Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[S:15]2)=[C:6]([CH2:35][CH2:36][CH3:37])[C:5]=1[OH:38])(=[O:3])[CH3:2].[OH-].[Li+]>C(O)C>[C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[S:15]2)=[C:6]([CH2:35][CH2:36][CH3:37])[C:5]=1[OH:38])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2COC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCSCC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
The product of Example 2 (3 g, 0.0052 mol) was dissolved in ethanol (50 ml). Aqueous lithium hydroxide solution (2 M, 9.2 ml) as added and the reaction solution was stirred at room temperature for 3 hrs. Ethanol was removed using the rotary evaporator and the aqueous residue was acidified to pH2 using aqueous 0.5 N sodium bisulfate solution. The oil which separated was extracted with ethyl acetate and the organic layer dried over anhydrous magnesium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 2.53 g of a colorless oil which was dried at 70° (0.1 mm Hg) for 5 hrs. to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:41]1[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1

Procedure:
Following general procedure M, tert-butyl 4-((trans-4-((3-acetyl-6-bromoquinolin-4-yl)amino)cyclohexyl)methyl)piperazine-1-carboxylate (55 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (66 mg, >99%) as an off-white solid. ESI MS m/z 611 [C33H40ClFN4O4+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)[C:5]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)=[CH:4][N:3]=1>CO.[Pd]>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:12][CH:9]([O:8][C:6]2[C:5]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:4][N:3]=[CH:2][N:7]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(Cl)nc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cncnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of tert-butyl 4-(2-chloro-4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (472 mg, 0.95 mmol) in MeOH (10 mL) was added Pd/C (10%, 200 mg). The reaction solution was stirred at room temperature overnight under H2 atmosphere. The mixture was filtered through CELITE® and concentrated to give the product (307 mg, 0.66 mmol, yield: 78%). ESI-MS (M+1): 462 calc. for C26H31N5O3 461.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH3:13])[C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.[NH:23]1[CH:27]=[C:26]([C:28]#[N:29])[N:25]=[CH:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH3:13])[C:9]=1[CH2:14][O:15][C:16]1[N:17]=[CH:18][C:19]([N:23]2[CH:27]=[C:26]([C:28]#[N:29])[N:25]=[CH:24]2)=[CH:20][CH:21]=1
Reactant: N#Cc1c[nH]cn1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(I)cn1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(-n2cnc(C#N)c2)cn1
Temperature: 90 °C
Yield: 39.3 %

Procedure:
The mixture of 2-[5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-5-iodo-pyridine (0.5 g, 1.22 mmol), 1H-imidazole-4-carbonitrile (0.170 g, 1.82 mmol), cesium carbonate (0.79 g, 2.43 mmol), copper(I)oxide (0.017 g, 0.122 mmol), ferric acetylacetonate (0.129 g, 0.365 mmol) in DMF (10 ml) was heated at 90° C. for 20 h. The reaction was monitored by TLC and UPLC. The reaction mixture was concentrated under reduced pressure, water was added and extracted with ethylacetate (3×50 ml). The organic layer was washed with brine (15 ml), dried over Na2SO4 and concentrated under reduced pressure to afford crude mass (500 mg, 109% mass balance). It was purified in grace column using 2% methanol in chloroform as an eluent to furnish desired 1-{6-[5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridin-3-yl}-1H-imidazole-4-carbonitrile (0.180 g, 39.38%) as off-white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH:34]=[N:35][NH:36]3)O1>>[NH:36]1[C:37]2[C:33](=[C:32]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=4[N:7]=3)[CH:40]=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)S(C)(=O)=O

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide was reacted with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification on silica yielded 273. NMR: (400 MHz, CDCl3) 10.20 (br s, 1H), 9.02 (br s, 1H), 8.28 (d, J=7.4, 1H), 7.60 (d, J=8.3, 1H), 7.51 (t, J=7.7, 1H), 7.47 (s, 1H), 4.67 (s, 2H), 4.09 (t, J=4.8, 4H), 3.92 (t, J=4.8, 4H), 2.95 (s, 3H), 2.93 (s, 3H). MS: (ESI+)[M+H]+ 459.06
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:23])[CH2:10][N:9]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C:5]([F:24])=[CH:4][N:3]=1.[CH2:25]([O:27][C:28](=[O:36])[C@:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH3:26].[H-].[Na+]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:36])[C@:29]([O:35][CH2:10][C:8]([C:6]1[C:5]([F:24])=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)([NH:9][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH3:23])([CH3:34])[C:30]([F:31])([F:32])[F:33])[CH3:26]
Reactant: CCOC(=O)[C@@](C)(O)C(F)(F)F
Reactant: CC1(c2cc(Br)ncc2F)CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-5-fluoro-4-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine (795 mg, 1.91 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (498 mg, 2.67 mmol) in DMF (8 ml, soln. predried over mol. sieves) was added NaH (99 mg of a 60% dispersion in mineral oil, 2.48 mmol) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with aq. 1N HCl and diluted with H2O and TBME. The phases were separated and the aq. phase was twice extracted with TBME. The combined org. phases were washed with H2O, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (heptane:EtOAc 1:1) yielded the title compound (diastereomer mixture) as a colourless solid. HPLC RtH4=1.26 min; ESIMS: 602, 604 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 7.99 (m, 1H), 7.95-7.93 (m, 1H), 7.79-7.61 (m, 4H), 6.94 (m, 1H), 4.45-4.33 (m, 2H), 3.94-3.81 (m, 2H), 1.85 (m, 3H), 1.61 (m, 3H), 1.40-1.34 (m, 3H).
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[S:20])=[C:14]([OH:29])[C:13]=1[S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31].[Si:36](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].N1C=CN=C1>>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:31])=[O:32])[C:14]=1[O:29][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[S:20]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2F)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2F)c1O[Si](C)(C)C(C)(C)C
Yield: 68.5 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-fluorophenyl)thiourea (440 mg, 1.09 mmol), tert-butyldimethylsilyl chloride (817 mg, 5.45 mmol) and imidazole (148 mg, 2.18 mmol) were reacted to form the desired product (387 mg, 69%). EI-MS m/z 518.2 (M+).
Reaction SMILES: [CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].C1(=O)CCCC1.II>>[CH2:1]([C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC=C1CCCC1=O
Agent: II
Solvent: O=C1CCCC1
Product: CCCCCC1=CCCC1=O
Yield: 84.3 %

