product was extracted with diethyl ether (3×10 mL), dried over Na2SO4, and concentrated in vacuo to give 13a (1.01 g, 75% yield).