Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[O:21])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: CCCCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCC(Nc1ccc(-c2ccc(C#N)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared by the general method exemplified in Example 1 using 3-(4-hexanoyl-benzoylamino)-propionic acid methyl ester (Preparation 5) and 4′-amino-biphenyl-4-carbonitrile as starting materials. MS (ES): 470.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]4=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]4[CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]3[C:19]4=[N:20][S:21](=[O:24])(=[O:25])[CH2:22][CH2:23][N:18]4[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
To a suspension of NaH (60%, 418 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.659 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (690 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (579.1 mg) as a slightly yellow solid. Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (505 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at room temperature under hydrogen for 6 hr. Platinum(IV) oxide (30 mg), MeOH (15 mL) and THF (dry) (15 mL) were added and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (297.2 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(O)=O.[Br:24]Br.OS([O-])=O.[Na+]>O>[Br:24][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: BrBr
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of (3,4-dichlorophenyl)(indolin-1-yl)methanone (2.6 g, 8.90 mmol) in AcOH (8.2 mL, 142 mmol) was added bromine (504 μL, 9.79 mmol) dropwise via syringe at 0° C. Additional AcOH (6.0 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. Cold water was added to the reaction mixture followed by sat. aq. NaHSO3 solution. The resulting mixture was stirred for 10 min, and the precipitate was collected via filtration to give the title compound (3.30 g, 100%) as a light brown solid. 1H NMR (DMSO-d6) δ 7.90 (d, J=1.5 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.38 (br s, 1H), 4.02 (t, J=8.3 Hz, 2H), 3.10 (t, J=8.3 Hz, 2H); MS(ESI+) m/z 371.9 (M+H)+.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[F:15][C:14]([F:17])([F:16])[C:7]1([OH:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9][CH2:8]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
1,4-cyclohexandione mono-ethylene ketal (1.5 g, 9.6 mmol) was dissolved in THF (35 ml), followed by sequential addition of trimethyl(trifluoromethyl)silane (2.8 ml, 19.2 mmol) and tetrabutylammonium fluoride (1.0M solution in THF, 20 ml, 20.0 mmol) at 0° C., and then the resulting mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (10 ml) was added to the resulting reaction liquid, and then, the resulting mixture was stirred for 10 minutes, followed by concentration under reduced pressure. Distilled water (10 ml) was added to the residue thus obtained, followed by extraction with MC (50 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 2.1 g of yellow oil (97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.C(Br)C.[Mg].[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].[NH4+].[Cl-]>O1CCCC1>[CH3:14][Si:15]([C:9]#[C:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)([CH3:17])[CH3:16]
Reactant: C#Cc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere, 9.5 g of the compound of Step A were introduced into 100 g of tetrahydrofuran, and at 25° C.±3° C., over 15 minutes, 69 ml of a 0.8M solution of magnesium ethyl bromide were added, with stirring for 15 minutes at 25° C. Then, over 2 minutes and without cooling, 8 ml of trimethylsilyl chloride were added with stirring for 30 minutes at 25° C. The reaction mixture was poured into a 2M aqueous solution of NH4Cl and was extracted with ether, dried, filtered, and the filtrate was concentrated to dryness by distilling under reduced pressure then rectified to obtain 12.1 g of 3-(trimethylsilylethynyl)bromobenzene with a boiling point at 0.05 mm/Hg=78° to 84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([CH3:11])[CH:3]=1.ClC1C=C(Cl)C=CC=1C1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)[N:21]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:25]([C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=3)[N:21]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: Cc1cc(Cl)ccc1-c1nc(NCCNc2ccc([N+](=O)[O-])cn2)ncc1-c1ncc[nH]1

Procedure:
[4-(4-chloro-2-methylphenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 4-chloro-2-methylbenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:32]/[OH:33])/[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O-:29])=[S:28])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][O:22][C:21]([CH3:26])([CH3:25])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:32]/[OH:33])/[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O:29][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[S:28])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][O:22][C:21]([CH3:26])([CH3:25])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC1(C)OCCC(CC2=C(C([O-])=S)N3C(=O)C(NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)O1
Agent: [Na+]
Product: CC1(C)OCCC(CC2=C(C(=S)OCOC(=O)C(C)(C)C)N3C(=O)C(NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)O1
Yield: 59.7 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(2,2-dimethyl-1,3-dioxan-4-yl)methylthio-3-cephem-4-carboxylate (60 mg) was reacted with iodomethyl pivalate (40 mg),followed by purifying the reaction product in accordance with the procedure of Example 4, yielding the titled compound (42 mg; 60%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:11][CH2:10][C:8]1[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)cs1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CBr)cs1

