Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.[CH:6]([O:9][C:10](=[S:24])[NH:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=1)([CH3:8])[CH3:7].CN(OC)[C:27](=[O:30])[CH2:28][Cl:29]>CC1OCCC1>[C:20]([O:19][C:14]1[CH:15]=[C:16]([C:27](=[O:30])[CH2:28][Cl:29])[C:17]2[S:24][C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[N:11][C:12]=2[CH:13]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CON(C)C(=O)CCl
Reactant: CC(C)OC(=S)Nc1cc(F)cc(OC(C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: CC1CCCO1
Product: CC(C)Oc1nc2cc(OC(C)(C)C)cc(C(=O)CCl)c2s1
Temperature: -35 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyllithium (481 ml, 737.6 mmol, 1.6 M) was added dropwise to a solution of (3-tert-Butoxy-5-fluoro-phenyl)thiocarbamic acid O-isopropyl ester (200 g, 700.83 mmol) in 2-Me-THF (1600 ml) at temperature below −65° C. The reaction temperature was warmed to −35° C., and a second portion of tert-butyllithium (388 ml, 737.6 mmol, 1.9 M) was added slowly while keeping the temperature below −35° C. The reaction mixture was then stirred at this temperature for 3 h and cooled down to −70° C. A solution of N-methyl-N-methoxy chloroacetamide (96.4 g, 700.83 mmol) in 2-MeTHF (300 ml) was added to the reaction mixture while keeping the temperature below −70° C. The mixture was then warmed to −30° C. and stirred for 45 minutes. The cold reaction mixture was quenched by dropwise addition of 30% HCl in isopropanol (240 g) followed by the addition of 1500 ml water. The organic layer was washed sequentially with 1000 ml water, 1500 ml saturated aqueous NaHCO3 and 1500 ml brine. After concentration, the resulting light brown residue was added to isopropanol (135 ml). The mixture was warmed to 50° C. and cooled down slowly to 25° C. n-heptane (135 ml) was added dropwise to the solution and the mixture was stirred overnight. The slurry was filtered and the filter cake was washed with n-heptane (40 ml) followed by another portion of n-heptane (20 ml). The cake was dried under vacuum to yield 1-(5-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanone as off-white powder (42.8 g, 17.9% yield).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:10][N:9]=1.[H-].[Na+]>>[CH3:1][NH:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:10]=2[N:9]=1
Reactant: CNC(=O)CCCCc1ccc(CCCCN)cn1
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)CCCCc1ccc2c(n1)NCCCC2

