Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]1[O:19][CH2:18]1>C1C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]([OH:19])[CH2:18][NH:13][CH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccccc1C1CO1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(CCNCC(O)c2ccccc2C)cc1OC
Yield: 36.2 %

Procedure:
Homoveratrylamine (13.6 g, 0.0753 mole) and o-methylstyrene oxide (10.1 g, 0.0753 mole) were stirred at 100° under argon for 16 hours and then diluted with benzene and hexane and cooled in ice. The solid which precipitated was filtered and recrystallized from benzene-hexane to give 8.6 g (36%) of 2-methyl-α-[N-(3,4-dimethoxyphenethyl)aminomethyl]benzyl alcohol, mp 91°-94°.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[N:7]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCN(c2ccc(-c3nc4ccccc4c(=O)[nH]3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(-c2ccc(N3CCNCC3)cc2)nc2ccccc12
Temperature: 100 °C
Yield: 90.4 %

Procedure:
A mixture of 2-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one (2.27 g, 6.5 mmol) and 2 N HCl (100 mL) were heated at 100° C. for 4 hours. Then, the mixture was cooled to room temperature, basified to pH 8 with 2 N NaOH, extracted with CH2Cl2 (3×150 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford 2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one as a pale yellow solid (1.8 g, 90%).
Reaction SMILES: ClC(OC(C)C)=O.[CH3:8][N:9]1CCOCC1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].Cl.CN.C(N(CC)CC)C>CN(C)C=O.CCOCC>[CH3:8][NH:9][C:29](=[O:31])[CH2:28][N:25]1[C:26](=[O:27])[N:21]2[CH:20]=[N:19][C:18]([C:15](=[O:17])[NH2:16])=[C:22]2[N:23]=[N:24]1
Reactant: CN1CCOCC1
Reactant: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Agent: CC(C)OC(=O)Cl
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl chloroformate (1 M in toluene, 1.155 mL, 1.155 mmol) then N-methyl morpholine (0.127 mL, 1.155 mmol) were added to a stirred solution of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.25 g, 1.050 mmol) in dimethylformamide (1.34 mL) under nitrogen at −10° C. to −15° C. After 1 hour, methylamine hydrochloride (142 mg, 2.100 mmol) then triethylamine (0.292 mL, 2.100 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one hour then allowed to warm to room temperature. After 16 hours, ether (5 mL) was added and the resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL), then purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane), recrystallized from acetonitrile and triturated with ether to furnish the desired product as a pale pink solid. Yield: 82 mg, 0.33 mmol, 31%. LCMS (ES+) m/z 252 (M+H)+ at solvent front. 1H NMR (400 MHz, d6-DMSO) δ: 8.86 (1H, s), 8.14 (1H, br q), 7.83 (1H, br s), 7.69 (1H, bs), 4.89 (2H, s), 2.60 (3H, d).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([NH:9][C:10]2=O)[CH2:7]3)=[CH:4][C:3]=1[F:15].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[Cl:17])[CH2:7]3)=[CH:4][C:3]=1[F:15]
Reactant: O=C1NC2CC(C2)c2cc(F)c(Br)cc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cc2c(cc1Br)C(Cl)=NC1CC2C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Into a 20000-mL 4-necked round-bottom flask was placed a solution of 5-bromo-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one (800 g, 2.96 mol, 1.00 equiv) in toluene (10000 mL), followed by the addition of PCl5 (1540 g, 7.40 mol, 2.50 equiv) in several batches at 25° C. over 1 hour. The resulting solution was heated to reflux for 5 hr, cooled to room temperature and diluted with 5000 mL of ether. The solids were collected by filtration and dissolved in 10000 mL of ether. The resulting mixture was washed with 5000 mL of ammonia (10%), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 700 g (82%) of 5-bromo-8-chloro-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(N(CC)CC)C.[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29](O)[CH:30]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:30]=1)[CH3:24]
Reactant: CCc1ccc(CCCOC)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1ccc(CCCOC)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (0.47 mL, 2.8 mmol) followed by triethylamine (0.42 mL, 3 mmol) was added to a cooled 0° C. solution of 5-ethyl-2-(3-methoxy-propyl)-phenol (0.45 g, 2.3 mmol). The reaction was stirred for 1 hour and then warmed to room temperature. The reaction was partitioned between 1 N HCl and EtOAc. The organic extracts were washed with bring, dried over Na2SO4 and concentrated to a black oil. 1H NMR (400 MHz, CDCl3): δ 1.24 (t, J=7.6 Hz, 3H), 1.89 (m, 2H), 2.65 (d, J=7.6 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H), 3.35 (s, 3H), 3.40 (t, J=7.6 Hz, 2H), 7.07 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:21][C:22]1[C:23](=[O:43])[N:24]([C:29]2[CH:30]=[C:31]([CH:38]=[C:39]([F:42])[C:40]=2[CH3:41])[C:32]([NH:34][CH:35]2[CH2:37][CH2:36]2)=[O:33])[CH:25]=[C:26](Br)[N:27]=1)([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:21][C:22]1[C:23](=[O:43])[N:24]([C:29]2[CH:30]=[C:31]([CH:38]=[C:39]([F:42])[C:40]=2[CH3:41])[C:32]([NH:34][CH:35]2[CH2:37][CH2:36]2)=[O:33])[CH:25]=[CH:26][N:27]=1)([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2SCCOCc2ccccc2)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCOCc2ccccc2)c1=O