Procedure:
A stirred mixture of 4-methyl-2-thiophenecarboxylic acid methyl ester (0.252 g) (Coll. Czechoslov. Commun. 1958, 23, 452, Synth. Commun. 1994, 24, 1721) and N-bromosuccinimide (0.287 g) in benzene (20 ml) was irradiated under a 500 W halogen lamp for 2 hours. The mixture was diluted with ethyl acetate, washed with water and dried (MgSO4). The residue was evaporated and purified by chromatography eluting with 50% ethyl acetate in isohexane. Yield 0.29 g.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11](O)=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[F:5][C:6]1[C:11]([O:3][C:1](=[O:4])[CH3:2])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 0.40 M solution of acetic acid (46 μL, 0.800 mmol) in EtOAc (2.00 mL, filtered through activated alumina) were added pentafluorophenol (162 mg, 0.880 mmol) and 1,3-dicyclohexylcarbodiimide (182 mg, 0.88 mmol). The reaction mixture was stirred for 12 h at rt at which time it was filtered (washing with EtOAc) and concentrated. Ester 19 was used immediately without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:3]=1
Reactant: CC1(c2cccc(Br)c2)COCC(N)=N1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC1(c2cccc(-c3ccc(F)cc3F)c2)COCC(N)=N1
Temperature: 100 °C

Procedure:
A degassed solution of (RS)-5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (intermediate XII-1) (100 mg, 0.37 mmol) in 1,2-dimethoxyethane was treated with tetrakis(triphenylphosphine)palladium(0) (42.7 mg, 0.037 mmol), then purged again with argon for 15 minutes. Thereafter, a solution of sodium hydrogencarbonate (1 M, 0.5 ml) and 2,4-difluoro-benzene-boronic acid (116.5 g, 0.74 mmol) were added. The tube was sealed and the mixture heated to 100° C. for 3 hours. For the workup, the reaction mixture was filtered through Celite®, then extracted with dichloromethane (2×15 ml). The combined organic layers were evaporated and the residue was repeatedly (3×) purified by chromatography on a silica-amine phase. The (RS)-5-(2′,4′-difluoro-biphenyl-3-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as an off-white solid (20 mg, 18% of theory). MS (ISP): m/z=303.4 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[CH2:13][N:12]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])[C:9]2=[CH:10][CH:11]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:47][C:48]([S-:50])=[O:49].[K+]>O1CCCC1.O>[C:48]([S:50][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15]3)[CH2:13][N:12]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])=[O:27])[C:9]2=[CH:10][CH:11]=1)(=[O:49])[CH3:47]
Reactant: CC(=O)[S-]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CCCCO)cc12
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)SCCCCc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(4-hydroxybutyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (120.7 mg, 0.246 mmol) was dissolved in tetrahydrofuran (2.5 mL). Thereafter, triethylamine (46 μL, 0.32 mmol) and methanesulfonyl chloride (21 μL, 0.27 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, insoluble matters were filtered, and the filtrate was then concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (2.4 mL), and S-potassium thioacetate (62 mg, 0.54 mmol) was then added to the above solution. The thus obtained mixture was stirred at room temperature for 15 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with water and brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(4-(acetylthio)butyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (89.2 mg, 66%) in the form of a brown oily product.
Reaction SMILES: [Cl:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:11][CH:10]=1>O1CCCC1>[Cl:1][C:2]1([C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:20][CH:21]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C1(Cl)CC1
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)C2(Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.3 %

Procedure:
3.9 g (28.1 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride are added, with stirring, to 4.5 g (23.3 millimoles) of 3-(p-aminobenzoyl)-propionic acid in 100 ml of absolute tetrahydrofuran. The reaction mixture is then stirred for 20 hours at room temperature, followed by 7 hours under reflux. A small amount of solid is filtered off and discarded, and the filtrate is concentrated. The residue obtained is recrystallized from ethyl acetate, giving 3.4 g (49% of theory) of 3-[p-(1-chlorocyclopropylcarbonylamino)-benzoyl]-propionic acid as colorless crystals, of melting point 178°-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of the above alcohol (0.79 g, 3.9 mmol) in CH2Cl2 (20 mL) was treated with molecular seives (1.95 g), N-methylmorpholine oxide (0.69 g, 5.9 mmol), and TPAP (0.14 g, 0.40 mmol). The mixture was stirred for 2 hours at room temperature and then filtered through a plug of silica gel, eluting with Et2O. The filtrate was then concentrated under reduced pressure to afford the desired 4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.69 g, 89%). 1H NMR (CDCl3) δ 1.49 (s, 9H), 2.44 (t, 4H, J=7.0 Hz), 3.72 (t, 4H, J=7.0 Hz).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>O>[CH3:3][C:2]([CH3:4])=[CH:1][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CC(C)C=O
Reactant: C1COCCN1
Solvent: O
Product: CC(C)=CN1CCOCC1

