Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.C1COCC1.NN>C(O)C.[Ni]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[CH:14]([O:13][C:6]1[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[CH:12]=[C:4]([NH2:1])[CH:5]=1)[CH2:15]2
Reactant: O=[N+]([O-])c1cc(OC2CN3CCC2CC3)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(OC2CN3CCC2CC3)c2occc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
3-[(5-Nitro-1-benzofuran-7-yl)oxy]quinuclidine (1.38 g, 4.79 mmol; obtained in Step 1) was dissolved in ethanol:THF (100 mL: 25 mL) and Raney-nickel (slurry in ethanol; 6 mL) and hydrazine (891 μL, 0.18 mmol) were added. The mixture was stirred at room temperature for 3 h and then filtered through Celite and the solvent was removed in vacuo. The crude product was purified by flash chromatography [eluent: DCM:methanol (6:1) and chloroform:MeOH:triethylamine (9:1:0.1)] to give 7-(1-azabicyclo[2.2.2]oct-3-yloxy)-1-benzofuran-5-amine (500 mg; 40%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][N:8]([CH2:10][CH2:11][OH:12])[CH2:7][N:6]([CH2:13][CH2:14][OH:15])[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O.C(Cl)Cl>[C:22]([O:12][CH2:11][CH2:10][N:8]1[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][N:6]([CH2:13][CH2:14][OH:15])[CH2:7]1)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: OCCN1CN(CCO)CN(CCO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN1CN(CCO)CN(CCO)C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1,3,5-tris(2-Hydroxyethyl)perhydro-s-triazine (21.6 g, 0.1 mole) and potassium carbonate (35 g) are combined in a mixture of 50 ml of water and 150 ml of methylene chloride at 0° C. Oleic acid chloride (30 g, 0.1 mole) in 50 ml of methylene chloride is added at a rate such that the reaction mixture is retained at a temperature below about 10° C. After complete addition, the mixture is stirred at 0° C. for 15 hours and then at about 25° C. for an additional 16 hours. The organic layer is separated, dried over magnesium sulfate and concentrated to a yellow oil. Analysis by infrared spectroscopy and nuclear magnetic resonance spectroscopy identify the product as 1,3,5-triazine-1,3,5-(2H,4H,6H)triethanol monooleate.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:27]1([C:30]([O:32]CC)=O)[CH2:29][CH2:28]1)[CH:10]([N:12](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-].[C]>[Si:1]([O:8][CH:9]1[C:27]2([CH2:29][CH2:28]2)[C:30](=[O:32])[NH:12][CH:10]1[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1NC(=O)C2(CC2)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
To a solution of ethyl 1-[(1RS,2RS)-1-(tert-butyldimethylsilyloxy)-2-(dibenzylamino)propyl]cyclopropanecarboxylate (1.36 g) in methanol (16 mL) was added 10% palladium hydroxide-carbon (containing 50% water, 280 mg), and the mixture was stirred at room temperature for 18 hr under a hydrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/4) to give the title compound as a colorless solid (yield: 164 mg, yield:22.8%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](N(OC)C)=[O:11])=[N:4][CH:5]=[C:6]([S:8][CH3:9])[N:7]=1.CC(C[AlH]CC(C)C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH:10]=[O:11])=[N:4][CH:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CON(C)C(=O)c1ncc(SC)nc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSc1cnc(C=O)c(Cl)n1
Temperature: 78 °C
Reaction time: 2 h

Procedure:
To a solution of 55C (750 mg, 3.03 mmol) in THF at 78° C., DIBAL-H (3.33 mL, 3.33 mmol) in toluene was added to the solution slowly. Then, it was stirred for 2 hours at 78° C. HCl (4 mL, 1 N) was added to the solution and warmed to 0° C. The mixture was stirred for 20 minutes at 0° C. then extracted with EtOAc twice. The organic layer was dried and concentrated to provide the crude product which was used without further purification. MS (m/z) 189 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5].[CH2:18]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH3:2][O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][C@@H:27]([C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:30])[CH3:29])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5]
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(O[C@H](C)C(=O)OCc2ccccc2)c2ccc(C)cc2n1
Reaction time: 2 h

Procedure:
To a solution of 1.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester hydrochloride and 0.83 g benzyl-L-lactate in 30 ml THF were added 1.81 g triphenylphosphine and 1.20 g diethylazodicarboxylate. After 2 h LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.80 g
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:11].[B-](F)(F)(F)F.CN(C(O[N:36]1[C:41](=[O:42])[CH2:40][CH2:39][C:37]1=[O:38])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:38]=[C:37]1[CH2:39][CH2:40][C:41](=[O:42])[N:36]1[O:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[CH2:9][CH2:8][N:3]1[C:4](=[O:7])[CH:5]=[CH:6][C:2]1=[O:1]
Reactant: O=C(O)CCCCCCCNC(=O)CCN1C(=O)C=CC1=O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1C(=O)C=CC1=O)NCCCCCCCC(=O)ON1C(=O)CCC1=O
Yield: 37 %

