Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1CC=CCC=1.C([N:15]1[CH2:21][CH2:20][C:19]2[C:22](Cl)=[N:23][C:24]([CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])=[N:25][C:18]=2[CH2:17][CH2:16]1)C1C=CC=CC=1.[CH2:35]([OH:37])[CH3:36]>[OH-].[Pd+2].[OH-]>[CH2:35]([O:37][C:22]1[C:19]2[CH2:20][CH2:21][NH:15][CH2:16][CH2:17][C:18]=2[N:25]=[C:24]([CH:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27])[N:23]=1)[CH3:36]
Reactant: CC(c1ccccc1)c1nc(Cl)c2c(n1)CCN(Cc1ccccc1)CC2
Reactant: CCO
Agent: [Pd+2]
Agent: CC1=CCC=CC1
Agent: [OH-]
Product: CCOc1nc(C(C)c2ccccc2)nc2c1CCNCC2
Yield: 69 %

Procedure:
Palladium hydroxide (20% on carbon) (43 mg, 0.3 mmol) and 1-methyl-1,4-cyclohexadiene (3.42 ml, 30.5 mmol) was added to a solution of 7-benzyl-4-chloro-2-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of preparation 30, Step B, (1.15 g, 3.04 mmol) in ethanol (30 ml) and refluxed, under nitrogen, for 16 h. The reaction mixture was filtered through Arbocel then the filtrate was concentrated in vacuo. The residue was purified by column chromatography on Biotage 40S cartridge, eluting with DCM:MeOH (100:0 to 90:10), to afford the title compound as a solid in 69% yield, 629 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:20](=[O:21])[NH:19][CH:18]=[CH:17][C:11]=3[N:12]=[C:13]([S:15][CH3:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C)C=O>[Br:29][C:17]1[C:11]2[N:12]=[C:13]([S:15][CH3:16])[N:14]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:10]=2[C:20](=[O:21])[NH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(Nc2cccc(C)c2)c2c(=O)[nH]ccc2n1
Solvent: CN(C)C=O
Product: CSc1nc(Nc2cccc(C)c2)c2c(=O)[nH]cc(Br)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
4-[(3-methylphenyl)amino]-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (500 mg, 1.676 mmol) was dissolved into N,N-Dimethylformamide (DMF) (8 mL) and NBS (298 mg, 1.676 mmol) was added. The reaction mixture was stirred at rt for 2 h. It was quenched with water (12 mL) and EtOAc (5 mL) was added. The mixture was filtered to collect the precipitate, which was further dried under high vacuum to give 470 mg of crude product (83% pure based on LC-MS).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:18][OH:19])[CH2:9]1)=O)(C)(C)C.ClC1[NH:30][C:29](=[O:31])[C:28]2[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=2)[N:22]=1.C(=O)(O)[O-].[Na+].O>FC(F)(F)C(O)=O.ClCCl.CS(C)=O>[OH:19][CH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][N:8]([C:6]1[NH:30][C:29](=[O:31])[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=3)[N:22]=1)[CH2:9]2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCc2c(CO)cccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc2nc(N3CCc4c(CO)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 85 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
5-Hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 21a (0.31 g, 1.17 mmol) was dissolved at room temperature in 10 mL of 10% trifluoroacetic acid in dichloromethane and stirred for 2 h. The volatiles were evaporated, the residue was suspended in toluene, evaporated again and dried under vacuum. The trifluoroacetic salt of the deprotected amine, was mixed with 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (0.269 g, 1.11 mmol) and sodium bicarbonate (0.148 g, 1.76 mmol) in dimethyl sulfoxide (6 mL), and the mixture was heated to 85° C. with stirring for 28 h. After cooling to room temperature, water (20 mL) was added and the precipitated product was separated by filtration, rinsed with water, and dried to yield 0.2 g of 2-(5-hydroxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 22a, mp. 200.1-206.3° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.C(N)(C)(C)C.[PH2](O)=O>[Pd].CO>[OH:28][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: [Pd]
Agent: O=[PH2]O
Solvent: CO
Solvent: CC(C)(C)N
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a 500 mL capacity stainless steel autoclave equipped with a stirrer, external heating jacket and internal heating and cooling coils are added 5.0 g (0.013 mole) of 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene, 0.25 g (dry weight) of (4% Pd/C+1% Pt/C) catalyst, 3.82 g (0.052 mole, 4 equivalent) of tert-butylamine, 5.16 g (0.039 mole, 3 equivalent) of aqueous hypophosphorous acid and 150 mL of methanol. The autoclave is purged with nitrogen gas and then hydrogen gas and then sealed and charged with hydrogen gas to a pressure of 53,000 Kg/m2. The reaction is stirred at room temperature and at 53,000 Kg/m2 pressure (recharging if necessary) for one hour. After one hour the temperature is raised to 50° C. and held at the same temperature and pressure for an additional 12 hours. Then the autoclave and its contents are cooled to 45°-47° C., removed and filtered through a Celite filter-aid pad to remove the catalyst. The catalyst and the residue on the filter pad are further washed with some ethyl acetate for complete recovery of the product. The organic solvents are removed on a rotary evaporator. The residue is diluted with about 500 mL of brine (saturated aqueous sodium chloride solution) and treated with hydrochloric acid dropwise until the Congo Red Indicator paper turns blue. The light brown insoluble material (the desired product) was filtered on a sintered glass funnel, washed with cold distilled water to remove any contaminated salt, and air-dried. This crude solid material was recrystallized from isopropanol/water to obtain 4.56 g of 2-(2'-hydroxy-3',5'-di-tert-amylphenyl)benzotriazole as white solid (yield 99%; melting point 80°-81° C.) showing a retention time of 25.89 min. in HPLC analysis.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:1])=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OCCCOCc2ccccc2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc(OCCCOCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 4-hydroxybenzaldehyde (1 g), benzyl 3-bromopropyl ether (1.88 g), cesium carbonate (3.2 g) and a catalytic amount of sodium iodide in N,N-dimethylformamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(3-benzyloxypropoxy)-benzaldehyde (2.21 g). To a suspension of methyltriphenyl-phosphonium bromide (2.92 g) in tetrahydrofuran (30 mL) was added n-butyl lithium (2.71 mol/L n-hexane solution, 3.02 mL) under ice-cooling, and the mixture was stirred for 5 minutes. To the reaction mixture was added a solution of 4-(3-benzyloxy-propoxy)benzaldehyde (2.21 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (1.4 g).
Reaction SMILES: [N:1]([CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)=[N+:2]=[N-:3].[OH-].[Na+].O1CCCC1.Cl>CO>[N:1]([CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)c1ccc(COc2cccc(C(N=[N+]=[N-])c3ccccc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a stirred suspension of methyl 4-((3-(azido(phenyl)methyl)phenoxy)-methyl)benzoate (1 g, 2.79 mmol) in methanol (25 mL), was added 2M sodium hydroxide (25 mL). The reaction was allowed to stir at room temperature for 3 days. Tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was stirred at 50° C. for 4 hours followed by 16 hours at room temperature. The reaction mixture was acidified with 10% hydrochloric acid, extracted with dichloromethane, dried (sodium sulphate), filtered, and concentrated under reduced pressure to give the title compound (1 g, quantitative).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=[O:16]>>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC(C)=O
Product: ON(C1CCCCC1)C1CCCCC1
Yield: 82.6 %