Procedure:
A mixture of 5-7 (24 g, 91.2 mmol) and NaH (10.9 g of a 60% weight dispersion in mineral oil, 273 mmol) in xylenes (500 mL) was purged with argon for 30 min, and then heated at reflux for 72 hours. The mixture was cooled, quenched with ethanol, diluted with 10% aqueous potassium carbonate and extracted with ethyl acetate. The organics were dried over MgSO4, and concentrated to an oil. The residue was chromatographed on silica gel (70:25:5 CHCl3/EtOAc/MeOH/H2O) to give 5-8 as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:12][CH:13]=[C:5]([C:6]=23)[CH2:4][N:3]1[CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[NH:17]1[CH2:16][CH2:15][CH:14]([N:3]2[CH2:4][C:5]3=[CH:13][NH:12][C:7]4[C:6]3=[C:11]([CH:10]=[CH:9][N:8]=4)[C:2]2=[O:1])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccnc3[nH]cc(c23)CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
tert-Butyl 4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate (18 mg, 0.051 mmol) was dissolved in TFA (1 mL) and DCM (2 mL) and allowed to stir at room temperature for 15 min. The mixture was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 12 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.71-8.72 (s, 1H), 8.42 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 7.48-7.49 (m, 2H), 5.02 (s, 1H), 4.69-4.75 (m, 2H), 3.58-3.61 (m, 2H), 3.19-3.26 (m, 2H), 2.33-2.39 (m, 2H), 2.10-2.15 (m, 2H). [M+H] found 257.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:15][C:14]([CH3:38])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)[CH2:13][C:12]2=[O:39])(=[O:7])[CH3:6].Cl>C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:15][C:14]([CH3:38])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)[CH2:13][CH:12]2[OH:39])(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 g of sodium borohydride was added, whilst ice-cooling, to a mixture of 100 ml of methanol and 10 ml of benzene containing 13 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one (prepared as described in Preparation 19), and the mixture was stirred for 30 minutes whilst ice-cooling. The reaction mixture was then poured into ice-water, neutralized with 10% w/v aqueous hydrochloric acid and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:11][C:12]1[C:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1>N1C=CC=CC=1>[C:1]([O:18][C:16]1[CH:17]=[C:12]([Cl:11])[C:13]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=2)=[N:14][CH:15]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)CCCCCCC)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
1.2 ml (7.1 mmol) of octanoyl chloride are added dropwise at 0° C. to 1.57 g (4.7 mmol) of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)pyridine in 20 ml of pyridine, and the mixture is stirred at 0° C. for 3 hours. The mixture is subsequently poured into ice water and filtered, and the residue is purified by chromatography (silica gel/ hexane:ethyl acetate 9:1) and by recrystallization from acetonitrile, giving 1.34 g of 3-chloro-2-(4-octyloxyphenyl)pyridin-5-yl octanoate. ##STR20##
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][N:46](C(OC(C)(C)C)=O)[CH:47]=2)O1>O>[CH3:12][C:6]1([CH3:13])[N:5]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C:4]2[CH:3]=[C:2]([C:43]3[CH:44]=[N:45][NH:46][CH:47]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1CC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)cc2N1CC(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
A flask was charged with 6-bromo-2,2-dimethyl-1-(2-(morpholin-4-yl)-2-oxoethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (115 mg, 0.296 mmol), Na2CO3 (89 mg, 1.48 mmol), 1,2-dimethoxyethane (2 mL), water (1 mL) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (261 mg, 0.888 mmol). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (24 mg, 0.0296 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 3 h, water and EtOAc were added to quench the reaction. The insoluble materials were filtered off, and NaCl was added to the filtrate. The organic materials were extracted with EtOAc/THF, and the extract was concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 80:20 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane to give the title compound (31 mg, 27%) as a pale brown solid:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14]1COCC1.OS(O)(=O)=O>CO.O>[CH3:14][O:12][C:11]([C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:7]([OH:9])=[O:8])=[O:13]
Reactant: C1CCOC1
Reactant: Cc1cc(C(=O)O)cc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C)cc(C(=O)O)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To 5-methylisophthalic acid (Aldrich, 5 g, 27.7) in MeOH (37.5 ml)/THF (112.5 ml), conc. H2SO4 (1.25 ml) was added and stirred at 65° C. for 8 h. Reaction mixture was cooled to room temperature and solvent removed. Then reaction mixture was diluted with water and extracted with ethylacetate. Crude residue was column chromatographed to yield 2.5 g of 3-(methoxycarbonyl)-5-methylbenzoic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:11]([CH3:10])(=[O:13])=[O:12])[S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N(c1cc(Br)cnc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyridin-3-amine (3.04 g, 14.7 mmol) of pyridine (20 mL) in 150-mL round-bottom flask, methanesulfonyl chloride (2.83 ml, 36.6 mmol) was added dropwise at 0° C. The ice bath was removed and the light brown solution was stirred at RT for overnight. Water (100 mL) was added and the precipitate was formed. The mixture was stirred at RT to break up lumps. The cream color solid was collcted via filtration and washed with water several times then air dried to afford N-(5-bromo-2-chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (5.16 g, 96.9% yield) as a cream colored powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.65 (s, 6H), 8.69 (d, J=2.3 Hz, 1H), 8.75 (d, J=2.3 Hz, 1H). m/z (ESI, positive ion): 362.8 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][Mg]Cl>C1COCC1>[OH:28][C@@:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2ccccc2)C1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1Oc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 26 %

Procedure:
To a solution of (3R)-1-(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine (6.17 g, 16.2 mmol) in THF (30 mL) at −10° C. was added dropwise 2.54 M 4-methoxybutylmagnesium chloride in THF (15 mL, 38 mmol). The resulting solution was warmed to rt slowly, and stirred over night. The reaction was quenched with satd NH4Cl (10 mL) and extracted with Et2O (4×10 mL). The combined organic layers were washed with water and brine. The solvent was removed and the residue was purified by flash chromatography to give (R)-tert-butyl 3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxylate (1.97 g, 26% from (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]1[CH:30]([NH:32][C:33]1[N:38]=[C:37]([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([N:48]4[CH2:52][CH2:51][N:50]([CH2:53][CH3:54])[C:49]4=[O:55])=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH:36]=[CH:35][N:34]=1)[CH3:31])=O)C1C=CC=CC=1.C=O.[BH3-]C#N.[Na+]>>[CH3:9][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]1[CH:30]([NH:32][C:33]1[N:38]=[C:37]([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([N:48]4[CH2:52][CH2:51][N:50]([CH2:53][CH3:54])[C:49]4=[O:55])=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH:36]=[CH:35][N:34]=1)[CH3:31]
Reactant: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)Nc4cccc5ccccc45)CCN3C(=O)OCc3ccccc3)n2)C1=O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)Nc4cccc5ccccc45)CCN3C)n2)C1=O

Procedure:
The title compound was prepared from 2-[1-(1-(benzyloxycarbonyl)-4-(N-naphth-1-yl-carbamoyl)-piperazine-2-yl)-ethylamino]-4-[5-(3-ethyl-imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (28 mg), 37% aqueous formaldehyde (19 μL), and NaBH3CN (4.8 mg) according to the procedure described in EXAMPLE 14, Step G. Mass spectrum (ESI) 619.3 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]([CH3:42])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:42])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc2c(c1)c(C(=O)CCCCCBr)cn2C
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1ccc2c(c1)c(C(=O)CCCCCN1CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC1)cn2C