Procedure:
In a 100 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-pentylidenecyclopentanone (30 g) synthesized in Reference Example 4, cyclopentanone (31.6 ml) and iodine (30 mg), followed by 4 hours of the reaction under refluxing. The reaction mixture was washed with water and the layers were separated from each other. The resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover cyclopentanone, whereby a crude product (30.2 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 25.3 g of 2-pentyl-2-cyclopentenone (boiling point: 101° C./900 Pa; GC purity: 97.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([Cl:27])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([Cl:27])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccno3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20](COCCOC)[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:28][C@H:29]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:30]I)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CO.C(OCC)(=O)C>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:28][C@H:29]([C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH3:30])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O[C@@H](CI)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](O[C@@H]1CC[C@@H]2N(Cc3ccccc3)[C@@]1(c1ccccc1)C[C@@]2(F)c1nnn[nH]1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
Palladium on charcoal (60 mg) was added to a solution of (1R*,2R*,5S*,6S*)-8-benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-iodoethoxy}-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Description 46; 193 mg, 0.23 mmol) and triethylamine (38 mg, 0.38 mmol) in methanol (3 ml) and ethyl acetate (5 ml). The mixture was hydrogenated at 40 psi. for 3 hours using the Parr™ apparatus. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was taken up in a mixture of 1.0M Hydrochloric acid in diethyl ether (5 ml) and methanol (5 ml) and stirred at reflux for 18 hours. The mixture was concentrated in vacuo to yield the title compound (90 mg, 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[C:31]2[CH2:32][CH2:33][CH:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH2:35][CH2:36][C:30]=2[CH:29]=[CH:28][C:27]=1[NH2:43]>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:43][C:27]2[CH:28]=[CH:29][C:30]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:33][CH2:32][C:31]=3[C:26]=2[O:25][CH3:24])=[N:3][CH:4]=1
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2OC)CCC(N2CCOCC2)CC3)ncc1Cl
Temperature: 130 °C

Procedure:
The title compound was prepared from (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to Example 179, heating at 130° C. Product was isolated as a greenish-brown foam (23.4, 18%). LCMS (m/e) 595 (M+H); 1H NMR (CDCl3, 400 MHz) δ 8.26 (d, 1H, J=9.6 Hz), 8.05 (d, 1H, J=8.34 Hz), 8.03 (s, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 6.84 (d, 1H, J=8.09 Hz), 6.54 (m, 2H), 3.90 (m, 7H), 3.72 (m, 7H), 3.33 (m, 1H), 3.17 (m, 4H), 2.84 (t, 1H, J=7.32 Hz), 2.58-2.69 (m, 6H), 2.37 (t, 1H, J=12.1 Hz), 2.13 (m, 2H), 1.41 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:14](=[O:44])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24](C(OCC4C5C(=CC=CC=5)C5C4=CC=CC=5)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].N1CCCCC1.O.C(OCC)(=O)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:14](=[O:44])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(NC(=O)c2ccc(N3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)cc2)CCCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: N#CCNC(=O)C1(NC(=O)c2ccc(N3CCNCC3)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-FMOC-piperazin-1-yl)-benzamide (4.4 mmol) is dissolved in DMF (15 ml), piperidine (4.4 mmol) is added and the mixture is stirred at RT for 4 hours. 4 additional drops of piperidine are added and the mixture is stirred over night. The reaction mixture is poured into water and ethyl acetate and the suspension is filtered and the filtrate is acidified with HCl 4N and then extracted with ethyl acetate. Saturated sodium carbonate solution is added to make the water phase basic and the mixture is extracted three times with ethyl acetate. The water phase is saturated with sodium chloride and extracted three times with ethyl acetate again. The organic fractions are dried over sodium sulfate and the solvent is evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 3N NH3)=95:5 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 206-210° C., Rf=0.28 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@@H:13]([OH:19])[CH2:14][NH:15][CH:16]3[CH2:18][CH2:17]3)[O:11][C:10]([CH3:21])([CH3:20])[N:9]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:36]([O:43][C:44]([N:15]([CH2:14][C@@H:13]([C@@H:12]1[O:11][C:10]([CH3:21])([CH3:20])[N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:8]1[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[OH:19])[CH:16]1[CH2:17][CH2:18]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CNC2CC2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CN(C(=O)OCc2ccccc2)C2CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.9 %