Procedure:
A solution of 0.057 M DMD in acetone (49.2 ml, 3.317 mmol) was added to a cold stirred solution of N,N-dicyclohexylamine (Kodak; 0.508 g, 3.317 mmol) in acetone (5 ml). The reaction mixture was stirred for ten minutes in an ice bath. The solution was dried over Na2SO4, filtered, and the solvent removed in vacuo to give a colorless crystalline solid. This solid was purified by flash chromatography on silica gel with ethyl acetate:petroleum ether (20:80) elution to give a white crystalline solid (0.457 g, 82.6% yield), mp 70-72.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1>CCCCCC.CCO>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1
Solvent: CCCCCC
Solvent: CCO
Product: C[C@H]1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1

Procedure:
1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea (50 mg, 0.12 mmol, Example 78) was separated by chiral HPLC (Chiraltech Chiralcel OJ 50×4.6 mm i.d.) using hexane/EtOH/DEA (90:10:0.2) to give a white solid. MS m/z: 409.3 (M+H). Calc'd for C21H24N6OS-408.52.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([O:42][CH2:43][CH3:44])[C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(OCC)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2>>[CH3:1][C:2]1[C:3]([CH:22]([O:42][CH2:43][CH3:44])[C:23]2[NH:27][C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CCOC(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCOC(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: CCOC(c1nc2cc(C#N)ccc2[nH]1)c1c(C)cc(C)c2[nH]ccc12

