Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Cl:10].ClCCCCCC(Cl)=[O:19].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Cl:10]
Reactant: O=C(Cl)CCCCCCl
Reactant: O=C(CCCl)CCCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCl)CCCCCCCl
Yield: 43 %

Procedure:
1,8 dichloro-3-octanone: A well stirred, ice-cooled solution of 30.35 g (179.6 mmol) of 6-chlorohexanoyl chloride in 300 ml of dry CCl4 was degassed with nitrogen for 1/2 hr. AlCl3 (26.34 g, 179.6 mmol) was added in portions, then ethylene was bubbled in at a rate so that no excess ethylene escaped from the reaction vessel. Ethylene was allowed to bubble through the reaction mixture at 0° C. for 2 hrs. and at ambient temperature overnight. The reaction mixture was poured into 800 ml ice-water and extracted with chloroform (2×400 ml). The combined chloroform extracted were washed with sat'd aq. NaHCO3 (500 ml), H2O (500 ml), sat'd NaCl (500 ml) and dried over MgSO4. After the removal of the solvent, 15.2 g (43%) of crude 1,8-dichlorooctanone was obtained, which was used without further purification. NMR(CDCl3): δ1.44 (6H, m, --CH2 --), δ2.34 (2H, t, ##STR19## J=3.0 Hz), δ2.85 (2H, t, ##STR20## J=3.0 Hz), δ3.52 (2H, t, --CH2Cl, J=3 Hz) δ3.74 (2H, t, --CH2Cl, J=3.0 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]#[N:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.CC(O)=O.[C:25]([CH:27](C)[CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)#[N:26].[BH3-]C#N.[Na+]>CO>[C:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][CH2:27][C:25]#[N:26])=[CH:38][CH:37]=3)=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)#[N:13]
Reactant: CC(C#N)CCOc1ccc(C=O)cc1
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CCCCOc1ccc(CNc2ccc(-n3nc(-c4cccnc4)cc3C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3-Pyridyl)-5-cyano-1-(4′-aminophenyl)pyrazole (0.5 mmol) was dissolved in MeOH (4 mL) and treated with HOAc (4 mL). The reaction was treated with a solution of 4-(3-cyanobutoxy)benzaldehyde (from Example above) (0.75 mmol) in MeOH (1 mL) and stirred at room temperature for 30 minutes. NaCNBH3 (1.25 mmol) was added in one portion. After 2 hr, volatiles were removed, the residue taken up in water, neutralized with NaHCO3 (aq) and extracted with dichloromethane. Organic extracts were combined, dried over MgSO4 and concentrated to leave a clear oil. Pure product was eluted from silica gel column using 50% dichloromethane in EtOAc giving a light yellow solid (140 mg, 64%), m.p. 128-129° C. 1H NMR (CDCl3): δ 1.98-2.04 (m, 2H), 2.63-2.66 (t, J=7.1 Hz, 2H), 4.00-4.04 (t, J=6 Hz, 2H), 4.27-4.29 (d, J=5.8 Hz, 2H), 6.72-6.79 (m, 3H), 6.92-6.94 (d, J=8.5 Hz, 2H), 7.31-7.33 (d, J=8.5 Hz, 2H), 7.42-7.44 (d, J=8.7 Hz, 2H), 7.50-7.53 (m, 1H), 7.96 (s, 1H), 8.24-8.26 (d, J=8 Hz, 1H), 8.60-8.61 (d, J=4.6 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: C([C:3]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[S:7][CH:6]([C:8]([O-:10])=O)[N:5]=[C:4]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])C.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[S:7][C:6]([C:8]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:10])=[N:5][C:4]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:20][CH:21]=1
Reactant: CCC1(c2ccc(Cl)cc2)SC(C(=O)[O-])N=C1c1ccc(Cl)cc1Cl
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
5-Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.65 gram, 4.0 mmol) is dissolved in anhydrous THF (25 mL) and aniline (0.37 mL, 4.0 mmol) is added. The resulting solution is cooled to 0° C. and sodium hexamethyidisilazide (4.4 mL of a 1M solution in THF) is added. The reaction mixture is stirred for 2 hours. Water is added and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is crystallised from diisopropyl ether to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-phenyl-thiazole-2-carboxamide (1.42 g, 77% yield). Melting point: 167-168° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CCCCCC.[F:20][C:21]([F:29])([F:28])[C:22]([C:24]([F:27])([F:26])[F:25])=[O:23]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([C:22]([OH:23])([C:24]([F:27])([F:26])[F:25])[C:21]([F:29])([F:28])[F:20])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cccc(Br)n1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2,6-dibromo pyridine 260 (2.37 g, 10 mmol) in dry THF, cooled to 0° C., n-BuLi 1.4 mmol in hexane (7.9 ml, 11 mmol) was added drop wise, and stirred for 10 min. Then hexafluoroacetone (CF3—CO—CF3) 244 was added to the reaction mixture and continued stirring for another 2 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude compound 2-(6-bromopyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 261, which was purified through 100-200 mesh silica gel by eluting the compound at 15% Ethylacetate in hexane to get the thick oil compound 261.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[NH2:9].O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:9][C:8]1[CH:10]=[C:11]([CH3:13])[C:12]([S:1][C:2]#[N:3])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)cc(C)c1SC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
251.2 g (3.30 mol) of ammonium thiocyanate are rapidly added to a solution, maintained under a nitrogen atmosphere, of 121.2 g (1 mol) of 3,5-dimethylaniline in 1.75 l of anhydrous N,N-dimethylformamide. The temperature rises from 18 to 35° C. One and a half hours later, the temperature of the solution having returned to room temperature, 263.3 g (1.65 mol) of anhydrous cupric sulphate are added rapidly. The reaction medium is left stirring at room temperature for 3 days and is then poured into 8 l of water. The pH is brought to 7.5 by addition of 550 g (6.55 mol) of sodium bicarbonate. The medium is then filtered, the solid part being washed with ethyl acetate and the liquid part being extracted with ethyl acetate. The combined organic liquid phases are washed with 500 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The pasty residue obtained is crystallized from 500 ml of hexane to give 128.8 g (72%) of 4-amino-2,6-dimethylphenyl thiocyanate which is used in the next step without further purification.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc([C@H]2CCNC[C@@H]2F)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41 mmol) in 1.5 mL DCM at rt was added TFA (0.5 mL, 6.5 mmol), and the mixture was stirred for 3 h. The mixture was then concentrated in vacuo to dryness to yield 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol trifluoroacetate (126 mg, 0.41 mmol), which was used directly in step D.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:8][CH:9]=2)[N:4]([CH3:20])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1>>[NH2:33][C:32]1[CH:34]=[CH:35][C:29]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[N:8][CH:9]=3)[N:4]([CH3:20])[N:3]=2)=[CH:30][CH:31]=1
Reactant: Cn1nc(Cl)c2cnc(NCCN3CCOCC3)nc21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Cn1nc(-c2ccc(N)cc2)c2cnc(NCCN3CCOCC3)nc21

