Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][C:27]([CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:27]3[CH:38]=[CH:39][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccc(OC)cc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccc(OC)cc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 82.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (140 mg, 0.48 mmol, 1.0 eq), L-isoleucine 4-methoxybenzylamide (238 mg, 0.95 mmol) and dichloromethane (2 mL), was treated with triethylamine (400 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (610 uL, 2.0 eq), to provide 207 mg (82%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] 4-methoxybenzylamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29](OCC1C=CC=CC=1)=[O:30])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1>>[C:1]([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29](=[O:30])[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1)[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CN1CCc2cc(F)ccc21
Product: COc1cccc(C(=O)N[C@@H](CC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CN2CCc3cc(F)ccc32)c1
Yield: 92 %

Procedure:
This material was prepared in 92% yield in an analogous fashion to example 158 except that 3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester was deprotected and m-anisic acid was used as the acid; 1H NMR (CDCl3, 400 MHz) δ 0.95 (s, 9H), 1.40 (s, 9H), 1.57 (dd, 1H, J1=8.5, J2=14.5), 1.88 (dd, 1H, J1=4.0, J2=14.5), 2.51 (dd, 1H, J1=5.9, J2=16.3), 2.61 (dd, 1H, J1=5.1, J2=16.3), 2.81-2.96 (m, 2H), 3.07 (dd, 1H, J1=7.4, J2=13.8), 3.22 (dd, 1H, J1=6.5, J2=13.8), 3.34 (dd, 1H, J1=8.5, J2=17.1), 3.44 (dd, 1H, J=8.6, J2=16.3), 3.82 (s, 3H), 4.34-4.43 (m, 1H), 4.64 (ddd, 1H, J=4.0, J2=J3=8.5), 6.39 (dd, 1H, J=4.1, J2=8.5), 6.57 (d, 1H, J=8.4), 6.66-6.75 (m, 1H), 6.73-6.78 (m, 1H), 6.97 (d, 1H, J=8.5), 6.98-7.04 (m, 1H), 7.23-7.33 (m, 3H); HPLC-MS calcd. for C31H42FN3O5 (M+H+) 556.3, found 556.5.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[CH:26]([O:28][CH2:29][CH3:30])=[O:27]>CC#N>[CH2:29]([O:28][C:26]([NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[O:27])[CH3:30]
Reactant: NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Reactant: CCOC=O
Solvent: CC#N
Product: CCOC(=O)NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21

Procedure:
[7-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid ethyl ester (482) was synthesized following the general scheme above, from amine (273-I) and ethyl formate. Overall yield (18%). HPLC ret. time 2.84 min, 10-99% CH3CN, 5 min run; ESI-MS 406.5 m/z (MH+).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:15]=[C:14]([CH:27]=O)[CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.ClCCCl>[CH3:10][O:11][C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[N:15]=[C:14]([CH2:27][NH:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:13]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cc(C=O)nn1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(CN[C@H](C)c2ccccc2)nn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with (R)-1-phenylethanamine 45 (0.135 g, 1.11 mmol), 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbaldehyde 74 (0.200 g, 0.740 mmol), 5 mL of DCE, 3 drops of concentrated AcOH, and sodium triacetoxyborohydride (0.314 g, 1.48 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 10 mL of saturated aqueous NaHCO3 and the mixture was extracted with CH2Cl2. The combined extracts were dried and concentrated. Purification via column chromatography on silica gel (1% to 6% MeOH in DCM) gave (1R)—N-({5-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}methyl)-1-phenylethanamine 75. Mass spectrum: calculated for C20H20F3N3O 375.2; found 376.2 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:15]=3[CH3:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: Cc1cccc(CN)c1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1C

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2,3-dimethyl-benzylamine (87 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2,3-dimethyl-benzylamino)-2H-phthalazin-1-one: 43 mg (23.6%): m/z (M+H)=314. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.92 (d, 1H), 7.44 (m, 1H), 7.10 (m, 4H), 6.85 (s, 1H), 4.36 (d, 2H), 2.62 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [ClH:1].Cl.Cl.C([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:20][CH:19]([N:21]([CH3:23])[CH3:22])[CH2:18]2)[CH2:13][CH2:12]1)C1C=CC=CC=1.O>CC(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[CH3:22][N:21]([CH3:23])[CH:19]1[CH2:18][N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH2:20]1
Reactant: CN(C)C1CN(C2CCN(Cc3ccccc3)CC2)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CN(C)C1CN(C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 297.8 %

