Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCOc1cccc(O)c1
Temperature: 90 °C
Yield: 34 %

Procedure:
A mixture of 11 g of resorcinol, 8.8 g of methyl 5-bromopentanoate, and 13.8 g of potassium carbonate in 150 mL of dimethylformamide was heated in an oil bath at 90° C. for 24 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether providing the title intermediate in 34% yield, NMR.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15]>CCO.O.[Fe]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][CH2:4][C:3](=[O:15])[N:2]([CH3:1])[C:7]=2[CH:8]=1
Reactant: CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CN1C(=O)COc2ccc(N)cc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
Fe powder (4.1 g, 73.20 mmol) was added to a solution of 4-methyl-6-nitro-4H-benzo[1,4]oxazin-3-one (3.0 g, 14.42 mmol) in EtOH (100 ml) and water (50 ml). The mixture was stirred at 60° C. vigorously with a mechanic stirrer for 18 hours, then filtered through a celite cake. The filtrate was concentrated under reduced pressure to give 2.50 g of 6-amino-4-methyl-4H-benzo[1,4]oxazin-3-one as a solid, 98%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:16]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17][CH2:18][OH:19])=[C:13]([OH:15])[CH:14]=1>C(OCC)(=O)C>[OH2:3].[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:16]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17][CH2:18][OH:19])=[C:13]([OH:15])[CH:14]=1)(=[O:3])[CH3:2].[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:16]([CH2:17][CH2:18][OH:19])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[C:13]([OH:15])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(N(CCO)C(=O)OCc2ccccc2)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(N(CCO)C(=O)OCc2ccccc2)c(O)c1
Product: O
Temperature: 80 °C

Procedure:
0.24 mole (23 ml) of acetic anhydride is added dropwise to a solution of 0.24 mole (72 g) of 5-amino-2-[N-benzyloxycarbonyl-N-(β-hydroxyethyl)amino]phenol in one liter of ethyl acetate heated to 80° C. After evaporation of the solvent under vacuum, the expected product is purified on a silica column. It then melts at 72° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].[CH3:12][Mg]Br>CCOCC>[CH3:8][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9][CH:10]([OH:11])[CH3:12]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CC(C)O

Procedure:
A mixture of 671.2 g of citral and 185.6 g of diethyl ether is added to an addition funnel. The citral mixture is then added dropwise over a five hour period to a nitrogen blanketed, stirred, 5 L, 3-neck, round bottom flask equipped with a reflux condenser containing 1.6 L of 3.0 M methylmagnesium bromide solution and an additional 740 ml of diethyl ether. The reaction flask is situated in an ice water bath to control exotherm and subsequent ether reflux. After addition is complete, the ice water bath is removed and the reaction allowed to mix for an additional 2 hours at 20-25° C. at which point the reaction mixture is added to 3.5 Kg of cracked ice with good mixing. To this mixture is added 1570 g of 30% sulfuric acid solution. The aqueous acid layer is drained and the remaining ether layer washed twice with 2 L of water. The ether layer is concentrated by evaporation of the ether under vacuum to yield 720.6 g of 4,8-dimethyl-3,7-nonadien-2-ol. To a glass autoclave liner is added 249.8 g of the 4,8-dimethyl-3,7-nonadien-2-ol, 5.8 g or 5% palladium on activated carbon and 200 ml of n-hexane. The glass liner is sealed inside a 3 L, stainless steel, rocking