Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18](Br)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:36]([Zn+])[CH2:37][CH3:38]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([CH2:36][CH2:37][CH3:38])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(Br)nc2CCN1C(=O)OCc1ccccc1
Reactant: CCC[Zn+]
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1nc2c(s1)C(c1cc(Cl)ccc1OCC(=O)O)N(C(=O)OCc1ccccc1)CC2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of (±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol, 1.00 eq.) and 0.5M propylzinc bromide in THF (0.36 mL, 0.18 mmol, 2.00 eq.) in THF (10 mL), tetrakis(triphenylphosphine) palladium (0) (5.1 mg, 4 μmol, 0.05 eq) was added. The mixture was stirred at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo. The resulting ester was dissolved in DMF (0.5 mL), 1M aq. NaOH soln. (0.5 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:19])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[CH:20][N:21]([CH3:23])[CH3:22])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=C(C(=O)c1cc(Br)cnc1Cl)c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of 1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethanone in dry THF was slowly treated with DMF-DMA under N2 atmosphere for 45 min and stirred at RT until completion of the reaction. The reaction mixture was concentrated under reduced pressure to obtain 1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one as semi solid. Washing the crude product with n-pentane and pet-ether resulted in a free flowing light brown solid (1.0 g, 58.8%) which was used as is in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8](S(C1C=CC=CC=1)(=O)=O)[CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[O-:30].[Li+].C[Si](N[Si](C)(C)C)(C)C.[Li]CCCC.CCCCCC.O1CC=CC1=O>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH:29]1[CH:28]=[CH:27][C:26](=[O:30])[O:25]1)[CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(C)C[C@H](NC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1
Reactant: [O-]c1ccco1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C1C=CCO1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=CCC(C)C[C@@H](NC(=O)OC(C)(C)C)C1C=CC(=O)O1
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
A solution of 17.15 g (46.7 mmol) of ((R)-1-benzenesulfonyl-3-methyl-hex-5-enyl)-carbamic acid tert-butyl ester in 100 ml dry THF under nitrogen atmosphere is cooled to −75° C. A solution A containing lithium furan-2-olate in THF is added over a period of 10 minutes via a canula using positive nitrogen pressure. Solution A is prepared as follows. A solution of 9.85 ml (46.7 mmol) HMDS in 100 ml dry THF under nitrogen atmosphere is cooled at −70° C. and 29.2 ml of a 1.6 M solution of BuLi in hexane (46.7 mmol) are added dropwise. After 30 minutes 3.92 g (46.7 mmol) 5H-furan-2-one in 2 ml dry THF are added dropwise and the temperature is kept at −40° C. After addition the reaction mixture is stirred at −75° C. for 1.5 h and then poured directly, with stirring, in 200 ml water and 200 ml EtOAc. The organic phase is washed successively with 5% aqueous citric acid, water (2×), 5% aqueous NaHCO3 solution and water (4×). The reaction mixture is evaporated and the residue chromatographed over silica gel (EtOAc/hexane 1:3) to yield the title compound as an oil.
