Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:14][CH:13]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: ClCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc(CCCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
1.07 g of 7-chloroheptylbenzene and 0.89 g of 4-chlorobenzoyl chloride were dissolved in 10 ml of nitrobenzene and treated with 0.82 g of aluminium chloride under argon and while cooling with ice. The mixture was then stirred at room temperature for 18 hours, taken up in 100 ml of ice-cold 2N hydrochloric acid solution and extracted three times with 50 ml of ether each time. The organic phases were washed with 50 ml of a 10 percent sodium bicarbonate solution and 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The nitrobenzene was removed by distillation at 80°-100° C. and 20 Pa. By distillation at 240°-250° C. and about 13.4 Pa there were obtained 1.32 g (74%) of 4-chloro-4'-(7-chloroheptyl)benzophenone as a light yellow oil.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Yield: 86.8 %

Procedure:
Cyclohexylamine (0.67 mL, 5.85 mmol) was added to a solution of Compound 6 (1.0 g, 2.92 mmol) in toluene (20 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystalized by ether to yield 1.0 g (87%) of white solids. M.P. 168° C. 1H NMR (DMSO-d6): δ 1.26 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.89 (m, 2H), 3.88 (m, 1H), 5.51 (s, 2H), 7.13 (m, 2H), 7.25 (m, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.70 (t, J=8.4 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H), 10.35 (s, 1H), 17.66 (s, 1H),. EIMS m/z 395 (M+1), 417 (M+23). Anal. (C23H23FN2O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10]Br.[CH3:29][NH2:30]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:30][CH3:29]
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1)c1ccccc1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)c(Br)c1)c1ccccc1
Yield: 90 %

Procedure:
Following the same procedure as described in example 11, step D, 4-(1-(3-bromo-4-(2-bromoethoxy)phenyl)-2-phenylbut-1-enyl)phenol (0.09 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give 73 mg desired product (90% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 6.98-7.20 (m, 7H), 6.87 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H), 4.17 (t, J=5.2 Hz, 1H), 4.01 (t, J=4.8 Hz, 1H), 3.06 (t, J=4.8 Hz, 1H), 2.96 (t, J=5.2 Hz, 1H), 2.40-2.60 (m, 5H), 0.88 (t, J=5.2 Hz, 3H); m/z=452 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CC#N>[CH3:36][O:35][C:31](=[O:34])[CH:32]=[CH:33][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][CH2:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:21]=1
Reactant: O=S(=O)(Oc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1)C(F)(F)F
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1

Procedure:
Prepared by the Heck coupling of 3b and methyl acrylate in accordance with the general method described in Example IV. Yield (94%); APcI m/z: 410 (M+H+CH3CN+, 100%).
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].CC#N.O.[ClH:42]>O.Cl[Cu]>[Cl:42][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: Cl
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (1.1 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:23][CH2:22][O:21][CH2:20]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCOC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCOC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (3-(2-methylpyrimidin-5-yl)tetrahydrofuran-3-yl)methanamine. LCMS (MH+): m/z=366.0, tR (minutes, Method E)=0.45
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 58 %

Procedure:
Condensation of BocDPro-Phe-PheNHNH2 (0.932 g.) and HGly-Leu-MetNH2 hydrochloride salt (Example 7, 0.630 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocDPro-Phe-Phe-Gly-Leu-MetNH2 in 58% yield. De-t-butoxycarbonylation of BocDPro-Phe-Phe-Gly-Leu-MetNH2 (0.838 g.) using hydrogen chloride in acetic acid gave HDPro-Phe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 72% yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:17][C:15]1[S:16][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[N:14]=1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
A mixture of 2-bromo-3′-nitroacetophenone (12.2 g) and thiourea (3.81 g) in ethanol (100 ml) was stirred at room temperature for 15 minutes. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-amino-4-(3-nitrophenyl)thiazole (10.21 g).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.II.[O:19]1[CH:21]([CH3:22])[CH2:20]1.[NH4+].[Cl-]>C1COCC1>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([CH2:20][CH:21]([OH:19])[CH3:22])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC1CO1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 14.5 h