autoclave and the autoclave purged twice with 250 psig N2, once with 250 psig H2 and then charged with 100 psig H2. Upon mixing, the reaction initiates and begins consuming H2 and exotherms to 75° C. The autoclave is heated to 80° C., boosted to 500 psig with H2, mixed for 3 hours and then cooled to 30° C. The reaction mixture is removed from autoclave, filtered to remove catalyst and concentrated by evaporation of n-hexane under vacuum to yield 242 g of 4,8-dimethyl-2-nonanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:17]2[CH2:20][CH:19]([C@H:21]([C:26]3[CH:31]=[C:30](F)[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:25])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.C([O-])([O-])=O.[K+].[K+].CCOCC>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:17]2[CH2:18][CH:19]([C@H:21]([C:26]3[CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:25])([CH3:23])[CH3:24])[CH2:20]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: CC(C)(F)[C@@H](c1cc(F)cc(F)c1)C1CN([C@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(F)[C@@H](c1cc(F)cc(-n2ccnc2)c1)C1CN([C@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of 90 mg (0.192 mmole) of 3-((R)-(4-chlorophenyl){3-[(1R)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile, 17 mg (0.25 mmole) of imidazole and 40 mg (0.288 mmole) of K2CO3 l in 1.5 mL DMSO was stirred at 150° C. in a microwave (with cooling). After 4 h, the mixture was poured into 30 mL of ether and 5 mL of water. The layers were separated and the aqueous layer was washed with three 10 mL portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 25% acetone-hexane to afford the title compound; Mass Spectrum: m/e=517 (M+1, 35Cl); 519 (M+1, 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[I:8].C(O)=O>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: Fc1cc(C2CCC3(CC2)OCCO3)ccc1I
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCC(c2ccc(I)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
128.0 g of 8-(3-fluoro-4-iodophenyl)-1,4-dioxaspiro-[4.5]decane and 320 ml of formic acid were dissolved in 750 ml of toluene and stirred at 25° C. overnight, the HCOOH phase was run off, diluted with 2 1 of water and extracted twice with toluene, and the toluene phases were washed with water and sodium hydrogencarbonate solution until neutral, dried and evaporated. The crude product was recrystallized at -25° C. from 100 ml of hexane containing a few drops of ethyl acetate, giving 4-(3-fluoro-4-iodophenyl)cyclohexanone.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])=S>C(#N)C.CN(C)C=O>[C:2]([NH:3][C:16]([NH:15][CH2:14][CH2:13][S:12][CH2:11][C:10]1[NH:9][CH:8]=[N:7][C:6]=1[CH3:5])=[N:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])#[N:1]
Reactant: N#CN
Reactant: Cc1nc[nH]c1CSCCNC(=S)NCCSCc1[nH]cnc1C
Agent: [Pb]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCSCc1[nH]cnc1C
Reaction time: 24 h

Procedure:
Lead cyanamide (8.7 g.) was added to a solution of N,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea in acetonitrile (100 ml.) and dimethyl formamide (20 ml.) and the resultant suspension was heated under reflux with stirring for 24 hours. Additional lead cyanamide (8.7 g.) was added and heating was continued for 24 hours. Following filtration and concentration, the residue was chromatographed on a column of silica gel, eluting with ethyl acetate-isopropyl alcohol (5:1). Recrystallisation from isopropyl alcohol-isopropyl acetate afforded N-cyano-N',N"-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (0.6 g.), m.p. 92°-95°.
