Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([NH:9][C:10](=[O:21])[O:11][CH2:12][C:13]23[CH2:20][CH2:19][N:16]([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[N:8]=1)(=O)[NH2:2].P(Cl)(Cl)([Cl:30])=O.C([O-])(O)=O.[Na+].Cl.CCOC(C)=O>CN(C=O)C.CCOC(C)=O>[ClH:30].[C:1]([C:4]1[S:5][C:6]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:7]([NH:9][C:10](=[O:21])[O:11][CH2:12][C:13]23[CH2:14][CH2:15][N:16]([CH2:17][CH2:18]2)[CH2:19][CH2:20]3)[N:8]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1nc(NC(=O)OCC23CCN(CC2)CC3)c(-c2ccccc2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc(NC(=O)OCC23CCN(CC2)CC3)c(-c2ccccc2)s1
Reaction time: 1 h

Procedure:
To a solution of 1-azabicyclo[2.2.2]oct-4-ylmethyl (2-carbamoyl-5-phenyl-1,3 thiazol-4-yl)carbamate (100 mg) in DMF (5 mL) was added phosphorous oxychloride (48 μL) at 0° C., followed by stirring for 1 hour. To the reaction mixture was added EtOAc, followed by dilution, addition of an aqueous NaHCO3 solution, and extraction with EtOAc. The organic layer was washed with water and brine in this order, then dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH:28% aqueous ammonia=9:1:0.1), and the brown oily substance obtained was dissolved in EtOAc, followed by addition of 4 M HCl/EtOAc and stirring. The mixture was concentrated under reduced pressure, EtOAc was added thereto, and the solid precipitated was collected by filtration to obtain 1-azabicyclo[2.2.2]oct-4-ylmethyl (2-cyano-5-phenyl-1,3-thiazol-4-yl)carbamate hydrochloride (33 mg) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[C:12]([F:19])[CH:11]=2)=[CH:4][CH:3]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:17](=[O:18])[NH:26][N:25]=[N:24]3)=[C:12]([F:19])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C=Nc1ccc(OCc2ccc(F)cc2)cc1F
Product: O=c1[nH]nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of 7.10 g (0.027 mole) of 4-(4-fluorophenylmethoxy)-2-fluorophenyl isocyanate and 7.0 g (0.060 mole) of trimethylsilyl azide was heated at reflux for approximately seventeen hours. The solution was then allowed to cool to room temperature before being poured over ice. A solid formed and was recovered by filtration. The solid was dried, leaving 8.08 g of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-5H-tetrazol-5-one, m.p. 171°-172° C.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]1>CN(C)C=O>[CH2:1]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.3 %

Procedure:
Benzyl chloride (5.5 ml, 47.8 mmol) and potassium carbonate (8.3 g, 60.1 mmol) were added to a solution of ethyl 3-piperidinecarboxylate (6.55 g, 40.0 mmol) in N,N-dimethylformamide (20 ml), and the resulting mixture was stirred at 100° C. for 10 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was subjected to azeotropic concentration with toluene. The resulting residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1) to obtain ethyl 1-benzyl-3-piperidinecarboxylate (7.45 g, 75.3%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(OCC)C.C([Li:21])(C)(C)C>CCCCC>[F:1][C:2]1[C:7]([Li:21])=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: [Li]C(C)(C)C
Reactant: Fc1cc(F)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CCCCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 ml volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 5 g (29.8 mmol) of pentafluorobenzene and 30 ml of diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 12.3 g (29.8 mmol) of 15.5 wt. % pentane solution of tert-butyllithium charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:20]N(C)P(N(C)C)(N(C)C)=O.CI>O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH3:20])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 28.2 parts of p-(2-thenoyl)hydratropic acid, sodium salt and 250 parts of hexamethylphosphoramide are added 56.8 parts of methyl iodide at room temperature (slightly exothermic reaction). The whole is stirred at room temperature for 1 hour. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with 140 parts of diisopropylether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The residue is crystallized from 35 parts of diisopropylether at 0° C, washed with cooled ether and dried, yielding methyl p-(2-thenoyl)hydratropate; mp. 62° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>CN1C(=O)CCC1.O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:7][C:4]1[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(N)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of benzene-1,4-diamine (5.0 g) in NMP (30 ml) was added dropwise, over 0.5 h, a solution of 2-chlorobenzo[d]oxazole (6.03 g) in NMP (50 mL). After the addition was complete, the mixture was stirred at ambient temperature for 1 h. After this time, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (150 ml), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (9.20 g) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>ClCCl>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:45]([NH:44][C:42]([O:41][CH2:40][CH:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:31]3[C:39]2=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:43])=[S:46])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=S)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (2.5 g) synthesized in Example 303-2 in dichloromethane (20 mL) was added dropwise 9H-fluorene-9-ylmethyloxycarbonylisothiocyanate (2.5 g), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and subjected to silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (3.1 g) as a pale-brown solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.0 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (0.1 M) was added acetic anhydride (1.1 equiv.). The resulting mixture was stirred at RT for 45 min. After concentration, the residue was partitioned between EtOAc and water. The organic phase was washed with water and then with brine. After drying over sodium sulfate the solution was concentrated in vaccuo to give crude (R)-tert-butyl 2-(acetamidomethyl)morpholine-4-carboxylate which was used in the next step without further purification. LCMS (m/z) (M+H)=159.1 (-Boc), Rt=0.53 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccccc1F
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccccc1F)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH3:14])[CH3:13])=[O:3].[CH3:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18]>>[CH:12]([C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[O:4][C:2]([O:18][CH2:17][C:16]([CH3:21])([CH3:15])[CH2:19][OH:20])=[O:3])([CH3:14])[CH3:13]
Reactant: CC(C)(CO)CO
Reactant: Cc1ccc(C(C)C)c(OC(=O)Cl)c1
Product: Cc1ccc(C(C)C)c(OC(=O)OCC(C)(C)CO)c1

