Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([CH3:14])[CH2:9]2.Cl[C:25]1[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27][C:26]=1[C:32]#[N:33]>C1COCC1.CCOC(C)=O>[Cl:31][C:29]1[N:28]=[C:27]([NH:3][C:4]2[CH:5]=[CH:6][C:7]([N:15]3[CH2:16][CH2:17][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:20]3)=[C:8]3[C:12]=2[C:11](=[O:13])[N:10]([CH3:14])[CH2:9]3)[C:26]([C:32]#[N:33])=[CH:25][CH:30]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ccc3C#N)c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (0.557 g, 13.93 mmol) was added portionwise to 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (1.004 g, 3.48 mmol), in THF (30 mL) at room temperature under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 30 minutes and then 4,6-dichloropyridine-3-carbonitrile (0.602 g, 3.48 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (50 mL). The mixture was washed sequentially with water (50 mL), a saturated solution of NaHCO3 (50 mL), water (25 mL) and finally with a saturated solution of NaCl (20 mL). The mixture was filtered and the organic layer separated, dried over Na2SO4 and then evaporated. The residue was triturated in Et2O and MeOH and the mixture filtered. The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 5-10% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to leave 6-chloro-[[2-methyl-3-oxo-7-(4-propan-2-ylpiperazin-1-yl)-1H-isoindol-4-yl]amino]pyridine-3-carbonitrile (316 mg, 21% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.02 (6H, d), 2.60 (4H, t), 2.70 (1H, t), 3.02-3.08 (7H, m), 4.51 (2H, s), 7.04 (1H, d), 7.15 (1H, dd), 7.44 (1H, dd), 8.53 (1H, d), 9.68 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=425.30.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:20])([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]#[N:14])(=O)[CH3:2].C(Cl)(Cl)(Cl)Cl.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:20][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:21]=[C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][C:4]=1[CH2:1][CH3:2])[C:13]#[N:14]
Reactant: CCCCCC(C)(C#N)CCCCCOc1cc(OCc2ccccc2)ccc1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(C)(C#N)CCCCCOc1cc(OCc2ccccc2)ccc1CC
Reaction time: 24 h
Yield: 90 %

Procedure:
7-(2-Acetyl-5-benzyloxyphenoxy)-2-methyl-2-n-pentylheptanenitrile was dissolved in carbon tetrachloride containing 6 equivalents of triethylsilane. After addition of 60 equivalents of trifluoroacetic acid, the solution was stirred 24 hours and then evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether to provided the title product as an oil in 90% yield, NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[NH2:13].[CH3:14][O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17]>CC(C)=O>[CH3:14][O:15][C:16]([NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[NH:13][C:19]([NH:18][C:16]([O:15][CH3:14])=[O:17])=[S:20])=[O:17]
Reactant: CCCCSc1ccc(N)c(N)c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: CCCCSc1ccc(NC(=S)NC(=O)OC)c(NC(=S)NC(=O)OC)c1

Procedure:
1.5 G. of 1,2-diamino-4-n-butylthiobenzene in 30 ml. acetone is treated overnight with 4.5 g. methoxy carbonyl isothiocyanate at room temperature. The solution is concentrated, and the residue triturated with methanol and recrystallized from methanol, yielding 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-n-butylthiobenzene.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:9]CCC(OC)=O)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].[OH-].[Na+].[H][H]>O1CCCC1>[SH:9][C:4]1[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: COC(=O)CCSc1nccnc1C#N
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1nccnc1S
Temperature: 50 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
To a solution of methyl 3-(3-cyanopyrazin-2-ylthio)propanoate (1.56 g, 6.96 mmol) in anhydrous tetrahydrofuran at room temperature was added 60% sodium hydroxide suspension (0.34 g, 8.4 mmol). Vigorous hydrogen evolution was observed. After 1 h at room temperature there appeared to be no reaction, the reaction temperature was raised to 50° C. for 6 h, whereupon the starting material was consumed by TLC. The reaction was quenched by the addition ice, followed by 5% aqueous citric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 3-mercaptopyrazine-2-carbonitrile (1.1 g) as an orange solid. MW=137 confirmed by LC-MS, tr=4.79 min (Method Y) MH+=136-138.
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N([SiH3:18])C(C)C)(C)C>>[CH:1]([N:4]([SiH3:18])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)N([SiH3])C(C)C
Reactant: CC(C)NC1CCCCC1
Product: CC(C)N([SiH3])C1CCCCC1
Yield: 16.7 %

