Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(Cl)([Cl:20])(=O)=O>C(OCC)C>[Cl:20][CH:10]([C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1OC
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1OC
Yield: 94.8 %

Procedure:
Using ethyl 3-(2-methoxyphenyl)-3-oxopropanoate (1.7 g, 7.4 mmol), sulfuryl chloride (1.2 g, 8.9 mmol) and diethyl ether (100 mL) as starting materials and in the same manner as in Example 20(i), the title compound (1.8 g, 97%) was obtained as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)=[CH:15][CH:16]=3)[N:11]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[CH:28]=3)[CH:10]=2)=[CH:5][CH:4]=1>[Ni].CO.CN(C=O)C>[NH2:24][C:20]1[CH:19]=[C:18]([C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][N:11]3[C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[CH:28]=3)=[CH:16][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc(N)c4)cc32)ncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methanol/DMF (1:1, 20 mL) was added to 6-(3-(4-methoxyphenyl)-6-(3-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (100 mg, 0.22 mmol) and Raney nickel (about 50 mg). The mixture was stirred at room temperature for 24 hours under hydrogen gas (1 atm). The reaction solution was filtered using a diatomite pad and then concentrated under reduced pressure. The target compound was obtained as brown solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([SH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:27][CH2:28][O:29][CH3:30])(=O)=O>C1COCC1>[C:3]1([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:22][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
To sodium hydride (2.17 g, 0.09 mol) under nitrogen was added anhydrous THF (50 ml). The mixture was cooled to 0° C. and triphenylmethylmercaptan (24.88 g, 0.09 mol) in anhydrous THF (50 ml) added dropwise over 15 minutes. After a further 10 minutes at 0° C. the mixture was warmed to room temperature, at which it was stirred for 1 hour. The mixture was then recooled to 0° C. and ethylene glycol methyl ether tosylate (20.72 g, 0.09 mol) in dry THF (50 ml) added dropwise over 15 minutes. After warming to room temperature the mixture was left to stir for 16 hours. The mixture was filtered and the precipitate washed with dichloromethane. The combined filtrates were concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water (3×50 ml), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (gradient from 100% petrol to 100% EtOAc) and recrystallisation (petrol) gave the title compound (12.39 g, 41%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[OH:31].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][N:18]([CH3:20])[C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:31][C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[F:21])[CH:8]=2)=[O:12])[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Temperature: 190 °C
Yield: 70.5 %

Procedure:
A mixture of the amide 24 (1.44 g, 4.65 mmol), 2-fluoro-4-nitrophenol (2.21 g, 14.1 mmol) and K2CO3 (2.56 g, 18.5 mmol) in Ph2O (5.0 mL) was heated at 190° C. for 3 hrs. CHCl3 (100 mL) was added to the resultant dark brown mixture and then the mixture was extracted with 1M HCl. The aqueous phase was washed with CHCl3 and basified with NH4OH (pH 11). The resultant cloudy mixture was extracted with CHCl3 and the organic phase was collected, washed with water, dried over anhydrous Na2SO4 then concentrated under reduced pressure. The remaining yellow solid material was purified by flash chromatography, eluent CHCl3/MeOH (95:5, then 80:20) to afford title compound 25 as a white solid (1.41 g, 3.28 mmol, 71% yield). MS (m/z): 431.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18](O)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[CH3:21][N:22]1[CH:29]=[CH:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([C:28]3[C:26](=[O:27])[NH:25][C:23](=[O:24])[N:22]([CH3:21])[CH:29]=3)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: Cc1nc2c(n1CCO)C=Cc1cc(Cl)ccc1C2O
Product: Cc1nc2c(n1CCO)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product from step (ii) (1.85 g) and 1-methyluracil (0.4 g) according to the method of example 42 step (iv). Purification was by biotage chromatography on silica eluting with 5% methanol in dichloromethane with 1% 0.880 ammonia present.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:38]=[CH:37][C:14]([O:15][CH2:16][CH2:17][NH+:18]2[CH2:36][CH2:35][C:21]3([O:26][CH2:25][CH2:24][N:23]([C:27]([C:29]4[N:30]=[C:31]([CH3:34])[S:32][CH:33]=4)=[O:28])[CH2:22]3)[CH2:20][CH2:19]2)=[CH:13][CH:12]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOCC>[CH3:34][C:31]1[S:32][CH:33]=[C:29]([C:27]([N:23]2[CH2:22][C:21]3([CH2:35][CH2:36][N:18]([CH2:17][CH2:16][O:15][C:14]4[CH:37]=[CH:38][C:11]([CH2:10][CH:9]=[O:8])=[CH:12][CH:13]=4)[CH2:19][CH2:20]3)[O:26][CH2:25][CH2:24]2)=[O:28])[N:30]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CC[NH+](CCOc4ccc(CCO)cc4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CC=O)cc4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (0.04 mL) was added to a solution of 9-(2-(4-(2-hydroxyethyl)phenoxy)ethyl)-4-(2-methylthiazole-4-carbonyl)-1-oxa-4-aza-9-azoniaspiro[5.5]undecane (example 3, step c) (0.22 g) in DCM (3 mL) and the resulting mixture was stirred for 5 min. Dess-Martin periodinane (0.31 g) was then added and the resulting mixture stirred for 5 min. A mixture of saturated sodium thiosulphate solution (0.5 mL), sodium bicarbonate solution (0.5 mL) and ether (5 mL) was then added and the resulting mixture stirred for 5 min. The organic layer was separated and washed with sodium bicarbonate solution (1 mL) and water (1 mL), then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a clear oil which was used immediately. Yield 0.19 g.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[CH2:20][OH:21])=O)(C)(C)C>C1COCC1>[CH3:12][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCOCC1CO
Temperature: -10 °C
Yield: 84.9 %

