Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N+:3]=1[O-].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[O:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][O:19][C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccccc2)c[n+]1[O-]
Product: CC(=O)OCc1ccc(Oc2ccccc2)cn1

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1, 3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12])=O.[CH3:15][O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[NH2:23]>O>[CH3:15][O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:24][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]([F:14])([F:13])[F:12])[N:23]=1
Reactant: COC(=O)CCCCC(N)=O
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Solvent: O
Product: COC(=O)CCCCc1nc(-c2ccccc2C(F)(F)F)co1

Procedure:
Combine 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone (6.6 g, 24.7 mmol) with 5-carbamoyl-pentanoic acid methyl ester (7.8 g, 49 mmol) and heat the neat mixture in a sealed vessel at 140-150° C. for about 4.5 hours. Cool the mixture, dilute with water, and extract with EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatography over silica gel (CH2Cl2) allows for recovery of 5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.47 g, 43%). MS (ES): (M+1)+ 328.2 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH:13]=C.[O:15]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:15]
Reactant: C=CCc1c(Br)ccc2c1COC2=O
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1OCc2c1ccc(Br)c2CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4-prop-2-en-1-yl-2-benzofuran-1(3H)-one (1.27 g, 5.02 mmol) in MeOH (50 mL) and DCM (50 mL) was bubbled O3 at −78° C. until the solution turned blue; excess ozone was removed on high vacuum. After the solution's color changed into colorless, NaBH4 (0.8 g, 20 mmol) was added to the reaction mixture and subsequently stirred at room temperature for 30 min; LC and TLC indicated that reaction had gone to completion; solvent was removed on high vacuum, the residue was then re-dissolved in EtOAc and washed with water, dried over Na2SO4, filtered and concentrated to dryness. The organic residue was absorbed into silica gel and was separated on silica gel column to give 5-bromo-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.7 (d, J=7.8 Hz, 1H), 7.5 (d, J=7.8 Hz, 1H), 5.37 (s, 2H), 3.94 (t, J=6.3 Hz, 2H), 2.98 (t, J=6.3 Hz, 2H)
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1nc2ccccc2s1
Solvent: ClCCl
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nc3ccccc3s2)c1
Reaction time: 16 h
Yield: 79 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (7.0 g) and 2-chlorobenzthiazole (5.26 g) were dissolved in dichloromethane to ensure good mixing. The solvent was then evaporated and the residue fused at 130° C. for 16 hours. The cooled reaction mixture was subjected to chromatography on silica (chloroform:methanol 10:1) to give the title compound as an oil (8.5 g). This was treated with maleic acid in isopropanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]benzthiazole dimaleate, m.p. 113° C. (decomp) (recrystallised from ethylacetate and isopropanol-ethyl acetate).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10]>CO.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:8][C:9](=[O:11])[CH3:10])[CH3:12]
Reactant: CC(=O)CC(C)(O)c1ccccc1-c1ccccc1
Solvent: CO
Solvent: O
Product: CC(=O)C=C(C)c1ccccc1-c1ccccc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a 70° C. warm solution of 104.2 g 4-(p-biphenylyl)-4-hydroxypentan-2-one in a mixture of 450 ml methanol and 80 ml water 206 g ca. 65% sulphuric acid is added dropwise and the mixture is stirred 21/2 hours at 75° C. After cooling to 25° C. the resulting solid is filtered off, washed with water, then with diluted sodium hydroxide solution, again with water, dried and then recrystallised from toluene to give the title compound, m.p. 134°-136° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)C=CC=CC=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[O:39]1[CH2:40][CH2:41][N:36]([C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:14])[CH2:37][CH2:38]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1COCCN1
Product: NCCSC(=O)N1CCOCC1

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and morpholine (162 μl) were subjected to similar reactions to those described in References 2 and 4 to give 2-morpholinocarbonylthioethylamine (crude formate: 134 mg). The product was dissolved in anhydrous methanol (3 ml). To the reaction solution were added triethylamine (486 μl) and mitomycin A (195 mg: 0.8 molar equivalent). The mixture was treated in a similar manner to that described in Example 1 to obtain Compound 33 (176 mg) in the form of grayish blue powders with a yield of 50%.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].[CH:14]([CH:16]=O)=[O:15].Cl>C(O)(=O)C>[CH3:4][C:2]([C:5]1[C:6]2[O:13][C:14](=[O:15])[CH2:16][C:7]=2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(c(C(C)(C)C)c1)OC(=O)C2
Temperature: 120 °C
Reaction time: 4 h
Yield: 21.5 %