Procedure:
To a solution of a crude product of N-[1-(1-benzylpiperidin-4-yl)azetidin-3-yl]-N,N-dimethylamine trihydrochloride (14.1 g) in 2-propanol (380 ml)-water (380 ml) was added 10% palladium on carbon (5.0 g), followed by stirring at room temperature under a hydrogen atmosphere for 12 hr. The catalyst was removed by filtration. Concentration of the filtrate provided a crude product of the titled compound as colorless crystals (10.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12][OH:13])([CH2:10][OH:11])[CH:8]=[CH2:9])(C)(C)[CH3:2].C(OC(C1(C=C)COC(C)(C)OC1)=O)C>>[CH2:1]([O:5][C:6](=[O:14])[C:7]([CH2:10][OH:11])([CH2:12][OH:13])[CH:8]=[CH2:9])[CH3:2]
Reactant: C=CC(CO)(CO)C(=O)OC(C)(C)C
Agent: C=CC1(C(=O)OCC)COC(C)(C)OC1
Product: C=CC(CO)(CO)C(=O)OCC
Yield: 78 %

Procedure:
Compound 99c was prepared in the same manner as 2,2-bis-hydroxymethyl-but-3-enoic acid tert-butyl ester using 2,2-dimethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid ethyl ester instead of 2,2-dimethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester in 78% yield. 1H NMR (300 MHz, d6-DMSO) 61.17 (t, J=7.0 Hz, 3H), 3.59-3.71 (m, 4H), 4.06 (q, J=7.0 Hz, 2H), 4.65 (t, J=5.6 Hz, 2H), 5.13 (d, J=18.5 Hz, 1H), 5.15 (d, J=10.5 Hz, 1H), 5.80 (dd, J=18.5, 10.5 Hz, 1H). LCMS (m/z) 197.1 [M+Na], Tr=0.96 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH2:31]([NH2:33])[CH3:32].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:33][CH2:31][CH3:32])=[O:17])=[N:14][CH:15]=1
Reactant: CCN
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 168 h
Yield: 90 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (126 mg, 0.30 mmol) obtained in Example 12 in methylene chloride (3 ml), ethylamine hydrochloride (27 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (0.073 ml, 0.66 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.33 mmol) were added at room temperature. After stirring for 7 days at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=7:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration, to obtain the title compound (120 mg, 0.27 mmol, 89%) as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6][NH:5]1.[Br:18][CH2:19][CH2:20]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][N:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[C:4]1=[O:3]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCBr)c(=O)c2c1
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 0.81 g, 20.2 mmol) in DMF (30 mL) under an atmosphere of nitrogen was added methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (2.05 g, 10.1 mmol) in DMF (20 mL) dropwise. The mixture was stirred for 30 mins, then 1,2-dibromoethane (8.7 mL, 101 mmol) was added quickly and the resulting solution was stirred for 2 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 40% EtOAc/hexanes) to afford methyl 2-(2-bromoethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.20 g, 38%). LC-MS: (FA) ES+ 311.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:43]([BH3-])#N.[Na+].C(O)(=O)C.C=O>CO>[CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:43])[CH:28]4[CH2:29][CH:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:31]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)CC1CC(NC[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC1CC(N(C)C[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of methyl 2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)acetate (267 mg, 0.459 mmol) in methanol (12 mL) was treated with sodium cyanoborohydride (380 mg, 6.1 mmol). The pH of the solution was adjusted to ˜6 by the dropwise addition of a 10% (v/v) solution of glacial acetic acid in methanol. The mixture was treated with 37% formaldehyde (0.57 mL, 7.6 mmol) dropwise and the mixture was stirred at room temperature for 1 h at which time, HPLC indicated the starting material was consumed. The reaction mixture was concentrated to remove the methanol. The aqueous solution that remained was diluted with 25 mL NaHCO3 and the aqueous phase was extracted with three 20 mL portions of CH2Cl2. The organic phase was washed with 20 mL sat NaHCO3, dried over Na2SO4, filtered and concentrated to yield the title compound (272 mg, 100%) as a colorless stiff foam which was found to be of sufficient purity for use in the next step: MS (ESI+) for C31H41N5O7 m/z 596.5 (M+H)+; HPLC purity >95% (ret. time, 2.89 min).
Reaction SMILES: Br[C:2]1[S:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:11].[CH2:12]([Sn](CCCC)(CCCC)CC=C)[CH2:13][CH2:14]C.[Cl-].[Li+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:11][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[S:10][C:2]=1[CH2:14][CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)sc2c1COC2=O
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1sc2c(c1C)COC2=O

