Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: O=C(Nc1ccccc1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCN(Cc2ccc(Br)c(Br)c2)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3,4-dibromo-benzyl)-piperazine-1-carboxylic acid phenylamide (0.02 g) in DMF (0.6 mL) was added NaH (60% dispersion in oil; 3 mg) in one portion. The resulting mixture was allowed to stir for 30 min, then was treated with MeI (0.005 mL), and was stirred at rt for 12 h. The mixture was concentrated and the residue was purified by column chromatography (5% MeOH/DCM), giving the product as a white solid (0.015 g). 1H NMR (400 MHz, CDCl3): 7.54-7.50 (m, 2H), 7.33-7.31 (m, 2H), 7.12-7.05 (m, 4H), 3.34 (s, 2H), 3.22-3.20 (m, 6H), 2.23-2.21 (m, 4H), 1.63 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].C[C:15](C)([O-:17])C.[K+].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH3:21][C:20]1([CH2:15][O:17][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6])[O:22][CH2:25][CH2:24][O:23]1
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(COc2cc(C#N)ccc2C(F)(F)F)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-fluoro-4-(trifluoromethyl)benzonitrile (12.1 g, 63.9 mmol) and the compound of Preparation 8 (21.0 g, 160.0 mmol) in tetrahydrofuran (345 ml), at 0° C. and under nitrogen, was added dropwise potassium tert-butoxide (1M in tetrahydrofuran, 70.3 ml, 70.3 mmol). The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature. To the mixture was added ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (250 ml) and the two layers were separated. The organic phase was washed with saturated aqueous ammonium chloride solution, water and brine, dried (MgSO4) and concentrated in vacuo. To the residue was added cyclohexane (100 ml) and the mixture was allowed to stand for 1 h. The solid residue was collected by filtration and dried to give the title compound (16.3 g).
Reaction SMILES: C(CO[C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8](O)=[O:9])(O)=O.[C:27](Cl)(=[O:31])[C:28]([Cl:30])=[O:29].C(Cl)[Cl:34]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:30][C:28]([CH2:27][O:31][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8]([Cl:34])=[O:9])=[O:29]
Reactant: O=C(O)COc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)COc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1C(=O)Cl
Temperature: -8 °C
Yield: 95.4 %

Procedure:
A mixture of 2-(carboxymethoxy)-5-[(2-chloro -α,α,α-trifluoro-p-tolyl)oxy]benzoic acid (16.0 g, 40.95 mmol) in methylene chloride is cooled to -8° C., treated with oxalyl chloride (20.8 g, 163.8 mmol) and four drops of N,N-dimethylformamide, stirred for several minutes and concentrated in vacuo to obtain a solid. The solid is dissolved in toluene and the resultant organic solution is concentrated in vacuo to give the title product as an off-white solid (16.7 g, 95.4%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14](O)=[O:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:15])[CH:17]=[CH:18][N:19]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccnc(Cl)c1)N1CCc2ccccc21
Reaction time: 8 h

Procedure:
400 μL (3.53 mmol) 2,3-dihydro-1H-indole were added to 500 mg (3.17 mmol) 2-chloroisonicotinic acid, 600 μL (3.49 mmol) DIPEA and 1.10 g (3.43 mmol) TBTU in 20 mL THF. The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with 15% potassium carbonate solution (1×), water (1×) and 1M hydrochloric acid (1×). The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with diisopropylether and suction filtered. The solid was dried at 40° C. in the circulating air dryer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:11][CH:10]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 3 h

Procedure:
116 g (0.5 mole) of 4'-chloro-4-hydroxybenzophenone, 84 g (0.6 mole) of potassium carbonate and 500 cm3 of DMF are placed in a 1 liter flask. The mixture is brought to reflux and 90 g (0.5 mole) of methyl 5-chloro-2,2-dimethylpentanoate in 200 cm3 of DMF are then added from a dropping funnel. Reflux is continued for 3 hours. The mixture is then cooled and poured into 1 liter of water, so that the desired product precipitates. The precipitate is extracted with diethyl ether, washed with aqueous soda, then with water, dried and decolourised, and the solvent is evaporated under vacuum. 160 g of a white solid are obtained, which are recrystallised from diisopropyl ether. 130 g of the desired product are obtained, m.pt. 64° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17](=[CH2:28])[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])CCC>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Cl>[CH3:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:17](=[CH2:28])[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C:3]2=[N:10][N:9]=1
Reactant: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nnc2c(Br)cccn12
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCc1ccccc1)c1cccn2c(C)nnc12
Temperature: 60 °C
Yield: 72.7 %

