Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (20%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.NCCN(CCN)CCN>ClCCl>[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: OCCN1CCOCC1
Agent: NCCN(CCN)CCN
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(OCCN1CCOCC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A 8 mL vial was charged with 2-morpholinoethanol (200 μL, 1.63 mmol), dichloromethane (5 mL), polystyrene-linked diisopropylamine (4.90 mmol), and 4-iodobenzoyl chloride (479 mg, 1.80 mmol), and the reaction mixture was shaken at room temperature. After 16 hours, the reaction mixture was charged with polystyrene-linked tris(2-aminoethyl)-amine (1.63 mmol), and shaken at room temperature for 2 hours. The reaction was filtered, and the resin was washed with dichloromethane (3×10 mL), tetrahydrofuran (2×10 mL), and diethyl ether (2×10 mL). The combined filtrates were concentrated in vacuo to give 2-morpholinoethyl 4-iodobenzoate (434 mg, 1.19 mmol) as a white solid.
Reaction SMILES: Cl[C:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Si](C)(C)C)=[N:19][CH:20]=1>CCCCCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:2]([C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[N:19][CH:20]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: C[Si](C)(C)c1ccc(Br)cn1
Solvent: CCCCCC
Product: COC(=O)[C@H]1CC[C@H](C(=O)c2ccc(Br)cn2)CC1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a flask containing methyl trans-4-(chlorocarbonyl)cyclohexanecarboxylate (8.19 g, 40 mmol) was added 5-bromo-2-(trimethylsilyl)pyridine (8.4 g, 36.4 mmol). The resulting mixture was heated to 110° C. for 10 hours. The reaction was allowed to cool to 70° C., and hexane (30 mL) was added dropwise. The resulting mixture was stirred for 14 hours at room temperature, filtered, and the residue was washed with hexane (20 mL). The beige solid was dried under nitrogen to afford methyl trans-4-[(5-bromopyridin-2-yl)carbonyl]cyclohexanecarboxylate. MS ESI calcd for C14H17BrNO3 [M+H]+ 326 and 328. found 326 and 328. 1H NMR (600 MHz, CDCl3) δ 8.70 (d, J=1.8 Hz, 1H), 7.94 (dd, J=8.4, 2.3 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 3.78 (tt, J=11.9, 3.4 Hz, 1H), 3.66 (s, 3H), 2.32 (tt, J=12.2, 3.6 Hz, 1H), 2.08 (dd, J=13.8, 3.5 Hz, 2H), 1.99 (dd, J=13.9, 3.1 Hz, 2H), 1.60 (m, 2H), 1.45 (m, 2H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C([NH:15][C@H:16]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17]([OH:19])=[O:18])(OC(C)(C)C)=O>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:15][C@H:16]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 ml of TFA were added to a solution of (R)-N-Boc-2-amino-3-cyclohexylpropanoic acid (3.0 g, 11.1 mmol) in 20 ml of CH2Cl2, and the mixture was stirred at RT overnight. After deprotection was complete, the CH2Cl2 was evaporated off, and the remaining solid was mixed with 50 ml of H2O and lyophilized. Yield: 2.84 g (90%) of (R)-2-amino-3-cyclohexylpropanoic acid trifluoroacetate as colorless solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (69.2 mg, 53%).