Procedure:
The reaction of 2-isopropyl-5-methylphenyl chloroformate with 2,2-dimethyl-1,3-propanediol is conducted on a 0.01 mole scale employing the same conditions as described in Example I. A 1.3 g yield of the pure product is obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc([N+](=O)[O-])c(F)c1
Yield: 97.7 %

Procedure:
By the method of Example 1, Step K, 1.71 g (0.010 mole) of 3-fluoro-4-nitrophenol and 2.85 g (0.011 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate were reacted in the presence of 1.66 g (0.012 mole) of anhydrous potassium carbonate in 100 mL of N,N-dimethylformamide, yielding 3.55 g of methyl 2-[2-(3-fluoro-4-nitrophenoxymethyl)-5-methylphenoxy]propionate as a yellowish solid, m.p. 92°-94° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7]1)[C:3](=[O:5])[CH3:4]>C(O)C.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH2:7]2)=[CH:16][CH:15]=1
Reactant: CC(=O)N(C)C1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N(C)C1CCN(c2ccc(N)cc2)C1
Reaction time: 3 h

Procedure:
A suspension of N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (3.5 g) and palladium(II) hydroxide (20% on carbon; 0.9 g) in ethanol (150 ml) and ethyl acetate (300 ml) was vigorously stirred under a hydrogen atmosphere (atmospheric pressure) for 3 hours. The catalyst was then removed by filtration, and the filtrate was concentrated. This resulted in the product with the molecular weight of 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>C1COCC1>[C:7]([C:6]1[C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=[CH:10][C:9]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:32]([NH:31][CH2:28][CH2:29][CH3:30])=[O:33])[CH2:16]1)#[N:8]
Reactant: N#Cc1c(OCC2CCCNC2)cccc1[N+](=O)[O-]
Reactant: CCCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.4 %

Procedure:
To a solution of 2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 262d) (0.10 g, 0.34 mmol) in THF (6 mL) were added triethylamine (0.10 mL, 0.76 mmol) and propylisocyanate (0.05 mL, 0.52 mmol) and the reaction mixture was stirred at r.t. under nitrogen for 3 hour then filtered and evaporated, to give 3-((2-cyano-3-nitrophenoxy)methyl)-N-propylpiperidine-1-carboxamide (0.13 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 0.81 (t, J=7.2 Hz, 3H), 1.34-1.41 (m, 4H), 1.62-1.64 (bm, 1H), 1.87-1.95 (bm, 2H), 2.64-2.77 (m, 2H), 2.93-2.98 (m, 2H), 3.77 (bd, J=12.8 Hz, 1H), 3.98 (bd, J=12.8 Hz, 1H), 4.09-4.13 (m, 1H), 4.17-4.20 (m, 1H), 6.38 (d, J=5.6 Hz, NH), 7.74 (bdd, J=1.6 Hz, J=8.0 Hz, 1H), 7.88-7.94 (m, 2H). MS 347 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[CH:21][N:22]([CH3:34])[C:23]=2[C:24]2[S:33][C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH2:32])[C:26]=3[CH:25]=2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C1COCC1>[NH2:32][C:31]1[C:26]2[CH:25]=[C:24]([C:23]3[N:22]([CH3:34])[CH:21]=[N:20][C:19]=3[C:15]3[CH:14]=[C:13]([NH:12][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:18]=[CH:17][CH:16]=3)[S:33][C:27]=2[N:28]=[CH:29][N:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1cnc(-c2cccc(NC(=O)OCc3ccccc3)c2)c1-c1cc2c(N)ncnc2s1
Reaction time: 1 h
Yield: 28 %