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:8][CH:14]=1
Reactant: NC(=O)C1CCCCC1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(C2CCCCC2)n1
Yield: 2.7 %

Procedure:
In substantially the same manner as in Reference Example 31, cyclohexanecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-cyclohexyloxazole as an oily product. The yield was 2.7%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:29][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[C@@H:14]([CH3:15])[N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:12][C:11](=O)[O:10]1.[OH-:35].[NH4+:36]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:14]([N:13]([C:16](=[O:27])[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=1)[C:12](=[O:35])[CH2:11][NH2:36])[CH3:15]
Reactant: [OH-]
Reactant: [NH4+]
Reactant: C[C@H]1N(C(=O)c2ccc(C(F)(F)F)cc2)CC(=O)O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC(C)=O
Product: C[C@@H](N(C(=O)CN)C(=O)c1ccc(C(F)(F)F)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of (5R*,6R*)-6-[2,4-difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone (0.5 g, 1 mmol) (obtained in example 29) in acetone (15 mL) was added dropwise 30% ammonium hydroxide (5 mL) and the mixture was stirred at room temperature during 1 h. The volatiles were removed under reduced pressure and the residue was partitioned between 1N NaHCO3 and chloroform. The organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was filtered and the solvent removed in vacuo to afford the title product as a white solid (0.38 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57%). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90% (UV254).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.O>C(OCC)C>[C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]([S:14]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CO
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)COS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A suspension of ethyl glycolate (374 μl, 3.957 mmol) and biphenyl-4-sulfonyl chloride (1 g, 3.957 mmol) in anhydrous diethyl ether (2 ml) at 0° C. was treated dropwise with triethylamine (1.1 ml, 7.914 mmol). The temperature was maintained at 0° C. with stirring for a further 2 h. After this time, water was added and the phases separated. The aqueous phase was extracted with fresh diethyl ether. The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel (Rf=0.26, 25% ethyl acetate in hexane) affording 16 as a colourless oil (1.055 g, 83%). δH (400 MHz, CDCl3) 1.25 (3H, t, J=6.8 Hz, CH3), 4.20 (2H, q, J=6.8 Hz, CH2), 4.65 (2H, s, CH2), 7.44-7.51 (3H, m, ArH), 7.61 (2H, d, J=7.6 Hz, ArH), 7.76 (2H, d, J=8 Hz, ArH), 8.01 (2H, d, J=8 Hz, ArH); δc (100.6 MHz, CDCl3) 14.2, 62.2, 65.0, 127.6, 128.1, 128.9, 129.0, 129.4, 134.4, 139.2, 147.4, 166.2; MS (ES+) 338.1 (100%, [M+H2O]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: CN1CCc2ccc(Cl)cc2N(N)CC1
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCCO
Product: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To a solution of 9-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (3.5 g, 15.5 mmole) in 1-propanol (200 mL) was added cyclopentanone (20.0 ml, 226.1 mmole), followed by p-toluenesulfonic acid monohydrate (11.0 g, 57.8 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with methylene chloride (300 mL) and washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 1.3 g of the title compound. 0.11 g of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt (0.12 g, mp 209-211° C.). MS (ES) m/z 275.1 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:21])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12]([C:19]#N)[CH:11]=2)[CH:9]=1)[CH3:2].[O:22]1CCOC[CH2:23]1.C[OH:29]>Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:21])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12]([C:19]([O:22][CH3:23])=[O:29])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: CO
Reactant: CCOc1ccc(F)c(-c2cc(C#N)nc(C(C)C)c2)c1
Reactant: C1COCCO1
Agent: Cl
Product: CCOc1ccc(F)c(-c2cc(C(=O)OC)nc(C(C)C)c2)c1

Procedure:
A mixture of 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carbonitrile (which may be prepared as described in Description 114) (1.09 g, 3.8 mmol) in 4M HCl in dioxan (12 mL, 48 mmol) and methanol (12 mL) was heated to reflux under nitrogen overnight. The solvents were evaporated and ethyl acetate (150 ml) and NaHCO3 solution (150 ml) were added. The product was extracted into ethyl acetate (3 x) and the extracts were dried (Na2SO4) and concentrated. Chromatography (0-10% diethyl ether in DCM) gave methyl 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carboxylate (D115) (730.8 mg);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[Na].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(Cl)n1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Nc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
