Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][NH:18][N:19]=3)=[N:8][C:4]=2[CH:3]=1.IC.[C:28]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][N:18]([CH3:28])[N:19]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(Br)ccc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a vial is added 5-bromo-1-tert-butyl-2-[2-(2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (158 mg, 0.4 mmol) in DMF (5 mL), followed by the addition of iodomethane (114 mg, 0.8 mmol) and K2CO3 (110 mg, 0.8 mmol). The reaction mixture is stirred at room temperature for 0.5 hour. The reaction mixture is diluted with EtOAc, washed with water then, brine, dried with Na2SO4, filtered and concentrated. The residue is loaded to a silica gel column. The column is eluted with 0-3% MeOH/CH2Cl2. The product fractions are collected and is concentrated to afford 5-bromo-1-tert-butyl-2-[2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (62 mg, 38%). LCMS (ESMS): m/z 411.59, 413.47 (M++1)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]1.O>C(O)(CC)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:42][C:40]3[C:39]([CH3:43])=[N:38][N:37]([CH3:36])[CH:41]=3)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: Cc1nn(C)cc1N
Solvent: O
Solvent: CCC(C)O
Product: Cc1nn(C)cc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 110 °C
Yield: 66.1 %

Procedure:
(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.100 g, 0.186 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine (0.413 g, 3.72 mmol) were placed in s-BuOH (2 mL), heated to 110° C. overnight, then poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:10 DCM/MeOH) to give the product (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.070 g, 66.2% yield).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:6]1([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3][C:2]1=[O:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC1C(=O)Oc2ccccc21
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC1(CC(=O)OCc2ccccc2)C(=O)Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of 0.204 mol of 2,3-dihydro-2-oxo-3-propylbenzofuran in 200 ml of anhydrous dimethylformamide is added to a suspension of 0.204 mol of sodium hydride in 100 ml of anhydrous dimethylformamide. The medium is maintained with stirring at room temperature for one hour, 0.224 mol of benzyl bromoacetate is then added and the medium is left for 12 hours at room temperature. The reaction mixture is concentrated under vacuum and hydrolyzed using one liter of water, the aqueous phase is extracted with twice 250 ml of benzene, the organic phase dried over anhydrous sodium sulfate and the solvent evaporated off. The crystallized residue is washed with isopropyl ether and filtered, yielding 0.173 mol of a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>C1COCC1.O>[CH3:44][S:45]([NH:48][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:14]([N:11]3[CH2:10][CH2:9][C:8](=[CH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:13][CH2:12]3)=[O:15])=[CH:18][CH:19]=2)=[CH:24][CH:25]=1)=[O:28])(=[O:47])=[O:46]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NC(=O)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
The compound (80 mg, 193 μmol) obtained in Example 28 was dissolved in THF (5 mL), and CDI (47 mg, 290 μmol) was added thereto, followed by stirring at 60° C. for 2 hours. Thereafter, methanesulfonamide (28 mg, 290 μmol) was added to the mixture, followed by stirring for 10 minutes, and diazabicycloundecene (hereinafter referred to as DBU) (51 μL, 347 μmol) was added thereto, followed by stirring at room temperature for 16 hours. Water was added to the resulting mixture, and after extraction with methanol:chloroform (1:6), the extract was washed with a saturated ammonium chloride aqueous solution and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:6), thereby giving the title compound (30 mg, 32%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[CH:24])[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.N1CCCCC1>C1(C)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[C:24][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1cccs1
Reactant: C#CCN(CCN(C(=O)C(=O)OCC)C(C)C)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C

Procedure:
A solution of 340 mg of 10g, 130 μl of 2-iodothiophene, 12 mg of CuI, 21 mg of PdCl2(PPh4)2 and 200 μl of piperidine in 2 ml of degassed toluene was stirred under N2 for 3 h. The mixture was concentrated and applied to a silica column and chromatographed with a gradient of heptane/ethyl acetate, to provide 400 mg of 10h as an orange oil. Rf 0.60 (hept/ethyl acetate 1/1).
Reaction SMILES: [C:1]([C:10]1[CH:28]=[CH:27][C:13]([O:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Li+]>>[C:1]([C:10]1[CH:28]=[CH:27][C:13]([O:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(OC(CCCCCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCC(=O)c1ccc(OC(CCCCCC)C(=O)O)cc1
Yield: 84 %

