Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=2[CH3:21])=[O:8])=[CH:5][CH:4]=1.Cl[C:27]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH:15]([CH3:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=2[CH3:21])=[O:8])=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C(F)(F)F)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(C(F)(F)F)cc2)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 89) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(p-trifluoromethylbenzoyl)-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C1C=CC(COC([NH:34][C@H:35]([C:40](O)=[O:41])[CH2:36][C:37]([NH2:39])=[O:38])=O)=CC=1>>[NH2:34][C@@H:35]([CH2:36][C:37](=[O:38])[NH2:39])[C:40]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:41]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: NC(=O)C[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Step 4, Example 1, Method A, and employing ((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-asparagine-OH as the starting materials. Subsequent hydrogenation of the resulting product in accordance with the procedures of Step 5, Example 1, Method B, and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.26-4.13 (m, 1H), 4.12-3.98 (m, 1H), 3.42-3.32 (m, 2H), 2.98-2.71 (m, 2H), 1.93 (br.d, 2H), 1.84-1.58 (m, 6H), 1.51 (dd, 2H), 1.42-1.15 (m, 3H), 1.13-0.94 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 40.16. LCMS m/z: [M+H]+=350.3.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[N:10][C:9]([C:12]([O:14]CC)=[O:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO.O>[C:1]1([N:7]2[N:11]=[N:10][C:9]([C:12]([OH:14])=[O:13])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nnn(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nnn(-c2ccccc2)n1
Temperature: 60 °C
Yield: 56.4 %

Procedure:
To a solution of ethyl 2-phenyl-2H-tetrazole-5-carboxylate (0.84 g, 3.9 mmol, 1 eq) in 7.6 mL of EtOH/H2O (1.5:1) was added NaOH (0.31 g, 7.8 mmol, 2 eq). The reaction mixture was heated at 60° C. for 30 min and was then quenched with 0.65 mL of conc. HCl. The contents were filtered and washed with MeOH and the filtrate was dried with Na2SO4 and concentrated in vacuo. Purification by silica gel flash chromatography (100% EtoAc) afforded 2-phenyl-2H-tetrazole-5-carboxylic acid (0.41 g, 2.2 mmol, 55%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)c1cccnc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1cccnc1

Procedure:
The title compound, white solid (18.3 mg, 51.4%), MS (ISP) m/z=437.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and nicotinic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:34])[CH:21]([N:25](C(OC(C)(C)C)=O)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:34])[CH:21]([NH:25][CH3:26])[CH:22]([CH3:23])[CH3:24])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(N-tert-butoxycarbonyl-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamide (8.03 g, 16.42 mmol) in methylene chloride (80 ml), TFA (40 ml) was added and stirred at room temperature for 30 min. The reaction mixture was evaporated to remove the solvent under reduced pressure; the thus obtained residue was mixed with methylene chloride, washed with a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: acetone:hexane=1:2), giving two diastereoisomers A and B of the titled compound, A (2.37 g, 37%) being eluted first and then B (2.17 g, 34%). (A)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[F:16][C:17]([F:22])([F:21])C([O-])=O.[K+].C1(C)C=CC=CC=1.[OH-].[Na+]>CN(C=O)C.CO.[Cu]I>[CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[C:17]([F:22])([F:21])[F:16])([CH3:15])[CH3:14]
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1ccc(OC(C)C)c(Br)c1
Agent: [Cu]I
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Methyl 3-bromo-4-iso-propyloxybenzoate (828 mg; 3.03 mmol) in DMF (25 ml) was treated with potassium trifluoroacetate (922 mg; 6.06 mmol), copper (I) iodide (1.15 g; 6.06 mmol) and toluene (50 ml). The resulting mixture was heated at reflux for 1.5 h (Dean and Stark with removal of ca 50 ml of distillate) followed by reflux for 18 h then cooled. The mixture was poured into Et2O (100 ml) and H2O (100 ml). The two-phase mixture was stirred at room temperature for 0.5 h then filtered through Celite. The two phases were separated, the aq. phase further extracted with EtO (50 ml) and the organic extracts combined, washed with saturated, aq. Na2S2O3, H2O, saturated brine, dried (MgSO4) and evaporated in vacuo to give a brown oil. This was dissolved in MeOH (ca 20 ml) and treated with 2M NaOH (2 ml; 4 mmol) and the resulting solution heated at reflux for 3 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc and H2O. The phases were separated, the aq. phase acidified to pH1 with 2M HCl in the presence of EtOAc and the phases separated. The aq. phase was further extracted with EtOAc, the extracts combined, washed with H2O, saturated brine, dried (MgSO4) and evaporated to dryness in vacuo to give the title compound as a white solid (671 mg; 89%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.O>CN(C=O)C.[Cu](I)I>[CH3:15][C:4]1[N:5]=[C:6]([S:13][CH3:14])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1SC
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(Oc2cccc(C(F)(F)F)c2)nc(C)nc1SC