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([NH:33]C(OC(C)(C)C)=O)([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1)[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:14]C(C)(C)C(C)(C)[O:11]1)C.[ClH:42]>O>[ClH:42].[ClH:42].[ClH:42].[NH2:33][C:5]([CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)[CH2:25][CH2:26]1)([CH2:6][CH2:7][CH2:8][CH2:9][B:10]([OH:11])[OH:14])[C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN1CCN(c2ncccn2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Product: NC(CCCCB(O)O)(CCN1CCN(c2ncccn2)CC1)C(=O)O
Temperature: 25 °C
Yield: 83 %

Procedure:
2-Amino-6-borono-2-[2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl]-hexanoic acid trihydrochloride is prepared in a manner analogous to that set forth in Example 16, except 1-2-(1-piperidinyl)pyrimidine is used as the amine in step 6. The final step is as follows: a solution of (R/S)-2-tert-butoxycarbonylamino-2-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (126 mg) in 6 N hydrochloric acid (6 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give the title compound as a white solid (80 mg, 83%); 1H NMR (D2O, 300 MHz) δ 8.47 (d, J=5.5 Hz, 2H), 6.96 (t, J=5.5 Hz, 1H), 3.48-3.76 (m, 4H), 3.14-3.40 (m, 6H), 2.29 (t, J=8 Hz, 2H), 1.81 (m, 2H), 1.28 (m, 3H), 1.11 (m, 1H) and 0.62 (t, J=7.5 Hz, 2H).
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)([CH3:7])([CH3:6])[CH3:5].[C:15](=O)([O:26]C1C=CC([N+]([O-])=O)=CC=1)[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.CCCCCC.C(OC(=O)C)C>[C:15](=[O:26])([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:4]([CH3:7])([CH3:5])[CH3:6])[CH:9]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
An oven-dried 25 mL flask was charged with dry CH2Cl2 (5 mL), 3-t-butylphenol (100 mg, 0.67 mmol), bis(4-nitrophenyl) carbonate (405 mg, 1.34 mmol) and 4-DMAP (162 mg, 1.34 mmol). The reaction was stirred overnight at room temperature and then evaporated. Column chromatography (n-hexane/ethylacetate 8:1) yielded 3-t-butylphenyl 4-nitrophenyl carbonate (189 mg, 0.60 mmol, 90%). This carbonate was dissolved in dry CH2Cl2 (8 mL) and 4-DMAP (162 mg, 1.34 mmol) was added. After 15 min, propargylamine (73 mg, 0.085 ml, 1.34 mmol) was added by syringe. The reaction was allowed to stir overnight at room temperature and then evaporated. Column chromatography (n-hexane/ethylacetate 15:1) yielded N-propargyl-3-t-butylphenyl carbamate (93 mg, 0.40 mmol, 60%). 1H NMR (CDCl3, 400 MHz) δ 1.32 (t, 9H), 2.30 (s, 1H), 4.08 (d, J=5.2 Hz, 2H), 5.27 (broad, 1H), 6.97 (d, J=7.2 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.23˜7.31 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 30.9, 31.2, 34.7, 72.0, 79.3, 118.5, 122.5, 128.8, 150.6, 152.9, 154.2.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]1C2NC3C(=CC=C(C(O)=O)C=3)C=2CCC1.[CH2:21]1[C:33]2[NH:32][C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:34]([OH:36])=[O:35])[C:26]=3[C:25]=2[CH2:24][CH2:23][CH2:22]1>CO>[CH2:21]1[C:33]2[NH:32][C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:34]([O:36][CH3:5])=[O:35])[C:26]=3[C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cccc2[nH]c3c(c12)CCCC3
Reactant: O=C(O)c1ccc2c3c([nH]c2c1)CCCC3
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cccc2[nH]c3c(c12)CCCC3

Procedure:
By adding thionyl chloride to a methanol solution of a mixture of 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid and 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid at −10° C., followed by the reaction under heating and subsequent separation and purification by a column chromatography, methyl 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylate [Reference Example 17a: ESI: 2230 (M+H)+] and methyl 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate [Reference Example 17b: ESI: 230 (M+H)+] were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](S(C)(=O)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:20]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([O:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: Cc1cc(OCc2ccccc2)nc(S(C)(=O)=O)n1
Product: Cc1cc(OCc2ccccc2)nc(Oc2ccccc2)n1

Procedure:
