Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4([C:26](O)=O)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH:33]1[CH2:38][CH2:37]C[CH2:35][CH:34]1[CH2:39][CH2:40][NH2:41].CN([C:45]([O:49]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4([CH:26]5[CH2:37][CH2:38][NH:33][CH:34]([CH2:39][CH2:40][NH:41][CH:45]=[O:49])[CH2:35]5)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: NCCC1CCCCN1
Reactant: Cn1c(Nc2ccc(Cl)c(C(F)(F)F)c2)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Cl)c(C(F)(F)F)c2)nc2cc(OC3(C4CCNC(CCNC=O)C4)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[4-chloro-3-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-chloro-3-trifluoromethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide. MS: MH+=558.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][NH:2]2.F[C:9](F)(F)[C:10]([OH:12])=O.[OH-].[Na+].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([O:12][C:10]2[CH:9]=[C:6]([N:2]3[CH2:3][C@@H:4]4[CH2:7][C@H:1]3[CH2:6][NH:5]4)[CH:1]=[N:2][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: C1NC2CNC1C2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Oc2cncc(N3C[C@@H]4C[C@H]3CN4)c2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of unpurified (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-5-tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane (0.37 g) in anisole (3.0 mL) at 0-5° C. under a nitrogen atmosphere, trifluoroacetic acid (2.0 mL) was added dropwise over a 10 min. period. After 0.5 h at 0-5° C. the solution was adjusted to pH 5 using 10% NaOH, followed by extraction with diethyl ether (1×10 mL) to remove the anisole. The aqueous portion was adjusted to pH 11 using 10% NaOH, followed by extraction with diethyl ether (3×25 mL). The combined diethyl ether extracts were dried (Na2SO4), filtered and concentrated under vacuum to give a yellow oil (0.26 g). The material was used without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].[ClH:28].[C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1)#[N:30]>>[ClH:27].[ClH:28].[C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:20](=[O:22])[C@H:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH:18][S:24]([CH3:23])(=[O:26])=[O:25])[NH2:11])#[N:30]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N#C[C@@H]1CCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C#N

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, methanesulphonyl chloride and (S)-2-cyano-pyrrolidine hydrochloride, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NC1CCCCC1
Yield: 100 %

Procedure:
32 g (0.11 mol) of N-cyclohexyl-2-nitro-4-trifluoromethylaniline dissolved in 250 ml of methanol were hydrogenated under a pressure of about 1 bar of hydrogen in the presence of 1.5 g of palladium/active carbon (10% by weight Pd) at room temperature. The reaction mixture was filtered. Conventional workup of the filtrate gave a 100% yield of the abovementioned compound. Melting point 70° C.
Reaction SMILES: [F:1][C:2]([F:11])([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C>[F:1][C:2]([F:11])([CH3:10])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C=C/C(C)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(F)(F)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of step C was dissolved in ethanol (24 ml), 4M NaOH was added (12 ml) and the mixture was stirred at room temperature for two hours. The mixture was acidified with 1M HCl and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, the solvent was removed under reduced pressure. 2.67 g of a colourless oil were obtained. MS (ESI) m/z=135.0 [M−1]−.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[CH:13]=[CH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:9][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[CH2:13][C@@H:12]1[CH:31]1[O:34][CH2:35][CH2:36][O:33]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=C1C=C[C@@H](COC(=O)c2ccccc2)O1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: O=C1C[C@H](C2OCCO2)[C@@H](COC(=O)c2ccccc2)O1
Yield: 80 %

