Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[CH:4]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:13][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([CH3:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c([N+](=O)[O-])cc1Br
Temperature: 100 °C
Yield: 88.1 %

Procedure:
To a solution of 4-methoxy-2-methyl-1-nitrobenzene (2.0 g, 12 mmol) in N,N-dimethylformamide (5 mL) was added N-bromosuccinimide (8.52 g, 47.9 mmol). The reaction was heated to 100° C. for 1.5 hours. The reaction was cooled to room temperature and diluted with saturated aqueous sodium thiosulfate. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with water, saturated sodium thiosulfate, and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via flash column chromatography (0-30% ethyl aceate/heptanes) to provide the title compound (2.6 g, ˜43% pure) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.32 (s, 1 H), 6.74 (s, 1 H), 3.97 (s, 3 H), 2.63 (s, 3 H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)Cc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(dimethylaminomethyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C26H25N3O3
Reaction SMILES: [C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5]1)([OH:3])=[O:2].[CH2:14]=O.Cl>C(O)=O.O>[CH3:14][N:5]1[CH:4]([C:1]([OH:3])=[O:2])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: C=O
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: CN1Cc2ccccc2CC1C(=O)O
Yield: 53 %

Procedure:
A solution of 0.364 g (2.07 mmol) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline in 25 mL of formic acid was combined with 2.5 mL of 37% formaldehyde. The resulting mixture was allowed to reflux for approximately 17 hours. After cooling, the mixture was contentrated under reduced pressure to provide a gum. This gum was dissolved in 3.0 mL of water, adjusted to a pH 2 using hydrochloric acid and then purified using ion-exchange chromatography (Dowex 50x-8, 100 meshcation) to provide 0.21 g of a yellow powder.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])C1=S)[CH:2]=[CH2:3].[CH:19]1(N)CCC1>O>[Cl:16][C:15]1[C:10]([NH:6][CH2:7][CH2:8][CH2:9][NH:4][CH:1]2[CH2:2][CH2:3][CH2:19]2)=[C:11]([CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Reactant: NC1CCC1
Solvent: O
Product: Cc1cccc(Cl)c1NCCCNC1CCC1
Temperature: 90 °C
Yield: 51.5 %

Procedure:
A mixture of the hydrobromide salt of Example 12, Step B (6.64 g) and cyclobutylamine (4.15 g) was heated at 90° C. for 1.5 hours. The cooled mixture was diluted with water and extracted with dichloromethane. The extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potassium carbonate and evaporated to a brown oil, which was flash chromatographed on Merck-60 flash silica gel (eluant: hexane-EtOAc 1:1 to remove less polar impurities, followed by dichloromethane-methanol-ammonium hydroxide 95:5:0.1) to provide the title compound (3.08 g, 63.5%), which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-benzyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of benzylamine. LC/MS [7.55 min; 448 (M+1)]
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[OH:21])O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[OH:21]
Reactant: COCOc1ccccc1C(O)c1cccc(OC)c1O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCOc1ccccc1Cc1cccc(OC)c1O
Temperature: 0 °C
Yield: 130.6 %

Procedure:
(2-Methoxymethoxyphenyl)(2-hydroxy-3-methoxyphenyl)methanol (15.54 g, 54 mmol) and triethylsilane (7.53 g, 0.064 mol) were dissolved in 150 ml of methylene chloride and the solution cooled to 0° C. and blanketed with nitrogen. A solution of 7.39 g (64.8 mmol) of trifluoroacetic acid in 70 ml of methylene chloride was added with stirring and cooling and the mixture was allowed to react for 2 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate, more methylene chloride added, and the organic layer recovered. This was extracted with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain 19.34 g of orange oil. This was purified by preparative liquid chromatography eluting with a 5:95 mixture of acetone and hexane to obtain 3.95 g (27 percent of theory) of the title compound as an oil. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]([CH3:18])([CH2:14][C:15](O)=O)[C:11]([OH:13])=[O:12].[OH-].[Na+]>Cl.O>[CH3:9][C:10]([CH3:18])([CH2:14][C:15]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[C:11]([OH:13])=[O:12]
Reactant: Nc1ccccc1N
Reactant: CC(C)(CC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(Cc1nc2ccccc2[nH]1)C(=O)O
Yield: 82.5 %