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=[CH:38][C:35]=1[CH:36]=O.C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH2:36][C:35]3[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([O:42][CH3:43])[C:34]=3[O:33][CH3:32])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 1.27 g of the compound (9) synthesized in Example 2 and 0.8 g of 2,3,4-trimethoxybenzaldehyde was stirred at 120° C., then, 0.18 ml of formic acid was added dropwise. This was stirred for one hour at the same temperature, then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added and the results were shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the above-referenced compound (29) in an amount of 1.46 g (yield 73%).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:20]=[CH:19][C:12]3[NH:13][C:14]([CH2:16][CH2:17][CH3:18])=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27]Br>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][N:13]1[C:12]2[CH:19]=[CH:20][C:9]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[CH:10][C:11]=2[N:15]=[C:14]1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1nc2cc(C(=O)c3ccccc3)ccc2[nH]1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2cc(C(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of phenyl-(2-propyl-1H-benzoimidazol-5-yl)methanone (5.28 g; 0.02 mol) in DMF (80 mL) was stirred under an atmosphere of nitrogen. Sodium hydride (60% dispersion in oil, 0.8 g; 0.02 mol) was added. The mixture was then stirred for 0.5 hour at ambient temperature. 3,4-dichlorobenzyl bromide (4.8 g; 0.02 mol) was then added in portions. The mixture was stirred at 80-90° C. for 3.5 hours, then at ambient temperature for 18 hours. The solvent was evaporated under vacuum. The residue was extracted with ethyl acetate (300 mL) and washed with water (2×200 mL). The organic phase was evaporated. Purification was achieved by flash chromatography on silica gel (EtOAc/Hexane; 1:9 to 1:3). Recrystallization from ethyl acetate affords the tide compound (4.2 g; 50% yield) as a white solid, m.p. 168-169° C. Anal. Calcd. for C24H20Cl2N2O: C, 68.09; H, 4.76; N, 6.62. Found: C, 67.70; H, 4.46; N, 6.49. Mass spectrum (DEI; M+) m/z 422, 424, 426. 1H-NMR (DMSO -d6; 400 MHz) δ7.94 (d, 1H), 7.73 (d, 2H), 7.64-7.72 (m, 3H), 7.59 (m, 1H), 7.56 (t, 2H), 7.47 (d, 1H), 6.98 (dd, 1H), 5.59 (s, 2H), 2.84 (t, 2H), 1.76 (m, 2H) and 0.94 ppm (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].I[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: OCC1CCCCN1
Reactant: CCCCCCI
Product: CCCCCCN1CCCCC1CO
Yield: 102.7 %

Procedure:
2-Piperidine methanol (2.30 g, 20 mmol) and 1-iodohexane (1.5 mL, 10 mmol) were converted to product by the procedure of Preparation 1 to yield 2.048 g (51%) of the title compound. 3H NMR consistent with desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N1C=CC=CC=1.[N:27]([CH:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](Cl)=[O:32])=[N+:28]=[N-:29]>C(Cl)Cl>[N:27]([CH:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31]([NH:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32])=[N+:28]=[N-:29]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reactant: [N-]=[N+]=NC(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: [N-]=[N+]=NC(C(=O)NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of benzyl 6-amino-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (0.2 mmol) in methylene chloride (2 ml) containing anhydrous pyridine (0.1 ml) is added α-azidophenylacetyl chloride (0.2 mmol). After stirring in the cold for 60 mins, the solution is washed with water, pH 3 phosphate buffer, 5% sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to give benzyl 6-(α-azido-phenylacetamido)-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:15])([F:14])[CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH2:13])[CH2:8]1>C1(C)C(C)=CC=CC=1>[F:5][C:6]([F:14])([F:15])[CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([N:13]=[C:1]=[O:2])[CH2:8]1
Reactant: O=C(Cl)Cl
Reactant: NC1CCCC(C(F)(F)F)C1
Solvent: Cc1ccccc1C
Product: O=C=NC1CCCC(C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 130 parts of phosgene in 450 parts of xylene at 0° to 5°C. is added dropwise a solution of 100 parts of 3-trifluoromethylcyclohexylamine (prepared as in Example 1) in 450 parts of xylene. The reaction mixture is stirred at 0°C. for 1 hour, allowed to come to ambient temperature, and then refluxed 4 hours. The excess phosgene is trapped in a gas scrubber. The xylene is stripped on a rotary evaporator and the residue is distilled under reduced pressure to yield 62.4 parts of 3-trifluoromethylcyclohexyl isocyanate, b.p. 68°-69°C/9mm.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]1[C:41]([CH3:42])=[N:40][C:39]([CH3:43])=[CH:38][N:37]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[C:41]([CH3:42])=[N:40][C:39]([CH3:43])=[CH:38][N:37]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: Cc1cnc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)c(C)n1
Yield: 72 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 72% yield starting from (S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine and 2-chloro-3,5-dimethylpyrazine (1.2 equiv); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1 H), 7.24-7.31 (m, 8 H), 7.17-7.22 (m, 2 H), 7.11-7.17 (m, 1 H), 6.82 (dd, 1 H), 6.74 (dd, 1 H), 4.27-4.34 (m, 1 H), 4.07 (t, 1 H), 3.56-3.67 (m, 4 H), 2.95-3.05 (m, 1 H), 2.56-2.67 (m, 1 H), 2.54 (s, 3 H), 2.28-2.40 (m, 1 H), 2.24 (s, 3 H); MS (APPI/APCI) m/z 436[M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1)([O-])=O.[H][H]>[Pd].C1COCC1.CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1
