Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([F:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-:15].[Na+].[Mn]([O-])(=O)(=O)=[O:18].[K+].N1C=CC=CC=1>O>[F:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:18])=[O:15])=[CH:10][CH:9]=1)([F:7])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(C(F)(F)C(C)(C)C)cc1
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(F)(F)c1ccc(C(=O)O)cc1
Reaction time: 4 h

Procedure:
A mixture of 13.5 grams (68.1 mmoles) of 4-(1,1-difluoro-2,2-dimethylpropyl) toluene, 6.8 grams (170 mmoles) of sodium hydroxide and 21.5 grams (136 mmoles) of potassium permanganate in 250 ml. of 1:1 pyridine:water is heated to 95° C. and stirred for 4 hours. This suspension is filtered, and the residue is wash with 300 ml. of water and 400 ml. of ethyl acetate. The filtrate is concentrated in vacuo and then redissolved in 300 ml. of water. The aqueous solution is washed with 500 ml. of ethyl acetate and then acidified to pH2 with concentrated hydrochloric acid. This is extracted 3 times with 300 ml. of ethyl acetate, and the combined extracts are dried over magnesium sulfate and concentrated in vacuo to yield 4-(1,1-difluoro-2,2-dimethyl propyl)benzoic acid as a fine white powder. A portion of this material is recrystallized from diethyl ether to give colorless crystals of the acid (m.p. 196°-198° C.).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2([CH2:38][NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:39][CH2:38][C:32]2([C:29]3[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=3)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1ccc(C2(CN)CCCCC2)cn1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C2(CNC(=O)c3cn(-c4ncccn4)nc3Cl)CCCCC2)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (75 mg, 0.33 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.11 mL, 0.66 mmol), 1-[1-(6-methylpyridin-3-yl)-cyclohexyl]methanamine (67 mg, 0.33 mmol), and BOP (177 mg, 0.40 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by preparative chromatography (2% MeOH/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (1H, s), 8.90 (2H, d, J 4), 8.43 (1H, s), 8.03 (1H, s), 7.64 (1H, d, J 8), 7.56 (1H, s), 7.18 (1H, d, J 7.6), 2.41 (3H, s), 2.13 (2H, m), 1.56 (5H, m), 1.22 (5H, m). MS (M+1)=411.18; RT=1.08 min. *IC50.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=1.CCCCCC.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C.[Fe]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:2]([CH3:22])[CH3:1])[N:8]=1)(=[O:11])=[O:12]
Reactant: CN(C)c1cccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)c1cccc(NS(=O)(=O)c2ccccc2N)n1
Yield: 77.1 %

Procedure:
In a sealed tube, a mixture of N-[6-(dimethylamino)pyridin-2-yl]-2-nitrobenzenesulfonamide (1.0 g, 3.10 mmol) and Fe powder (0.85 g, 11.5 mmol) in acetic acid (10 mL) was heated at 60° C. for approximately 15 min with TLC monitoring (hexane:EtOAc, 1:1). The reaction mixture was poured into saturated aqueous NaHCO3 solution (100 mL) and extracted with EtOAc (3×50 mL), the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 0-45% EtOAc in hexane yielded the title compound (0.7 g, 2.39 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][CH:18](OC(=O)C(F)(F)F)[C:19]2[C:20]([O:26][CH3:27])=[N:21][CH:22]=[CH:23][C:24]=2[I:25])=[C:11]([N+:35]([O-:37])=[O:36])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]([N+:35]([O-:37])=[O:36])[C:12](/[CH:17]=[CH:18]/[C:19]2[C:20]([O:26][CH3:27])=[N:21][CH:22]=[CH:23][C:24]=2[I:25])=[CH:13][C:14]=1[O:15][CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(CC(OC(=O)C(F)(F)F)c2c(I)ccnc2OC)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C/c2c(I)ccnc2OC)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of crude trifluoro-acetic acid 2-(4-tert-butoxycarbonylamino-5-methoxy-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester (crude 1.35 g, 2.12 mmol) in THF (10 mL) was added 8-diazabicyclo[5.4.0]undec-7-ene (1.48 g, 9.75 mmol) at 25° C. The reaction was allowed to stir at 70° C. for 3 h, cooled to 25° C. and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded {4-[(E)-2-(4-iodo-2-methoxy-pyridin-3-yl)-vinyl]-2-methoxy-5-nitro-phenyl}-carbamic acid tert-butyl ester (560 mg, 55%) as an oil. MH+ 527.8.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][N:3]=1.CC1C=C(O)C=CC=1C.[CH3:21][O:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])=[CH:25][CH:24]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:37][C:30]1([C:8]2[C:9]([OH:11])=[CH:10][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]=2)[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:40][CH:39]=2)[C:29]1=[O:38]
Reactant: Cc1noc2cc(O)ccc12
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COc1ccc(CN2C(=O)C(O)(c3cc4c(C)noc4cc3O)c3ccccc32)cc1