Procedure:
Prepared as described above in Example 15 starting from (3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound [3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine; LC/MS (m/e)=354.4 (MH+), Rt=1.12 min.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCOCC.[Cl:23][CH:24]([F:28])[C:25](Cl)=[O:26]>O>[Cl:23][CH:24]([F:28])[C:25]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:26]
Reactant: O=C(Cl)C(F)Cl
Reactant: Nc1ccc(Cl)cc1C(=NO)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)cc1C(=NO)c1ccccc1)C(F)Cl
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Water, 250 ml, was added to a solution of 50 g (0.203 mole) of 2-amino-5-chlorobenzophenone oxime (mixture of isomers) in 1 l. of ether, and the mixture was stirred rapidly and cooled to 5°. Solutions of (A) 100 ml of 10% sodium hydroxide in water and (B) 33.5 g (0.228 mole) of chlorofluoroacetyl chloride made up to 100 ml with ether were simultaneously added at the same rate over 30 min., keeping the temperature of the reaction mixture at about 10° with cooling. The reaction mixture was stirred for 30 min. after the addition, and the ether layer was separated, washed with water, dried (MgSO4), and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene to give 61.2 g (88%) of 2-(chlorofluoroacetamido)-5-chlorobenzophenone oxime (mixture of isomers) as light yellow crystals, mp 110°-129°. The 19F nmr (acetone-d6) indicates a mixture of two isomers in a 70:30 ratio: δ -143.2 ppm (d, d, J=50, 2.5 Hz, 30%) and δ -144.3 ppm (d, d, J=50, 2.5 Hz, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([S:25]([CH3:24])(=[O:27])=[O:26])[S:25]([CH3:24])(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N(c1cnccc1OCc1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(Benzyloxy)-3-nitropyridine (14 g, 69.8 mmol, 1 eq) was dissolved in dichloromethane and cooled to 0° C. Then added TEA (29.2 ml, 209.6 mmol, 3 eq), followed by the addition of potassium carbonate (9.96 g, 69.8 mmol, 1 eq) at 0° C. and stirred for 15 minutes. Methane sulfonyl chloride (20 g, 174 mmol, 2.5 eq) was added slowly at 0° C. to the above mixture and stirred for 14 h. After the completion of reaction, monitored by TLC, the reaction mixture was diluted with water and organic layer was separated. Water layer was extracted twice with 200 ml of dichloromethane, and the combined dichloromethane mixture was washed with water (500 ml) and brine (500 ml). The organic solution was concentrated under vacuum to yield the pure product. Yield: 19.5 g (78%). 1HNMR (400 MHz, DMSO-d6): δ 3.47 (S, 6H), 5.35 (s, 2H), 7.32 (d, J=5.76 Hz, 1H), 7.40-7.49 (m, 3H), 7.51 (t, J=4.12 Hz, 2H), 8.52 (d, J=5.68 Hz, 1H), 8.57 (s, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH2:20])[CH2:14]2)[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:29](=[O:30])[O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)[CH2:14]2)[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CN)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C