Procedure:
To a solution of 8-[3-(2,5-dioxo-2,5-dihydropyrrol-1-yl)propionylamino]octanoic acid (917 mg, crude) in dry THF (15 ml) was added TSTU (1.07 mg) and DIPEA (0.65 ml). The mixture was stirred under nitrogen over night. The mixture was concentrated. To the residue was added EtOAc and the precipitate was filtered off. The filtrate was extracted with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give an off-white solid. Overall yield 37% (444 mg). LC-MS, M/z: 408.39 (M+1).
Reaction SMILES: [CH3:1][N:2]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]([C:15]([O-:17])=O)=[CH:5]1)[CH3:3].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:15]([C:6]2[C:7](=[O:14])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([N:2]([CH3:1])[CH3:3])[CH:5]=2)=[O:17])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CN(C)n1cc(C(=O)[O-])c(=O)c2ccccc21
Product: CN(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccccc21

Procedure:
Ethyl 1-(dimethylamino-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.21 g) of Preparation No. 59 and 4-chlorobenzylamine (1.2 mL) are heated to 180° C. for 10 hrs under nitrogen. The product is precipitated from the cooled reaction mixture by dilution with a mixture of toluene and hexanes. The crude product is then recrystallized from aqueous acetic acid to give 0.030 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH:32](B1OC(C)(C)C(C)(C)O1)=[CH2:33].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:32]=[CH2:33])=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(I)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)cc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(4-iodo-3-methyl phenoxy)-2-propylbenzene (265 mg, 0.471 mmol) was dissolved in N,N-dimethylformamide (4.7 mL) and water (0.9 mL). The resultant mixture was sequentially added with vinylboronic acid pinacol ester (280 μL, 1.65 mmol), tetrakis triphenylphosphine palladium (54 mg, 0.0471 mmol), and sodium carbonate (300 mg, 2.83 mmol), and stirred at 80° C. for 1 hour. After completion of the reaction, the reaction solution was filtered using celite and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/chloroform), and 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(3-methyl-4-vinylphenoxy)-2-propylbenzene (218 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:13].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:13])[C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C#N)cc(N)c1N
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 4-amino-3-methyl-5-nitro-benzonitrile (3.24 g, 18.3 mmol) in ethanol (80 mL) was added tin chloride dihydrate (8.67 g, 49.75 mmol). The reaction mixture was heated to reflux for 14 h, then cooled to room temperature, and concentrated in vacuum. The residue was diluted with ethyl acetate (100 mL) and treated with triethylamine (20 mL). The resulting slurry was filtered through a pad of celite and the filtercake was rinsed with three-portion ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na2SO4 and filtered. After removal of solvent, the residue was purified by flash chromatography on silica gel (30%-50% EtOAc/hexane) to yield the title compound (2.17 g, 81%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.94 (1H, s), 6.85 (1H, s), 2.16 (3H, s). LCMS (M+H)+ m/z 148 (t=0.67 min.). Procedure for the Preparation of 5-bromo-3-methyl-benzene-1,2-diamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[C:13]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH:30][C:25]1[C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:31]=[CH:32][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:8]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1cc(C(=O)O)ccc1C
Product: COc1cc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)ccc1C
Yield: 28 %