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 3-methylbenzo[d]isoxazol-6-ol (Iranpoor, N., et al., Tetrahedron Lett. (2006), 47:8247) to replace 3,4-dimethylphenol, and 1-(4-methoxybenzyl)-1H-indole-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one was obtained (76%): mp 199-201° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.52 (d, J=9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.18-7.13 (m, 1H), 7.05-7.03 (m, 1H), 6.89-6.75 (m, 5H), 4.83 (AB, 2H), 3.71 (s, 3H), 2.77 (s, 3H); MS (ES+) m/z 417.0 (M+1).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[F:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[CH:31]=[CH:32][C:33](O)=[O:34].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[CH:31]=[CH:32][C:33]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=1)=[O:34]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)Cc1cn(C(C)C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C(C)C)c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 93.4 %

Procedure:
The same procedures as in Example 146 were carried out from the compound obtained in Example 144 (0.7 g), triethylamine (0.4 mL), 2-fluorocinnamic acid (0.44 g), WSC.HCl (0.50 g), and methylene chloride (20 mL), to give the captioned compound (0.9 g, 98%) as an oily product.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:45]([NH:52][CH2:53][CH:54]([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:45]([N:52]([CH2:53][CH:54]([O:55][CH2:56][CH3:57])[O:58][CH2:59][CH3:60])[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:23])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid 1.98 g (6.0 mmol), a solution of 1-hydroxybenzotriazol 1.01 g (7.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 1.44 g (7.5 mmol) in dichloromethane 20 ml, and a solution of N-benzyl-2,2-diethoxyethanamine (Compound IV-1) 1.12 g (5.0 mmol) and 4-dimethylaminopyridine 61 mg (0.5 mmol) in dichloromethane 5 ml were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 20 ml and washed with saturated aqueous sodium bicarbonate 20 ml, water 20 ml and brine 20 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 70:30) to obtain the title compound 1.1 g (yield 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21](O)=[O:22])=[CH:12]2)[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:48][CH2:49][CH2:50][NH2:51].C(N(CC)CC)C>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21]([NH:51][CH2:50][CH2:49][F:48])=[O:22])=[CH:12]2)[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: NCCF
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3cc(F)c(C)nc3C)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cnc2c(C(=O)NCCF)cn(Cc3cc(F)c(C)nc3C)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
See FIG. 23(a). In a 25 mL thermal vial was charged with 1-((5-fluoro-2,6-dimethylpyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.32 mmol) and HATU (146 mg, 0.38 mmol) were taken in NMP (4 mL) and stirred for 10 min at rt. Then 2-fluoroethanamine (20.13 mg, 0.32 mmol) and Triethyl amine (133 mL, 0.96 mmol) were added and stirred for 1 h at rt. The LCMS showed completion of the reaction. The reaction mixture was poured into water and extracted with chloroform. The organic layer was dried and concentrated and crude was submitted to reverse phase purification. The pure fractions were concentrated to get 1-((5-fluoro-2,6-dimethylpyridin-3-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (75 mg, 65.6%) as a solid. ES+MS m/z: 359 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.37 (d, J=2.64 Hz, 3 H ) 2.42 (s, 6 H ) 3.66 (d, J=5.46 Hz, 1 H ) 3.75 (d, J=5.27 Hz, 1 H ) 4.49 (t, J=4.90 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 5.52 (s, 2 H ) 6.85 (d, J=10.17 Hz, 1 H ) 7.86 (s, 1 H ) 8.15 (s, 1 H ) 8.34-8.46 (m, 1 H ) 8.89 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[N:8]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])[N:12]=[C:11]([C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)[N:10]=2)[CH2:7][CH2:6][O:5][CH2:4]1.