Procedure:
The title compound was synthesized from a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 64-B and 64-C. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 10.96 (br.s, 1H) 7.98 (s, 1H) 7.65 (d, J=8.25 Hz, 1H) 7.55 (m, 1H) 7.21 (t, J=2.78 Hz, 1H) 6.74 (s, 1H) 6.56 (dd, J=2.78, 2.02 Hz, 1H) 6.30 (s, 1H) 3.56-3.64 (m, 1H) 3.42-3.50 (m, 1H) 2.42 (s, 3H) 2.41 (s, 3H) 1.22 (t, J=6.95 Hz, 3H). HRMS calcd. for C21H20N4O (M+H)+ 345.1710. found 345.1717.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](SC)=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[CH3:23][NH:24][CH3:25]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:24]([CH3:25])[CH3:23])=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CNC
Reactant: CSC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Solvent: C1CCOC1
Product: CN(C)C1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21

Procedure:
400 mg of 6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline (compound 1) were heated with 20 ml of dimethylamine in THF at 120° C. in a shaking autoclave under inert gas for 20 hours. Removal of the solvent by distillation was followed by MPLC chromatography on an MPRC cartridge with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. Semisolid, partly amorphous product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=O)[CH3:12].Cl.[NH2:15][OH:16].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=[N:15][OH:16])[CH3:12]
Reactant: NO
Reactant: COc1ccccc1C=CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C=CC(C)=NO
Yield: 54 %

Procedure:
In a 250 ml single neck flask was charged 5.28 g (.30.0 mmoles, 1.0 eq.) of 4-(2-methoxyphenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.1 g of 4-(2-methoxyphenyl)-3-buten-2-one 2-oxime (E/Z mixture of isomers) as an oil in 54.1% yield.
Reaction SMILES: C(N(CC)CC)C.[N:8](=[CH:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:25])[C:16]3[C:21]([C:22]=2[N:23]=1)=[CH:20][CH:19]=[C:18]([Br:24])[CH:17]=3)O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[C:10]([C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:25])[C:16]3[C:21]([C:22]=2[N:23]=1)=[CH:20][CH:19]=[C:18]([Br:24])[CH:17]=3)#[N:8]
Reactant: O=C1c2cc(Br)ccc2-c2nc(C=NO)ccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(n1)-c1ccc(Br)cc1C2=O
Reaction time: 8 h