Temperature: 75 °C
Yield: 86.1 %

Procedure:
To 3-[3-{[1-(2-{[2-(Benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-5-bromo-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 320e, 1.7 g) in ethanol (35 mL) was added ammonium formate (2.255 g) and Pd/C (0.544 g) and the resulting solution heated at 75° C. for 1 h. After cooling to room temperature, type 490 paste 10% Pd/C (0.272 g) slurried in ethanol (5 mL) was added and the reaction heated to 75° C. for 1 hr. The reaction was filtered through celite then the filtrate concentrated in vacuo then extracted into DCM. The organic solution was dried (MgSO4) and concentrated in vacuo to give the sub title compound (1.290 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH4+:18].[OH-].C([O-])([O-])=O.[K+].[K+]>>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([NH2:18])[N:7]=1
Reactant: [NH4+]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(N)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 5.4 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol) with NH4OH (Aldrich Chemical Company) (2.5 mL, 21.4 mmol) and K2CO3 (0.33 g, 2.4 mmol). The crude reaction mixture was concentrated to dryness and the residue extracted with hot MeOH and concentrated. The resulting yellow oil was purified by flash chromatography on silica gel (1:40 MeOH/CH2Cl2 followed by 1:20 MeOH/CH2Cl2) to give 0.005 g (5%) of the title compound as an off-white solid. Mp: >280° C. 1H NMR (CD3OD; 500 MHz): δ 2.53 (s, 3), 6.74 (s, 1), 7.44 (t, 1, J=7.2), 7.52 (t, 2, J=7.5), 7.82 (d, 2, J=7.5); MS m/z: 225 (M+1).
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:14]>>[NH2:14][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Reactant: N
Product: Nc1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
It has also been reported [see J. Amer. Chem. Soc. 49, 1748 (1927)] that treatment of 2-mercapto-6-nitrobenzothiazole with concentrated aqueous ammonia under pressure at 160° C. followed by crystallization from alcohol and treatment with bone black gives 2-amino-6-nitrobenzothiazole in small yield.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:35]=[CH:34][C:24]4[C:25]([C:31](O)=[O:32])=[C:26]([CH3:30])[C:27](=[O:29])[O:28][C:23]=4[CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O.O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:35]=[CH:34][C:24]4[C:25]([CH2:31][OH:32])=[C:26]([CH3:30])[C:27](=[O:29])[O:28][C:23]=4[CH:22]=3)[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: Cc1c(C(=O)O)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2oc1=O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(CO)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2oc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.7 g. (3 mmol) 7-{3-{4-[(4-chlorophenyl)-methyl]-1-piperazinyl}-propoxy}-3-methyl-2H-1-benzopyran-2-one-4-carboxylic acid dihydrochloride, 0.98 g. (8.7 mmol) anhydrous triethylamine and 20 ml. anhydrous tetrahydrofuran is stirred for 30 minutes at ambient temperature. The reaction mixture is then cooled and a solution of 0.38 g. (3.5 mmol) ethyl chloroformate and 10 ml. anhydrous tetrahydrofuran added dropwise thereto at an internal temperature of from -5° to -10° C. The reaction mixture is allowed to react for 30 minutes at -5° C. and subsequently the precipitated triethylamine hydrochloride is filtered off with suction with the exclusion of moisture. The filtrate is added dropwise at +10° C. to a suspension of 93 mg. (2.5 mmol) sodium borohydride and 1.5 ml. water. The reaction mixture is now stirred for 2 hours at ambient temperature, subsequently evaporated in a vacuum and the residue mixed with a mixture of ice and sodium hydrogen carbonate solution. It is then extracted several times with ethyl acetate and the extract is dried with anhydrous sodium sulphate and finally evaporated. After recrystallisation from ethanol, there is obtained 0.84 g. (59% of theory) of base; m.p. 135° C.; dihydrochloride m.p. 241° C., after recrystallisation from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Cl.[N:13]([O-])=O.[Na+]>O1CCCC1>[I:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[N:13][CH:10]=[C:9]2[OH:11]
Reactant: CC(=O)c1cc(I)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnnc2ccc(I)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 1-(2-amino-5-iodophenyl)ethanone (as prepared in the previous step, 6.5 g, 24.90 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) and 1N HCl (49 mL, 2.00 equiv) and NaNO2 (2.3 g, 27.06 mmol, 1.10 equiv). The reaction mixture was stirred for 1 h at 0° C., and then was heated to reflux for 2 h. after cooled to room temperature, the solid were collected by filtration and washed with ice water. The title compound was obtained as a brown solid.