Procedure:
LiAlH4 (4.2 g, 110 mmol) was suspended in anhydrous THF (60 mL) under nitrogen, cooled to −10° C. with stirring and a solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 4.1 g, 18.4 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 minutes at 0° C., heated to reflux for 3 h and then stirred at room temperature overnight. The reaction mixture was cooled to −10° C. and quenched with the dropwise addition of 10% water in THF. The reaction mixture was diluted with THF (50 mL), stirred for 1 h at room temperature, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM, dried (MgSO4) and the solvent removed in vacuo to give (4-methyl-morpholin-3-yl)-methanol (2.05 g, 85%) as a colourless liquid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([F:28])[CH:20]=3)[O:18][C:13]=2[C:12]([F:30])=[CH:11][C:10]=1[F:31].[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[F:31][C:10]1[CH:11]=[C:12]([F:30])[C:13]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([F:28])[CH:20]=3)=[CH:16][C:15](=[O:29])[C:14]=2[C:9]=1[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: c1c[nH]cn1
Reactant: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCBr)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCn4ccnc4)c(F)cc(F)c3o2)cc1F
Reaction time: 1.5 h

Procedure:
500 mg (1.01 mmol) of Compound 59 obtained in Example 59 was dissolved in 10 ml of tetrahydrofuran, 137 mg imidazole and 80 mg of sodium hydride (60% oil dispersion) were added and the mixture was heated at reflux for 2.3 hours. At 1.5 hours after the reaction was started, 40 mg of sodium hydride (60% oil disperison) was added. An aqueous solution of ammonium chloride was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine=200:10:1) and triturated with n-hexane to give Compound 64 which was converted into hydrochloride according to the same manner as that in Example 16 to give 447 mg (73%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C>[N:18]([CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8]1)=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)OCC1Cc2ccccc2C(=O)N1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2ccccc2C(=O)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Dissolve (1-oxo-3,4-dihydro-2H-isoquinolin-3-yl)methyl methanesulfonate (3 g, 11.7 mmol) in DMF (10 mL). Add NaN3; heat to 70° C. and stir overnight. Concentrate under reduced pressure; add water; and extract with EtOAc. Combine the extracts and remove the solvents under reduced pressure to provide the title compound (1.7 g, 71.5%). 1H NMR (400 mHz, CDCl3): δ 8.1 (s, 1H), 7.6 (m, 1H), 7.5 (m, 1H), 7.0 (s, 1H), 3.9 (m, 1H), 3.5 (m, 2H), 3.0 (m, 2H).
Reaction SMILES: [C:1]([C:4](=[CH:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].[NH2:15][C:16]1[N:20]=[CH:19][NH:18][N:17]=1>C(O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:17]2[N:18]=[CH:19][N:20]=[C:16]2[NH:15][C:1]=1[CH3:2])=[O:6]
Reactant: COC(=O)C(=Cc1cccs1)C(C)=O
Reactant: Nc1nc[nH]n1
Solvent: CCO
Product: COC(=O)C1=C(C)Nc2ncnn2C1c1cccs1
Yield: 44.9 %

