Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22].CN(C)C=O>O>[CH3:1][O:2][N:3]=[C:4]([O:13][CH2:22][C:21]#[CH:20])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12]
Reactant: CONC(=O)c1ccc(Cl)cc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC(=NOC)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 29.8 %

Procedure:
1.0 g of N-methoxy-2,4-dichlorobenzamide, 0.75 g of potassium carbonate and 0.65 g of propargyl bromide were added to 10 ml of N,N-dimethylformamide, and the mixture was stirred for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.35 g of propargyl N-methoxy-2,4-dichlorobenzimidate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1.[H][H]>[Ni].C1COCC1.CO>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1

Procedure:
2-(4-(6-Bromo-3-nitroquinolin-4-ylamino)phenyl)-2-methylpropane nitrile (Compound of Preparation C, 16 g, 42 mmol) was hydrogenated using Raney-Ni (7 g), THF-MeOH [(1:1), 250 mL] under 25 psi of hydrogen for 1 hour at RT. After completion of the reaction, the catalyst was filtered-off and the filtrate was evaporated to dryness to obtain the title compound. Yield: 13 g (88%); 1H NMR (DMSO-d6, 300 MHz): δ 8.609 (s, 1H), 7.908 (s, 1H), 7.829-7.836 (d, 1H, J=2.1 Hz), 7.744-7.773 (d, 1H, J=8.7 Hz), 7.425-7.462 (dd, 1H, J=9 Hz, 2.1 Hz), 7.236-7.265 (d, 2H, J=8.7 Hz), 6.511-6.540 (d, 2H, J=8.7 Hz), 5.448 (s, 2H), 1.600 (s, 6H); MS: m/z 381 (M+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=O.[H][H]>C1C(Cl)=CC=C(Cl)C=1>[CH2:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: [H][H]
Reactant: CC(=O)c1cccc2ccccc12
Solvent: Clc1ccc(Cl)cc1
Product: CCc1cccc2ccccc12
Yield: 90 %

Procedure:
A 2 mL reactor was charged with 0.150 mL of a 1.00 M solution of 1-acetonaphthalene and 0.050 mL of a 0.030 M solution of [Cp*Ru(CO)2]2(μ-H)}+OTf− in dichlorobenzene. The reaction was heated at 90° C. for 12 hours at 820 psi (5.7 MPa) of hydrogen gas. The reaction was cooled, and analyzed using gas chromatography/mass spectroscopy. Analysis indicated 100% conversion of the 1-acetonaphthalene, with a greater than 90% yield of 1-ethylnaphthalene. Note that in this example, the alcohol itself (presumably initially formed from hydrogenation of the C═O double bond) undergoes a hydrogenation reaction to yield in the final product, 1-ethylnaphthalene.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:13][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[CH2:9][CH3:10]
Reactant: CCC(O)c1cccc(Cl)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Br)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(6-chloropyridin-2-yl)propan-1-ol (0.497 g, 2.90 mmol), CBr4 (1.2 g, 3.62 mmol) and triphenylphosphine (0.987 g, 3.76 mmol) in 25 mL of THF was stirred at room temperature for 2 h. The solid was filtered off and washed with THF. The filtrate was concentrated and residue was purified by chromatography on silica gel, eluting with 10 to 50% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=236 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O>N1C=CC=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][CH:10]([CH2:11][CH2:12][S:13](=[O:15])(=[O:14])[NH2:16])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)CCC(O)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(CCS(N)(=O)=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of hydroxyl-sulfonamide 5 (77 g, 0.30 mol) in pyridine (730 mL, 9.5 vol) was cooled to <10° C. in a 2 L round bottom flask. Tosyl chloride (56.6 g, 0.30 mol) is added to the solution over 5 minutes maintaining the internal temperature below 10° C. The reaction was allowed to warm to room temperature with stirring overnight. The completed reaction was poured into water (10 vol, 770 mL) to give an orange solution which was extracted with iPrOAc/MTBE (1:1, 2×1.5 L). The combined organics were washed with brine (2×500 mL), aqueous HCL (2M, 2×500 mL) then brine (1×500 mL). The organic portion was dried (Na2SO4), filtered and evaporated to give sulfonate 6 as an orange oil (78 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[F:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:25]3=[C:26]([CH2:28][O:29][CH2:30][CH2:31][N:24]3[C@H:23]3[CH2:32][CH2:33][NH:34][CH2:35][C@@H:22]23)[CH:27]=1>>[CH:3]1([CH2:2][N:34]2[CH2:33][CH2:32][C@@H:23]3[N:24]4[CH2:31][CH2:30][O:29][CH2:28][C:26]5[CH:27]=[C:19]([NH:18][C:9]6[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:8]=6[F:7])[CH:20]=[C:21]([C:25]4=5)[C@@H:22]3[CH2:35]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Fc1c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Reactant: BrCC1CCC1
Product: Fc1c(Nc2cc3c4c(c2)[C@@H]2CN(CC5CCC5)CC[C@@H]2N4CCOC3)cccc1C(F)(F)F