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(5-methoxy-1-methyl-1 H-indol-3-yl)-l-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(5-methoxy-1-methyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:30]O>C(O)CC>[CH2:16]([N:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[OH:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: OO
Reactant: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Solvent: CCCO
Product: CCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCC

Procedure:
The general procedure of Example 12 is followed using at 50° to 55° C. 50 grams (0.12 mol) of ditetradecylamine, 200 ml of n-propanol and 8.3 grams (0.12 mol) of 50% aqueous hydrogen peroxide solution. The above-named product is obtained in a yield of 33.4 grams (64%) as white needles melting at 97°-99° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([Br:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH-].[K+].[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.O>[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][C:13]([Br:16])=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:33][CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(Br)s3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product of Example 241b (1.50 g, 4.34 mmol) was dissolved in DMF to which KOH (469 mg, 8.69 mmol), and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester (909 mg, 4.34 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water that was then extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound to provide the title compound (2.11 g, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23](O)=[O:24])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.Cl.[C:38]([O:42][C:43](=[O:46])[CH2:44][NH2:45])([CH3:41])([CH3:40])[CH3:39].C(N(C(C)C)CC)(C)C>CN(C=O)C.ON1C2C=CC=CC=2N=N1>[C:38]([O:42][C:43](=[O:46])[CH2:44][NH:45][C:23]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1)=[O:24])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.83 g, 9.54 mmol) and 1-hydroxybenzotriazole (HOBt) (0.086 g, 0.64 mmol). The mixture is stirred for 15 minutes after which time glycine tert-butyl ester hydrochloride (1.60 g, 9.54 mmol) and diisopropylethylamine (DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution is stirred at room temperature for 48 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc) to afford 3.04 g (99% yield) of the desired compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.19 (1H, t, J=5.2 Hz), 8.01-8.08 (2H, m), 7.27-7.54 (9H, m), 6.97 (1H, d, J=2.4 Hz), 5.24 (2H, s), 5.13 (2H, s), 4.17 (2H, d, J=5.2 Hz), 1.51 (9H, s). HPLC-MS: m/z 449 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:13][CH:11]=1
Reactant: Nc1cnccc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2cnccc12
Temperature: 160 °C
Yield: 72 %

Procedure:
A mixture of 3-amino isonicotinic acid (485 mg, 3.51 mmol) in formamide (3 mL) is heated to 160° C. for 12 h. Upon cooling, the resulting solid is filtered and washed with H2O and dried in a vacuum oven to yield 3H-pyrido[3,4-d]pyrimid-4-one (373 mg, 72%). 1H NMR (DMSO) δ 12.60 (1H, brs), 9.06 (1H, s), 8.68 (1H, d, J=5.3 Hz), 8.23 (1H, s), 7.96 (1H, d, J=5.1 Hz).
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]C.[CH3:11][C:12]([C:15]([NH2:17])=[NH:16])([CH3:14])[CH3:13].Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:11][C:12]([C:15]1[NH:17][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:16]=1)([CH3:14])[CH3:13]
Reactant: COC1=C(Br)C(=O)CCC1
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nc2c([nH]1)CCCC2=O
Temperature: 100 °C
Yield: 36.8 %

Procedure:
To a stirred solution of 2-bromo-3-(methyloxy)-2-cyclohexen-1-one (0.957 g) in anhydrous N,N-dimethylformamide (20 mL) at ambient temperature was added solid tert-butylcarbamidine hydrochloride (0.638 g) and potassium carbonate (1.613 g, 11.67 mmol). The reaction was then heated to 100° C. under an atmosphere of nitrogen for 2.5 h. The reaction was diluted with dichloromethane (50 mL) the resultant solid was removed by filtration. The filtrate was concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (330 mg).
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[O:22]([NH2:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:23][O:22][N:24]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: CON
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON=C1CCC(N(C)C(=O)c2ccc3nonc3c2)CC1
Reaction time: 8 h
Yield: 70.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), methoxylamine hydrochloride (0.75 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.32 g). Mp=167-168° C., NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.84 (m, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.85-4.70 and 3.80-3.30 (m, 1H); 3.83 (s, 3H); 2.99 and 2.88 (s+s, 3H); 2.60-1.60 ppm (s, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:40])[CH2:37][O:38][CH3:39]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:40]=[C:36]([CH2:37][O:38][CH3:39])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COCC(N)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mol) and the solution was stirred at room temperature for 1 hour. The N′-hydroxy-2-methoxyethanimidamide (J.Med.Chem,; 40; 8; 1997; 1230-1246) (177 mg, 1.70 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as an oil (350 mg).