Reactant: [H][H]
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc([N+](=O)[O-])c5)c4)c3c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(N)c5)c4)c3c2)c1
Yield: 16.1 %

Procedure:
N-(3-(3-(1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (Example-7) (80 mg, 0.163 mmol), was reduced by palladium on carbon (8 mg, 10% W/W) in THF/MeOH (2/2 mL) under positive pressure of hydrogen using a bladder. The catalyst filtered off and concentrated to get crude compound. This was then purified by preparative TLC using 10% ethyl acetate in hexanes as eluent yielded 12 mg (16% yield) of pure titled compound. 1H NMR (DMSO-d6, 400 MHz): δ11.85 (s, 1H), 9.83 (s, 1H), 8.47-8.46 (d, 1H), 8.33-8.32 (m, 2H), 7.92 (s, 1H), 7.775-7.770 (d, 1H), 7.53-7.44 (m, 3H), 7.24-7.22 (d, 1H), 6.96-6.94 (t, 1H), 6.46-6.42 (m, 2H), 5.20 (s, 2H), 5.10 (b, 2H), 3.05 (s, 3H). MS: m/z=459.3 (M+1), HPLC: 92.06% (method B).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)c1cccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1cccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0 %

Procedure:
N-tert-Butyl-2-(3-(1-hydroxyethyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (143 mg, 296 mol) was dissolved in dichloromethane (4.5 mL) and treated with trifluoroacetic acid (674 mg, 456 μL, 5.91 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (3 mL) and ammonium hydroxide (0.7 mL) and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated then purified by chromatography (silica, methanol in dichloromethane) gave N-tert-butyl-2-(3-(1-hydroxyethyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (55 mg, 156 μmol, 53%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.29 (s, 1H), 9.44 (s, 1H), 8.00 (s, 1H), 7.99 (s, 1H), 7.98 (d, J=2.8, 1 H), 7.78 (s, 1H), 7.19 (m, 2H), 6.91 (d, J=7.5, 1 H), 5.17 (d, J=4.0, 1 H), 4.70 (m, 1H), 3.38 (q, J=7.2, 1 H), 1.43 (s, 9H), 1.34 (d. J=6.3, 3 H), 1.09 (t, J=7.2, 1 H); MS (EI/CI) m/z: 354.2 [M+H].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][CH2:41][N:42]1[C:46](=[O:47])[C:45]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:44]2[C:43]1=[O:52]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][CH2:41][N:42]5[C:43](=[O:52])[C:44]6[C:45](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]5=[O:47])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Reactant: O=C1c2ccccc2C(=O)N1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CC[C@@H](Cc2nn(CCN3C(=O)c4ccccc4C3=O)c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.8 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, 0.699 mmol) in N,N-dimethylformamide (3 mL) in a 5 mL microwaveable vial was added potassium carbonate (300 mg, 2.1 mmol, 3 eq) and N-(2-chloroethyl)phthalimide (300 mg, 1.43 mmol, 2 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 90° C. Analysis by LC/MS displayed the reaction had progressed to 20% completion. The reaction was irradiated in the microwave at 185° C. for 60 min. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 30-60% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the intermediate compound (142 mg, 33%). MS(ES)+ m/e 602.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([Br:17])[N:15]=2)[N:10]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)=[O:6].[H-].[Na+]>CN(C=O)C>[Br:17][C:14]1[N:15]=[C:16]2[C:8]([N:7]3[CH2:2][C:3]4[C:4](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:5]3=[O:6])=[CH:9][N:10]([C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:11]2=[N:12][CH:13]=1
Reactant: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reaction time: 2 h
Yield: 92.1 %

Procedure:
2-(bromomethyl)-N-(2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl)benzamide (1.45 g, 2.223 mmol) dissolved in DMF (20 mL) under N2 and solution cooled in an ice bath. NaH (60% w/w suspension in mineral oil, 89.43 mg, 2.334 mmol) added in two portions and the reaction mixture stirred with cooling. After 2 h, an additional ˜20 mg NaH added. After a further 30 mins, reaction quenched by careful addition of water. The resulting yellow precipitate collected by filtration, washing with water. Precipitate dried at 50° C. in vacuuo to give title compound as a pale yellow solid (1.17 g, 92%); 1H NMR (400 MHz, DMSO) δ 5.37 (2H, s), 7.20-7.22 (5H, m), 7.30-7.39 (10H, m), 7.54 (1H, t), 7.68 (1H, t), 7.74 (1H, d), 7.79 (1H, d), 8.23 (1H, s), 8.59 (1H, s) ppm; MS (ES+) 571.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9](=O)[O:10]C)=[C:6]([NH2:21])[N:5]=[C:4]([N:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])=[N:23]2)[N:3]=1.[H-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])=[N:23]2)[N:5]=[C:6]2[C:7]=1[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:9](=[O:10])[NH:21]2
Reactant: COC(=O)N(Cc1ccc(F)cc1)c1c(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc2[nH]c(=O)n(Cc3ccc(F)cc3)c12
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
21 mg (0.04 mmol) of the compound from example 50A were initially charged in tetrahydrofuran (1.0 ml), 1.8 mg (0.04 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at 65° C. for 30 min. The reaction mixture was admixed with saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 8.5 mg (44% of theory) of the title compound in solid form.