Procedure:
In 1600 ml of acetic acid were dissolved 400 g of 2-(1,1-dimethylethyl)-4-methoxyphenol, 360 g of 40% glyoxal solution and 20 ml of 36% hydrochloric acid and the solution was heated at 120° C. with stirring for 4 hours. The reaction mixture was concentrated under reduced pressure and allowed to stand overnight. The resultant solid residue was washed with diethyl ether to give 105 g of 7-(1,1-dimethyethyl)-5-methoxy-2(3H)-benzofuranone as a light red solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)=[O:5])C>CO.[OH-].[Na+].O>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([F:21])[CH:17]=1)[CH2:13][NH:12][C:11]1[CH:10]=[C:9]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cc(F)cc(F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
2.99 g of 4-[(3,5-difluorobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxylic acid ethyl ester was dissolved in 30 mL of methanol, to which 12 mL of 4 mol/L sodium hydroxide in water was added at room temperature, and stirred at 80° C. for 1.5 hour. After cooling, methanol was evaporated, weakly acidified (about pH 4) by adding 6 mol/L hydrochloric acid in water under ice cooling, the deposited crystals were filtered, and washed with water and methanol. After air-drying, they were dried under reduced pressure (60-70° C., for 3 hours) to obtain 2.72 g (yield 97%) of 4-[(3,5-difluorobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxylic acid as a light reddish purple crystalline powder.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][NH:13][CH3:14])[NH:10][CH:11]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[CH2:27]([N:13]([CH3:14])[CH2:12][C:9]1[NH:10][CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:2][CH:3]=2)[N:8]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CNCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)Cc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reaction time: 48 h
Yield: 16 %

Procedure:
(4-(1,1′-biphenyl)-4-yl-1H-imidazol-2-yl)-N-methylmethanamine (1 g; 0.003 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 20 ml dimethylformamide. Potassium carbonate (1.23 g; 0.009 mol) was added at about 23° C. and then benzyl bromide (0.34 ml; 0.003 mol) was added quite slowly. The reaction mixture was agitated at this temperature for about 48 hours then poured in icy water. The mixture was extracted with ethyl acetate and the organic phase washed with water. After drying over magnesium sulfate, the solvents were concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/8-2), a white solid was obtained in the form of a glue (yield of 16%). Free base. Melting point: 106-108° C. MH+=354.2.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[CH:3][CH:2]=1.[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:7]([O:8][CH2:9][CH:10]1[CH2:11][O:12][C:16]([CH2:17][CH3:18])([CH2:15][CH3:14])[O:13]1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: OCC(O)COCc1ccccc1
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)OCC(COCc2ccccc2)O1
Reaction time: 22 h
Yield: 67.1 %

Procedure:
To a tetrahydrofuran (30 ml) solution of DL-α-O-benzyl glycerol (3 g, 16.5 mmol), 3-pentanone (17.5 ml, 165 mmol) and p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol) were added at room temperature and the mixture was stirred at the same temperature for 22 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (5 ml) was added to adjust pH to about 8. The generated precipitate was removed by filtration and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 3/1 gradient). A desired fraction was concentrated to obtain the title compound (2.77 g, 67.1% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:21][C:22]([O-])(C)[CH3:23].[K+].C(Br)C=C>C(O)(C)(C)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH:22]=[CH2:21])[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C=CCBr
Product: C=CCC1(C(=O)OCC)CN(C(=O)c2ccccc2)CCC1=O
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
1.16 g (4.22 mmol) of ethyl-1-benzoyl-4-oxo-3-piperidine carboxylate, 9 ml of tert-butanol and 0.57 g (4.93 mmol) of potassium tert-butylate (97 percent) were used at 25° C. and stirred for 30 minutes. Then 0.70 g (5.67 mmol) of allylbromide was instilled in 2 minutes. The mixture was stirred with reflux for 16 hours, the reaction mixture was concentrated by evaporation and divided between 30 ml of methylene chloride and 30 ml of water. The emulsion was adjusted to pH 7 with hydrochloric acid (1N). The phases were separated and the aqueous phase was extracted three more times with 30 ml of methylene chloride. The combined organic phases was dried with magnesium sulfate and concentrated by evaporation. 1.34 g of crude product was obtained which was purified by column chromatography. The yield was 0.850 g of pure ethyl-1-benzoyl-4-oxo-3-(2-propenyl)-3-piperidine carboxylate, which equals 64 percent. Data concerning the compound was:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[CH3:35])=[O:21]>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:32]3[CH2:33][CH2:34][CH:29]([C:27]4[CH:26]=[CH:25][C:24]([CH3:35])=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:36])[CH3:18])[CH:28]=4)[CH2:30][CH2:31]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1ccc(C2CCNCC2)cc1NC(=O)C(C)C
Product: CCn1c2ccccc2c2cc(CN3CCC(c4ccc(C)c(NC(=O)C(C)C)c4)CC3)ccc21