Procedure:
Using the procedure described in Example 102, Part A, 3-methoxy-4-methylbenzoic acid (3.6 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 210 mg (28%) of the title compound.
Reaction SMILES: [CH:1]1([C:4](=[O:26])[C:5](=[CH:22]OCC)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18]([CH3:21])(=[O:20])=[O:19])=[O:7])[CH2:3][CH2:2]1.Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4](=[O:26])[CH:5]([CH:22]=[N:31][O:30][CH2:28][CH3:29])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:9]=2[S:18]([CH3:21])(=[O:19])=[O:20])=[O:7])[CH2:3][CH2:2]1
Reactant: CCON
Reactant: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCON=CC(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-cyclopropyl-2-ethoxymethylene-1-(2-methylsulphonyl-4-trifluoromethylphenyl)propan-1,3-dione (3.5 g), O-ethylhydroxylamine hydrochloride (0.97 g) and sodium acetate (0.83 g) in ethanol (15 ml) was stirred at 25° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated and the residue purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and 3-cyclopropyl-2-(ethoxyiminomethyl)-1-(2-methylsulphonyl-4-trifluoromethylphenyl)propan-1,3-dione (compound 1) was obtained as white crystals (2 g), m.p. 46° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:12][N:13]([CH3:14])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNC
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 5-bromopyridine-2-carboxylic acid (3.00 g, 14.85 mmol), dimethyl amine hydrochloride (1.82 g, 22.30 mmol) and triethylamine (6.21 ml, 44.60 mmol) in 20 mL of DMF was added HATU (8.47 g, 22.30 mmol). The mixture was stirred at room temperature overnight, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried with Na2SO4, concentrated and purified by Biotage column chromatography with 60-70% EtOAc in hexanes to give a yellow oil (1.56 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.77 Hz, 1 H) 7.88 (dd, J=8.34, 2.27 Hz, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 3.06 (d, J=14.15 Hz, 6 H); LCMS for C8H9BrN2O m/z 229.00 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:33][C:34]([F:68])([F:67])[C:35]1[CH:36]=[C:37]([CH:64]=[CH:65][CH:66]=1)[CH2:38][NH:39][C:40](=[O:63])[C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([N:53]([CH2:58][CH2:59][O:60][CH3:61])[CH2:54][CH2:55][O:56][CH3:57])[CH:50]=[CH:49][C:48]=2[NH2:62])[CH:42]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:67][C:34]([F:33])([F:68])[C:35]1[CH:36]=[C:37]([CH:64]=[CH:65][CH:66]=1)[CH2:38][NH:39][C:40]([C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([N:53]([CH2:54][CH2:55][O:56][CH3:57])[CH2:58][CH2:59][O:60][CH3:61])[CH:50]=[CH:49][C:48]=2[NH:62][C:14]([C:13]2[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])[CH:42]=1)=[O:63]
Reactant: COCCN(CCOC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCN(CCOC)c1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Into a 10-mL vial, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (188.64 mg, 0.64 mmol, 2.00 equiv) in dichloromethane (5 mL), EDC.HCl (120.8 mg, 0.63 mmol, 1.98 equiv), 4-dimethylaminopyridine (77.6 mg, 0.64 mmol, 2.00 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(bis(2-methoxyethyl)amino)phenyl)-isonicotinamide (160 mg, 0.32 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane, and washed with 3×50 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5˜1). The product was obtained as 160 mg (64%) of a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([Br:16])=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(OCc2ccccc2)ccn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1cc(OCc2ccccc2)c(Br)cn1
Yield: 47 %

Procedure:
A flask was charged with 4-(benzyloxy)pyridin-2-amine (10.69 g, 53.39 mmol) and 20 mL acetic acid was added. Bromine (2.735 ml, 53.39 mmol) and the reaction was stirred for 10 minutes. The reaction mixture was concentrated and purified using silica gel column chromatography eluting with 50%-100% ethyl acetate/hexane provide the desired product (7.0 g, 42.28% yield) as brown solid
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])=[N:35][C:34]=1[C:45](O)=[O:46])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])=[N:35][C:34]=1[C:45]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:46]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: COC1CCN(c2c(NC(=O)c3nc(-c4ccccc4F)sc3N)cnn2C)CCC1N
Yield: 63 %