Procedure:
To a solution of (4-bromobenzyloxy)(tert-butyl)dimethylsilane (3.080 g) in THF (20 mL) were added Mg (0.288 g) and I2 (cat) at room temperature under an Ar atmosphere. The mixture was heated at 50° C. for 1 hour, and then cooled to room temperature. To the mixture was added 1,2-epoxypropane (0.77 mL) at room temperature under an Ar atmosphere, and the mixture was stirred at room temperature for 14.5 hours, and then heated at 50° C. for 1 hour, and then cooled to room temperature. To the mixture was added saturated aqueous NH4Cl, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to afford 1-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]propan-2-ol (1.485 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:44])=[C:6]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:43])[NH:24][CH2:25][C@@H:26]([N:34](C(OC(C)(C)C)=O)[CH3:35])[CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][O:30][CH2:29]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:44])=[C:6]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:43])[NH:24][CH2:25][C@@H:26]([NH:34][CH3:35])[CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][O:30][CH2:29]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)NC[C@H](C[C@H]2CCCOC2)N(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](CNC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cc(Cl)ccc2C)C1)C[C@H]1CCCOC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
A 25 mL flask was charged with methyl 2-((R)-(5-chloro-2-methylphenyl)((R)-1-((S)-2-(Boc-methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (60 mg, 0.094 mmol). 20% TFA/CH2Cl2 solution (8 mL) was added and stirred for 0.5 h at 0° C. The mixture was concentrated to give the residue, which was purified by preparative HPLC to give the desired product methyl 2-((R)-(5-chloro-2-methylphenyl)((R)-1-((S)-2-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (4.35 mg, 9%) as its TFA salt. 1H-NMR (MeOD): 1.25 (m, 2H), 1.35-1.50 (m, 4H), 1.60-1.80 (m, 3H), 1.95 (m, 2H), 2.35 (s, 3H), 2.75 (s, 3H), 3.65 (s, 3H), 3.85 (m, 4H), 4.45 (d, 1H), 7.15 (m, 2H), 7.30 (s, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH2:35]([N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:20][CH:19]=1)[C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21
Yield: 69.9 %

Procedure:
A solution of 86 mg (0.16 mmole) of 1-[N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl]-1,2,3,4-tetrahydroquinoline (from Step A), 30 μL of anisole, and 0.8 mL of anhydrous TFA was stirred at room temperature for 16 hours. The residue obtained after evaporation of excess TFA was flash chromatographed over silica gel (elution with 0.5% MeOH in CH2Cl2) to give 55 mg (71%) of the title compound as an off-white foam, homogeneous by TLC (95:5 MeOHCH2Cl2), FAB-MS m/e 492 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[NH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1ccccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
That is, 1-acetyl-aminobenzene (300 mg, 2.2 mmol) was dissolved in methanol, sodium borohydride (418 mg, 11 mmol) was added, the temperature was raised from under ice-cooling to room temperature, and the mixture was stirred for 1 hr. Then, water was added to the reaction mixture, and unreacted sodium borohydride was decomposed. Then, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (30:1)) to give 1-(aminophenyl)ethanol (yield; 242 mg, 80%). According to the final step in Example 2 (step for condensing Y222 and Y491), compound Y491 (the aforementioned) (196 mg, 4.3 mmol) and 1-(aminophenyl)ethanol (147 mg, 10.8 mmol) were condensed to give the title compound (yield; 157 mg, 66%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]23[CH2:24][N:21]([CH2:22][CH2:23]2)[CH2:20][CH2:19][CH2:18]3)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]34[CH2:24][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19][CH2:18]4)=[CH:13][N:12]=2)[CH:4]=[N:3]1
Reactant: Brc1ccc(C23CCCN(CC2)C3)cn1
Reactant: Cn1cc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccc(C34CCCN(CC3)C4)cn2)cn1
Temperature: 105 °C
Yield: 93.2 %