Procedure:
A solution containing 180 mg (0.825 mmol) compound (2e) and 22.5 mg (0.123 mmol) benzophenone in 110 mL [1,3]-dioxolane was irradiated at 20° C. for 7 hours according to the general procedure. Column chromatography (silica gel 40 g, ethyl acetate in hexanes 40%) gave compound (3e) (193 mg. 80%) as a colorless solid, Rf=0.29, [α]25D 35.2°, c 1.2, CHCl3, IR (neat) 2360, 2342, 1779, 1721, 1272, 1118 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 2.53 (d, 1H J=11.6 Hz), 2.62-2.73 (m, 2H), 3.83 (mc, 2H), 3.94 (mc, 2H), 4.37 (dd, 1H, J=5.1 Hz, J=12.3 Hz), 4.53 (dd, 1H, J=2.9 Hz, J=12.3 Hz), 4.74 (ddd, 1H, J=2.9 Hz, J=5.1 Hz, J=6.9 Hz), 4.88 (d, 1H, J=3.4 Hz), 7.37 (dd, 2H, J=7.7 Hz, J=7.9 Hz), 7.49 (dd, 1H, J=1.0 Hz, J=7.7 Hz), 7.92 (dd, 2H, J=1.0 Hz, J=7.9 Hz). 13C-NMR (100.6 MHz, CDCl3, Dept) δ: 29.77 (−), 40.06 (+), 65.37 (−), 65.50 (−), 65.99 (−), 77.56 (+), 103.14 (+), 128.51 (+), 129.31 (quat), 129.57 (+), 133.30 (+), 166.00 (quat) 175.62 (quat). C15H16O6; Exact Mass: 292.09; Mol. Wt.: 292.28; C, 61.64, H, 5.52, O, 32.84.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH2:23][CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCN(c3ccccn3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 1-(2-pyridyl)piperazine (9.8 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C20H20N4O2: 348.1586, found 348.1593.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.[NH3:19]>CO.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:19])=[N:13]2)[C:5]([F:18])=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1ccc(Br)nc1[C@]1(C(F)F)COCC(=S)N1
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1=N[C@@](c2nc(Br)ccc2F)(C(F)F)COC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 31 %

Procedure:
To a solution of (R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-morpholin-3-thione (611 mg, 1.79 mmol) in methanol (15 ml) was added ammonia (5.12 ml, 35.8 mmol, 7M in methanol), the vial was sealed and the reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with aq. sodium thiosulfate solution (10%), water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (640 mg) was chromatographed over silica gel (14 g, dichloromethane/methanol 95/5+0.5% NH3) to give the title compound. 180 mg (31% yield).
Reaction SMILES: C(CC[N:5]1[C:9]([C:10]2[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=2)[CH2:13][O:14][CH2:15][C@@H:16]([NH:19][C:20](=[O:37])[C@H:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]#[N:18])=[N:8][N:7]=[N:6]1)#N.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[NH:8]1[C:9]([C:10]2[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=2)[CH2:13][O:14][CH2:15][C@@H:16]([NH:19][C:20](=[O:37])[C@H:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]#[N:18])=[N:5][N:6]=[N:7]1
Reactant: Cc1cccc(C[C@H](Nc2ccccc2)C(=O)N[C@@H](C#N)COCc2cccc(-c3nnnn3CCC#N)c2)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(C[C@H](Nc2ccccc2)C(=O)N[C@@H](C#N)COCc2cccc(-c3nnn[nH]3)c2)c1
Reaction time: 2 h

Procedure:
To a solution of N-[2-[3-(1-(2-cyanoethyl)-5-tetrazolyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-phenyl-L-phenylalaninamide (prepared according to examples 1(g) and 7 using intermediate of Example 1(e)), 160 mg, 0.30 mmol) in CH2Cl2 (10 mL) is added DBU (0.22 mL, 1.5 mmol) in one portion, and the solution is stirred at room temp. for 2 h., after which time the solution is washed with 1 N HCl (30 mL), brine (30 mL), dried (MgSO4), evaporated, and chromatographed (2% MeOH/CH2Cl2, 0 to 0.05% acetic acid) to yield N-[2-[3-(5-tetrazolyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-phenyl-phenylalaninamide, as an off-white solid; m.p. 120-122° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:59][C:60]([CH3:62])=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH:60]([CH3:62])[CH3:59])[C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (45.8 mg, 0.079 mmol) and sodium triacetoxyborohydride (83.7 mg, 0.395 mmol) in DMF (1 mL) was added acetic acid (23.7 mg, 22.6 μL, 0.395 mmol) and acetone (18.3 mg, 23.2 μL, 0.316 mmol). The reaction mixture was heated at 60° C. for 6.5 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].CS(O[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=1)(=O)=O>C1COCC1.CN(C=O)C>[Br:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([CH2:14][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:20]=1
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)(F)COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
2,2,2-Trifluoroethanol (0.434 g, 4.34 mmol) was added to a suspension of NaH (0.198 g, 4.96 mmol) in THF (10 mL). When gas evolution had ceased, a solution of (5-bromopyridin-3-yl)methyl methanesulfonate (see WO2007/076247; 1.10 g, 4.13 mmol) in DMF was added. The resulting mixture was stirred for 2 h at r.t. and then the volatile solvent was evaporated. The remaining solution was diluted with water and extracted with EtOAc (3×30 mL). The combined extracts were dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica using gradient elution with EtOAc in heptane to give 227 mg of the title compound (20% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.92 (q, 2H), 4.70 (s, 2H), 7.87 (m, 1H), 8.50 (m, 1H), 8.66 (d, 1H); MS (EI) m/z 269 M+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.O.[CH:51]([C:53]1[CH:63]=[CH:62][C:56]([CH:57]=[CH:58][C:59]([OH:61])=[O:60])=[CH:55][CH:54]=1)=O>CO.[Pd]>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:51]([C:53]4[CH:63]=[CH:62][C:56](/[CH:57]=[CH:58]/[C:59]([OH:61])=[O:60])=[CH:55][CH:54]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Agent: [Pd]
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Yield: 91 %