Procedure:
1-[4-Hydroxyphenyl]-1-octanone (440 mg, 2.0 mmol) and ethyl (RS)-2-bromooctanoate (552 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Octanoylphenoxy]octanoate (605 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 4.66 (dd, J=5.1, 7.4 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 1.88-2.02 (m, 2H), 1.70 (tt, J=7.2, 7.2 Hz, 2H), 1.41-1.56 (m, 2H), 1.25-1.37 (m, 14H), 1.23 (t, J=7.1 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.41, 171.48, 161.81, 131.01, 130.54 (2C), 114.77 (2C), 76.75, 61.62, 38.56, 32.90, 31.94, 31.78, 29.60, 29.38, 29.07, 25.33, 24.80, 22.85, 22.75, 14.39, 14.31, 14.26. The resulting ester (605 mg, 1.6 mmol) was saponified with lithium hydroxide (186 mg, 7.8 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Octanoylphenoxy]octanoic Acid (487 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 9.70 (br s, 1H), 7.89 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.69 (dd, J=5.9, 6.6 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 1.95-2.01 (m, 2H), 1.67 (tt, J=7.2, 7.2 Hz, 2H), 1.43-1.58 (m, 2H), 1.24-1.37 (m, 14H), 0.851 (t, J=6.8 Hz, 3H), 0.849 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 200.38, 176.08, 161.84, 130.85, 130.78 (2C), 114.83 (2C), 76.20, 38.56, 32.79, 31.93, 31.76, 29.57, 29.35, 29.05, 25.34, 24.92, 22.84, 22.74, 14.29, 14.23. The acid (500 mg, 1.4 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Octanoylphenoxy]octanoate (404 mg, 76%) as a white solid. mp 165-170° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.58 (dd, J=6.1, 6.3 Hz, 1H), 2.91 (t, J=7.3 Hz, 2H), 1.91-1.96 (m, 2H), 1.62-1.69 (m, 2H), 1.44-1.58 (m, 2H), 1.25-1.39 (m, 14H), 0.87-0.90 (m, 6H); 13C NMR (101 MHz, CD3OD): δ 200.50, 176.40, 162.96, 130.28 (2C), 129.94, 114.71 (2C), 78.38, 38.00, 32.98, 31.79, 31.74, 29.27, 29.20, 29.05, 25.50, 24.79, 22.56, 22.51, 13.36, 13.34; LRMS (ESI): m/z 769 (M2H+), 748 (2M−Na++2H+), 363 (M−Na++2H+); HPLC: 3 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([NH:22][C:23]([N:13]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[C:9]([C:16]#[N:17])=[C:10]([CH3:15])[NH:11][C:12]1=[O:14])=[O:24])[CH3:21]
Reactant: CC1=C(C#N)C(c2cccc(Br)c2)NC(=O)N1
Reactant: CCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-(2H)-pyrimidine (2.92 g, 10 mmol) in THF (30 mL) was added 95% sodium hydride (0.30 g, 12 mmol). After gas evolution ceased, ethyl isocyanate (0.44 mL, 12 mmol) was added via syringe. The reaction mixture was stirred for 0.5 h, quenched with water and extracted twice with EtOAc. The combined extracts were washed with 0.5 N aqueous NaOH, with water and with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (25% to 35% EtOAc/hexane) to give, after evaporation of solvent, 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl amide as a colorless solid (2.91 g; 80%): 1H NMR (CDCl3, 400 MHz) δ 8.65 (t, 3H, J=5.3 Hz), 7.91 (s, 1H), 7.39 (m, 1H), 7.35 (m, 1H), 7.21 (m, 1H), 7.15 (d, 1H, J=7.9 Hz), 6.24 (s, 1H), 3.25 (m, 2H), 2.10 (s, 3H), 1.10 (t, 3H, J=7.0 Hz); LC/MS (ES+) 363 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.ClC([O-])=O>ClC(Cl)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:11]2([C:14]#[N:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22][CH:21]=1
Reactant: N#CC1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])Cl
Solvent: CC(Cl)Cl
Product: N#CC1(Nc2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
To 1-Benzyl-4-(4-chloro-phenylamino)-piperidine-4-carbonitrile (163 mg, 0.5002 mmol) in dichloroethane (5 ml) was added 1-chloroethyl chloroformate (65 μl, 0.600 mmol). The mixture was heated to reflux and stirred under N2. After 1 hour 15 minutes, an additional 86 μl (0.800 mmol) of the chloroformate was added to the reaction and stirred for an additional 2 hours at reflux. After cooling to room temperature the reaction was concentrated under reduced pressure. To this residue was added methanol (5 ml) and the reaction was heated at reflux for 2 hours. Next, the reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water. The organic layer was removed and sodium hydroxide (1N) was added to the aqueous layer until pH≈9. The aqueous layer was extracted with ethyl acetate 2 times and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (84 mg, 71%).
Reaction SMILES: [H][H].[CH2:3]([O:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:25]CC3C=CC=CC=3)=[CH:13][C:14]=2[O:17]CC2C=CC=CC=2)[O:9][CH:8]1[C:33]1[CH:38]=[CH:37][C:36]([O:39]CC2C=CC=CC=2)=[C:35]([O:47]CC2C=CC=CC=2)[CH:34]=1)[CH:4]=[CH2:5]>[Pd].C(OCC)(=O)C.C(O)C>[OH:47][C:35]1[CH:34]=[C:33]([CH:8]2[CH:7]([O:6][CH2:3][CH2:4][CH3:5])[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][C:12]([OH:25])=[CH:11][C:10]=3[O:9]2)[CH:38]=[CH:37][C:36]=1[OH:39]
Reactant: [H][H]
Reactant: C=CCOC1Cc2c(OCc3ccccc3)cc(OCc3ccccc3)cc2OC1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOC1Cc2c(O)cc(O)cc2OC1c1ccc(O)c(O)c1
Reaction time: 2 h