Procedure:
A solution of methyl 2-(4-chloro-2-methyl-6-methylthio-pyrimidin-5-yl)-acetate (4.9 g) in DMF is added to a suspension of anhydrous potassium carbonate 5.6 g), copper iodide (1.0 g) and 3-trifluoromethylphenol (3.3 g) in DMF (50 ml) at room temperature. The mixture is heated to +120° C. for 90 minutes and then cooled. The cooled mixture is poured into water and extracted successively with ethyl acetate (2×50 ml) and then the organic phase is dried over anhydrous sodium sulfate. Evaporation and drying under high vacuum gives the methyl 2-[2-methyl-4-methylthio-6-(3-trifluoromethyl-phenoxy)-pyrimidin-5-yl]-acetate in form of a dark oil. NMR (CDCl3): 7.25-7.55 (m, 4H); 3.78 (s, 3H); 3.70 (s, 3H); 2.62 (s, 3H); 2.46 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 346 (M+, 32), 91 ([PhCH2]+, 100).
Reaction SMILES: C([N:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:6]=2[CH2:5]1)(=O)C.Cl>[OH-].[Na+].CO.O.C(OCC)C>[CH2:17]([N:7]1[C:6]2[CH2:5][NH:4][CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCn1c2c(c3ccccc31)CCN(C(C)=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCCCCn1c2c(c3ccccc31)CCNC2

Procedure:
A portion of the crude 2-acetyl-9-(n pentyl)1,2,3,4-tetrahydro-β-carboline (1.7 g) as heated at reflux for 4.5 hours in 2 N NaOH (50 mL) in methanol:water (2:3, v/v). The methanol was removed by evaporation under vacuum, and the crude 9-(n-pentyl)1,2,3,4-tetra-hydro-β-carboline free base was extracted into chloroform. This extract was dried over anhydrous MgSO4, filtered, and the filtrate evaporated under vacuum. The hydrochloride salt was prepared by passing dry HCl through a solution of the crude free base in diethyl ether. The resulting precipitate was filtered and recrystallized from acetonitrile to yield pure 9-(n-pentyl)1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A 0° C. solution of Example 1E (80 mg, 0.31 mmol) in dichloromethane (4 mL) was treated with pyridine (0.03 mL, 0.38 mmol) and benzoyl chloride (0.038 mL, 0.32 mmol), stirred at 0° C. for 1 hour, then at room temperature overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate to provide 39 mg (35%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H); 8.28 (s, 1H); 7.98 (d, J=8.1 Hz, 4H); 7.63-7.54 (m, 3H); 7.40 (d, J=8.1 Hz, 2H); 2.31 (s, 3H); HRMS(ESI) Calcd. for C20H17N4OS: 361.1118. Found: 36.1122.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[C:11]([CH2:32][CH3:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6]C=CC=1.BrCC1CC1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=4[N:31]=3)=[C:11]([CH2:32][CH3:33])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CCc1cc(OCc2ccccc2)ccc1-c1nc2cnc(OC[C@H](C)NC(C)=O)cc2o1
Agent: BrCC1CC1
Product: CCc1cc(OCC2CC2)ccc1-c1nc2cnc(OC[C@H](C)NC(C)=O)cc2o1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-2-ethylphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (bromomethyl)cyclopropane, and in the same manner as in Step D of Example 68, the title compound was obtained.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:11][CH2:10][N:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:8]2[N:23]=[CH:24][CH:25]=[CH:26][C:7]=2[C:6]1=O)C.O.[NH2:29]N>CO>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:9]2[CH2:10][CH2:11][C:5]3[CH:4]=[N:2][NH:29][C:6]=3[C:7]3[CH:26]=[CH:25][CH:24]=[N:23][C:8]2=3)=[O:22])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: NN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc2C1=O
Solvent: CO
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cn[nH]c2-c2cccnc21
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a slurry of 0.51 g of 6-[(dimethylamino)methylene]-6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 17 ml of methanol under argon is added 0.14 g of hydrazine hydrate. The mixture is stirred overnight and the solvent removed under vacuum. The residue is dissolved in hot chloroform-methanol (95:5) and filtered through silica gel and washed filter pad with chloroform-methanol (95: 5). The filtrate is concentrated to dryness to give 0.48 g of yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH2:27][CH3:28])([O-:26])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[C:27](/[N+:24]([O-:26])=[O:25])\[CH3:28])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(/C=C(\C)[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (8.0 g, 33.05 mmol), ammonium acetate (2.55 g, 33.05 mmol) and nitroethane (120 ml) were stirred under reflux for 22 h. The reaction mixture was cooled to rt and nitroethane was removed in vacuo. The solid residue was dissolved in ethyl acetate (200 ml), washed with water (40 ml) and brine (2×40 ml), dried (MgSO4) and concentrated in vacuo. Recrystallisation from ethanol afforded the title compound (6.19 g, 63%) as yellow crystals. mp=102-104° C. 1H NMR (270 MHz; CDCl3) 2.27 (3H, s, CH3), 3.94 (3H, s, OCH3), 5.19 (2H, s, CH2Ph), 6.91 (1H, d, J=2.0 Hz, CH), 6.94 (1H, d, J=8.4 Hz, CH), 7.05 (1H, dd, J=8.4, 2.0 Hz, CH), 7.30-7.43 (4H, m, 4×CH), 7.97 (1H, s, CH). 13C NMR (67.5 MHz; CDCl3) 14.03 (CH3), 56.15 (OCH3), 71.25 (CH2Ph), 111.69 (CH), 115.77 (CH), 124.93 (C), 124.94 (CH), 127.16 (CH), 128.19 (CH), 128.83 (CH), 133.84 (CH), 136.65 (C), 145.92 (C), 148.00 (C), 151.51 (C). LC/MS (APCI−) tr=1.07 min, m/z 297.93 (M−H)−.
Reaction SMILES: ClC1C=C(NC2C=CC(N3CCC(O)(C)CC3)=CN=2)C(=O)N(C)N=1.[CH3:25][N:26]1[CH2:32][C@H:31]2[N:33]([C:34]3[CH:35]=[N:36][C:37]([N+:40]([O-])=O)=[CH:38][CH:39]=3)[C@H:28]([CH2:29][CH2:30]2)[CH2:27]1>CO.[Pd]>[CH3:25][N:26]1[CH2:32][CH:31]2[N:33]([C:34]3[CH:39]=[CH:38][C:37]([NH2:40])=[N:36][CH:35]=3)[CH:28]([CH2:29][CH2:30]2)[CH2:27]1
Reactant: CN1C[C@H]2CC[C@@H](C1)N2c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Agent: Cn1nc(Cl)cc(Nc2ccc(N3CCC(C)(O)CC3)cn2)c1=O
Solvent: CO
Product: CN1CC2CCC(C1)N2c1ccc(N)nc1