Procedure:
The title compound was prepared from 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil by the method of J. Perutmattam, Syn. Commun. 1989, 19:3367–3370. 1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was freshly prepared by shaking a mixture of 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (from step (c), 5.00 g) in methanol (250 ml)-water (25 ml) with 10% palladium on carbon (0.50 g) under hydrogen (50 psi) on a Parr shaker for 2 h. The catalyst was filtered off (Celite) and the colorless filtrate was concentrated to 25 ml. 4-Formylcinnamic acid (Aldrich, 2.53 g, 14.35 mmol) was added to this solution of 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil and the resulting yellow mixture was concentrated and the residual yellow solid dried by evaporation of several portions of absolute ethanol. The resulting yellow powder (Schiff base intermediate) was stirred in dimethoxyethane (115 ml) with iodine (4.0 g) at 60° C. (oil bath) for 20 h. A saturated aqueous solution of sodium thiosulfate was added to the warm reaction mixture until complete decolorization of iodine resulted. The pale yellow precipitate was filtered off, washed with water, and dried at 0.5 Torr to give (E)-4-[1,3 bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid as a pale yellow powder (6.73 g, 91%), m.p.>300° C. Such samples were further purified by dissolving them in 1N aqueous sodium hydroxide, filtering the resulting hazy solution through Celite, and acidifying the clear filtrate with hydrochloric acid. The resulting precipitate was filtered and washed with water to give title compound as a pale yellow powder, m.p.>300° C.; 1H-NMR (DMSO-d6) δ: 13.80 and 12.40 (both br m, 1 each, CO2H and NH), 8.12 (d, J=8.3 Hz, 2, 2 phenyl CH), 7.84 (d, J=8.4 Hz, 2, 2 phenyl CH), 7.64 (d, J=16.0 Hz, 1, CH═), 6.64 (d, J=16.0 Hz, 1, CH═), 3.93 (d, J=7.0 Hz, 2, CH2N), 3.79 (d, J=6.8 Hz, 2, CH2N), 2.0–1.4 and 1.3–0.85 (both br m, 22 total, 2 cyclohexyl).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]([CH3:19])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26]([N:28]([CH2:31][CH2:32][Cl:33])[CH2:29][CH3:30])[CH3:27]>O.CC(C)=O>[ClH:33].[CH2:26]([N:28]([CH2:31][CH2:32][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]([CH3:19])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: CCN(CC)CCCl
Reactant: Cc1cc(C(C)CC(=O)c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(C(C)CC(=O)c2ccccc2)cc1C
Product: Cl
Yield: 43.5 %