Procedure:
In a 500 ml Schlenk flask 247.3 g (1.75 mol) N-isopropylcyclohexylamine and 229.9 g (1.75 mol) di-isopropylaminosilane were refluxed for 8 days under nitrogen. The byproduct di-isopropylamine was removed with vacuum at a pressure of 40 mmHg and 50° C. Fractional vacuum distillation provided 50 g of pure N-isopropylcyclohexylaminosilane. The normal boiling point (measured at 1 atmosphere) is about 199° C. measured by differential scanning calorimetry (DSC). The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 1 with peaks at 171 (M+), 156 (M-CH3).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][C:36]2([O:44][CH2:43][CH2:42][O:41]2)[CH2:35]3)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1>CCOC(C)=O.CCCCCC.[Pd]>[CH2:37]1[C:38]2[C:34](=[CH:33][C:32]([N:27]3[C:28]([OH:31])=[N:29][N:30]=[C:26]3[C:10]3[CH:11]=[C:12]([CH:23]([CH3:25])[CH3:24])[C:13]([OH:15])=[CH:14][C:9]=3[OH:8])=[CH:40][CH:39]=2)[CH2:35][C:36]21[O:41][CH2:42][CH2:43][O:44]2
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(O)cc1O
Yield: 97.2 %

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-(1′,3′-dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-yl)-4H-[1,2,4]triazol-3-ol (550 mg, 0.93 mmol) was subsequently hydrodebensylated using Pd/C (10%, dry, 100 mg) and H2 in THF/MeOH (1/1, 25 mL) at 1 atm at r.t. for 2 h. The reaction mixture was filtered through a pad of celite and the mother liquid was concentrated. It was again filtered through a pad of silica gel and the filtrate was concentrated to give the title compound as a white solid (370 mg, 97%).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH2:22][C:23](Cl)=[N:24][OH:25])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.[C:27]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)c(F)c2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (3-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 94-1-3 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (18.0 mg, 13.5%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.CN(C)C=O.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>ClCCl.O.C(N(CC)CC)C>[C:27]([C:26]1[CH:25]=[C:24]([NH:23][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[CH:31]=[CH:30][CH:29]=1)#[N:28]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
2-Naphtoic acid (10 g, 58 mmol) was dissolved in dichloromethane (100 mL) and N,N-dimethylformamide (0.2 mL) was added followed by thionyl chloride (5.1 ml, 70 mmol). The mixture was heated at reflux temperature for 2 hours. After cooling to room temperature, the mixture was added dropwise to a mixture of 3-aminobenzonitril (6.90 g, 58 mmol) and triethyl amine (10 mL) in dichloromethane (75 mL). The resulting mixture was stirred at room temperature for 30 minutes. Water (50 mL) was added and the volatiles was exaporated in vacuo. The resulting mixture was filtered and the filter cake was washed with water followed by heptane (2×25 mL). Drying in vacuo at 50° C. for 16 hours afforded 15.0 g (95%) of N-(3-cyanophenyl)-2-naphtoic acid amide.
Reaction SMILES: [F:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:22]([O-])([O-])[O:23][CH2:24][CH3:25].C(OC(=O)C)(=O)C>>[CH2:24]([O:23][CH:22]=[C:6]([C:4](=[O:5])[C:3]1[C:12]([N+:19]([O-:21])=[O:20])=[C:13]([F:18])[C:14]([F:17])=[C:15]([CH3:16])[C:2]=1[F:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:25]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]