Procedure:
Using bromomethylcyclobutane and following the procedures described in EXAMPLE 144, (7bR,11aS)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine free base from EXAMPLE 95 was converted into the title compound of EXAMPLE 145. 1H NMR(CDCl3) δ: 7.15 (dd, 1H, J=7.8, 6.8 Hz), 7.05-6.95 (m, 2H), 6.89 (d, 1H, J=1.9 Hz), 6.77 (d, 1H, J=2.0 Hz), 5.73 (d, 1H, J=3.0 Hz), 4.63 (ABq, 2H, JAB=14.1 Hz), 4.24 (app d, 1H, J=12.8 Hz), 3.75 (app t, 1H), 3.50-3.30 (m, 2H), 3.25 (dd, 1H, J=13.1, 2.8 Hz), 2.95-2.30 (overlapping multiplets, 7H), 2.15-1.65 (overlapping multiplets, 9H). LRMS (ES)+: 476.4 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]([O:18][C:19](ON1C(=O)CCC1=O)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:18][C:19]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CO)c1ccccc1)OCc1ccccc1
Reaction time: 48 h

Procedure:
4.5 g (295 mmol) of (R)-2-amino-2-phenylethanol are dissolved in 385 ml of absolute dimethylformamide. 73.5 g of N-(benzyloxycarbonyloxy)succinimide (295 mmol) are added, at 0° C. and while stirring, and the mixture is then stirred at 0° C. for 1 hour. The ice bath is removed and the mixture is left to stand at room temperature for 48 h. The reaction solution is concentrated in vacuo and the residue is then taken up in 500 ml of ethyl acetate. The organic phase is washed twice with a 10% aqueous solution of citric acid and once with water. It is then dried over anhydrous sodium sulphate and concentrated. The resulting crystalline crude product (82.3 g) is once again dissolved in ethyl acetate. The organic phase is washed twice with a 10% aqueous solution of citric acid and once with water. Recrystallization subsequently takes place from ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](SC)=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH:13]=[CH:14][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:26][NH2:27]>CO>[NH2:20][C:19]1[NH:27][N:26]=[C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:11]=2)[C:18]=1[C:21]#[N:22]
Reactant: NN
Reactant: CSC(Nc1cccc(CNC(=O)OC(C)(C)C)c1)=C(C#N)C#N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Nc2n[nH]c(N)c2C#N)c1

Procedure:
A mixture of 145.4 g (422 mmol) of 3-[3-(N-Boc-aminomethyl)-phenylamino]-2-cyano-3-methylmercapto-acrylonitrile, 21.96 ml (443 mmol) of hydrazine hydrate and 1000 ml of methanol is heated under reflux for 2 hours and then concentrated by evaporation in vacuo, yielding 5-amino-[3(N-Boc-aminomethyl)-phenylamino]4-cyano-pyrazole; TLC-Rf=0.28 (methylene chloride/methanol [9:1]).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.C(=O)([O-])[O-].[K+].[K+].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[N:23]1([C:29]([N:9]2[CH2:10][CH:11]3[CH2:15][C:14](=[O:16])[CH2:13][CH:12]3[CH2:8]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2CN(C(=O)N3CCOCC3)CC2C1
Yield: 100 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (574 mg, 2.4 mmol) was dissolved in 20 mL of acetonitrile with stirring followed by addition of potassium carbonate (0.397 g, 2.88 mmol), and morpholine-4-carbonyl chloride (0.323 mL, 2.64 mmol) upon cooling by an ice-water bath. The reaction mixture was reacted overnight at the same temperature. The mixture was concentrated under reduced pressure and diluted with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(morpholine-4-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 7a (0.572 g, yield 77.3%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].[Br:11][C:12]1[CH:25]=[CH:24][C:15]([NH:16][S:17]([CH2:20][C:21](O)=[O:22])(=[O:19])=[O:18])=[CH:14][CH:13]=1>C(O)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([NH:16][S:17]([C:20]2[C:21](=[O:22])[O:10][C:3]3[C:4]([CH:5]=2)=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])(=[O:19])=[O:18])=[CH:24][CH:25]=1
Reactant: O=Cc1cccc(Cl)c1O
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=c1oc2c(Cl)cccc2cc1S(=O)(=O)Nc1ccc(Br)cc1