Procedure:
Benzylchloroformate (0.027 mL) was added to a solution of 6-[4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 110) (40 mg) and pyridine (0.02 mL) in THF (7 mL). The mixture was stirred under an inert atmosphere for 1 hour, then quenched with H2O (10 mL) and extracted EtOAc (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with CH2Cl2:MeOH (0-10%) gave the title compound as a gum (16 mg, 28%);
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12]/[C:13](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:14]/[C:15](O)=[O:16]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:15](=[O:16])/[CH:14]=[C:13](/[CH3:12])\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: C/C(=C/C(=O)O)c1ccccc1
Agent: Cl
Product: C/C(=C/C(=O)N[C@H]1CN2CCC1CC2)c1ccccc1

Procedure:
Prepared as a free base by a procedure analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and Z-3-methyl-3-phenylpropenoic acid; MS (ES+) 271 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1Br.[OH-].[Na+].[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1>COCCOC.O.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:15]1[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23]
Reactant: Clc1cccc(Cl)c1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 61.6 %

Procedure:
To a solution of 2,6-dichlorobromobenzene (3.5 g, 15.7 mmol) and sodium hydroxide (3.14 g, 78.5 mmol) in DME-water (2:1) was added 5-fluoro-2-methoxybenzene boronic acid (4.0 g, 23.5 mmol) at 90° C., followed by tetrakis(triphenylphosphine)palladium (0) (0.9 g, 0.78 mmol). The reaction mixture was heated at 90° C. overnight and cooled to room temperature. The mixture was extracted with methylene chloride and washed with water. The organic solvent was removed under vacuum. Chromatography with 5% ethyl acetate in hexanes afforded 2.62 g (87%) of 2′,6′-dichloro-5-fluoro-2-methoxybiphenyl as a colorless oil. MS (EI) m/z 270 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)c3ccncc3)c2c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b, 1.0 g, 3.15 mmol) in dry DMF (20 mL) was added isonicotinic acid (504 mg, 4.10 mmol), followed by EDCI (783 mg, 4.10 mmol), HOBt (554 mg, 4.10 mmol), and triethylamine (414 mg, 4.10 mmol) at room temperature under nitrogen. After it was stirred at room temperature for 12 hrs, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with EtOAc (3×). The aqueous layer was basified with 2N NaOH to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound as a yellow solid (1.1 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 1.29 (t, J=4 Hz, 3H), 1.51 (s, 6H), 2.94 (s, 3H), 4.28 (q, J=4 Hz, 2H), 4.42 (s, 2H), 6.93 (dd, J=1, 8 Hz, 1H), 7.24 (dd, J=1, 8 Hz, 2H), 7.52 (t, J=8 Hz, 1H), 7.69 (dd, J=2, 4 Hz, 2H), 8.14 (s, 2H), 8.37 (s, 1H), 8.67 (dd, J=2, 4 Hz, 2H). MS 423 (MH+).
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:23](O)(=[O:27])[CH2:24][CH2:25][CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:24]([C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C@@H:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:27])[CH2:25][CH3:26]
Reactant: CCCC(=O)O
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCCC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added butyric acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL), and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to to provide the title compound (53 mg, 56%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 0.94 (t, J=7.42 Hz, 3H), 1.25-1.48 (m, 6H), 1.51-1.65 (m, 3H), 1.68 (d, J=11.72 Hz, 1H), 1.74-2.01 (m, 7H), 2.19-2.32 (m, 3H), 2.35 (t, J=7.62 Hz, 2H), 2.55 (t, J=12.11 Hz, 2H), 2.89-3.11 (m, 5H), 3.56-3.69 (m, 1H), 4.01 (d, J=13.28 Hz, 1H), 4.57 (d, J=13.28 Hz, 1H). MS (M+1): 377.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccnc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccn1

Procedure:
Prepared analogously to example 366a from 4-aminopicolinic acid and sulfuric acid in methanol.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:29])[C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34].O.Cl>N1C=CC=CC=1>[Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:29])[C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][O:19][C:32](=[O:35])[CH2:33][CH3:34])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1
Reactant: CCC(=O)Cl
Reactant: CCC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)OCC(=O)[C@@]1(OC(=O)CC)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C

Procedure:
A solution of 11β-chloro-21-hydroxy-16β-methyl-17-propionyloxypregna-1,4-diene-3,20-dione(75 mg) in pyridine (1 ml) was cooled to 0° and treated with stirring with propionyl chloride (0.04 ml). After 90 minutes a little water was added and the solution poured into dilute hydrochloric acid. The precipitated solid was removed by filtration and recrystallized from methanol to give the title compound, m.p. 220°-222° (K), [α]D + 105° (c 0.6, chloroform) λmax 240nm (ε 15,060) (Found C, 65.9; H, 7.2; Cl, 6.7. C28H37ClO6 requires C, 65.7; H, 7.55; Cl, 7.0%).