2-Amino-4-chloro-5-nitropyrimidine (0.70 g, 4.0 mmol) was added to a solution of sodium (0.12 g, 5.2 mmol) in benzyl alcohol (8 mL) under argon. The solution was heated in a 130° C. oil bath for 3 h, and approximately half of the benzyl alcohol was evaporated under reduced pressure. The residue was poured into water (50 mL) with constant stirring for 10 min. After neutralization with glacial acetic acid, a brown precipitate formed which was collected by filtration and washed with water. This solid was crystallized from benzene to give 5a as a golden crystalline solid: yield, 126 mg (13%); mp 164°-167° C.; UV (pH 1) λmax 262 nm (ε=0.879×104), 295 (sh) (0.571×104); (pH 6.9) 235 (sh) (0.448×104), 273 (0.360×104), 326 (1.085×104); (pH 13) 273 (0.404×104), 327 (1.055×104); 1H NMR δ5.51 (s, 2H, ArCH2), 7.35-7.54 (m, 5H, ArH), 8.05 (d, 2H, NH2, exchange with D2O), 8.92 (s, 1H, H-6); MS (EI) calcd. m/z for C11H10N4O3 246.0752, found 246.0758; Anal. (C11H10N4O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH:7]=[CH:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.S(=O)(O)[O-:18].[Na+].[OH2:22]>N1C=CC=CC=1.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:22])[C@@H:6]([OH:18])[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1
Reactant: O
Reactant: Cc1cc2c(cc1Br)C(C)(C)C=CC2(C)C
Reactant: O=S([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc2c(cc1Br)C(C)(C)[C@H](O)[C@H](O)C2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 9.41 g (33.7 mmol) of 2-bromo-3,5,5,8,8-pentamethyl-5,8-dihydronaphthalene in 110 ml pyridine was added 8.65 g (34.0 mmol) osmium tetroxide under an atmosphere of nitrogen. After stirring at room temperature for 18 hours, 17.3 g (166 mmol) of sodium bisulfite in 110 ml water was added. After 2 hours the resulting solution was partitioned between ethyl acetate and aqueous hydrochloric acid. The organic layer was washed with water, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography with elution with 30% ethyl acetate/hexane to yield 7.97 g (75%) of 2-bromo-cis-6,7-dihydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene as a white solid (M+=312).
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42]OC)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.Br[CH2:48][CH2:49][CH2:50]Br.BrCCOC.[NH:57]1[CH2:61]CC[CH2:58]1>>[Cl:1][C:2]1[CH:46]=[CH:45][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42][CH2:58][N:57]3[CH2:61][CH2:50][CH2:49][CH2:48]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: COCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: BrCCCBr
Agent: COCCBr
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OCCCN5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized as described for Compound 475, except 1,3-dibromopropane was used for alkylation instead of 1-bromo-2-methoxy ethane. The resulting 3-bromopropyl derivative was treated in situ with an excess of pyrrolidine to give the final product.
Reaction SMILES: [CH2:1]([C:8]1([NH2:14])[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:8]1([NH:14][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(Cc2ccccc2)CCOC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1(Cc2ccccc2)CCOC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1.55 g of α-benzyl-α-amino-γ-butyrolactone in 16 ml of tetrahydrofuran is added 2.0 g of powdered sodium carbonate, followed by 1.27 ml of benzylchloroformate. After stirring at room temperature for 18 hours, water is added to dissolve the salt and the resulting mixture is diluted with 100 ml of ethyl acetate. It is washed with 50 ml of saturated aqueous sodium chloride. The aqueous phase is extracted with two 50 ml portions of ethyl acetate. The combined organic phase is dried (magnesium sulfate), filtered, and then concentrated. The residue is passed through 20 g of silica gel with ethyl acetate, and the filtrate concentrated to the title product as a white solid, 2.6 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32](=[O:35])[NH:33][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32](=[O:35])[NH:33][CH:34]=4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NCc1ccc(=O)[nH]c1
Product: Cn1c(=O)c(C(=O)NCc2ccc(=O)[nH]c2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 57.5 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(10 mg, 0.028 mmol) described in example 92 and 5-(aminomethyl)-2(1H)-pyridinone (50 mg, 0.403 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-N-[(6-oxo-1,6-dihydro-3-pyridinyl)methyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (7 mg, 58% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.51 (br s, 1 H), 8.59 (s, 1 H), 7.49 (d, J=9.6 Hz, 1 H), 7.39 (s, 2 H), 7.17-7.13 (m, 2 H), 7.04-6.94 (m, 2 H), 6.56 (d, J=9.6 Hz, 1 H), 4.38 (d, J=6 Hz, 2 H), 4.13 (s, 2 H), 3.56 (s, 3 H); HRMS m/z calcd for C23H20N4O4F: 435.1469 Found: 435.1470.