Procedure:
A mixture of 180 mg (0.45 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-2-(cyclopropylamino)-1-hydroxyethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, 0.126 ml (0.98 mmol) of triethylamine and 136 mg (0.545 mmol) of N-(benzyloxycarbonyloxy)succinimide in 5 ml of methylene chloride is stirred at room temperature for 2 hours. Subsequently, the residue is poured on to ice and 2N sodium bicarbonate solution and then extracted three times with 150 ml of ether each time. The organic phase is washed with 70 ml of water, then dried over magnesium sulphate and evaporated. There are obtained 296 mg of tert-butyl (4S,5R)-5-[(S)-2-[1-(benzyloxy)-N-cyclopropylformamido]-1-hydroxyethyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a colourless oil; MS: 531 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1C=CC(C2(N(C)C)CCC(=O)CC2)=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH3:27])[CH2:16][CH2:17][C:18](=[O:21])[CH:19]([CH3:29])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Reactant: CCCCN(C)C1(c2cccc(OCc3ccccc3)c2)CCC(=O)CC1
Product: CCCCN(C)C1(c2cccc(OCc3ccccc3)c2)CCC(=O)C(C)C1

Procedure:
Following the procedure of Preparation VIIA but substituting 4-(m-benzyloxyphenyl)-4-n-butylmethylamino)cyclohexanone (prepared according to Preparation VI) for 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone there is obtained 4-(m-benzyloxyphenyl)-4-(n-butylmethylamino)-2-methylcyclohexanone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Cu](C#N)[C:13]#[N:14].O>CN1C(=O)CCC1>[C:13]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[N:14]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1ccc(Br)cn1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C#N)cn1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
A mixture of methyl 5-bromopyridine-2-carboxylate (2.8 g) and copper cyanide (3.6 g) in NMP (30 mL) was heated with stirring at 170° C. for 1.5 h. Water was added to the reaction solution at RT, and the insoluble matter was removed by filtration. The filtrate was extracted with EtOAc. The extract was washed with a saturated NaCl solution and then dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (EtOAc-heptane system) to obtain the title compound (920 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.06 (s, 3H), 8.16 (dd, J=2.0, 8.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:22][CH:21]3[N:17]([CH2:18][CH2:19][CH2:20]3)[C:16]3[N:23]=[C:24]([NH:27][CH2:28][CH3:29])[N:25]=[CH:26][C:15]=3[C:14]2=[O:30])[CH:8]=1)(=[O:3])[CH3:2].ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:28]([NH:27][C:24]1[N:25]=[CH:26][C:15]2[C:14](=[O:30])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]4[O:3][C:1]([CH3:2])=[N:4][N:5]=4)[CH:8]=3)[CH2:22][CH:21]3[N:17]([CH2:18][CH2:19][CH2:20]3)[C:16]=2[N:23]=1)[CH3:29]
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(C(=O)NNC(C)=O)c1)C2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(-c3nnc(C)o3)c1)C2=O
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
Compound 19 (136 mg, 0.320 mmol) obtained in Example 19 was dissolved in acetonitrile (2.1 mL), and the mixture was stirred for 1 hour under microwave (CEM; Discover, 300 watts, 150° C.) irradiation after adding trichloroacetonitrile (0.0646 mL, 0.640 mmol) and triphenylphosphine-supported resin (Triphenylphosphine, polymer-supported; 3.08 mmol P/G, 320 mg, 0.960 mmol). The resin was separated by filtration, and the filtrate was collected, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (Compound 20) (108 mg, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]#[N:14])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-]>C1COCC1.O>[C:13]([C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:14]
Reactant: COC(=O)c1cc(C#N)cc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C#N)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Methyl 3,5-dicyanobenzoate (400 mg, 2.1 mmol) was dissolved in THF—H2O (7:3 v/v, 30 mL), the solution was cooled to 0° C. and LiOH (51 mg, 2.1 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. THF was removed under reduced pressure and the aqueous layer was washed with EtOAc, acidified to pH ˜2-3 using 1.5N HCl, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 20% MeOH in CHCl3) to get pure product 3,5-dicyanobenzoic acid (100 mg, yield 28%): 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.50 (s, 2H). MS (ESI) m/z: Calculated for C9H4N2O2: 172.03. found: 171.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:37]2[S:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][CH2:36][N:30]([C:37]4[S:38][C:39]5[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=5[N:41]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-[1.4]diazepan-1-yl-benzothiazole.