Procedure:
A solution of o-phenylenediamine (5.4 g, 0.05 mole) and 2,2-dimethylsuccinic acid (7.5 g, 0.05 mole) in 50 mL of 4.8 N HCl was refluxed without condenser until the total volume was reduced to about 20 mL. Evaporation at 100° and 40 torr afforded a green paste which was taken up in 100 mL H2O and made alkaline (pH 9) with 20% NaOH. The mixture was filtered removing tarry matter and the clear yellow filtrate was concentrated, cooled and the pH adjusted to about 6 by addition of acetic acid. A light yellow solid precipitated and was isolated by filtration and dried in air to give 9 g of α,α-dimethyl-1H-2-benzimidazolepropanoic acid, m.p. 223°-226° (dec). Recrystallization from acetonitrile-methyl ethyl ketone-methanol (30-30-40) afforded 6.7 g (61%) of colorless needles, m.p. 266°-267° (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:19][CH:20]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25].[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:23]([CH2:22][CH2:21][CH:20]([CH3:19])[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)[C:24]2=[O:25])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCC(C)c1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(CCc1cc2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O)c1ccncc1
Yield: 37 %

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-methyl-5-(pyridin-4-yl)pentanoate (1.5 eq.; prepared in Synthetic Example 8) and LDA(1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-methyl-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 37%). The product was purified through flash column chromatography and recrystallization (mp 154–155° C./DMF).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:7]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(C(=O)OC(C)C)c1
Reaction time: 0.08 h
Yield: 76 %