Procedure:
2 Equivalents of triethylamine are added to a suspension of the oxime in dry methylene chloride at -78° under nitrogen. 1.1 equivalent of triflic anhydride are then added dropwise over 3 minutes. After stirring overnight, the reaction mixture is diluted with ethyl acetate and washed with 10% sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate. Solvent removal provides the desired 3-cyano-7-bromo-4-aza-9-fluorenone.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.CCN(CC)CC.[P:24](Cl)([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:14][C:12]([F:15])([F:13])[C:7]([C:4]1[S:3][C:2]([NH:1][P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])=[N:6][CH:5]=1)([OH:16])[C:8]([F:9])([F:10])[F:11]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of (2-amino-1,3-thiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (133 mg 0.5 mmol) from step 1 of example 1-1-1, DMAP (61 mg, 0.5 mmol), Et3N (100 μL, 0.72 mmol) and CH2Cl2 (5 ml) was added diethyl chlorophosphate (87 μL, 06 mmol). The reaction mixture was stirred at r.t. for 96 h. Solvent was removed and EtOAc was added. The solution was washed with water. After removal of solvent, the residue was purified by a short Ion Exchange Column (Dowex-50W, ethanol) to afford the title compound as a white solid (43 mg). 1H NMR (DMSO-d6) δ 1.20 (t, 6H), 3.89 (m, 4H), 7.46 (s, 1H), 9.18 (s, 1 H); ESIMS: m/z 401 (M−H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CS(C)=O.C1C=CC=CC=1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)c1ccc(C(O)C(=O)O)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COc1ccc(COC(=O)c2ccc(C(O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.9 g of the dipotassium salt of DL-α-hydroxy-4-carboxyphenylacetic acid (mp 201° ~ 203° C) in 40 ml of dimethylsulfoxide were added 6.2 g p-methoxybenzylchloride and stirred overnight at ambient temperature. 50 ml of ice-water were added to the reaction mixture, adjusted to pH 7.5 and extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue was dissolved in 60 ml of 50% acetone. To the solution was added a phenolphthalein reagent and then dropwise a 2N-sodium hydroxide solution at 40° ~ 45° C with stirring. The reaction was continued until the red color was maintained for 5 minutes. Then acetone was removed under weakly reduced pressure. The aqueous layer was washed several times with ethyl ether, and then adjusted to pH 2.5 with a 20% hydrochloric acid solution after the addition of ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed several times with a small amount of an aqueous sodium chloride saturated solution, dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give an oily residue. The residue was dissolved in benzene and left overnight in an ice-box, yielding crystals of DL-α-hydroxy-4-(p-methoxybenzyloxycarbonyl) phenylacetic acid of 7.4 g (78.5%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]=O)=[CH:12][CH:11]=2)[C:4](=[S:21])[N:3]1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1.[CH2:34]([NH2:37])[CH2:35][NH2:36].BrN1C(=O)CCC1=O>ClCCl>[NH:36]1[CH2:35][CH2:34][N:37]=[C:19]1[CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:5]2[C:4](=[S:21])[N:3]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=3)[C:2](=[O:1])[C:6]32[CH2:7][CH2:8][CH2:9]3)=[CH:15][CH:14]=1
Reactant: NCCN
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC=O)cc3)C2=S)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC4=NCCN4)cc3)C2=S)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
The mixture of 4-(8-Oxo-5-(4-(4-oxobutyl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (68) [ND-10] (15 mg, 0.03 mmol) and ethylene diamine (2 μL, 0.04 mmol) in dry dichloromethane (3 mL) was stirred at 0° C. for 30 min under argon. N-Bromosuccinimide (NBS, 6 mg, 0.04 mmol) was added to the mixture and the resulting solution was stirred overnight at 21° C. Reaction was quenched by the addition of saturated NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4, and evaporated in vacuo. The residue was purified by flash column chromatography (ethanol:ethyl acetate, 1:4) to give 4-(5-(4-(3-(4,5-Dihydro-1H-imidazol-2-yl)propyl)phenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (65) [ND-11] (6 mg, 35%): 1H NMR δ 7.98 (d, 1H, J=1.9 Hz) 7.97 (d, 1H, J=8.3 Hz) 7.85 (dd, 1H, J=8.3, 1.9 Hz), 7.46 (d, 1H, J=8.2 Hz) 7.25 (d, 1H, J=8.2 Hz), 4.72 (br s, 1H), 3.67-3.80 (m, 4H), 2.85-3.05 (m, 2H), 2.57-2.70 (m, 2H), 2.43-2.57 (m, 4H), 2.15-2.30 (m, 1H), 1.63-1.80 (m, 3H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][P:35]([O:39]C)([O:37]C)=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].C(ON=C(C1N=C(NP(OC)(OC)=O)SN=1)C([O-])=O)C=C.[Na+].Cl.Cl.NC1C(=O)N2C(C([O-])=O)=C(C[N+]3C=CC=CC=3)CS[C@H]12.C[Si](Br)(C)C.C(OC(C)C)(C)C>C(O)(=O)C>[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][P:35]([OH:37])([OH:39])=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NP(=O)(OC)OC)n1
Agent: C=CCON=C(C(=O)[O-])c1nsc(NP(=O)(OC)OC)n1
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NP(=O)(O)O)n1
Reaction time: 1 h

Procedure:
To a solution of 7-[2-allyloxyimino-2-{5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl}acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) in the reaction mixture prepared from sodium 2-allyloxyimino-2-[5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl]acetate (syn isomer) (502 mg) and 7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate dihydrochloride (560 mg) according to a similar procedure to that of Example 1 was added dropwise trimethylsilyl bromide (3.22 g) under cooling in an ice bath and stirring, which was continued for one hour at room temperature. To the mixture was added acetic acid (0.5 ml) and the mixture was poured into diisopropyl ether (500 ml) under stirring. The resulting oily product was separated out by decantation and dissolved in water (50 ml). The aqueous solution was subjected to column chromatography on a non ionic adsorption resin "Diaion HP-20" (50 ml). The elution was carried out with water and 10% aqueous methanol. The fractions containing the object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-allyloxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (250 mg), mp. 175° to 181° C. (dec.).