Procedure:
Intermediate 33 (0.724 g) in dichloromethane (5 ml) was treated with triethylamine (1.14 ml), forming a slurry which was added portion-wise over 5 min to a solution of 4-nitrophenyl chloroformate (0.444 g) in anhydrous dichloromethane (5 ml) at 0° C. under nitrogen. The stirring solution was allowed to warm to room temperature over 2 h, then filtered; the filtrate was purified directly by chromatography on silica gel (Biotage 90 g column), eluting with 35–40% ethyl acetate in cyclohexane, and appropriate fractions evaporated in vacuo to give the title compound (Isomer I) as an opaque yellow film (0.202 g).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=1[F:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CCCCNCc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCN(Cc1nc2ccccc2[nH]1)C(=O)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
2-butylaminomethylbenzimidazole (2.6 g, 13 mmol) was dissolved in 30 mL toluene. Saturated NaHCO3 solution (30 mL) was added followed by 2,3-difluorobenzoyl chloride (1.3 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100 mL ethyl acetate then washed 1×100 mL 1N NaOH followed by 1×100 mL H2O. The organic phase was dried over MgSO4, filtered, and then concentrated. The residue was purified by flash chromatography eluting with 1/1 ethyl acetate/hexane followed by ethyl acetate to afford 2.0 g N-butyl-N-(1H-benzoimidazol-2-ylmethyl)-2,3-difluorobenzamide.
Reaction SMILES: C(OC([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)C)[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[NH2:8][C@@H:9]([CH2:13][CH3:14])[C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:11]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CC[C@H](N)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-N-(tert-butoxycarbonyl)-2-aminobutyric acid for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.33 (d, J=7.1, 1H), 7.57 (d, J=8.7, 2H), 6.61 (d, J=8.7, 2H), 4.38-4.30 (m, 1H), 3.52 (ddd, J=12.9, 8.7, 4.2, 2H), 3.32 (dd, J=10.1, 7.9, 1H), 3.21 (dd, J=9.7, 8.1, 1H), 3.00 (dd, J=9.9, 4.1, 1H), 2.75-2.61 (m, 2H), 2.34-2.10 (m, 2H), 2.11-1.96 (m, 2H), 1.92 (dtd, J=13.1, 7.9, 5.1, 1H), 1.81-1.71 (m, 1H), 1.62 (dq, J=12.7, 7.9, 1H), 1.40-1.30 (m, 1H), 1.03 (t, J=7.4, 3H); MS (ESI+) m/z 356 (M+H)+.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C=CC=CC=1.Cl>O.[Zn]>[C:5]([CH2:4][CH2:3][CH2:2][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([OH:7])=[O:6]
Reactant: COc1ccc(Cl)cc1C(=O)CCC(=O)O
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cl)cc1CCCC(=O)O
Temperature: 80 °C

Procedure:
The acid compound of step 1 above is added to a stirring mixture of toluene (22 ml), conc HCl (41 ml), water (17 ml) and the recovered product of mossy zinc (22.2 g) and mercuric chloride (2.2 g) stirred in an aqueous HCl solution for about 10 minutes. The mixture is stirred under reflux for about 16 hours, diluted with water, extracted with ethyl acetate and the organic layer is dried filtered and evaporated. The residue is taken up in 10% aqueous NaOH, and dimethyl sulfate (about 25 ml) added to the mixture which is heated to 80° C. The mixture is stirred at a constant temperature for about 4 hours, cooled, acidified and the resulting precipitate is filtered dried and used in the next step.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([NH:13][C:14](=[O:16])[CH3:15])[CH3:12])=[N:9][CH:10]=1.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][N:26]=[CH:25]2.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][C:20]=2[C:20]2[CH:21]=[CH:22][C:23]([CH2:15][C:14]([NH:13][C@@H:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:18])=[CH:10][N:9]=3)[CH3:12])=[O:16])=[CH:24][CH:29]=2)[CH:25]=[N:26][CH:27]=1
Reactant: Brc1cccc2cncnc12
Reactant: CC(=O)N[C@H](C)c1ccc(OCC(F)(F)F)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](NC(=O)Cc1ccc(-c2cccc3cncnc23)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 150 °C
Yield: 75 %