Procedure:
(Intermediate 136, 0.6 g, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) was treated with a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (4.6 mL, 4.6 mmol) and the resulting reaction mixture was stirred in an ice bath for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was purified by flash column chromatography using 5%-30% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.33 g, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].N1C=CC=CC=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
m-Nitroaniline, 10.0 g (0.072 mole), is dissolved in 150 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoyl chloride, 12.9 g (0.073 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column and crystallized at -20° C. There is obtained N-(3-nitrophenyl) nonanamide (M.P. 63.0°-63.5° C.). Analysis shows 9.88% nitrogen as against a calculated value of 10.06% for C15H21N2O3.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[NH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH2:1]([N:17]1[C:18]2[C@@:19]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:22]([CH2:21][CH2:20]3)[C:23]=2[C:24](=[O:25])[N:16]1[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(Cc3ccccc3)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(Cc2ccccc2)n1Cc1ccccc1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A mixture of benzyl bromide (300 μL, 2.5 mmol), (4S,7R)-2-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 23; 159 mg, 0.56 mmol), and tetra-n-butylammonium iodide (160 mg, 0.43 mmol) in N,N-dimethylformamide (2 mL) was heated in an oil-bath at 100° C. for 17 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane (125 mL). The solution was washed with water (5×25 mL) and sodium thiosulfate solution (25 mL), dried (magnesium sulfate), filtered, and evaporated and the residue was purified on an Isco 40 g column, eluting with 20-100% ethyl acetate/hexanes to give (4S,7R)-1,2-dibenzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (89 mg, 42%) as a yellow gum. ES(+)-MS (M+H) 373.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.576 ml (6 mmol) 4-fluoroaniline is heated for 2 h at 90° C. The residue is then distributed between acetate and 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 and 25:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV (6 h, 100° C.); m.p. 129-131° C.; ESI-MS: (M+H)+=331.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccco1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCc2ccco2)cc1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To a stirred solution of 2-furan-2-yl-ethanol (1.6 g, 14.0 mmol) in a mixture of pyridine (5 mL) and chloroform (15 mL) was added para-toluenesulfonyl chloride (5.5 g, 28.0 mmol) and heated at 60° C. for 3 hrs. The reaction was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, sat. sodium bicarbonate solution and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the crude compound purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate/petroleum ether as eluent to afford toluene-4-sulfonic acid 2-furan-2-yl-ethyl ester (2.0 g, 32%) as an oil.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)=[O:7]>O.O1CCCC1>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Lithium hydroxide monohydrate (5.42 g, 141 mmol, 3 equiv.) in water (50 ml) was added to a solution of quinoline-7-carboxylic acid methyl ester (8.8 g, 47 mmol) in tetrahydrofuran (200 ml) and the solution was stirred at room temperature for 16 hours. The tetrahydrofuran was evaporated under reduced pressure and the solution adjusted to pH 7 with 1N HCl (aq) (141 ml), forming a white precipitate. The precipitate was filtered and washed with water and heptane. The solid was dried in a vacuum oven at 50° C. to give quinoline-7-carboxylic acid, 8.4 g (100% yield) as a white solid. LC @215 nm; Rt 0.66: 100%, m/z (ES+): 174 (M+H+.); δH (400 MHz; d6-DMSO) 9.02 (1H, dd), 8.58 (1H, s), 8.48 (1H, d), 8.09 (2H, m), 7.66 (1H, dd).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:6]#N.[H-].[OH2:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH:6]=[O:18]
Reactant: COc1cc(C#N)ccc1-c1ccccn1
Reactant: O
Agent: [H-]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1-c1ccccn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 3-methyoxy-4-pyridin-2-ylbenzonitrile (600 mg, 2.64 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. and was treated with diisobutylalumnium hydride (3.2 mL of 1M in CH2Cl2, 3.2 mmol). After stirring the reaction mixture at −78° C. for 2 h, the temperature was raised to −40° C. before quenching the reaction with a mixture of silica gel (6 g) and water (2 mL) and then warmed to rt. The reaction mixture was dried (K2CO3 and MgSO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:4 to 1:1) to afford 3-methoxy-4-pyridin-2-ylbenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:54]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:59]=[CH:58][C:57]([CH:60]([NH:67][CH3:68])[CH2:61][N:62]2[CH2:66][CH2:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:59]=[CH:58][C:57]([CH:60]([N:67]([CH3:68])[C:11](=[O:13])[CH2:10][N:6]2[C:5]3[CH:14]=[C:15]([O:16][CH3:17])[C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:7]2=[O:9])[CH2:61][N:62]2[CH2:66][CH2:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc2c(cc1C)oc(=O)n2CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C)oc(=O)n2CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
[6-Methyl-5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetic acid (59 mg, 0.25 mmol) and BOP reagent (133 mg, 0.30 mmol) were dissolved in CH2Cl2 (1 mL), and diisopropylethylamine (32 mg, 0.25 mmol) was added to it. The resulting mixture was stirred at room temperature for 5 min, then 1-(4-biphenylyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (70 mg, 0.25 mmol) was added. Stirring was continued for 16 h and then the mixture was concentrated. The residue was dissolved in CH3OH, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50×50 mm, 50 mL/min, A: acetonitrile B: water with NH4OH at pH=10, A: 20% to 70% during 12 min, UV detection at 214 nm) to give 92 mg (74%) of the title compound as a white solid. MS (ES) m/e 500 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)[C:2]([NH2:4])=[S:3].Br[CH:15]([CH:18]=O)[CH:16]=[O:17].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH:16]([C:15]1[S:3][C:2]([NH:1][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=2)=[N:4][CH:18]=1)=[O:17]
Reactant: NC(=S)Nc1ccc(C(=O)O)cn1
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cnc(Nc2ccc(C(=O)O)cn2)s1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
A mixture of 6-thioureido-nicotinic acid (197 mg, 1 mmol), 2-bromomalonaldehyde (166 mg, 1.1 mmol) and sodium acetate (100 mg) in acetic acid (2 mL) was stirred at 100° C. for 20 min. The mixture was then cooled to RT, diluted with water and the precipitates were collected. The solid was washed with water, then methanol and dried in vacuo to afford 6-(5-formyl-thiazol-2-ylamino)-nicotinic acid, (240 mg, 96%). MS m/z 250 (M+H)+. 1H NMR (DMSO-d6) δ 12.7 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.38 (s, 1H), 8.24 (d, 1H, J=5.6 Hz), 7.21 (d, 1H, J=5.6 Hz). 13C NMR (DMSO-d6) δ 183.5, 166.0, 165.1, 153.3, 151.5, 148.8, 139.1, 131.2, 120.3, 110.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:13])=[N:10][O:11][N:12]=2)=[CH:4][CH:3]=1.C([N:21]1[CH2:26][CH:25]2[C:27](=O)[CH:22]1[CH2:23][CH2:24]2)C1C=CC=CC=1>>[CH:22]12[CH:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9]([NH2:13])=[N:10][O:11][N:12]=4)=[CH:6][CH:7]=3)[CH:25]([CH2:24][CH2:23]1)[CH2:26][NH:21]2
Reactant: O=C1C2CCC1N(Cc1ccccc1)C2
Reactant: Nc1ccc(-c2nonc2N)cc1
Product: Nc1nonc1-c1ccc(NC2C3CCC2NC3)cc1