Procedure:
A mixture of 50 g of methyl 2-acetyl-3-(2-thienyl)acrylate, 20 g of 3-amino-1,2,4-triazole and 300 ml of ethanol is heated under reflux for 4 hours. The precipitated white crystals are collected by filtration to give 29.5 g of 6-methoxycarbonyl-5-methyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 239°-240° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH3:12])[CH2:9][CH2:8][N:7]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5])C.[OH-].[Na+].Cl>CO.C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:7]2[CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][CH:6]2[C:4]([OH:5])=[O:3])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1CN(C)CCN1S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(F)cc2)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
To a solution of 0.390 (1.182 mmol) of the product of Example 53 dissolved in 12 mL of methanol/THF (1:1) was added 5.9 mmol of 1.0N sodium hydroxide solution and the resulting mixture was stirred for 15 h at room temperature. The reaction was then brought to pH 6 with 5% HCl and extracted with dichloromethane. The organics were dried over Na2SO4, filtered and concentrated in vacuo to provide 0.265 g (74%) of the carboxylic acid as a pale yellow solid. Electrospray Mass Spec: 302.9 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.N([O-])=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1c(F)cc(F)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(F)cc(F)c1

Procedure:
Thus WO 96/02493, starting from 2,4-difluoroaniline, discloses a synthesis proceeding via five stages. 2,4-Difluoroaniline is first reacted with acetic anhydride, the resulting acetanilide is nitrated by means of HNO3 /H2SO4, the acetyl radical is removed and 2,4-difluoro-6-nitroaniline is obtained. By reaction of the 2,4-difluoro-6-nitroaniline with sodium nitrite, the amino group can be removed and 3,5-difluoronitrobenzene is obtained, which can be converted into 3,5-difluoroaniline by reduction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:20]([Zn]CC)[CH3:21].CCCCCC>O1CCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH2:20][CH3:21]
Reactant: CC[Zn]CC
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(Br)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(C(=O)O)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
3-Bromo-4-(3,4-dichlorophenoxy)benzoic acid (Preparation 8, 240 mg, 0.663 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to 0° C. Bis(tributylphosphine)palladium (0) (33.7 mg, 0.07 mmol) was added followed by the slow addition of a 1M solution of diethyl zinc in hexane (3.32 mL, 3.32 mmol). The reaction mixture was stirred overnight under an atmosphere of nitrogen. The reaction mixture was then quenched with a 1M aqueous solution of hydrogen chloride and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo and the resulting residue then purified by reverse phase column chromatography (Trilution method) to afford the title compound as a white solid (75 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:15]([NH2:17])=O>>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:15][NH:17][C:4]2=[O:5]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: NC=O
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 190 °C