Reaction SMILES: [CH2:1]([C:4]1[C:19]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[C:29]([OH:31])[C:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][C:26]=2[CH2:39][CH3:40])=[CH:18][CH:17]=[CH:16][C:5]=1[S:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:46]>C(Cl)Cl>[CH2:1]([C:4]1[C:19]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[C:29]([OH:31])[C:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][C:26]=2[CH2:39][CH3:40])=[CH:18][CH:17]=[CH:16][C:5]=1[S:6]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:46])[CH2:2][CH3:3]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1Sc1ccccc1C(=O)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1S(=O)c1ccccc1C(=O)O
Yield: 82.4 %

Procedure:
To a solution of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]thiophenoxy]benzoic acid (450 mg, 0.803 mmol) in methylene chloride (10 mL) at −78° C. was added a solution of 85% m-chloroperoxybenzoic acid (138 mg) in methylene chloride (2 mL). After 40 minutes the mixture was concentrated in vacuo. Purification of the residue via silica gel chromatography (95% chloroform/4.5% methanol/0.5% acetic acid) provided 380 mg (80%) of the title product as an off-white solid: mp >100° C. (dec); NMR (CDCl3) 8.53 (d, J=8 Hz, 1H), 8.14 (d, J=8 Hz, 1H), 7.93 (t, J=8 Hz, 1H), 7.63 (t, j=8 Hz, 1H), 7.43 (m, 2H), 7.13 (m, 2H), 6.94-7.06 (m, 2H), 6.88 (d, J=8 Hz, 1H), 6.50 (d, J=8 Hz, 1H), 7.46 (s, 1H), 6.38 (bs, 1H, —OH), 4.15 (m, 4H), 3.32 (m, 1H), 3.08 (m, 1H), 2.57 (q, J=7.5 Hz, 2H), 2.29 (quintet, J=6 Hz, 2H), 1.75 (m, 2H), 1.17 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H); MS (high resolution) calc 577.202642 (MH+), found 577.203800; IR (CHCl3, cm−1) 2969, 1708, 1497, 1455, 1266, 1146, 1018.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[OH-].[Na+]>CO.O>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2B (3.637 g, 13.3 mmol) in methanol was added dropwise at 0° C. a solution of NaBH4 added to 3.9 g NaOH dissolved in 7.8 mL H2O. The solution was allowed to stir at room temperature overnight. Water was added and the product was extracted with ether (2×) and washed with brine (2×). The combined ether extracts were dried over MgSO4. The solvent was removed and the product was purified using flash chromatography with a hexanes and then ethyl acetate. The ethyl acetate fraction was collected and the solvent removed to reveal 2.667 g (74%) of a honey yellow crystal solid. 1H NMR (CDCl3): δ4.63 (d, 2H), δ6.97-7.06 (m, 6H), δ7.09 (m, 2H), δ7.20-7.28 (m, 6H); m/z 298.1 (M++Na), 276.1 (M++H), 258.1 (M+-H2O).