Procedure:
To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethylamine bis-HCl (0.75 g, 2.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylacetic acid (0.67 g, 2.6 mmol), EDC (0.59 g, 3.1 mmol), and 1-hydroxy-7-azabenzotriazole (0.42 g, 3.1 mmol) in DMF (5 mL) was added diisopropylethylamine (1.8 mL, 10.2 mmol). After stirring for 90 min at room temperature, the reaction mixture was loaded directly onto a silica gel column and purified by normal phase chromatography (20-80% EtOAc/hexanes) to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (0.77 g, 65%) as a viscous oil that slowly solidified to a white solid. MS (Electrospray): m/z 465.1 (M+H). To a microwave vial containing 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (50 mg, 0.11 mmol), 8-bromoquinazoline (25 mg, 0.12 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) in acetonitrile (1 mL) was added aqueous 1M sodium carbonate (1 mL, 1.0 mmol) and the mixture was heated in a microwave at 150° C. for 10 min. The top organic layer was removed, loaded onto a silica gel column and purified by normal phase chromatography (30-100% EtOAc/hexanes) to give 2-(4-quinazolin-8-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (21 mg, 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 9.37 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.96 (m, 2H), 7.75 (m, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.22 (m, 2H), 6.79 (d, J=7.2 Hz, 1H), 5.16 (m, 1H), 4.37 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 1.44 (d, J=6.8 Hz, 3H); MS (Electrospray): m/z 467.1 (M+H). FLIPR alpha1I IP=19 nM.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][C@H:3]([C:8]([NH:10][C:11]1([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]1)=[O:9])[NH:2]2.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:2]2[C@@H:3]([C:8]([NH:10][C:11]3([C:14]4[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=4)[CH2:12][CH2:13]3)=[O:9])[CH2:4][CH2:5][CH:6]3[CH:1]2[CH2:7]3)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D142) (6.8 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-((3R)-2-azabicyclo[4.1.0]heptane-3-carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D101) (17.5 mg) and 4-(trifluoromethyl)-benzylbromide (0.01 ml). (Cs2CO3: 1.5 eq; Reaction time: 20 hrs; RT).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[S:10])[NH2:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=2)[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cc(Cl)nc(Cl)c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(-c2cc(Cl)nc(Cl)c2)n1
Temperature: 25 °C

Procedure:
2,6-Dichloropyridine-4-thiocarboxamide (1.0 g, 4.83 mmol) was dissolved in dry 1,4-dioxane followed by adding ethyl bromopyruvate (0.9 mL, 7.24 mmol) and pyridine (0.4 mL, 4.83 mmol). The resulting mixture was heated to reflux under N2 for 5 h. After cooling to RT, solvent was removed. The residue was extracted with CHCl3. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated to give a brownish solid. This crude was purified by chromatography on silica gel. Elution with hexane:acetone (90:10) gave a title compound as yellow solid. MS m/z: 303 (M+H). Calc'd. for C11H8Cl2N2O2S-303.16.
Reaction SMILES: C([O-])(=O)C.[K+].C(O)(=O)C.[NH2:10][C:11]1[N:12]=[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:14][C:15]=1[C:16]#[N:17].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>ClCCl>[CH2:18]([C:13]1[NH:14][C:15]([C:16]#[N:17])=[C:11]([N:10]2[CH:24]=[CH:28][CH:27]=[CH:26]2)[N:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc(N)c(C#N)[nH]1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCc1nc(-n2cccc2)c(C#N)[nH]1
Temperature: 25 °C

Procedure:
A solution of potassium acetate (5.0 g), acetic acid (22 mL) and 4-amino-2-butyl-5-cyanoimidazole (Example 7, 1.45 g) was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran (1.25 mL). The reaction was held at reflux for 1 minute then cooled back to room temperature with an ice bath. The majority of the acetic acid was evaporated at reduced pressure then the residue was partitioned between ethyl acetate and 10% aqueous K2CO3 (120 mL) each. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (90:10 to 80:20). Evaporation of solvents gave a gum that was redissolved in dichloromethane and evaporated once again. The residual oil was held under a vacuum overnight to afford a waxy solid. 1H-NMR (CDCl3) δ9.9 (br, 1H), 7.4 (s, 2H), 6.3 (s, 2H), 2.7 (t, 2H), 1.7 (m, 2H), 1.4 (m, 2H), 1.0 (t, 3H).