Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]1=[O:15].[F:26][CH2:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:26][CH:27]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30])[C:7]1([OH:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:19][C:2]=2[F:1])[C:6]1=[O:15]
Reactant: Cn1cc(-c2ccc(CN3C(=O)C(=O)c4ccccc43)c(F)c2)cn1
Reactant: O=S(=O)(CF)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(CN3C(=O)C(O)(C(F)S(=O)(=O)c4ccccc4)c4ccccc43)c(F)c2)cn1
Temperature: -78 °C

Procedure:
1-(2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)indoline-2,3-dione (1 g, 3.0 mmol) was added to a flame-dried round bottom flask with stir bar and dissolved in THF (30 mL). Next, ((fluoromethyl)sulfonyl)benzene (780 mg, 4.5 mmol) was added, and the mixture was cooled to −78° C. Lithium hexamethyldisilazide (1M in THF, 4.5 mL, 4.5 mmol) was added dropwise to the cooled solution, and the mixture was allowed to gradually warm to room temperature overnight. The reaction was quenched by addition of excess saturated brine, and then extracted with 3×50 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated and purified by silica gel chromatography (30-100% EtOAc in hexanes gradient) to afford 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one as a yellowish foam. To a scintillation vial containing a magnetic stir bar was added 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one (305 mg, 0.6 mmol), followed by DMF (6 mL), magnesium powder (150 mg, 6 mmol), and 3 mL of an acetic acid/sodium acetate (1:1) buffer solution (8 mol/L). The vial was sealed and allowed to stir at room temperature overnight. The mixture was diluted with water (100 mL), and then extracted with 5×25 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated, and purified by reversed-phase HPLC using 0.1% TFA in water/acetonitrile as a mobile phase to afford the title compound. LCMS: RT=0.67 min, >99% @ 254 nm, >99% @ 215 nm; m/z (M+1)+=370. 1HNMR (400 MHz, CDCl3, δ (ppm)): 7.53 (s, 1H), 7.47 (s, 1H), 7.3 (dt, J=7.8, 1.1 Hz, 1H), 7.2-7.1 (m, 2H), 7.1-7.0 (m, 2H), 6.9 (d, J=7.9 Hz, 1H), 5.0 (d, J=15.8 Hz, 1H), 4.9 (d, J=15.8 Hz, 1H), 4.8 (quartet, J=3.6 Hz, 1H), 4.6 (quartet, J=9.1, 4.0 Hz, 1H), 3.9 (s, 3H), HRMS calculated for C20H18N3O2F2 (M+H)+ m/z: 370.1367, measured: 370.1366.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([CH:10]3[CH2:15][CH2:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=4[F:23])=[CH:12][CH2:11]3)[CH2:6][CH2:5]2)[O:3]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>O>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH2:14][CH2:15][CH:10]([CH:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)[CH2:11][CH:12]=1
Reactant: Fc1cccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC(C2CC=C(c3cccc(F)c3F)CC2)CC1
Yield: 81.3 %

Procedure:
First, 8 g of 4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanone ethylene ketal, 0.5 g of p-toluenesufonic acid, 40 ml of dioxane, and 110 ml of water were placed in a 300 ml flask. The mixture was stirred under reflux for 5 hours. The reaction mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled away. The residue was recrystallized from hexane to obtain 5.65 g of 4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanone (Y: 81.4%). The compound thus obtained had a purity of 98.4% by GC.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5](=[O:14])[CH2:4]1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Si:15]([O:1][CH2:2][C@@H:3]1[CH2:4][C:5](=[O:14])[CH2:6][C@H:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 129.3 %

Procedure:
To a solution of (+)-trans-3-hydroxymethyl-4-phenylcyclopentan-1-one from Example 8, Step F (3.3 g, 16 mmol) in methylene chloride (100 mL) was added t-butyldimethylsilyl chloride (11 g, 49 mmol) and DIPEA (22 mL, 74 mmol). The reaction was stirred at rt for 16 h, poured into dilute aq. hydrochloric acid and extracted twice with ether. The organic layers were washed with brine, dried over sodium sulfate, a combined and concentrated. The residue was purified by FC (5% ethyl acetate in hexanes) to afford of (+)-trans-1-t-butyldimethylsilyloxymethyl-4-oxo-2-phenylcyclopentane (6.3 g) as a oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr

Procedure:
To a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mole) in CCl4 (150 mL) was added NBS (14.2 g, 0.080 mole). The resulting reaction solution was heated under reflux with the starting material being completely consumed within 2 hr. CCl4 was removed under reduced pressure and the residue was diluted dissolved in ether, washed with brine (3×), dried over MgSO4, concentrated. Chromatographed/hexane yielded 5-bromo-2-fluorobenzyl bromide. The product was immediately used for the reaction below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.CS(O[CH:32]([C:34]1[CH:38]=[CH:37][O:36][N:35]=1)[CH3:33])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:21]3[CH2:26][CH2:25][N:24]([CH:32]([C:34]4[CH:38]=[CH:37][O:36][N:35]=4)[CH3:33])[CH2:23][CH2:22]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(OS(C)(=O)=O)c1ccon1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(C(C)c3ccon3)CC2)n1

Procedure:
A mixture of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-N-methylpyrimidin-2-amine (C8, which can be prepared by the method of J. Sisko, U.S. Pat. No. 6,239,279 B1, May 29, 2001) (75 mg, 0.21 mmol), 1-isoxazol-3-ylethyl methanesulfonate (C7) (60 mg, 0.31 mmol) and cesium carbonate (139 mg, 0.43 mmol) in acetonitrile (2 mL) was heated at 70° C. for 24 hours. Removal of solvent under reduced pressure provided a residue, which was purified by silica gel chromatography (Eluants: 0%, then 5%, then 15% methanol in ethyl acetate). The resulting colorless oil was dissolved in ethyl acetate/heptane, then concentrated in vacuo to provide the product as a white solid. Yield: 57 mg, 0.13 mmol, 62%. APCI m/z 448.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.46 (d, J=6.9 Hz, 3H), 1.93-2.07 (m, 2H), 2.12-2.24 (m, 4H), 2.98-3.08 (m, 2H), 3.02 (d, J=5.0 Hz, 3H), 3.94 (q, J=6.9 Hz, 1H), 4.59 (br m, 1H), 5.14 (br d, J=5 Hz, 1H), 6.35 (d, J=1.7 Hz, 1H), 6.40 (d, J=5.0 Hz, 1H), 7.00 (dd, J=8.8, 8.8 Hz, 2H), 7.46 (dd, J=9.0, 5.5 Hz, 2H), 7.77 (s, 1H), 8.15 (br d, J=5 Hz, 1H), 8.38 (dd, J=1.7, 0.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH3:40][O:39][C:37](=[O:38])[CH2:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:28][N:18]([CH2:17][CH2:16][CH2:15][N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[CH:35][CH:34]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCCN(C)C
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCN(C)C)Cc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from step (vi) (0.25 g), methyl (4-formylphenyl)acetate (0.15 g) and sodium triacetoxyborohydride (0.2 g) in NMP (10 mL) was stirred at rt for 18 h then heated at 45° C. for 3 h. A further portion of methyl(4-formylphenyl)acetate (0.1 g) and sodium triacetoxyborohydride (0.2 g) were added then stirred at 45° C. for 6 h. The mixture was purified by RPHPLC, yield 0.035 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH3:19])=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1
Yield: 75 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-hydroxy-2-methylindole (1 mmol) in 5 ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting oil residue was purified by column chromatography to give 5-(2-chloropyrimidin-4-yloxy)-2-methyl-1H-indole in a yield of 75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:14][C:15]2[N:16]=[C:17]([S:23][CH3:24])[N:18]=[CH:19][C:20]=2[CH:21]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
Into a solution of 2,6-dichlorophenylacetonitrile (0.55 g) in dimethylformamide (5 mL) was added one equivalent of 60% sodium hydride suspension (0.12 g). After 10 minutes, 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (0.50 g) obtained from Example 76 was added. After stirring overnight at room temperature, the reaction was quenched with water. The aqueous solution was acidified with 1N hydrochloric acid to a pH of 7 and extracted several times with dichloromethane. The combined dichloromethane layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. Chromatography of this residue down silica gel with ethyl acetate:hexane (2:1) gave 0.32 g of the title compound, CIMS (1% NH3 in CH4): 365=M+ +C2H5, 337=M+ +H (Base), 336=M+.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1cccnc1
Product: O=C(Nc1cccnc1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminopyridine (25 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 10-50 EtOAc in dichloromethane. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(pyridin-3-yl)benzamide as a white solid. Yield: 48 mg (47%). 1H-NMR: 10.66 (s, 1H), 8.89 (d, J=2.5 Hz, 1H) 8.33 (dd, J=4.5, 1.5 Hz, 1H), 8.15 (ddd, J=8.0, 2.5, 1.5 Hz, 1H) 8.08 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.41 (ddd, J=8.5, 4.5, 0.5 Hz, 1H), 7.24-7.08 (m, 3H), 3.85-3.81 (m, 2H), 2.45 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [C:1]([N:20]([CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)=[CH:33][CH:32]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[CH:26])([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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1>C(N)CCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([N:20]([CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)=[CH:35][CH:36]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#CCOCCN(CCOCc1ccc(-c2nc3ccccc3o2)cc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCN
Product: Cc1ccc(C#CCOCCN(CCOCc2ccc(-c3nc4ccccc4o3)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 75 °C