Procedure:
A mixture of 31.9 g of ethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acetate, 26.2 ml of ethyl orthoformate and 23.8 ml of acetic anhydride was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure to give 46.2 g of ethyl 3-ethoxy-2-(2,4,5-trifluoro-3 -methyl-6-nitrobenzoyl)acrylate as brown oil. To a solution of 45.4 g of the above compound in 328 ml of ethanol, 9.6 ml of cyclopropylamine was added dropwise with stirring under ice cooling, and then stirring was continued for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, n-hexane-methylene chloride (1:1)) to give 28.8 g of yellow crystals. The crystals were recrystallized from isopropyl ether to give yellow needles, m.p. 115°-115.5° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:38]=[CH:37][O:36][N:35]=3)=[CH:30][CH:29]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15]C2CCCCO2)=[O:13])[CH:8]=1>O1CCOCC1>[F:2][C:3]1[C:4]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:38]=[CH:37][O:36][N:35]=3)=[CH:32][CH:33]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][OH:15])=[O:13])[CH:8]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(-c3ccon3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(-c3ccon3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A solution of 1.0 M aq HCl (15 mL) was added slowly to a solution of (2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (655 mg, 1.23 mmol) in 1,4-dioxane (30 mL) at rt. The reaction was allowed to stir at rt overnight. The reaction was concentrated to a crude material. Water (30 mL) was added to the crude material and the mixture was boiled for 5 minutes. The mixture was allowed to cool to rt and the solid that formed was collected via filtration and dried under high vacuum to afford the title compound as a light yellow solid (314 mg, 56.9%). MS (APCI) m/z 450.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3 H) 2.10-2.21 (m, 1 H) 2.42-2.49 (m, 1 H) 3.09 (s, 3 H) 3.66-3.85 (m, 1 H) 3.96-4.09 (m, 1 H) 6.59 (d, J=7.61 Hz, 1 H) 7.21 (d, J=1.56 Hz, 1 H) 7.71 (dd, J=8.39, 1.76 Hz, 2 H) 8.00 (d, J=8.39 Hz, 2 H) 8.04 (d, J=6.44 Hz, 1 H) 9.03 (d, J=1.56 Hz, 1 H) 9.16-9.28 (m, 1 H) 11.06 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1>>[CH3:41][N:42]1[CH:46]=[C:45]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)[CH:44]=[N:43]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Product: Cn1cc(-c2ccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step A. MS (ESI): mass calcd. for C35H33N5O3, 571.26; m/z found, 572.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=8.4, 1H), 8.11 (d, J=8.4, 1H), 7.83 (d, J=8.0, 1H), 7.76-7.67 (m, 3H), 7.58-7.53 (m, 2H), 7.42-7.37 (m, 3H), 7.24-7.20 (m, 1H), 7.12-7.08 (m, 1H), 7.03-6.99 (m, 2H), 5.43 (s, 2H), 5.32 (s, 2H), 3.93 (s, 3H), 3.14-3.08 (m, 2H), 2.41-2.30 (m, 4H), 1.73-1.67 (m, 2H), 1.46-1.43 (m, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH2:11][CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCCC(=O)C1
Solvent: Cc1ccccc1
Product: O=C1C=C(NC2CCN(Cc3ccccc3)CC2)CCC1

Procedure:
1,3-Cyclohexanedione (10.0 g) is dissolved in toluene (100 ml) with heating and thereto is added 4-amino-1-benzylpiperidine (18.6 ml). The mixture is refluxed for 2 hours by using Dean-Stark apparatus. After cooling, the precipitated crystal is washed with diethyl ether, and recrystallized from toluene to give 1-(1-benzyl-4-piperidinylamino)-1-cyclohexen-3-on (24.2 g) as light yellow prisms, m.p.: 171°-172° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](I)=[C:6]([F:12])[CH:5]=1)[CH2:2][CH3:3].[CH2:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]#[CH:30])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C.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.[Cu]I.CCOCC>[CH2:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C@H:23]2[CH2:24][CH2:25][C@H:26]([C:29]#[C:30][C:7]3[C:8]([F:10])=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][C:6]=3[F:12])[CH2:27][CH2:28]2)[CH2:19][CH2:18]1)[CH2:14][CH:15]=[CH2:16]
Reactant: C#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=C)CC2)CC1
Reactant: CCCc1cc(F)c(I)c(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#Cc3c(F)cc(CCC)cc3F)CC2)CC1
Temperature: 90 °C