Procedure:
Prepared by Procedure AA and Scheme AJ using 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[2-methyl-5-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 468.1 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:31][CH:32]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3ccc(NS(=O)(=O)c4ccccc4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Benzenesulfonyl chloride (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. The title compound was obtained by pre-HPLC in 34% yield. Mass: M+H+: 434.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:18]=[N-:19].C[O-].[Na+].[OH-].[Na+]>CO>[CH2:1]([O:8][CH2:9][C:10]1[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:19][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)COCc1ccccc1
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nnn(-c2ccccc2)c1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Methyl 4-(benzyloxy)-3-oxobutanoate (5.00 g) and azidobenzene (2.68 g) were dissolved in methanol (30 ml), sodium methanolate (28% methanol solution, 6.5 g) was added and the mixture was stirred at room temperature for 2 hr, and then heated under reflux for 18 hr. 1M Aqueous sodium hydroxide solution (10 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water and washed with ethyl acetate-hexane (1:1, v/v). The obtained aqueous solution was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (6.03 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[O:4]1.CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:16])([CH3:2])[O:4][B:5]([C:10]2[CH2:11][CH2:12][N:13]([C:24](=[O:26])[CH3:25])[CH2:14][CH:15]=2)[O:6]1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (2.9 g, 11.8 mmol) in DCM (30 mL) were added Et3N (3.6 g, 35.4 mmol) and acetyl chloride (AcCl) (932 mg, 11.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with DCM (20 mL), washed with H2O (2.0 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered, evaporated to give the crude product (3.2 g, crude). ESI-MS (M+1): 252 calc. for C13H22BNO3 251.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>C1COCC1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:19]#[N:20])[CH2:21][CH:23]2[CH2:24][OH:25])=[CH:14][CH:13]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: ClCC1CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cc2)CC1CO
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of NaHMDS (23 g, 127.5 mmol) in THF (80 mL), was added a solution of 4-bromophenylacetonitrile (10 g, 51.0 mmol) in THF (80 mL) at −10° C. and stirred for 10 min. Epichlorohydrin (4.7 mL, 56.11 mmol) was added to the reaction mixture at −10° C. and then stirred the mixture at r.t. for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with 2:1 dioxane:hydrochloric acid (10 mL) at 0° C. and extracted with diethyl ether (3×200 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated to yield the title compound (12.8 g, 100%) as brown oil which was used as such in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: [Li]c1ccccc1
Reactant: Fc1cccc(F)n1
Solvent: C1CCOC1
Product: Fc1cccc(-c2ccccc2)n1
Temperature: -40 °C
Yield: 12 %

Procedure:
Dissolve 2,6-difluoropyridine (5.0 mL, 5.51 mmol) in anhydrous THF (30 mL) and cool to −40° C. Add a solution of phenyl lithium (1.8 M hexanes, 30.6 mL) dropwise over 5 minutes. Stir the resulting purple reaction at −40° C. for 30 minutes and bring to room temperature. Quench the reaction with water and extract the solution with ethyl acetate several times. Combine the organic extracts, dry over MgSO4, filter and evaporate onto silica gel. Purification by flash column chromatography yields 2-fluoro-6-phenylpyridine 1.0 g (12%) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(CO)nc2ccccc21
Product: Cn1c(CCl)nc2ccccc21
Yield: 36 %

Procedure:
A solution of 2-hydroxymethyl-1-methylbenzimidazole (1.1 g, 6.7 mmol) in thionyl chloride (10 ml) was stirred at ambient temperature for 15 minutes and then heated at reflux for 15 minutes. The volatiles were removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 2-chloromethyl-1-methylbenzimidazole (506 mg, 36%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 4.07(s, 3H); 5.38(s, 2H); 7.6-7.7(m, 2H); 7.9(d, 1H); 8.05(dd, 1H) MS-ESI: 181 [MH]+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.O.[C:27](OCC)(=[O:29])C.Cl>C[O-].[Na+].CN(C)C=O>[CH3:27][O:29][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
A solution of 4-[4-(8-Bromooctyloxy)phenyl]benzoic acid (1 g) in a mixture of sodium methylate (28% solution in methanol) (10 ml) and N,N-dimethylformamide (5 ml) was refluxed for 5 hours. The reaction mixture was added to a mixture of water and ethyl acetate and adjusted to pH 2.0 with conc. HCl. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-(8-Methoxyoctyloxy)phenyl]benzoic acid (0.77 g).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:9]=[C:8]([C:19](O)=[O:20])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].Cl>>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:19]([C:8]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:12]=2[CH:11]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:9]=1)=[O:20]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(N3CCOCC3)cc21
Agent: Cl
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCOCC3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for example 39 from 1-(1-methylethyl)-6-(4-morpholinyl)-1H-indazole-4-carboxylic acid (55 mg, 0.19 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl (53.8 mg, 0.29 mmol) The product was collected as an off-white solid (48 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (br. s., 1H) 8.49 (br. s., 1H) 8.18 (s, 1H) 7.35 (d, J=1.77 Hz, 1H) 7.10 (s, 1H) 5.88 (s, 1H) 4.95 (quin, J=6.57 Hz, 1H) 4.36 (br. s., 1H) 4.34 (br. s., 1H) 3.75-3.80 (m, 4H) 3.21-3.25 (m, 4H) 2.20 (s, 3H) 2.12 (s, 3H) 1.44 (s, 3H) 1.43 (s, 3H); LC-MS (ES) m/z=423.9