Procedure:
Isobutyraldehyde (19.4 g; 0.27 mol) is added slowly with stirring to morpholine (21.75 g; 0.25 mol). The ensuing reaction is exothermic. On completion of the addition the reaction mixture is stirred and heated at reflux for 5 hours while water (4.1 ml) is being azeotroped out of it. The reaction mixture is then vacuum distilled. A fraction collected at 64°-67° C. and 13 mm Hg weighs 15.6 g and consists of 90% by weight of title product and 10% by weight of morpholine. A second fraction collected at 67°-67.5° C. and 13 mm Hg (lit. 56°-57° C.; 11 mm Hg) weighs 16.2 g (46%) and is shown to be pure title product by nuclear magnetic resonance (nmr) and infrared (ir).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](Cl)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:28]4[CH2:30][CH2:29]4)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 100 °C
Yield: 86.1 %

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate (15.80 g, 40.00 mmol), cyclopropylboronic acid (5.16 g, 60.00 mmol) and potassium phosphate (38.20 g, 180.00 mmol) in toluene (160 mL) and water (8 mL) was bubbled with a nitrogen atmosphere for 10 min, tricyclohexylphosphine tetrafluoroborate (1.47 g, 3.99 mmol) and palladium acetate (0.45 g, 2.00 mmol) was added to this reaction mixture. The reaction mixture was heated to 100° C. for 18 h and then cooled to ambient temperature. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3), the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) afforded the title compound as a colorless solid (13.8 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.4 Hz, 1H), 6.47 (d, J=12.9 Hz, 1H), 3.49 (s, 2H), 2.05-1.95 (m, 4H), 1.78-1.61 (m, 12H), 1.55 (s, 9H), 0.91-0.84 (m, 2H), 0.64-0.58 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:9][CH2:10]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:34][CH:33]2[O:35][CH:29]([CH2:30][NH:31][CH2:32]2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].[Br-].[Li+]>C(#N)C>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH:29]2[O:35][CH:33]([CH2:32][N:31]([CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:30]2)[CH2:34]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCN(Cc3ccccc3)S(C)(=O)=O)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A suspension of methanesulfonic acid 2-(benzyl-methanesulfonyl-amino)-ethyl ester (4 g, 0.0130 mol; from step (ii) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (3 g, 0.013 mol; see WO 01/28992)), dry K2CO3 (3.6 g, 0.026 mol) and lithium bromide (2.2 g, 0.026 mol) in dry acetonitrile (50 ml) was stirred at 60° C. overnight under N2. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 4% methanol in dichloromethane as eluent to yield (5 g) of the sub-title compound as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-])(=[O:3])[CH3:2].C(OC(=O)C)(=[O:25])C>>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:25])[NH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2c1ccc[n+]2[O-]
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5-Acetyl-8-benzyloxyquinoline-N-oxide (10 gms/0.034 moles) was charged in acetic anhydride (20 ml) at 25-30° C. The resulting slurry was heated to 40° C. and stirred for 2 hours at 40° C. After completion of reaction, the reaction mass was cooled to 25-30° C., chilled to 0-5° C. and stirred for 30 minutes at 0-5° C. The resulting 5-Acetyl-8-benzyloxycarbostyril was isolated by filtration and washed with diisopropyl ether (50 ml), dried under vacuum at 60-65° C. for 2-3 hours. Yield-7 gms.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CN(CCCl)Cc1ccccc1
Solvent: CCO
Product: CN(CCNCc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
128 g (0.7 mol) of the compound obtained in Step b dissolved in 600 ml of ethanol are added dropwise to 150 g ( 1.4 mol) of benzylamine diluted in 200 ml of warm ethanol. The mixture is stirred at room temperature for 24 hours and the solvent is evaporated off in vacuo. Benzylamine hydrochloride crystallises from a mixture of methylene chloride and acetone, and is removed by filtration. The tiltrates are saturated with gaseous hydrogen chloride and the hydrochloride of the desired compound crystallises from a methylene chloride/ether mixture. 105 g of white crystals are obtained.