Procedure:
A mixture of 0.65 g of 1-propyl-3,5-difluoro-4-iodobenzene (prepared according to Example 1a), 0.56 g of trans-4-[trans-4-(3-butenyl)cyclohexyl]cyclohexylacetylene, 0.053 g of tetrakis(triphenylphosphine)palladium (0), 0.009 g of copper(I) iodide and 6 ml of triethylamine was heated to 90° C. for 17 hrs. The reaction mixture was cooled, partioned between water and ether, the organic phase was separated and the aqueous phase was extracted several times with ether. The combined organic phases were dried over magnesium sulphate, filtered and evaporated. chromatography of the residue on silica gel with hexane and two-fold crystallization, firstly from hexane and then from isopropanol, gave 640 mg of 1-{trans-4-[trans-4-(3-butenyl)cyclohexyl]cyclohexylethynyl}-2,6-difluoro-4-propylbenzene, m.p. (C/N) 48.5° C., cl.p. (N/I) 189.8° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]([CH3:38])[CH2:35][CH2:36][N:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]([CH3:38])[CH2:35][CH2:36][N:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(C3=NCCN3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(C3=NCCN3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(1-methyl-imidazolin-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].C(#N)C.N(OC(C)(C)C)=O>CN(C)C=O>[CH2:13]([O:12][C:10]([C:4]1[S:3][CH:2]=[C:6]([C:7]#[N:8])[C:5]=1[CH3:9])=[O:11])[CH3:14]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1C
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1scc(C#N)c1C
Temperature: 5 °C
Reaction time: 7 h
Yield: 47.8 %

Procedure:
A solution of 20.5 g (97.5 mmol) of ethyl 2-amino-3-cyano-4-methylthiophene-5-carboxylate in 600 ml of a 1:1 mixture of acetonitrile and dimethylformamide was cooled to 5° C., and 15.7 g (146 mmol) of tert-butyl nitrite were added dropwise, the reaction mixture heating up and vigorous gas evolution beginning. Stirring was carried out for seven hours at room temperature, the mixture was evaporated down in a rotary evaporator and under greatly reduced pressure, the residue was purified by column chromatography (mobile phase: dichloromethane) and 9.1 g (48%) of the desired compound were obtained as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:29]#[N:30])=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:9]2=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>CCO>[C:29]([C:13]1[CH:12]=[N:11][N:10]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)#[N:30]
Reactant: CCOC(=O)c1ccc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cnn2c(C(=O)O)ccc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
A mixture of 406 (15.6 mg, 0.039 mmol) and 1N NaOH (150 μl, 0.15 mmol) in EtOH (5 ml) was stirred at 50-70° C. for 15 h. 1N HCl (150 μl, 0.15 mmol) was added, solvent was removed, and the residue was purified by preparative TLC to give the title compound (14.1 mg, 98%) as a tan solid. LCMS Found: (M+H)+=371.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:10]3[CH2:25][CH2:26][C:27](=[O:28])[C:9]2=3)=[C:4]([S:29][CH3:30])[CH:3]=1.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N>[O:14]=[C:12]1[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)[C:10]2[CH2:25][CH2:26][C:27](=[O:28])[C:9]=2[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]#[N:33])=[CH:3][C:4]=2[S:29][CH3:30])[NH:13]1
Reactant: CN(C)C=O
Reactant: CSc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-(methylthio)phenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-2,5-dione (intermediate 25, 1.74 g, 2.8 mmol based on 80% purity), zinc cyanide (430 mg, 3.64 mmol) and tetrakis (triphenylphosphine)palladium(0) (323 mg, 0.28 mmol) in N,N-dimethylformamide (12 mL) is heated at 110° C. over night and then cooled to room temperature. Water is added, and the mixture is extracted with dichloromethane. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 1.09 g. ESI mass spectrum: [M+H]+=444; Retention time HPLC: 0.58 min (X011_S03).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:46][CH2:45]1>C(#N)C.C(Cl)(Cl)Cl>[C:53]1([CH2:52][CH2:51][CH2:50][N:47]2[CH2:48][CH2:49][CH:44]([NH:43][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:45][CH2:46]2)[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: NC1CCN(CCCc2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(NC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While 39.11 g (0.1792 mol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 21.7 g (0.188 mol) of N-hydroxysuccinimide were stirred together in 500 ml of acetonitrile, 36.1 g (0.188 mol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. To this reaction mixture was added 30.0 ml (0.215 mol) of triethylamine and, then, a solution of 39.1 g (0.179 mol) of 4-amino-1-(3-phenylpropan-1-yl)piperidine in acetonitrile (100 ml)-chloroform (50 ml) was added. The mixture was stirred at room temperature for 1 hour and the resulting orange-colored precipitate was recovered by filtration and rinsed with acetonitrile (yield 55.75 g). This crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 4/1˜1/1) and recrystallization from chloroform-ethanol to provide the title compound.