Procedure:
N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(prop-2-ynyloxy)ethanamine (0.517 g; 0.87 mmol), 4-iodotoluene (0.262 g; 1.2 mmol) and copper (I) iodide (3.5 mg; 2%/wt) are dissolved in BuNH2 (4 ml) in an inert atmosphere (argon). To this is added (PPh3)2PdCl2, [bis(triphenylphosphine)palladium chloride], (6 mg; 1%/wt) and the reaction is heated at 75° C. for 1 hour. The mixture is then concentrated in vacuo and purified by column chromatography using 10 Et3N/10 CH2Cl2 /PE to obtain N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)prop-2-ynyloxy]ethanamine which is used directly in Step G.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:8]1[C:7](=[O:13])[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: CCOC(=O)Cn1cccc(C)c1=O
Solvent: O
Solvent: CCO
Product: Cc1cccn(CC(=O)NN)c1=O
Yield: 96 %

Procedure:
As described for example 112a, (3-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 96%). MS: m/e=204.4 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][OH:7].C(Cl)(Cl)Cl.[OH-:14].[Na+]>CC(C)=O>[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][C:2]([CH3:9])([CH3:8])[NH:1][C:2]([CH3:9])([CH3:8])[C:3]1=[O:14]
Reactant: [OH-]
Reactant: CC(C)(N)CNCCO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Temperature: 0 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
To a solution of 2-((2-amino-2-methylpropyl)amino)ethanol (12 g, 91 mmol) in 90 mL of acetone was added chloroform (10.9 mL, 136 mmol) and the solution was cooled to 0° C. with an external ice bath. A solution of NaOH (50% by weight, 43.6 g, 545 mmol) was added slowly to the cold solution over several minutes and the resultant solution was stirred at 0° C. for 2 hours then allowed to warm to room temperature and stirred for an additional 18 hr. The crude reaction mixture was filtered to remove solids, washing with acetone, and the solution was concentrated to 20 g of a clear oil. A portion of the crude material was purified by a bulb-to-bulb distillation under reduced pressure to give 1.45 g of a clear oil, which was used directly in the next step without further purification. LRMS (ESI/APCI) m/z 201 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]Br)=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:17][CH2:16]2)=[CH:21][CH:20]=1
Reactant: BrCCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc(Br)cc3)CC2)cc1