4-Benzyloxy-6-methyl-2-(methylsulfonyl)pyrimidine (Compound II-4) (0.45 g, 0.00162 mol) was added thereto and the resulting solution was allowed to react for about 2 hours at room temperature. The reaction solution was poured into water and extracted with ethyl acetate to separate an organic phase. The obtained organic phase was washed successively with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, then dried over anhydrous sodium sulfate and thereafter concentrated. The concentrate was purified on silica gel column to obtain the end product.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]([C@H:6]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:7]12[CH2:8]C(O)=O)[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:28])[CH:21]=[CH:22]1)[N:17](C(C)(C)C)[CH2:16]3)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:33]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:7]12[CH3:8])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:28])[CH:21]=[CH:22]1)[NH:17][CH2:16]3)=[O:5])[CH3:34]
Reactant: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A sample of 17β-N,N-diethylcarbamoyl-6-t-butylcarboxy-6-azaandrost-1,4-dien-3-one (188 mg, 0.400 mmol), prepared in part B above, is treated with trifluoroacetic acid as described in Example 4 above to give, after trituration with diethyl ether/hexanes 17β-N,N-diethylcarbamoyl-6-azaandrost-1,4-dien-3-one as a pale yellow solid; yield: 98 mg (66%); m.p.>250° C. Anal. Calcd. for C23H34N2O2 ·1/2H2O; C, 72.78; H, 9.29; N, 7.38. Found: C, 72.89; H, 9.20; N, 7.43.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([Si](C)(C)C)[C:5]1=[O:13].[Li+].[CH3:16][CH:17]([N-]C(C)C)[CH3:18].C(Br)C=C>C1COCC1>[CH3:1][CH:2]([CH3:14])[CH2:3][C:4]1([C:17]([CH3:18])=[CH2:16])[CH2:8][CH2:7][NH:6][C:5]1=[O:13]
Reactant: CC(C)CC1CCN([Si](C)(C)C)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=C(C)C1(CC(C)C)CCNC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of 3-(2-methylpropyl)-1-trimethylsilyl-2-pyrrolidinone (10.2 g, 47.8 mmol) and THF (153 mL) is cooled to -78° C., and LDA (2.0 M, 26.3 mL, 52.6 mmol) is added. The solution is stirred at -78° C. for 30 minutes and then allyl bromide (5.0 mL, 57 mmol) is added. The solution is allowed to warm to 5° C. over 2.5 hours, and is then stirred at 5° C. for 1 hour. After quenching with saturated aqueous ammonium chloride (25 mL), aqueous workup (EtOAc, MgSO4) and purification by column chromatography (1:9:10 v/v CH2Cl2 :EtOAc:hexane) provides 7.76 g (90%) of the title compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[N:26]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[N:25]=[C:24]4[CH2:37][C@@H:38]4[CH2:42][CH2:41][N:40]([C:43]([CH:45]5[CH2:47][CH2:46]5)=[O:44])[CH2:39]4)=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[CH:9]1>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C:27](=[O:28])[N:26]([CH2:29][C:30]([OH:32])=[O:31])[N:25]=[C:24]4[CH2:37][C@@H:38]4[CH2:42][CH2:41][N:40]([C:43]([CH:45]5[CH2:47][CH2:46]5)=[O:44])[CH2:39]4)=[CH:21][CH:22]=3)=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

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 (50 mg, 0.117 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (80 mg, 0.58 mmol, 5 eq) and tert-butylchloroacetate (21 mg, 0.14 mmol, 1.2 eq). The vial was capped, purged with nitrogen gas, and stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was cooled to room temperature and then poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude intermediate ester (MS(ES)+ m/e 487.3 [M+H]+). In a 50 mL round bottom flask, the crude 1,1-dimethylethyl (4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetate was dissolved in 9 mL dichloromethane. Trifluoroacetic acid (1 mL, 12.98 mmol) was added to the solution, which was allowed to stir at room temperature for 16 h under a nitrogen bubbler. Analysis by LC/MS displayed the reaction complete. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 10-75% 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 title compound (32 mg, 56%). MS(ES)+ m/e 487.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1[C:30]#[N:31])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:32].[Na+]>C(O)CC>[CH2:1]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:20]1[C:25]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:23]=[CH:22][C:21]=1[C:30]([NH2:31])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C#N)cccc2C(F)(F)F)cc1