Procedure:
To a solution of 0.13 g (0.61 mmol) of 8-bromo-3-methyl[1,2,4]triazolo[4,3-a]pyridine from Step B in 4 mL of anhydrous THF was added a solution of 0.36 g (0.80 mmol) of benzyl 2-(tributylstannyl)acrylate (see Intermediate 62, Step B) in 1 mL of anhydrous THF, 0.11 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.067 g (0.67 mmol) of copper(I)chloride. The reaction mixture was heated to 60° C. for 6 h, cooled and filtered through a pad of Celite®. The pad was washed with 15 mL of a dichloromethane and the combined filtrates were evaporated to dryness. The crude residue was purified by silica gel chromatography eluting with a 0-6% methanol in ethyl acetate gradient to afford the title compound (0.13 g, 73%). LC-MS: m/z (ES) 294 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:24][CH3:25])[CH:14]=2)[N:9]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:8]=1)[CH3:2].[Li+].[CH3:37][CH:38]([N-]C(C)C)C.[CH2:44]1COC[CH2:45]1.C(C1C=CC=CC=1)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:24][CH3:25])[CH:14]=2)[N:9]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)[CH:8]=1)([CH2:44][CH3:45])[CH2:37][CH3:38])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CCc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCc1ccccc1
Solvent: CCI
Product: CCOC(=O)C(CC)(CC)Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
To a solution of 3-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionic acid ethyl ester (120 mg, 0.25 mmol) in THF (3 mL) at −78° C. is added LDA (1.8 M solution in heptate/THF/ethylbenzene, 0.341 mL, 0.61 mmol). The mixture is stirred at −78° C. for 25 minutes and iodoethane (0.20 mL, 2.5 mmol) is added. The mixture is allowed to warm up to room temperature and stirred for 18 hours. To the mixture, an aqueous saturated NH4Cl solution (5 mL) is added, and THF is removed under reduced pressure. The product is extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under educed pressure. Chromatography of the residue on silica gel (Hexane/EtOAc, 4:1) gives 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-2-ethyl-butyric acid ethyl ester as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11][N:12]1C(=O)C2=CC=CC=C2C1=O.[O:23]=O.O=O>C(O)(=O)C>[N+:12]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)([O-:11])=[O:23]
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: O=O
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Product: O=[N+]([O-])C12CC3CC(CC(C3)C1)C2
Yield: 75 %

Procedure:
Into a flask, 1 mmole of adamantane, 0.1 mmole of N-hydroxyphthalimide, 0.0005 mmole of acetylacetonatomanganese(II) Mn(AA)2 and 5 ml of acetic acid were added to mix and the flask was equipped with a gas bag (about 1L) of nitrogen monoxide NO. The mixture was reacted for 8 hours at 100° C. with stirring. The reaction products were analyzed by gas chromatography, and, as a result, the conversion of adamantane was 95%, and nitroadamantane (yield 75%) was formed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:31]([O:34][BH-]([O:40][C:41](=[O:43])[CH3:42])OC(=O)C)(=[O:33])[CH3:32].[Na+].[C:45]([OH:48])(=[O:47])[CH3:46]>ClCCCl>[C:41]([OH:40])(=[O:43])/[CH:42]=[CH:46]\[C:45]([OH:48])=[O:47].[C:31]([OH:34])(=[O:33])/[CH:32]=[CH:46]\[C:45]([OH:48])=[O:47].[CH3:45][O:48][C:7]1[CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:4]=[CH:3][C:2]=1[NH:1][CH2:4][C:3]1[O:43][C:41]([CH3:42])=[CH:7][CH:2]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Product: O=C(O)/C=C\C(=O)O

Procedure:
A mixture of the cis-or trans-3-(4-amino-phenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (either intermediate . . . or . . . ) (1 eq.), aldehyde (1 eq.), sodium triacetoxyborohydride (3.4 eq.) and acetic acid (3.4 eq) was stirred in anhydrous 1,2-dichloroethane for 16 hours. The reaction mixture was concentrated under reduced pressure, quenched with saturated solution of sodium bicarbonate in water and concentrated again. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield the desired products.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[O:4][N:3]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2[N+](=O)[O-])n1
Agent: [Na+]
Agent: [S-2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(-c2ccccc2N)n1
Reaction time: 0.75 h
Yield: 62.1 %

Procedure:
3-methyl-5-(2-nitrophenyl)-1,2,4-oxadiazole (1.0 g, 4.8 mmol) in dioxane (11 mL) at 80°0 C. was treated with 11 mL of an aqueous solution of sodium sulfide nonahydrate (2.55 g, 10.6 mmol), also at 80° C. After stirring at that temperature for 45 minutes, the reaction was diluted with water (15 mL) and cooled in an ice bath. The resulting precipitate was collected by filtration and rinsed with water to afford 3-methyl-5-(2-aminophenyl)-1,2,4-oxadiazole (522 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:14](=[O:29])[C:13]=1[CH:12]=2.[NH2:30][CH2:31][C@@H:32]([OH:43])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1[CH3:42].CCN(CC)CC>CCO>[CH3:42][C:36]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C@H:32]([OH:43])[CH2:31][NH:30][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:14](=[O:29])[C:13]=1[CH:12]=2
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (448.3 mg, 1.35 mmol) and (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (303.0 mg, 1.55 mmol) in EtOH (10 mL) was added Et3N (410 mg, 4.05 mmol). After it was heated at 100° C. for 14 h, the reaction mixture was concentrated under reduced pressure. The chromatography of the crude residue (150:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) afforded the title compound (498 mg, 45%). 1H NMR (DMSO-d6) δ 1.60 (m, 2H), 1.95 (m, 2H), 2.18 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.39 (m, 2H), 2.90 (m, 2H), 3.57 (m, 1H), 3.71 (m, 1H), 3.90-4.08 (3H), 4.18 (m, 1H), 5.55 (d, J=6 Hz, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 6.92 (d, J=6 Hz, 1H), 6.97 (s, 1H), 7.39 (d, J=6 Hz, 1H), 7.64 (s, 1H), 8.09 (s, 1H), 10.96 (br s, 1H, NH), 11.31 (br s, 1H, NH); ESI-MS m/z 571.3 (MH+).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:37])([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:37])([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCC(O)(CC)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 74.5 %

