Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(F)cc2n(CCF)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1OCc1ccccc1
Yield: 83 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-(2-fluoroethyl)-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-4, 0.15 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][C:9](=[N:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2].C([BH3-])#N.[Na+].Cl>CO.O1CCCC1>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH:9]([NH:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:23][CH:22]=2)=[O:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(OCC(=NNC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(OCC(NNC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccccc2)cc1
Yield: 106.2 %

Procedure:
In a mixed solvent of 15 ml of methanol and 15 ml of tetrahydrofuran was dissolved 0.30 g (0.66 mmole) of 2-[2-(4-cyanophenoxy)-1-phenylethylidene]-N-(4-trifluoromethoxyphenyl)hydrazinecarboxamide, after which 0.20 g (3.2 mmoles) of sodium cyanoborohydride (NaBH3CN) was added to the resulting solution. The resulting mixture was maintained at pH 4 to 6 with hydrogen chloride (a methanolic solution) with stirring. After confirming the completion of the reaction by a thinlayer chromatography, the solvent was distilled off under reduced pressure and water was added to the residue, followed by neutralization with sodium hydrogencarbonate. The desired compound was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 0.32 g of the desired compound was obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]2[CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2)no1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2CC2CCOCC2)no1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg, 0.338 mmol) in N,N-dimethylformamide (2 mL) is added tetrahydro-pyran-4-carbaldehyde (77 mg, 0.676 mmol) and acetic acid (0.073 mL, 1.28 mmol). The reaction is stirred at room temperature for 45 minutes before adding sodium cyanoborohydride (42.5 mg, 0.676 mmol). The reaction is stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound with low purity and further purification by pre-HPLC yields pure title compound, m/z 352 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH:17][CH:18]1[CH:26]2[CH:21]([CH:22]3[CH2:27][CH:25]2[CH:24]=[CH:23]3)[C:20](=O)[O:19]1>C1C=CC=CC=1>[O:17]=[C:18]1[C@H:26]2[C@H:21]([C@@H:22]3[CH2:27][C@H:25]2[CH:24]=[CH:23]3)[C@@H:20]([NH:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[O:19]1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C1OC(O)C2C3C=CC(C3)C12
Solvent: c1ccccc1
Product: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1

Procedure:
A mixture of 5.2 g of benzyl L-leucinate, 4 g of (3RS, 3aRS,4RS,7RS,7aRS) 3-hydroxy-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one and 40 ml of anhydrous benzene was refluxed for 90 minutes while azeotropically distilling off the water of reaction formed and was then evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was vacuum filtered to obtain 2.3 g of benzyl (αS,3S,3aS,4R,7S,7aR) α-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl)-amino]isohexanoate melting at 95° C.
Reaction SMILES: S(Br)([Br:3])=O.[F:5][C:6]1[N:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1.CC(OO)=O>C(Cl)Cl>[Br:3][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([F:5])=[N:11][CH:10]=1)[CH3:13]
Reactant: O=S(Br)Br
Reactant: CC(O)c1ccc(F)nc1
Agent: CC(=O)OO
Solvent: ClCCl
Product: CC(Br)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
Thionyl bromide (11.60 mL, 149 mmol) was added (dropwise over 15 min; gas evolution) to a solution of 1-(6-fluoropyridin-3-yl)ethanol (10.55 g, 74.7 mmol) in DCM (300 mL) at 25° C., and the resulting orange solution was stirred at 25° C. for 3 h. Excess SOBr2 was then carefully quenched with water (150 mL) at 0° C. with vigorous stirring, and 5.0N aqueous NaOH (100 mL) was then carefully added at 0° C. (over about 10 min) to neutralize HBr and SO2. (Yellow mixture results; final pH about 9; adjust with saturated aqueous NaHCO3,to a pH of about 9 as necessary.) The resulting mixture was vigorously stirred at 0° C. for 5 min to ensure complete quench of acidic species, and the resulting mixture was then partitioned between DCM (200 mL) and half saturated aqueous NaHCO3 to a pH of about 9 (600 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (300 mL). The combined organic extracts were sequentially washed with saturated aqueous NaHCO3 (500 mL) and brine (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-bromoethyl)-2-fluoropyridine (14.58 g, 96% yield) as a yellow oil (71% LCAP; m/z (ESI, +ve) 204.0 (M+H)+), which was used directly in Step 3.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:28]=[CH:27][C:26]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)=[CH:25][CH:24]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: CCOC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-ethoxycarbonyl-phenylboronic acid gives “A71”; method 1: HPLC/MS: 1.46 min, [M+H]=363;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH2:9]([NH2:11])[CH3:10].O=O>[Pd]>[CH2:9]([NH:11][C:7](=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=1)[CH3:10]
Reactant: O=Cc1cccnc1
Reactant: CCN
Agent: [Pd]
Agent: O=O
Product: CCNC(=O)c1cccnc1
Reaction time: 2 h
Yield: 47 %