Reaction SMILES: N#N.[Br:3][C:4]1[C:11]([F:12])=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([F:13])[CH:5]=1.CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[CH:10]=[C:11]([F:12])[C:4]([Br:3])=[CH:5][C:6]=1[F:13])(=[O:23])=[O:22]
Reactant: OCc1cc(F)c(Br)cc1F
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,5-difluorobenzyl alcohol (160 mg, 0.72 mmol) in dry CH2Cl2 (4 mL) was treated at 0° C. with Et3N (0.13 mL, 0.93 mmol) followed by DMAP (9 mg, 0.07 mmol) and Ms-Cl (0.06 mL, 0.75 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (3 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,5-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (51 mg, 0.78 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,5-difluorobenzene as a yellow oil. LC-MS-conditions 07: tR=0.89 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[OH:12].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24](Cl)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([O:12][C:3]3[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([F:10])[C:4]=3[F:11])(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,4,5,6-Pentafluorophenol (2.73 g, 14.82 mmol) was dissolved in DCM (49.4 ml). 1-chloroisoquinoline-6-sulfonyl chloride (2.59 g, 9.88 mmol) was added, followed by the dropwise addition of triethylamine (2.066 ml, 14.82 mmol). The reaction was stirred overnight at room temperature. The reaction was concentrated and purified by silica gel chromatography (40 g column, gradient elution 0 to 50% Et2O:Heptane) to afford perfluorophenyl 1-chloroisoquinoline-6-sulfonate as a white solid. m/z (ESI) 410.0 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[C:6]([C:9]1[N:24]=[CH:23][C:12]2[N:13]([CH:20]([CH3:22])[CH3:21])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)([OH:8])=[O:7].CC1(C)CCCC(C)(C)N1.CI>C1COCC1>[C:6]([C:9]1[N:24]=[CH:23][C:12]2[N:13]([CH:20]([CH3:21])[CH3:22])[C:14]3[C:19]([C:11]=2[C:10]=1[CH2:1][CH3:2])=[CH:18][CH:17]=[CH:16][CH:15]=3)([OH:8])=[O:7]
Reactant: [Li]CCCC
Reactant: CC(C)n1c2ccccc2c2cc(C(=O)O)ncc21
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(C(=O)O)ncc2c1c1ccccc1n2C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 3.2 ml, 8 mmol) and 3-carboxy-9-isopropyl-9H-pyrido[3,4-b]indole (Method 2; 504 mg, 2 mmol) were added to a solution of 2,2,6,6-tetramethyl piperidine (1.01 ml, 6 mmol) in THF (15 ml) at −50° C. The mixture was allowed to stir for 30 minutes warming to 0° C. Methyl iodide (0.15 ml, 2.4 mmol) was then added in a single portion and the mixture was left at 0° C. for a further 30 minutes and at room temperature for a further 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in DCM. The solution was washed with 1 M HCl and then with water. The organic phase was separated, dried and concentrated in vacuo. The crude product was purified by preparative HPLC eluting over a gradient of 20-90% MeCN in water (0.1% TFA). The product was obtained as a yellow solid (190 mg) after evaporation of the appropriate fractions. NMR (300 MHz) 9.16 (s, 1H), 8.39 (d, 1H), 8.01 (d, 1H), 7.72 (t, 1H), 7.43 (t, 1H), 5.39 (m, 1H), 3.60 (q, 2H), 1.67 (d, 6H), 1.38 (t, 3H).