Procedure:
A mixture of 3-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-pentan-3-ol (220 mg, 0.43 mmol) in ethanol (6 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 1.5 mL) was heated at 50° C. for 48 h. The mixture diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-pentan-3-ol (120 mg, 75%) which was used in the next step without further purification: LC/MS m/e calcd for C25H30N2O [M+H]+ 375.53, observed 375.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:16][OH:17].[OH-].[K+].O>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][C:11]([CH3:13])([CH3:12])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NO
Reactant: CC(C)=CC(=O)c1ccc(C)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C2=NOC(C)(C)C2)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(3-bromo-4-methylphenyl)-3-methylbut-2-en-1-one, (prepared herein before in step 2 of intermediate 1; 1.0 g, 3.95 mmol, 1.0 eq), and hydroxylamine hydrochloride (330 mg, 4.74 mmol, 1.2 eq) in ethanol (10 mL) at 0° C., was added an aqueous solution of potassium hydroxide (1N, 4 mL) until the pH of the reaction was basic. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (20 mL) followed by water (20 mL). The layers were separated and the organic layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc in hexane) to afford 250 mg of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.08 (s, 2H), 2.43 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 268, 270 [(MH)+, Br79,81].
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)OC1(C)C
Reactant: Cc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
A solution of the compound (300 mg, 0.54 mmol) synthesized in Example 52-2), 2-bromo-5-methylpyrazine (234 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.11 mmol), and potassium carbonate (149 mg, 1.08 mmol) in water (2 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (70 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=60:40 to 100:0) to obtain the title compound (139 mg, 49%) as a white solid.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.OCCCCCCCCCCCCCCCC(O)=O.[CH:45]1([N:51]=[C:52]=[N:53][CH:54]2[CH2:59][CH2:58][CH2:57]CC2)CCCCC1>O1CCCC1>[CH3:1][N:51]([C:52]1[CH:57]=[CH:58][CH:59]=[CH:54][N:53]=1)[CH3:45]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)CCCCCCCCCCCCCCCO
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 365 mg of radicicol, 681 mg of 16-hydroxyhexadecanoic acid, 20 ml of dry tetrahydrofuran, 516 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 661 mg of the title compound were obtained as crystals melting at 85°-86° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[OH:9][CH:10]([CH:15]=[CH2:16])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:8][C:4]1[CH:3]=[C:2]([CH2:16][CH2:15][C:10](=[O:9])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(I)c1
Reactant: C=CC(O)C(=O)OC
Product: COC(=O)C(=O)CCc1cccc(C)c1

Procedure:
Methyl 4-(3-methylphenyl)-2-oxobutyrate was prepared as a pale yellow oil from 3-iodotoluene and methyl 2-hydroxy-3-butenoate.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.Cl[S:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[NH:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:16])=[O:15]>C(OCC)(=O)C>[N:1]1([S:14]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[NH:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:16])=[O:15])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N1CCC1
Reaction time: 4 h
Yield: 60 %

Procedure:
Azetidine Ae (HCl salt) (0.2 g, 2 mmol) was dissolved in ethyl acetate (8 mL). Triethylamine (0.3 mL, 2 mmol) and 3-(chlorosulfonyl)-4-(methylamino)benzoic acid (1.2, 0.1 g, 0.5 mmol) were added. The reaction was left to stir for 4 hours, then extracted with 0.5 M HCl, washed with water and brine, and dried over magnesium sulfate. The ethyl acetate was evaporated and 3-(azetidin-1-ylsulfonyl)-4-(methylamino)-benzoic acid (1.3.Ae) was obtained (0.08 g, 60% yield). MS analysis (m−1)=269.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C)n2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C)N2)c1

Procedure:
A solution of 4-Methyl-2-[5-(6-methyl-pyridin-2-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester, compound 6b (161 mg, 0.35 mmol) in MeOH (12 mL), platinum oxide (8.0 mg, 0.35 mmol) and 4N HCl/dioxane (97.3 μL) was hydrogenated at 40 psi for 6 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane/Na2CO3 and extracted 3×, dried over MgSO4, filtered and concentrated to give the product as a pink oil (202 mg, quant.) (M+H) 461.56, Found 462.3.