Procedure:
A mixture of 2-amino-4,5-dimethoxybenzoic acid (9.9 mg, 0.050 mmol) and formamide (5 ml) was heated at 190° C. for 6 hours. The mixture was cooled to 80° C. and poured onto water (25 ml). Precipitated material was filtered off, washed with water and dried in vacuo. Yield 1.54 g (15%), brown powder. The structure was confirmed by 1H (500 MHz) and 13C NMR (125 MHz) analysis.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrCC(OCC)=O.[Br-].[CH2:28]([O:30][C:31]([CH2:33][P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:29].[PH4+].[OH-].[Na+]>C1C=CC=CC=1.O>[CH2:28]([O:30][C:31]([CH:33]=[P:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)CBr
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
Triphenyl phosphine (13 g.) was dissolved in dry benzene (60 ml.) and ethyl bromoacetate (8.3 g.) was added dropwise. The solution was heated at 70° for 2 days, and then cooled and filtered. The residue was washed with benzene and dried to give about 16 g. of (ethoxycarbonylmethyl) triphenylphosphonium bromide. The phosphonium salt (10 g.) was dissolved in water (250 ml.) and 5% aqueous sodium hydroxide was added dropwise with stirring until the solution became alkaline to litmus. The resulting precipitate was filtered off, washed with water and dried. Crystallisation from ethyl acetate/petroleum spirit gave (ethoxycarbonyl methylene) triphenyl phosphorane as a colourless solid in about 80% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].CC(C)([O-])C.[K+]>O1CCCC1>[CH3:22][O:21][C:17](=[O:20])[CH2:18][CH2:19][O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 42.6 g of N,N-dibenzylhydroxylamine, 25.8 g of methyl acrylate and 2.0 g of potassium-tert-butoxide in 200 ml of tetrahydrofuran is heated under reflux for 12 hours under N2. The crude reaction mixture is concentrated under reduced pressure and the residue is partitioned between water and ether. The orcanic layer is washed with water, saturated NaHSO4 solution and brine, dried (MgSO4) and then evaporated under reduced pressure to give the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N+:39]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1)([O-:41])=[O:40]>CN(C=O)C>[C:33]([O:32][C:30]([NH:29][C@H:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:19][C@@:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:46][C:45]1[CH:48]=[CH:49][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC[C@](Cc1ccc([N+](=O)[O-])cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)amino]hexanedioate (1 g, 1.970 mmol) was dissolved in DMF (20 ml) and sodium hydride (53 mg, 1.773 mmol) was added. After stirring for 60 min, a solution of 4-nitrobenzyl bromide (426 mg, 1.970 mmol) in 10 ml DMF was added and the mixture was stirred at 60° C. for 90 min. The mixture was then concentrated in vacuo, the residue was taken up in water (50 ml) and ethyl acetate (100 ml), and the organic phase was washed with brine (3×50 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed over silica gel (hexane, ethyl acetate) to yield 1.04 g (82%) of a clear oil.
Reaction SMILES: C([O:8][C:9]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:26]([O:25][C:23]([C:22]1[C:21](=[O:20])[C:12]2[C:10](=[C:9]([OH:8])[C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)[NH:11][CH:28]=1)=[O:24])[CH3:27]
Reactant: COc1cccc(N)c1OCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(O)c(OC)ccc2c1=O
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Two grams of 2-benzyloxy-3-methoxyaniline and 2.3 g of diethyl ethoxymethylenemalonate were heated at a temperature of 100°-120° C. for 1 hour. Fifty milliliter of diphenyl ether was added to the mixture, and the resulting mixture was further heated at 250°-270° C. for 1.5 hours. After the mixture was cooled down to room temperature, it was purified by silica gel column chromatography (Wako Gel C-200, 100 g). Elution with a mixed solvent of chloroform (95 parts) and methanol (5 parts) gave 980 mg of 3-ethoxycarbonyl-8-hydroxy-7-methoxy-4(1H)-quinolone.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]([CH2:20][CH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38]C2CCCCO2)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[OH:38][CH2:37][CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:22]([CH2:21][CH2:20][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.40) was added to a solution of ethyl 2-(2-phenoxyethyl)-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (738 mg), which is the product of Reference example 3(e), in ethanol (10 ml). The mixture was stirred at ambient temperature for 2 hours. At the end of this time the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=7/3-3/2 as the eluant to afford the desired compound (503 mg) as a syrup.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[NH:19][C:20](=[O:30])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[C:26]([O:25][C:23]([NH:22][CH2:21][C:20]([NH:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:30])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(7-benzyloxynaphthalen-1-yl)(tert-butoxycarbonylamino)acetamide, as described above in Step K, (1.22 g, 3.01 mmol) in EtOH (30 mL) was added 10% Pd-C on carbon (220 mg) and the reaction mixture was stirred under an atmosphere of hydrogen (ca. 1 atm) at ambient temperature for 18 hrs. The mixture was filtered through a pad of celite, washing with EtOH, and the filtrate was concentrated in vacuo to give a crude product. This was purified by flash column chromatography on silica, eluting with EtOAc, to yield the titled product as a pale solid.