Procedure:
In a 100 ml three-necked flask were charged 2 g of pyridine-3-aldehyde, 50 g of a 30 weight percent aqueous ethylamine solution and 3 g of the same commercially available palladium catalyst as in Example 1. The reaction was conducted at a reaction temperature of 30° C. for 2 hours by introducing oxygen at a rate of 10 l/hour into the flask from its gas inlet equipped with a filter to give nicotinic acid monoethylamide at a yield of 47%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[C:31]([F:37])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[NH:17][CH2:16][CH2:15][N:11]3[C:12](=[O:14])[N:13]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[C:31]([F:37])[CH:30]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(C#N)c1)nc2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Oc2ccc(COc3cc4n(c(=O)n3)CCN4)cc2C#N)cc1F

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3-cyano-4-(4-cyano-3-fluorophenoxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (70 mg, 0.139 mmol) in DCM (4 mL) and TFA (0.5 mL).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[H-].[Na+].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18](C=CN=2)[N:19]=1.C[N:24]([CH:26]=O)[CH3:25]>>[Cl:13][C:14]1[N:19]2[N:18]=[C:17]([O:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5](=[O:7])(=[O:6])[NH2:8])[CH:16]=[CH:15][C:25]2=[N:24][CH:26]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Clc1ccc2nccn2n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(COc1ccc2ncc(Cl)n2n1)CS(N)(=O)=O
Temperature: 70 °C

Procedure:
To a solution of 1.67 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 30 ml of DMF was added 0.8 g of sodium hydride, followed by heating at 70° C. for an hour. The mixture to which 1.88 g of 6-chloroimidazo [1,2-b]pyridazine was added was heated for 4.5 hours. The reaction mixture was distilled to remove the solvent under reduced pressure and 50 ml of ice-water was added to the residue. The mixture was adjusted to pH 6.0 with 1N-hydrochloric acid and then extracted with tetrahydrofuran and ethyl acetate (1:1). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to a silica gel column chromatography, eluting with chloroform and methanol (20:1). The corresponding combined fractions were concentrated to obtain 1.56 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](O)=[O:25])=[N:16]1.Cl.[CH3:28][NH:29][O:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([N:29]([O:30][CH3:31])[CH3:28])=[O:25])=[N:16]1
Reactant: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)O)c1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A mixture of 1-(2,5-difluoro-4-morpholin-4-ylphenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (2.5 g, 6.8 mmol), N,O-dimethylhydroxylamine hydrochloride (0.73 g, 7.5 mmol), HOBt (1.0 g, 7.5 mmol), triethylamine (2.0 mL, 14 mmol) and WSC (1.4 g, 7.5 mmol) in DMF (28 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound (1.6 g, 58% yield) as a brown solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.01-3.19 (4H, m), 3.24 (3H, s), 3.56 (3H, s), 3.62-3.91 (7H, m), 7.17 (1H, dd, J=12.7, 7.7 Hz), 7.62-7.82 (1H, m), 8.48 (1H, s). LC-MS (ESI) m/z 411 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:36]3[CH2:35][CH2:34][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
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: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg) in DMF (5 mL) was added tert-butyl piperazine-1-carboxylate (77.5 mg, 0.42 mmol), DIEA (89.6 mg, 0.69 mmol), HATU (158.3 mg, 0.42 mmol). The resulting solution was stirred at room temperature for 3 h and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3% MeOH in DCM to afford 279 mg of tert-butyl 4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazine-1-carboxylate as a yellow solid. LCMS (Method 22) [M+H]+=631.4, RT=1.49 min.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].ClC[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:27][CH2:28][N:30]2[CH2:31][CH2:32][N:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH2:34][CH2:35]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: O=C(CCCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccc(Cl)cc5)CC4)c3C2=O)cc1