Procedure:
A solution of 1-[2-(4-nitrophenyl)ethyl]piperazine (300 mg, 1.3 mmol), 1-bromo-4-(2-bromoethyl)benzene (400 mg, 1.5 mmol), and triethylamine (0.89 mL, 6.4 mmol) in DMF (5 mL) was heated to 60° C. for 16 hours. LC showed formation of the desired product. The desired product was purified by silica gel chromatography (10% MeOH in EtOAc). LC-MS (IE, m/z): 420 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH3:24])[CH:2]([CH3:4])[CH3:3].N1([CH2:35][C:36]([NH2:38])=[O:37])C2C=CC=CC=2N=N1.[OH-].[Na+]>CCO>[CH3:24][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([C:14]3[CH:13]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[NH:38][C:36](=[O:37])[CH:35]=3)[CH:16]=2)[NH:20][N:19]=1
Reactant: NC(=O)Cn1nnc2ccccc21
Reactant: Cc1n[nH]c2ccc(/C=C/C(=O)c3ccccc3OCC(C)C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1n[nH]c2ccc(-c3cc(-c4ccccc4OCC(C)C)[nH]c(=O)c3)cc12
Temperature: 90 °C
Yield: 21.4 %

Procedure:
To a mixture of (E)-1-(2-isobutoxyphenyl)-3-(3-methyl-1H-indazol-5-yl)prop-2-en-1-one (50 mg, 0.15 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetamide (Aldrich) (50 mg, 2.84 mmol), and 20 mg of NaOH in 10 mL of EtOH was heated to 90° C. for 4 h. The reaction mixture was concentrated down and purified by preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate) to afford 4-(3-methyl-1H-indazol-5-yl)-6-{2-[(2-methylpropyl)oxy]phenyl}pyridin-2(1H)-one (12 mg, 21.4%). 1H NMR (400 MHz, d6-DMSO): δ 12.78 (s, 1H), 8.15 (s, 1H), 7.71 (d, 1H), 7.53 (m, 2H), 7.45 (t, 1H), 7.15 (d, 1H), 7.07 (t, 1H), 6.77 (br s, 1H), 6.61 (s, 1H), 3.84 (d, 2H), 2.02 (m, 1H), 0.95 (d, 6H); MS (EI) for C23H23N3O2: 374 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[OH-].[Na+].[C:39](OC(=O)C)(=[O:41])[CH3:40]>S(=O)(=O)(O)O>[C:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), acetic anhydride (20 ml) and two drops of conc. sulfuric acid is stirred at room temperature for 3 hours. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution under ice-cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=200:1), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-acetylaminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.60 g) as colorless needles, m.p. 171°-172° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:30])[C:6]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[F:31]C1C=C2C(=CC=1)C(=O)CC(C)C2>>[C:26]([O:25][CH:19]([C:6]1[C:5]([CH3:30])=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([F:31])[CH:2]=2)[C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1-c1ccc(Cl)cc1
Reactant: CC1CC(=O)c2ccc(F)cc2C1
Product: Cc1cc2cc(F)ccc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)acetic acid (42) was prepared similarly to 2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 35, using 6-fluoro-3-methyl-3,4-dihydronaphthalen-1(2H)-one instead of 5-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one. 1H-NMR: 400 MHz, (CD3OD) δ: 7.67 (s, 1H), 7.57 (s, 2H), 7.55 (as, 1H), 7.45 (dd, J=9.8, 2.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.27 (dd, J=9.4, 5.2 Hz, 1H), 7.11 (td, J=9.0, 2.4 Hz, 1H) 5.16 (s, 1H), 2.60 (s, 3H), 0.98 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: −118.01 (s). LCMS-ESI− (m/z): [M—H]− calcd for C23H21ClFO3: 399.12; found: 399.19.
Reaction SMILES: CC(C)(OC([NH:7][C:8]1[S:9][CH:10]=[C:11](CC(O)=O)[N:12]=1)=O)C.[NH:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CCOC(=O)CN(CC(=O)OCC)c1csc(N)n1

Procedure:
The subtitle compound was prepared from 2-[[1,1-dimethylethoxy]carbonylamino]4-thiazoleacetic acid (0.75 g) (Chem. Pharm. Bull. 1993, 41, 758) and diethyl iminodiacetate (0.83 g) according to the method of example 15 step (i) followed by step (ii). Yield 0.91 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH3:32])[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.