Procedure:
A solution of 3-chlorosalicylaldehyde (1 mmol) and 4-bromoanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 202-204° C.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[NH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[CH2:16][CH2:17][CH2:18][CH:9]([C:10]=23)[C:8]1=[O:19].C(Br)C#C>CN(C)C=O.O>[CH2:3]([C:9]12[CH2:18][CH2:17][CH2:16][C:11]3[C:10]1=[C:15]([CH:14]=[CH:13][CH:12]=3)[NH:7][C:8]2=[O:19])[C:2]#[CH:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C1Nc2cccc3c2C1CCC3
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC12CCCc3cccc(c31)NC2=O
Reaction time: 0.25 h

Procedure:
Potassium tert.-butoxide, 4.94 g (0.044 mol), was added to a solution of 6.92 g (0.04 mol) of rac-2a,3,4,5-tetrahydro-benz[cd]indol-2(1H)-one in 50 ml of dimethylformamide. After stirring for 15 minutes under nitrogen, 5.23 g or 3.9 ml of propargyl bromide was added and stirring was continued for 30 minutes. The mixture was diluted with water and ice and the precipitate was collected by filtration, washed with water and sucked dry. The solids were dissolved in methylene chloride and the solution was dried and evaporated. Crystallization of the residue from ethyl acetate gave crude product of rac-2a,3,4,5-tetrahydro-2a-(2-propynyl)benz[cd]indol-2(1H)-one with m.p. 174-177° which was recrystallized from ethyl acetate to melt at 177°-180°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[S-:11][C:12]#[N:13].[K]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10][C:12]([NH2:13])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#C[S-]
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: [K]
Solvent: O
Product: NC(=S)NNc1ccc(Cl)c(Cl)c1
Yield: 95 %

Procedure:
A mixture of 3,4-dichlorophenylhydrazine (18.8 mmol) and thiocyanate of potassium (55.7 mmol) was dissolved in water (1 L) and heated for 17 hours. After cooling the product the solid was filtered and dried in vacuo to give 3,4-dichlorophenylthiosemicarbazide (4.20 g, yield=95%). H1NMR (300 MHz, DMSO, 25° C.) δ: 9.37 (s, 1H); 8.30 (s, 1H); 7.84 (s, 1H); 7.60 (s, 1H); 7.40 (d, J=8.7 Hz, 1H); 6.37 (d, J=2.52 Hz. 1H); 6.60 (dd, J=8.67 Hz, J=2.5 Hz. 1H) ppm. EM (ES+) m/z=236 (100%) [M+H]+.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:32])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]([NH2:31])=[O:30])[O:24][CH2:23]2)[CH:17]([CH:33]([OH:35])[CH3:34])[C:16]3=[O:36])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:41].O.[H][H]>[Pd].O1CCOCC1>[Na+:41].[NH2:31][C:29]([O:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:32])[CH:18]3[N:15]([C:16](=[O:36])[CH:17]3[CH:33]([OH:35])[CH3:34])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)=[O:30]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COC(N)=O)C3)C(C)C12
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Yield: 67 %

Procedure:
A mixture of 0.181 g of product from Example 17, 0.032 g of sodium bicarbonate, 2 ml of water, 11 ml of dioxane and 0.100 g of 10% palladium/carbon is reduced in a Parr apparatus at 42 psi of hydrogen for 3 hours. The reaction mixture is filtered through a pad of diatomaceous earth, washed with water and concentrated to 1/2 volume. The solution is extracted with ethyl acetate and the aqueous layer is freeze-dried. The product is purified using C18 reverse phase chromatography (95/5 water/ethyl alcohol) to give 0.095 g of the desired product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(=O)n(C3=CCN(Cc4ccccc4)CC3)c2cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2[nH]c(=O)n(C3=CCNCC3)c2cc1C

Procedure:
A solution of 5,6-dimethyl-1-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (D99) (1.05 mmol, 350 mg) in ethanol (10 mL) and acetic acid (2 mL) was treated with 10% palladium on charcoal (0.25 eq wt, 90 mg) then shaken under 50 PSI of hydrogen pressure for 24 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the acetate salt of the title compound also containing some saturated analogue (reduction of the C═C double bond in the piperidine core) as a beige solid (1.2 mmol, 370 mg, >100% yield) M+H 246.2, M−H 242.3.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].CCN(C(C)C)C(C)C.[CH2:49]([N:53]=[C:54]=[O:55])[CH2:50][CH2:51][CH3:52]>ClCCl>[CH2:49]([NH:53][C:54]([N:37]1[CH2:38][CH2:39][N:34]([C:2](=[O:1])[CH2:3][NH:4][C:5]([C:7]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21](=[O:27])[NH:22][CH:23]3[CH2:24][CH2:25][CH2:26]3)=[O:15])[N:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:8]=2)=[O:6])[CH2:35][CH2:36]1)=[O:55])[CH2:50][CH2:51][CH3:52]
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 5 ml dichloromethane were added at 0° C. 56 l DIPEA and 25 l butyl isocyanate. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 55 mg MS (ES+): m/e=637.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(#N)C>[N:19]1([CH2:2][C:3]2[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CC(C)(C#N)c1cc(CCl)cc(C(C)(C)C#N)c1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1