Procedure:
Reaction of 4-(4-aminophenyl)-1,2,5-oxadiazol-3-amine with 2-benzyl-2-azabicyclo[2.2.1]heptan-7-one (J. R. Malpass, S. Handa, and R. White, Org. Lett., 2005, 7, 2759-2762) affords the title compound as the benzyl-protected amine. Purification by chromatography followed by removal of the benzyl group by hydrogenolysis affords the title amine.
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[NH2:42][CH2:43][C:44]([NH2:46])=[O:45]>>[NH2:46][C:44](=[O:45])[CH2:43][NH:42][C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: NCC(N)=O
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CC(=O)NCC(N)=O)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and glycineamide were reacted to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[C:14](=[O:16])=[O:15]>>[Br:8][C:4]1[N:3]=[C:2]([C:14]([OH:16])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C=O
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Product: O=C(O)c1cccc(Br)n1
Yield: 63.4 %

Procedure:
To a suspension of 2,6-dibromopyridine (59 g, 0.25 mol) in ET2O (600 mL) at -70° C. there was added slowly n-BuLi 2.12M in hexanes (118 mL, 0.25 mol); the resulting mixture was stirred in the cold until a solution was obtained (45 min.); this mixture was poured onto a slurry of crushed dry ice (200 g) in ET2O (500 mL). The resulting suspension was allowed to warm up, then it was extracted with H2O (500 mL, then 250 mL). The combined aqueous extracts were extracted with Et2O, then acidified with 12N HCl, affording a precipitate which was filtered. This beige solid was washed with H2O and dried to afford the title acid (32 g), m.p. 186°-189° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].C(#N)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(OCC)(=O)C>[CH3:37][O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=2)=[CH:6][CH:7]=1)=[O:35]
Reactant: COC(=O)CBr
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
3-Phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether (3.0 g), 0.36 g of sodium hydride and 20 ml of acetonitrile were heated under reflux for about 20 minutes, followed by the dropwise addition of 2 ml of methyl bromoacetate at room temperature. The resulting mixture was stirred at 60° C. for 20 minutes. After concentration of the reaction mixture, about 50 ml of ethyl acetate were added to the concentrate, followed by washing with water, drying and concentration. The resulting concentrate was fractionated and purified by chromatography on a silica gel column, whereby 3.0 g of 3-phenoxybenzyl 2-{4-(methoxycarbonylmethyloxy)phenyl}-2-methylpropyl ether were obtained.