Procedure:
To a suspension of 20% palladium on carbon (80 mg) in 1:1 ethyl acetate/ethanol (15 mL) which had been stirred vigorously under 1 atmosphere of hydrogen for 10 minutes then cooled with an ice/methanol bath was added 3-Allyloxy-5,7-bis-benzyloxy-2-(3,4-bis-benzyloxy-phenyl)-chroman (200 mg). The ice bath was removed and the reaction was stirred for 2 h under 1 atmosphere of hydrogen. The mixture was filtered and concentrated, and purified by preparative reverse phase HPLC using a gradient of 5% to 100% acetonitrile/water over 10 min The appropriate fractions were frozen and lyophilized to yield 2-(3,4-Dihydroxy-phenyl)-3-propoxy-chroman-5,7-diol as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2Cl)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4Cl)cc23)cc1

Procedure:
The title compound, green solid (53 mg, 41%), MS (ISP) m/z=390.2 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 1 from 1-(2-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate L) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[CH2:11][CH:12]=O>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[CH:5]=1
Reactant: O=CCCl
Reactant: Nc1ncc(Cl)cc1Br
Solvent: CCO
Product: Clc1cc(Br)c2nccn2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 3-bromo-5-chloropyridin-2-amine (10 g, 49 mmol) and chloroacetaldehyde (50% in H2O, 12 mL, 98 mmol) in ethanol (100 mL) was heated at 50° C. overnight. It was then cooled to room temperature and concentrated. Acetone (30 mL) was added to the residue and the resulting mixture was stirred rapidly for 2 h. The resulting solid was collected through filtration and dried to afford 101a as a yellow solid (10.0 g, 89%). MS: [M+H]+ 231. 1H NMR (500 MHz, DMSO) δ 9.20 (s, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.09 (s, 1H)
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([N:20]3C(=O)C4C(=CC=CC=4)C3=O)=[N:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C1COCC1>[C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccccc2Oc2ccccc2)n1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccn(Cc2ccccc2Oc2ccccc2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of crude 2-(1-{[2-(phenyloxy)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (2.35 g, 5.94 mmol) in THF (30 ml) was added hydrazine hydrate (1.44 ml, 29.7 mmol, Aldrich). The resulting colourless solution was stirred at 50° C. for 2 h. A white solid precipitated. The suspension was cooled to ambient temperature and filtered through a sinter funnel. The filtrate was then filtered through a hydrophobic frit and concentrated under reduced pressure to give the title compound as a white solid (1.58 g); LCMS: (System 3) MH+=266, tRET=0.86 min.
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[C:18]([CH3:19])=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C([O-])(=O)C.[NH4+:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([CH3:19])=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:24])=[O:13]
Reactant: Cc1nccc(C(=O)O)c1Nc1ccc(I)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: Cc1nccc(C(N)=O)c1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-2-methyl-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]-2-methyl-isonicotinic acid and 0.4 mmol of ammonium acetate. LC/MS [1.85 min; 372 (M+1)].