Procedure:
Fifteen grams of the propiophenone derivative are dissolved in 100 ml water-free acetone. Twenty-four grams (200% excess) potash are added while stirring well. Subsequently, 24.0 grams (200% excess) diethylaminoethylchloride, dissolved in 100 ml acetone, are added dropwise. After having boiled it under reflux for 1 day, the precipitate is filtered off, the acetone evaporated and the residue taken up with dry ether. After having precipitated the hydrochloride and sucked off the residue, several recrystallizations from methanol/ether are effected. Ten grams [43.3%] 4-[2-(N,N-diethylamino)-ethoxy]-3,5-dimethyl-β-phenylpropiophenone hydrochloride (melting point of 128° C.) are obtained.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[Si:16]([O:23][CH2:24][CH:25]1[CH2:36][CH2:35][C:34]2[S:33][C:32]3[C:27](=[C:28](Cl)[N:29]=[CH:30][N:31]=3)[C:26]1=2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Si:16]([O:23][CH2:24][CH:25]1[CH2:36][CH2:35][C:34]2[S:33][C:32]3[C:27](=[C:28]([O:13][CH:10]4[CH2:9][CH2:8][CH:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[CH2:12][CH2:11]4)[N:29]=[CH:30][N:31]=3)[C:26]1=2)([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17]
Reactant: O[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
For the preparation of the starting material compound 65.1, please refer to the experimental procedure for Example 65. To a solution of trans-4-(morpholin-4-yl)cyclohexan-1-ol (277 mg, 1.50 mmol, 1.50 equiv) in distilled THF (20 mL) was added sodium hydride (605 dispersion in mineral oil, 200 mg, 5.00 mmol, 5.00 equiv) slowly at 0° C. under nitrogen. After stirring for 30 min at room temperature, a solution of 3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (355 mg, 1.00 mmol, 1.00 equiv) in 5 mL of THF was added dropwise and the resulting solution was stirred for 6 h at ambient temperature. The reaction was quenched with NH4Cl (sat.), extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was purified by a silica gel column with EtOAc/petroleum ether (1:1-3:1) to provide 350 mg (69%) of the title 3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene as a light yellow oil. MS: (ES, m/z): 504 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10](I)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C@H:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C(=O)([O-])[O-].[K+].[K+].N>CN1CCCC1=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:22]2[CH2:23][CH2:24][C@H:20]([OH:19])[C:21]2=[O:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(I)nc1Cc1ccccc1
Reactant: O=C1NCC[C@@H]1O
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(N2CC[C@H](O)C2=O)nc1Cc1ccccc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 73.4 %

Procedure:
14.3 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (Production Example 12) and 4.1 g of (3S)-3-hydroxy-2-pyrrolidinone synthesized according to a method well-known in a literature (Synthesis, 1978, 614), 4.6 g of cuprous iodide and 13.7 g of potassium carbonate were suspended in 30 ml of 1-methyl-2-pyrrolidinone, followed by heating under stirring at 140° C. in an oil bath for 20 minutes in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto. The mixture was extracted with ethyl acetate, and the organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 50-60% ethyl acetate as an eluent for separation and purification, to give 9.7 g of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][OH:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH2:35]Br)[CH:26]=1.CC(C)([O-])C.[Na+].CO>O1CCCC1.C(=O)(O)[O-].[Na+]>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:35][O:23][CH2:22][C:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2F)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl 4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (220 mg, 0.67 mmol) and 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (450 mg, 1.41 mmol) were combined in tetrahydrofuran (2 mL) and cooled to 0° C. The reaction was treated with sodium tert-butoxide (75 mg, 0.355 mmol) and stirred at 0° C. for 20 min. The reaction was treated with another aliquot of sodium tert-butoxide (75 mg, 0.355 mmol), allowed to warm to room temperature, and stirred for 30 min. The reaction was diluted with 10% sodium bicarbonate and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (1×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg (50%). Mass spec.: 586.04 (MH)+ LC tr=2.552 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].CN([CH:8]=[C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]1=O)C>>[CH2:1]([N:3]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:9]=2[CH:8]=[N:4]1)[CH3:2]
Reactant: CCNN
Reactant: CN(C)C=C1C(=O)CCCC1=O
Product: CCn1ncc2c1CCCC2=O

Procedure:
Prepared analogously to Example 1 starting from ethylhydrazine and 2-(dimethylaminomethylene)-cyclohexane-1,3-dione.