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[NH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C1COCC1.N1C=CC=CC=1>[CH3:2][C@@H:3]1[N:8]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])[N:12]=[C:11]([C:25]3[CH:26]=[CH:27][C:28]([NH:29][C:36]([NH:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:42])=[CH:30][CH:31]=3)[N:10]=2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc(-c2ccccc2S(C)(=O)=O)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3cccnc3)cc2)nc(-c2ccccc2S(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of (S)-4-(4-(3-methylmorpholino)-6-(2-(methylsulfonyl)phenyl)-1,3,5-triazin-2-yl)aniline hydrochloride (0.217 g, 0.47 mmol) in THF/pyridine (4:1 respective ratio, 10 ml) was added triphosgene (1 eq) portionwise. The resulting suspension was stirred for five minutes before adding to an ice cold solution of 3-aminopyridine (4 eq) in THF/pyridine (4:1 respective ratio, 2 ml). The reaction was stirred at 0° C. for 1 hr after which time it was quenched by addition of methanol and concentrated in vacuo. The residue was purified by high pH preparative HPLC to afford the title compound, (S)-1-(4-(4-(3-methylmorpholino)-6-(2-(methylsulfonyl)phenyl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea, 24 mg, 38% yield. 1H NMR (400 MHz, MeOD) δ 8.63 (d, 1H), 8.38-8.33 (m, 2H), 8.19 (dd, 1H), 8.18-8.10 (m, 1H), 8.02 (ddd, 1H), 7.82 (td, 1H), 7.77-7.68 (m, 2H), 7.60-7.56 (m, 2H), 7.38 (dd, 1H), 5.17-4.37 (m, 2H), 3.99 (br s, 1H), 3.84-3.67 (m, 2H), 3.57 (t, 1H), 3.48 (s, 3H), 3.38 (dd, 1H), 1.39 (d, 3H);
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:32][Si](C)(C)C.CO>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8]([NH2:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A solution of 3-cylopentyl-2-(4-phenoxy-phenyl)-propionic acid (200 mg, 0.64 mmol) in methylene chloride (10 mL) with one drop of N,N-dimethylformamide was cooled to 0° C. under a nitrogen atmosphere. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.48 mL, 0.97 mmol), and the resulting reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was then treated with 1,1,1,3,3,3-hexamethyldisilazane (0.47 mL, 2.24 mmol) and then allowed to warm to 25° C. where it was stirred for 16 h. After such time, the reaction mixture was treated with methanol (10 mL) and then allowed to stir at 25° C. for 10 min. The resulting reaction mixture was washed with a 5% aqueous sulfuric acid solution (2×10 mL). The combined aqueous extracts were further extracted with methylene chloride (2×10 mL). The combined organic extracts were then washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionamide (120 mg, 61%,) as a white solid: mp 91.6-94.4° C.; EI-HRMS m/e calcd for C20H23NO2 (M+) 309.1729, found 309.1733.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH2:8][C@@H:9]([C:11]2[C:12]([CH3:21])=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[O:15][CH2:14]3)[OH:10])[CH2:5]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:2][CH2:3][CH:4]2[CH2:7][N:6]([CH2:8][C@H:9]([OH:10])[C:11]3[C:12]([CH3:21])=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[O:15][CH2:14]4)[CH2:5]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: Cc1c([C@@H](O)CN2CC(CN)C2)ccc2c1COC2=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c([C@@H](O)CN2CC(CNS(=O)(=O)c3ccc(C#N)cc3)C2)ccc2c1COC2=O
Reaction time: 24 h