Procedure:
This reaction was carried out under similar conditions to those described above in preparation of 6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-2-methyl-pyridazin-3(2H)-one. (1R,5S)-3-methyl-8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane (500 mg, 2.01 mmol) in methanol (15 ml) was hydrogenated at 50 psi with 10% Pd/C (42.9 mg, 40.3 umol) overnight. The catalyst was filtered off and the resultant filtrate was concentrated in vacuo to afford 5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-amine. The product was carried to next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(I)c12
Yield: 74.6 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) (Toronto Research Chemicals, Inc) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10% solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6%) of the title compound as off-white crystals. The mother liquid was evaporated up to ⅓ volume and crystallized again from ethanol to give 2.47 g (12.3%) of the title product.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([F:29])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:30][C:31]1[CH:56]=[CH:55][C:34]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(=O)CN(C)CC(=O)O3)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C(O[Pd]OC(=O)C)(=O)C>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:56][CH:55]=3)=[CH:43][CH:42]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([F:29])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(F)CC2)c1Br
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(F)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
The diacetoxypalladium (4.0 mg, 0.018 mmol) was added to a argon purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(4-fluoro-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (85 mg, 0.18 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (73.3 mg, 0.197 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (14.7 mg, 0.036 mmol), and potassium phosphate tribasic (286 mg, 1.34 mmol) in dioxane (2 mL) and water (0.4 mL) and stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-40% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-fluoro-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 85.1 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.22-7.20 (m, 1H), 7.14 (t, J=9.2 Hz, 2H), 7.02-7.00 (m, 3H), 5.94 (br. s, 1H), 4.96-4.93 (m, 1H), 4.22 (t, J=7.3 Hz, 2H), 3.41-3.39 (m, 4H), 3.06 (t, J=6.6 Hz, 2H), 2.47 (br. s, 3H), 2.05 (s, 3H), 1.69-1.43 (m, 4H), 1.24 (br. s, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.13 (br. s, 12H). UPLC (M+H)=609.4.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:71]2[N:72]=[C:73]([NH:76]C(OC(C)(C)C)=O)[S:74][CH:75]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42]([CH2:60][CH2:61][CH2:62][NH:63]C(OC(C)(C)C)=O)[C:43]([NH:52]C(OC(C)(C)C)=O)=[N:44]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:63][CH2:62][CH2:61][CH2:60][N:42]([CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:71]3[N:72]=[C:73]([NH2:76])[S:74][CH:75]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[C:43]([NH2:52])=[NH:44]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)N(CCCN)Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 8.2 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((2,3-bis(tert-butoxycarbonyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)guanidino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (118 mg, 99 μmol), DCM (2 mL) and TFA (2.0 mL, 26 mmol). The crude residue was purified via reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (5.1 mg, 8%). LCMS: Rt=0.28 min, m/z=629.4 (M+1). Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13](=[O:33])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:16]2)[CH2:12][CH2:11][CH2:10]1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH:13]([OH:33])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH2:16]2)[CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccccc1C1(C(=O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccccc1C1(C(O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Yield: 59.7 %

Procedure:
1-[1-(2-Methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (15 mg) was dissolved in 2 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (5 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 1-[1-(2-methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanol (9 mg, 60%). Data for this mixture of diastereomeric amino alcohols: MS 464 (M+1); 1H NMR (300 MHz, CDCl3) partial: δ 6.8-7.6 (m, 8H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), the 63.09 singlet for the starting material was absent.