Procedure:
A target compound (117.9 mg, 0.239 mmol, 57.5%) was yielded as white solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (101 mg, 0.416 mmol) with potassium carbonate (86.2 mg, 0.624 mmol) and 3-chloro-1-{4-(4-chlorophenyl)piperazin-1-yl}propan-1-one (131.2 mg, 0.457 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[K].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12>>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]2=[O:33])[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(C(C#N)(CCCCCCl)SC2CCCCC2)cc1OC
Agent: [K]
Product: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)SC2CCCCC2)cc1OC

Procedure:
The procedure of Example 24 is repeated using 2.1 g of α-(5-chloropentyl)-α-(cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile and 0,954 g of the potassium salt of phthalimide. This affords 2.13 g of the desired product as a colorless oil.
Reaction SMILES: [C:1]([C:5]1([SiH2:11][C:12]([O:27][C:28]([C:47]2[CH:48]=[N:49][C:50](Cl)=[CH:51][CH:52]=2)([SiH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[SiH2:29][C:30]2([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]2)([C:20]2[CH:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=2)[SiH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:54](C([Sn])=C(CCCC)CCCC)[CH2:55]CC.[C:69]1(C)C=CC=C[CH:70]=1>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>[C:1]([C:5]1([SiH2:11][C:12]([O:27][C:28]([C:47]2[CH:48]=[N:49][C:50]([CH:69]=[CH2:70])=[CH:51][CH:52]=2)([SiH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[SiH2:29][C:30]2([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]2)([C:20]2[CH:21]=[N:22][C:23]([CH:54]=[CH2:55])=[CH:24][CH:25]=2)[SiH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1([SiH2]C(OC([SiH2]c2ccccc2)([SiH2]C2(C(C)(C)C)C=CC=CC2)c2ccc(Cl)nc2)([SiH2]c2ccccc2)c2ccc(Cl)nc2)C=CC=CC1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc(C(OC([SiH2]c2ccccc2)([SiH2]C2(C(C)(C)C)C=CC=CC2)c2ccc(C=C)nc2)([SiH2]c2ccccc2)[SiH2]C2(C(C)(C)C)C=CC=CC2)cn1
Temperature: 120 °C
Yield: 89.3 %