Procedure:
A solution of 2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), (0.23 g), and 1H-1,2,4-triazole (0.35 g) in acetonitrile (2 ml) was heated under reflux for 18 h, then evaporated to dryness. The residue was partitioned between 1N aqueous potassium hydrogen carbonate solution and ethyl acetate, the organic phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography. Elution with methanol:chloroform (1:49 by volume), gave 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), identical with the product of Example 1, and further elution with methanol:chloroform (2:23 by volume, gave 2,2'-[5-(4H-1,2,4-triazol-4-ylmethyl)-1,3-phenylene]di(2-methylpropiononit rile), mp. 158°-161°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:6]([Cl:19])=[O:7]
Reactant: COC(=O)c1ccc(C(=O)O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Cl)cc1OC
Yield: 100 %

Procedure:
To a stirred suspension of 3-methoxy-4-methoxycarbonylbenzoic acid (4.1 g, 19.5 mmol) and oxalyl chloride (2.4 ml, 27.3 mmol) in dry dichloromethane (100 ml) was added 2 drops of dimethylformamide. After 3 h at room temperature the clear solution was evaporated to an oil. The oil was redissolved in dry dichloromethane and evaporated, this procedure was repeated to give 3-methoxy-4-methoxycarbonylbenzoyl chloride as an oil (100%) which was used immediately in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)CCNC(=O)OCc2ccccc2)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Yield: 89.9 %

Procedure:
To a solution of 1.84 g of 3-(benzyloxycarbonyl)amino-N-({(3R)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl)propanamide in 2 ml of chloroform, 2 ml of trifluoroacetic acid was added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, and the residue was rendered basic with, 4N aqueous sodium hydroxide solution. Extracting the product with chloroform, the product was dried over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 1.26 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:13]#[N:14].O>CN1CCCC1=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:10]2[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[C:12]([CH:11]=2)[C:13]#[N:14])[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2cc(C#N)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 4-methyl-1H-imidazole (1.98 g, 24.11 mmol) in N-methylpyrrolidinone (NMP) (18 mL) is added to a solution of sodium hydride (0.82 g, 60%, 20.5 mmol) in NMP (18 mL) at 20-25° C. under an atmosphere of nitrogen. The mixture is stirred for 1 hour, before a solution of 3-fluoro-5-trifluoromethyl benzonitrile (XXI) (3.2 g, 16.4 mmol) in NMP (8 mL) is added. The reaction mixture is stirred for 2 hours at 20-25° C. and then water (120 mL) is added within 20 minutes and the resulting suspension is stirred for 16 hours.
Reaction SMILES: [C:1]([CH:11]([CH:27]1[NH:32][CH2:31][CH2:30][NH:29][CH2:28]1)[N:12]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:13]([CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])(OCC1C=CC=CC=1)=O.C(Br)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CO.CC#N.[Pd]>[CH2:1]([CH:11]([CH:27]1[NH:32][CH2:31][CH2:30][NH:29][CH2:28]1)[N:12]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:13]([CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccccc1NN(C(=O)C1CCC1)C(C(=O)OCc1ccccc1)C1CNCCN1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: Cc1ccccc1NN(C(=O)C1CCC1)C(CCc1ccccc1)C1CNCCN1
Reaction time: 12 h
Yield: 41.5 %

Procedure:
A solution of 213 (0.302 mmol, 127 mg) in CH3OH (1 mL) at 25° C. was treated with 30% Pd—C (25 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of celite. The solvents were removed in vacuo and the resulting oil was then treated with phenethyl bromide (1.5 equiv, 0.453 mmol, 62 μL) and K2CO3 (2.0 equiv, 0.604 mmol, 83 mg) in CH3CN (1.0 mL). The reaction mixture stirred for 12 h at 65° C. The reaction mixture was then purified directly by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, EtOAc-10% CH3OH) which provided 214 (51 mg, 118 mg theoretical, 43%) as colorless oil: Rf 0.45 (SiO2, EtOAc-10% CH3OH); LRMS m/z 390 (M+, C26H34N2O, requires 390).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>ClCCl>[CH2:31]([O:30][C:28]([NH:20][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CNC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CNC(=O)c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
0.12 g of triethylamine was added to 10 ml of a solution of 0.25 g of N-benzoyl-2-phenyl-1,2-ethylenediamine hydrochloride and 0.17 g of benzyl chloroformate in dichloromethane under ice cooling, and the mixture was stirred at 5° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was rinsed with water, the organic layer was dried over magnesium sulfate anhydrous, and the residual oily material obtained under a reduced pressure was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to obtain 0.28 g of the title compound as colorless crystals.