Agent: [Na+]
Solvent: CCCO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(N)=O)cccc2C(F)(F)F)cc1
Yield: 93 %

Procedure:
To a solution of 1.78 g (4.0 mmol) of the product of Example 122 in 30 mL of n-propanol was added 8 mL of 5N NaOH solution. The resulting mixture was refluxed for 66 h and concentrated. The residue was stirred in water and filtered to provide 1.725 g (93%) of the desired amide as a white solid. Electrospray Mass Spec 465.2(M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)=[N:13][CH:14]=1.[Cl-].[NH4+]>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl.CS(C)=O>[CH:8]([C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:7]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2cnc(CO)cn2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)COc1ccc(-c2cnc(C=O)cn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a methylene chloride (11 mL) solution of oxalyl chloride (355 μL) was added dropwise a methylene chloride (2 mL) solution of dimethylsulfoxide (450 μL) at −78° C., and the mixture was stirred for 15 minutes. To the mixture was added dropwise a methylene chloride (6 mL) solution of methyl 3-{4-[5-(hydroxymethyl)pyrazin-2-yl]-phenoxy}-2,2-dimethylpropanoate (655 mg) at −78° C., and the mixture was stirred for 10 minutes, and the mixture was stirred for 1 hour and 30 minutes. Triethylamine (2.05 mL) was added to the mixture, the temperature of the mixture was raised to 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with water, and with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5 to 75:25) to obtain methyl 3-{4-[5-formylpyrazin-2-yl]phenoxy}-2,2-dimethylpropanoate (585 mg).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17](=O)[CH:18]([CH3:42])[CH2:19][C:20](=O)[CH:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH:38]3[CH2:40][CH2:39]3)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:15][CH:16]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:48]>C(O)(=O)C.C(OCC)(=O)C>[Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:48][C:20]([CH:21]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:19][C:18]=2[CH3:42])=[N:15][CH:16]=1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccc(C(C)O[Si](C)(C)C(C)(C)C)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccc(C(C)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 1-[5-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridin-2-yl]-5-[4-(cyclopropylsulfonyl)phenyl]-2-methyl-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (180 mg) in acetic acid (5 mL) was added ammonium acetate (354 mg), and the mixture was stirred at 90° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (130 mg, yield 74%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 609 (MH+).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21](N)=[CH:20][CH:19]=2)[CH:17]=1)=[O:12])[CH3:9]>CN(C)C=O.[Cl-].[Na+].O>[CH2:8]([O:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn(-c2ccc(N)cc2)cn1
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)cn1
Temperature: 65 °C
Yield: 69.4 %

Procedure:
Tert-butyl nitrite (535 mg, 5.19 mmol) in dry dimethylformamide (15 ml) was heated to 65° C. under nitrogen and then 1-(4-aminophenyl)imidazole-4-carboxylic acid ethyl ester (see part (ii)) (800 mg, 3.463 mmol) in dry dimethylformamide (5 ml) was added over 10 minutes. The mixture was heated at 65° C. for a further 20 minutes and then cooled to room temperature. The mixture was poured into saturated brine (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with dichloromethane gave the title compound (520 mg, 70%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([OH:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([OH:16])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC[C@@H](O)C2)cc1
Agent: [Pd]
Product: Nc1ccc(N2CCC[C@@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(4-nitrophenyl)piperidin-3-ol was added Pd/C. The mixture was stirred under 1 atm H2 at room temperature overnight, and then filtrated through a pad of Celite. The filtrate was concentrated to afford (R)-1-(4-aminophenyl)piperidin-3-ol.