Procedure:
After dissolving 1-(tert-butyl)-1,1-diphenylsilyl [(6-chloro-3-pyridyl)methyl]ether (20 g, 52.3 mmol) in toluene (104 ml) and degassing the solution, tetrakis(triphenylphosphine)palladium (3.0 g, 2.6 mmol) and tributylvinyltin (16.5 ml, 56.5 mmol) were added under a nitrogen stream and the mixture was heated to reflux at 120° C. for 7 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (17.46 g) as a colorless oil. (89.3% yield)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15](=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].ClC[C:24](Cl)=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:25]=[C:24]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)cn1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCN2CCNCC2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TEA (1 eq) was added dropwise to a solution of tert-Butyl (2-{[2-(5-cyanopyridin-2-yl)ethyl]amino}ethyl)carbamate (1 eq) and chloroacetyl chloride (1 eq) in 200 mL of DCM at 0° C. The mixture was stirred at room temperature for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum. The resulting solid (1.0 g, 2.7 mmol) was added to the mixture of 10 mL TFA and 10 mL of DCM and stirred at RT for 1 hour then concentrated by vacuum. The residue was re-dissolved in CH3CN, K2CO3 was added and the mixture was stirred at RT for 2 hours. The mixture was poured into water and extracted with EtOAc twice. The combined organic layers were concentrated and the residue was purified by flash chromatography (DCM:MeOH=10:1) to afford the title compound 1H-NMR (400 MHz, CDCl3) δ ppm 8.74 (d, J=1.6 Hz, 1H), 7.81-7.83 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.71 (t, J=7.2 Hz, 2H), 3.42 (d, J=7.2 Hz, 2H), 3.24 (t, J=5.6 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17]Br)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].C12C[CH:33]([C:35](=[O:39])[CH2:36]OC)CC1CNC2>C(O)(C)C>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH:14]12[CH2:13][CH:12]([C:16](=[O:19])[CH2:17][O:39][CH:35]([CH3:36])[CH3:33])[CH2:11][CH:10]1[CH2:9][NH:8][CH2:15]2
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)CBr)CC2C1
Reactant: COCC(=O)C1CC2CNCC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CC(C)OCC(=O)C1CC2CNCC2C1

Procedure:
1-(3-Azabicyclo[3.3.0]oct-7-yl)-2-isopropoxy-1-ethanone trifluoroacetate was prepared from 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.087 g, 0.27 mmol) and isopropanol, according to the procedure described above for the preparation of 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-methoxy-1-ethanone trifluoroacetate, to give a mixture of cis and trans isomers (1H NMR (CD3OD, 300 MHz): δ 4.21 and 4.20 (s, 2H), 3.64 (heptet, J=6.1 Hz) 1H), 3.54-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.98-2.90 (m, 4H), 2.37-2.22 and 2.06-1.99 (m, 2H), 1.82-1.75 and 1.65-1.54 (m, 2H), 1.18 (d, J=6.1 Hz, 6H); MS (m/z): 212 (M+1)). This material exhibited Ki values at rat and human α4β2 of 427 nM and 261 nM respectively and did not pass HTS for α7.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[C-:33].[H-].[Na+].C1COCC1>C1COCC1>[CH2:38]([O:37][C:35]([C:34]1[N:32]=[CH:33][N:6]2[C:7]=1[CH:8]([CH3:17])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:20]=[CH:19][C:5]2=1)=[O:36])[CH3:39]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC1N=C(c2ccccc2)c2cc(Br)ccc2NC1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
7-Bromo-3-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 111 (16.6 g, 0.052 mol) was suspended in dry THF (250 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 4.36 g, 0.109 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (12.7 ml, 0.09 mol) was added. The cooling bath was then removed and stirring contined for 3 h. At this time, sodium hydride (60% dispersion in mineral oil, 4.2 g, 0.1 mol) was suspended in dry THF (250 mL) at −10° C. in another flask. Ethyl isocyanoacetate (6.78 mL, 0.06 mol) was added to the NaH/THF suspension, the solution which resulted was allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. and the solution in the 2nd reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, and then cooled with an ice-water bath and slowly quenched with acetic acid (10 mL). Water was added to the reaction mixture after which it was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:2, 1:1, 2:1). The ester 112 was a white solid (8.76 g, 40%). mp 164-165° C.; IR (KBr, cm−1) 2925, 1706, 1622, 1557, 1495, 1266, 1185; 1H NMR (CDCl3) δ 7.89 (s, 1H), 7.73 (dd, J=1.73 Hz, 1H), 7.51-7.36 (m, 7H), 6.66 (q, J=7.30, 1H), 4.45-4.30 (m, 2H), 1.40 (t, J=7.11, 3H), 1.25 (d, J=7.38 Hz, 3H). MS (EI) m/e (relative intensity) 426 (M++2, 15), 425 (M++1, 58), 424 (M+, 15), 423 (58), 380 (24), 379 (71), 378 (35), 377 (69), 352 (50), 351(100), 350 (67), 349 (92), 270 (38), 229 (16); [α]26D=−38.0 (c 0.45, EtOAc).