Procedure:
To a vial containing (R)-5-(2-(3-(aminomethyl)azetidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 12] (0.17 g, 0.54 mmol) was added commercially available 4-cyanobenzene-1-sulfonyl chloride (0.20 g, 1.0 mmol) as a solution in DMF (500 μL) followed by diisopropylethylamine (0.16 g, 1.2 mmol). The vial was shaken for 24 hours, and then was concentrated in vacuo. The resulting residue was dissolved in DMSO (1 mL) and purified by HPLC to provide (R)-4-cyano-N-((1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)azetidin-3-yl)methyl)benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13](Br)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(C)nn2c(C3CCCCC3)c(Br)cnc12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc12
Temperature: 80 °C
Yield: 93.3 %

Procedure:
A mixture of 187 mg (0.5 mmol) of 6-bromo-7-cyclohexyl-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, 105 mg (0.75 mmol, 1.5 equiv) of 4-fluorophenylboronic acid, 20 mg (0.025 mmol, 5 mol %) of Pd catalyst, and 318 mg (1.5 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (7 mL) was added, and the resulting mixture was heated at 80° C. under argon for 14 h. The reaction mixture was diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue which was chromatographed on silica gel (gradient elution with 2%, 5% to 10% ethyl acetate in dichloromethane) to afford 0.178 g (94%) of 7-cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as an off-white solid as indicated by 1H NMR; LC-MS—calcd for C22H24FN3O2 [M++H]+: 382.19, found: 382.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].C(C1C=[C:30](C(=O)C2C=CC(C)=CC=2)[N:31]2C3C(=CC=CC=3)C=C[C:32]=12)#N>>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:31]([CH3:32])[CH3:30])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(CBr)cc2)n2c1ccc1ccccc12
Reactant: Cc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1
Product: CN(C)Cc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
3-Cyano-1-[4-(bromomethyl)benzoyl]-pyrrolo[1,2-a]quinoline. The title compound was prepared similar as Example 53a, using 3-cyano-1-(4-methylbenzoyl)-pyrrolo[1,2-a]quinoline to yield 230 mg (68%). 1H NMR (CDCl3): 8.09–8.10 (m, 3H), 7.87–7.52 (m, 7H), 7.43 (s, 1H), 4.58 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>CC(N(C)C)=O.O>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:17]1[CH:18]=[CH:13][C:14]([C:23]([F:26])([F:24])[F:25])=[CH:15][C:16]=1[C:19]([F:20])([F:21])[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h

Procedure:
(2-Hydroxy-ethyl)-carbamic acid tert-butyl ester (0.2 mL, 1.29 mmol) is dissolved in 3 mL dry dimethyl-acetamide. 2-Potassium-1,1,1,3,3,3-hexamethyl-disilazane (0.52 g, 2.6 mmol, 2 equiv.) is added, followed by 1-bromo-2,4-bis-trifluoromethyl-benzene 31 (0.26 mL, 1.5 mmol, 1.2 equiv.). The mixture is stirred at 60° C. under nitrogen for 18 hours. The mixture is cooled, diluted with 50 mL water and extracted with dichloromethane (3×50 mL). The combined organic extracts are washed with water and 10% aqueous citric acid, dried over Na2SO4 and concentration. Silica gel chromatography (5% to 25% ethyl acetate in hexanes) yielded [2-(2,4-Bis-trifluoromethyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester 32 as a colorless, mobile oil: 1H-NMR (400 MHz, CDCl3) δ=7.61 (s, 1H), 7.00 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 5.10 (s, 1H), 4.26 (t, J=4 Hz, 2H), 3.65 (m, 2H), 1.45 (s, 9H). 19F-NMR (376 MHz, CDCl3) δ=−61.5, −62.0. No molecular ion could be obtained; a loss of tert-butyl group is observed: MS calculated for C11H10F6NO3 (M+H+—C4H8) 318.1, found 318.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1.[Br:22]Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:12]=2[Br:22])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: N#Cc1[nH]c(-c2ccc(Cl)cc2)cc1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(Br)c1-c1ccc(Cl)cc1
Yield: 44 %

Procedure:
Bromination of 2,4-bis(p-chlorophenyl)-5-cyanopyrrole is accomplished by treatment with 1 equivalent of bromine in acetic acid in the presence of anhydrous sodium acetate yields the desired product (0.47 g, yellow solid, 44% yield, mp 98°-100° C.