Procedure:
In a 100 mL round bottom flask was added 2-bromo-3-methylthieno[2,3-c]furan-6-(4H)-one (60 mg, 0.257 mmol, 1.0 eq), tributyl (prop-2-en-1-yl)stannane (102 mg, 0.309 mmol, 1.2 eq), palladium triphenylphosphane (1:4) (14.9 mg, 0.013 mmol, 0.05 eq) and lithium chloride (32.7 mg, 0.77 mmol, 3.0 eq). The mixture was dissolved in toluene (20 mL), degassed and filled with N2. The mixture was reflux for 3 hr, concentrated, extracted with EtOAc, washed with water. The organic phase was dried over MgSO4, filtered and concentrated. The desired product was obtained after purification by flash column chromatography. LC-MS (IE, m/z): 195.3 [M+1]+; 1H NMR (500 MHz, CDCl3, δ in ppm): 5.16 (2H, s), 2.19 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cc(F)cc(Cl)c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cc(F)cc(Cl)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-Spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.14 g, 0.2 mmol) prepared in Example 114 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.4 g, 3.5 mmol), then aqueous solution (1N) of NaOH (1.2 mL, 1.2 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.13 g, 87%)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17].[N:18]([Si](C)(C)C)=[N+:19]=[N-:20].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[N:17]1[NH:18][N:19]=[N:20][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCCN1C(=O)c2ccccc2C1=O
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCc1nn[nH]n1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
To a solution of 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanenitrile (6.84 g, 30 mmol) and azidotrimethylsilane (14 mL, 108 mmol) in toluene (40 mL) was added dibutyltin oxide (2.1 g, 6.0 mmol). The mixture was heated at 100° C. for 48 h, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (30 and 60%) followed by methanol/DCM (2.5 and 5%) to give the title compound (6.72 g, 83% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:32])([F:30])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)C1
Yield: 35.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]amide (35 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (95 mg), dimethyl-(S)-pyrrolidin-3-yl-amine (20 mg), HBTU (85 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 561.6. 1H NMR (DMSO-d6, 400 MHz): δ 8.67-8.66 (m, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.84-7.82 (d, 1H), 7.66-7.64 (d, 1H), 7.55-7.53 (d, 1H), 7.40-7.37 (d, 1H), 4.09-4.07 (m, 3H), 3.86-3.80 (m, 2H), 3.69 (s, 3H), 3.57 (s, 2H), 2.82-2.78 (m, 6H), 2.30-2.27 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35](OC)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:46]([NH2:48])[CH3:47]>CO>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH:48][CH2:46][CH3:47])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCN
Solvent: CO
Product: CCNC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Yield: 92 %

Procedure:
In a fashion analogous to Step D of Example 1A, 2.15 g of Boc-Tyr-DAla-Phe-Met-OCH3 was treated with 20 ml of ethylamine in 200 ml of methanol to give 2.01 g (92%) of Boc-Tyr-DAla-Phe-Met-NHCH2CH3, m.p. 159°-161° C., [α]D25 =5.04° (c, 0.97 in methanol).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH3:21].C1(C)C=CC=CC=1>[Pt].CC(O)C>[NH2:11][C:5]1[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]([CH3:1])=[C:3]([CH3:21])[C:4]=1[NH:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OCCNc1c(C)c(C)n2nnnc2c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(=O)OCCNc1c(C)c(C)n2nnnc2c1N
Yield: 91.3 %

Procedure:
A Parr vessel was charged with acetic acid 2-[(5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]ethyl ester (50.0 g, 170 mmol), 5% platinum on carbon (5.00 g), toluene (600 mL), and 2-propanol (50 mL) and purged with nitrogen. The vessel was then placed under hydrogen pressure (20 psi, ) for 20 hours at room temperature. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with 90:10 dichloromethane:methanol. The filtrate was concentrated under reduced pressure to provide a dark gray solid, which was triturated with diethyl ether, isolated by filtration, and dried to provide 41.0 g of acetic acid 2-[(8-amino-5,6-dimethyltetrazolo[1,5-a]pyridin-7-yl)amino]ethyl ester as a light gray solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:19])/[C:16]([OH:18])=[O:17])=[CH:10][C:9]=2[C:20]([F:23])([F:22])[F:21])=[CH:3][CH:2]=1.S[C:25]1C=CN=C[CH:26]=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:19])/[C:16]([O:18][CH2:25][CH3:26])=[O:17])=[CH:10][C:9]=2[C:20]([F:21])([F:23])[F:22])=[CH:3][CH:2]=1
Reactant: Sc1ccncc1
Reactant: C/C(=C\c1ccc(Sc2ccncc2)c(C(F)(F)F)c1)C(=O)O
Product: CCOC(=O)/C(C)=C/c1ccc(Sc2ccncc2)c(C(F)(F)F)c1

Procedure:
E-3-[4-(4-Pyridylthio)-3-(trifluoromethyl)phenyl]-2-methyl-propenoic acid guanidide dihydrochloride ##STR9## 4 a) The ester from 3 a was reacted with 4-mercaptopyridine analogously to 3 b. Ethyl E-3-[4-(4-pyridylthio)-3-(trifluoromethyl)phenyl]-2-methyl-propenoate was isolated.