Procedure:
0.162 g (0.78 mmol) of 1-methyl-4-pyrazolylboronic acid, 0.160 g (0.6 mmol) of (−)-5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (obtained by reacting 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (−)-hydrobromide (1:1), prepared in step 1.2, with saturated aqueous sodium carbonate solution) are successively introduced into a 10 ml three-necked round-bottomed flask, as a solution in 3 ml of toluene and 0.3 ml of ethanol. 0.035 g (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 0.6 ml of aqueous 2M sodium carbonate solution are then added and the mixture is heated at 105° C. for 18 hours. It is cooled to room temperature, the solvent is evaporated off under reduced pressure and the residue is taken up in 10 ml of chloroform and filtered through diatomaceous earth. The solvent is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 0.15 g of (−)-5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane is obtained, and is dissolved in 2 ml of isopropyl alcohol to add 0.196 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals obtained are collected by filtration and dried under vacuum.
Reaction SMILES: [CH2:1]([CH:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=O)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=O)C>>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:9])[O:13][C:11](=[O:12])[CH2:10]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CC(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)CC1CC(=O)OC(=O)C1

Procedure:
In another embodiment, the invention encompasses a process for recycling 3-isobutyl glutaric anhydride comprising: preparing a compound of formula 24 from 3-isobutyl glutaric anhydride by the process according to claim 29; crystallizing the recovered compound of formula 24 from an organic solvent; removing the crystals from the organic solvent; combining the remaining organic solvent with an acid to obtain a first mixture; maintaining the first mixture at a temperature of about 60° C. to about 130° C., to obtain 3-isobutyl glutaric acid; combining the 3-isobutyl glutaric acid with acetic anhydride to obtain a second mixture; heating the second mixture to a temperature of about 125° C. to about 145° C. to obtain 3-isobutyl glutaric anhydride; and recovering the 3-isobutyl glutaric anhydride from the second mixture.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=1>>[CH3:4][C@H:3]([CH2:5][CH3:6])[C@@H:2]([NH:1][C:16](=[O:17])[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Product: CC[C@@H](C)[C@@H](NC(=O)c1ccc(C)cc1)C(=O)O

Procedure:
(L)-Isoleucine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[C:23]([CH3:34])[C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19]>>[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[C:23]([CH3:34])[C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)[N:27]=1)=[O:19]
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide to yield an orange solid (11%). LCMS: m/z=485.08 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.05 (m, 2H), 7.65 (s, 1H), 7.45 (d, 1H, J=8.6 Hz), 7.29 (m, 1H), 7.01 (s, 1H), 6.75 (d, 1H, J=8.6 Hz), 6.11 (m, 1H), 3.52 (m, 3H), 2.93 (d, 3H, J=4.8 Hz), 2.35 (m, 2H), 2.06 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([C:23](=[O:25])[CH3:24])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Temperature: 80 °C
Yield: 101.7 %

Procedure:
In a screw top flask 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (1.6 g, 6.1 mmol), tributyl-(1-ethoxy-vinyl)-stannane (1.8 g, 4.8 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) (212 mg, 0.30 mmol) were combined in DMF (10 mL). Under nitrogen the flask was sealed and heated to 80° C. for 12 hours. The reaction mixture was cooled to rt, concentrated, and purified by flash column chromatography using ethyl acetate-hexanes (0%-20%) to provide the desired product as a clear oil (1.3 g, 73%). MS (ESI): mass calcd. for C15H13F3N2O, 294.0; m/z found 295.1 [M+H]+. The resulting clear oil was diluted with THF (60 mL) and 2N HCl (10 mL) and stirred. After 12 h, the resulting solution was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried with Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography using ethyl acetate-hexanes (0%-20%) to provide the desired product as a clear oil (1.1 g, 93%). MS (ESI): mass calcd. for C13H9F3N2O, 266.0; m/z found 267.1 [M+H]+. 1H NMR (CDCl3) δ 9.45 (d, J=1.3 Hz, 1H), 8.37 (d, J=1.3 Hz, 1H), 8.31 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H), 2.81 (s, 3H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=[O:4])[NH2:2].Cl[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C(=O)C>[CH3:23][N:14]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]([NH:1][NH:2][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4])=[CH:13]2
Reactant: CN(c1cccc2cc(C(=O)NN)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of N-[2-(hydrazinocarbonyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.88 g) in N,N-dimethylacetamide (16 mL) was added ethyl 3-chloro-3-oxopropanoate (0.35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. Diethyl ether was added to the obtained oil, and the resulting crystals were filtrated, washed with diethyl ether, and dried to give the title compound (0.96 g, yield 84%) as colorless crystals. melting point 119-121° C.