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave 324 (118 mg, 63% over two steps). 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.30 (t, J=8.2 Hz, 1H), 7.51 (s, 1H), 7.48-7.39 (m, 3H), 7.39-7.27 (m, 2H), 3.64 (s, 3H), 3.27 (s, 4H), 3.24-2.90 (m, 7H), 2.14-2.01 (m, 1H), 1.91-1.81 (m, 1H), 1.77-1.54 (m, 2H). LCMS (ES+) m/z 460 (M+1)
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[C:18]1([CH2:24]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[CH2:24]([O:17][C:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g (8.2 mmol) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (commercially available), 0.978 g (9.0 mmol) phenyl-methanol (commercially available), 3.16 g (9.8 mmol) O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 1.24 g (12.3 mmol) NEt3 in 10 mL DMF was stirred at room temperature for 1 h. The mixture was evaporated to dryness and extracted with DCM and Na2CO3 aq. The combined organic phases were dried with MgSO4 and evaporated. The residue was treated with 100 mL 4N HCl in dioxane at room temperature for 4 h. The mixture was evaporated to dryness to yield trans-4-amino-cyclohexanecarboxylic acid benzyl ester (MS (m/e): 360.4 (MH+)) which was used without further purification. 150 mL DCM was added, 2.95 g (14 mmol) 4-cyano-benzenesulfonyl chloride (commercially available) and 6.17 g (61 mmol) NEt3 and the mixture was stirred at room temperature for 16 h. The mixture was extracted with DCM and 1N HCl aq. and the combined organic phases were evaporated. The residue was recrystallized from methanol to yield 1.9 g (58%) of the title compound. MS (m/e): 397.0 (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([Br:17])=[CH:11][C:10]=2[OH:18])[C:6]([CH3:20])([CH3:19])[CH2:5][CH2:4][C:3]1=[O:21].[CH3:22][Li]>C1COCC1.CCOCC>[OH:21][C@@:3]1([CH3:22])[CH2:4][CH2:5][C:6]([CH3:19])([CH3:20])[C@H:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([Br:17])=[CH:11][C:10]=2[OH:18])[C:2]1=[CH2:1]
Reactant: C=C1C(=O)CCC(C)(C)[C@@H]1Cc1cc(OC)c(Br)cc1O
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C1[C@@H](Cc2cc(OC)c(Br)cc2O)C(C)(C)CC[C@]1(C)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flame-dried 50 mL round-bottomed flask containing a solution of (3S)-2-methylidene-3-(2-hydroxy-4'-bromo-5'-methoxyphenyl)methyl-4,4-dimethylcyclohexan-1-one (61) (150.0 mg, 0.322 mmol) in 15 mL THF at -70° C. under nitrogen atmosphere was added methyllithium (0.60 mL of a 1.40M solution in ether, 0.840 mmol, 2.61 equiv), and the mixture was allowed to stir for 5 min before quenching with saturated aqueous NH4C1. Upon warming to room temperature, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over Na2SO4, and concentrated under diminished pressure gave a 3:1 (1R,3S: 1S,3S) mixture of the diastereomeric tertiary hydroxyls. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 28 mg (18%) of the less polar, minor 1S,3S isomer (63), along with 88 mg (57%) of the more polar, major 1R,3S isomer (62), as well as 30.2 mg (20%) recovered starting material. The diastereomeric alcohols were then independently converted to the corresponding free phenols in the usual manner, providing the trans, 1R,3S isomer (62) 1H NMR (400MHz, CDCl3) δ0.84 and 1.04 (2s, 2×3 H, geminal-CH3 's), 1.39 (s, 3H, 5-CH3), 2.43 (br dd, 1H, J-- 11.3, 2.9 Hz, 3-H), 2.72 and 2.85 (d of ABq, 2H, JAB =16.1 Hz, JA =3.1 Hz, JB =11.5 Hz, benzylic-CH2) 3.77 (s, 3H, OCH3), 4.57 and 5.16 (2s, 2×1H, methylidene-CH2), 6.63 (s, 1H, 6'-H), 6.93 ppm (s, 1H, 3'-H); and the cis, 1S,3S isomer (63) 1H NMR (400MHz, CDCl3) δ0.77 and 1.08 (2s, 2×3H, geminal-CH3 's), 1.36 (s, 3H, 5-CH3), 2.65 and 2.82 (d of ABq, 2H, JAB =16.0 Hz, JA =3.0 Hz, JB =11.8 Hz, benzylic-CH2), 2.97 (br dd, 1H, J=11.7, 2.5 Hz, 3-H), 3.79 (s, 3H, OCH3), 4.64 and 4.96 (2s, 2×1H, methylidene-CH2), 6.73 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H). [Compound 63 is hereinafter also referred to as COMPOUND "J" or 120286, and Compound 62 is hereinafter also referred to as COMPOUND "P" or 120273] ##STR12##
Reaction SMILES: [Na].CC[O-].[Na+].[C:6]1([CH2:12][C:13]([N:15]([C:23]([CH3:31])([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:17][C:18]([O:20]CC)=O)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH3:30][C:23]([N:15]1[CH2:16][CH2:17][C:18](=[O:20])[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]1=[O:14])([CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCN(C(=O)Cc1ccccc1)C(C)(C)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(C)(c1ccccc1)N1CCC(=O)C(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 51.6 %

Procedure:
12.8 g of sodium metal was added to 500 ml of ethanol to prepare sodium ethylate, and 65.7 g (0.186 mol) of ethyl 3-(N-phenylacetyl-α,α-dimethylbenzylamino)propionate prepared by the method of Reference Example 17 was added thereto. The mixture was refluxed under heating for one hour. The reaction solution was cooled to room temperature, and then ethanol was distilled off under reduced pressure. The residue was poured into ice water and acidified with a 10% hydrochloric acid aqueous solution. Precipitated crystals were collected by filtration. The crude product thereby obtained was recrystallized from ethanol to obtain 29.5 g (yield: 51.6%) of the desired compound.