Reaction SMILES: C([Si](C)(C)O[C@@H]1CC[C@H]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])CC1)(C)(C)C.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.[Li+].CC([N-]C(C)C)C>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][CH:15]2[CH2:16][CH2:17][NH:13][C:14]2=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C1NCCC1Cc1ccc(C(F)(F)F)cc1
Yield: 39 %

Procedure:
Using the procedure to synthesize Example 202 and using cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 17), 4-trifluoromethyl benzylbromide and 1.5 equivalents of LDA affords an oil. Chromatography (silica, 4:1 hexanes/EtoAc) yields 4-[4-tert-butyl dimethyl-silanyloxy)-cyclohexyl]-3-(4-trifluoromethyl-benzyl)-pyrrolidin-2-one in 39% yield. The silylether is dissolved in THF, treated with 5.0 equivalents of TBAF and allowed to stir at room temperature overnight. Quench reaction with water, dilute with methylene chloride, separate, dry over sodium sulfate, filter and evaporate. Chromatography (silica, 4:6 hexanes/EtoAc) provides the titled compound in 21% yield: Mass spectrum (API-ES positive) m/z=342.3 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[OH-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>C1COCC1>[C:33]([O:32][C:30](=[O:31])[CH2:29][O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([C:18]4[CH:25]=[CH:24][CH:23]=[C:20]([C:21]#[N:22])[CH:19]=4)[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:4][CH2:3]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cccc(-c2nc(N3CCC(O)CC3)cc3cccnc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1CCN(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[6-(4-Hydroxy-piperidin-1-yl)-[1,7]naphthyridin-8-yl]-benzonitrile (570 mg, 1.73 mmol) THF (5 ml) is added to NaOH (60% dispersion in mineral oil) (166 mg, 6.9 mmol) suspended in THF (20 ml) at 0° C. Stirred at 0° C. for 30 minutes. tert-Butyl bromoacetate (0.51 ml, 3.45 mmol) is added and the reaction mixture is stirred at 0° C. for 5 minutes then at room temperature for 18 hours. Further tert-butyl bromoacetate (0.25 ml, 1.73 mmol) and NaOH (80 mg, 3.3 mmol) are added and the reaction mixture is stirred at room temperature for 2 hours. After cooling to 0° C. water (20 ml) is added and the mixture is extracted with ethyl acetate (×1). The ethyl acetate extract is dried (MgSO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 10-20% ethyl acetate in isohexane, gives the product. MS (ES+) Observed [M+H]+ 445.12
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1[C:43](C)=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:45].NC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:24])[NH:38][C:43]3[CH:45]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)Nc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 100 mg, 0.21 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (118 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution at 0° C. After 1 h, aniline (21 μL, 0.21 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-phenylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide was obtained (71 mg, 61%) as a white solid: ESI-LRMS m/e calcd for C27H31ClN4O4S [M+] 542.2, found 543.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.01-1.20 (m, 2H, CH2), 1.40-1.88 (m, 8H, 4×CH2), 2.11-2.26 (m, 1H, CH), 2.66-2.76 (m, 2H, COCH2), 3.25 (s, 3H, SO2CH3), 3.64 (t, J=7.5 Hz, 1H, CH), 4.22-4.30 (m, 2H, NCH2), 6.53 (d, J=2.2 Hz, 1H, Ar), 7.05 (t, J=7.4 Hz, 1H, Ar), 7.18-7.25 (m, 3H, Ar), 7.37 (d, Jo=7.8 Hz, 2H, Ar), 7.43 (dd, Jo=8.3, Jm=1.6 Hz. 1H, Ar), 7.58 (d, Jm=1.6 Hz, 1H, Ar), 7.88 (s, 1H, NH), 8.01 (d, Jo=8.3 Hz, 1H, Ar), 8.62 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[F:16][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([F:21])[C:18]([O-])=[O:19].O>O1CCCC1.CCCCC>[F:16][C:17]([F:21])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1)=[O:19]
Reactant: CN(C)c1ccc(Br)cc1
Reactant: O=C([O-])C(F)(F)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: CN(C)c1ccc(C(=O)C(F)(F)c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A solution of 4.0 g of 4-bromo-N,N-dimethylaniline in 50 ml of dry tetrahydrofuran at -78° C. was treated with 23.5 ml of 1.7M tert-butyllithium in pentane under nitrogen over 5 minutes with rapid stirring. After 0.5 hour, the slurry was warmed to -30° C. and added to a solution of 4.0 g of α,α-difluorophenylacetate in 50 ml of dry tetrahydrofuran at -78° C. After 1 hour at -78° C., the solution was allowed to warm to room temperature and stirred overnight. The solution was poured into water and extracted with ethyl acetate. Evaporation left a solid which was purified by flash chromatography (1:1 ethyl acetate-hexane) to give a powder. Recrystallization from ethyl acetate-hexane gave 1.75 g of 2,2-difluoro-1-[4-(dimethylamino)phenyl]-2-phenylethanone, m.p. 115°-116° C.