Reaction SMILES: O1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[CH:11]([N:14]4[CH2:19][CH2:18][CH:17]([N:20]5[C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=6[NH:22][C:21]5=[O:29])[CH2:16][CH2:15]4)[CH2:12][CH2:13][CH:4]([C:5]=23)[CH2:3][CH2:2]1.C1C2=C3C(=CC=C2)C(N)CCC3C1>>[CH2:2]1[C:10]2=[C:5]3[C:6](=[CH:7][CH:8]=[CH:9]2)[CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]2)[CH2:12][CH2:13][CH:4]3[CH2:3]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCC3CCOc4cccc2c43)CC1
Agent: NC1CCC2CCc3cccc1c32
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1

Procedure:
In the same manner as Example 75(2) and (3) and using 1,2,2a,3,4,5-hexahydroacenaphthylen-5-ylamine, the title compound was obtained as a white solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:33])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:33][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:34])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)N3CCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
Lithium hydroxide monohydrate (0.02 g, 0.68 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(pyrrolidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.075 g, 0.17 mmol) in a 3:1 mixture of THF—H2O mixture (8 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-fluoro-3-methyl-4-[4-(pyrrolidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.064 g, 88%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s, 1 H), 7.98 (d, J=8.31 Hz, 3H), 7.91 (s, 1 H), 7.51 (d, J=8.31 Hz, 2 H), 7.39 (td, J=8.80, 2.40 Hz, 1 H), 6.69 (dd, J=11.20, 2.40 Hz, 1 H), 3.85 (s, 2 H), 3.21-3.29 (m, 4 H), 2.07 (s, 3 H), 1.64-1.76 (m, 4 H). MS calcd. for C23H21FNO4S [(M−H)−] 426, obsd. 426.4.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(Cc2cc3ccccc3s2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1

Procedure:
2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride was prepared by the method of Example 40B with DMF (3.2 mmoles, 0.24 ml), sulfurylchloride (2.7 mmoles, 0.22 ml) and 2-(4-methoxybenzyl)benzo[b]thiophene (1.6 mmoles. 0.4 g). Flash chromatography using 2% ethyl acetate/hexanes provided 0.19 g (33%) of a light yellow solid.
Reaction SMILES: C([Cl:4])(=O)C.CO.[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>ClCCCl.C(Cl)Cl>[ClH:4].[C:8]1([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:20][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nn1cncn1
Reactant: CC(=O)Cl
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: ClCCCl
Product: Cl
Product: c1ccc(C(=Nn2cncn2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Anhydrous methanolic HCl was prepared by dissolving 6.4 mL (90.0 mmol) of acetyl chloride in 100 mL of methanol 10.0 gm (89.3 mmol) of 1-amino-1,2,4-triazole (approximately 75% pure) was added and the solvent was removed to afford a white solid which was dried in vacuo. A portion (4.62 g, 28.7 mmol) of the solid was suspended in 100 mL of 1,2-dichloroethane and 4.0 mL (24.5 mmol) of benzophenone imine were added. The mixture was heated at reflux for 16 h. After cooling to room temperature, it was diluted with methylene chloride, washed with saturated aqueous Na2CO3, water and brine and dried (MgSO4). Removal of solvent gave an oil from which desired product was crystallized in hexanes as off-white needles; yield 3.0 (49%), mp 126°-129° C.