Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:13]2[C:25]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[N:18]([CH:26]4[CH2:28][CH2:27]4)[C:17]=3[N:16]=[C:15]([CH3:29])[C:14]=2[C:30](OCC)=[O:31])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].ClCl.[OH-].[Na+].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>O1CCCC1.ClCCl.O>[CH:26]1([N:18]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=3[C:25]3[C:13]([C:4]4[C:5]([CH3:12])=[C:6]5[C:11](=[CH:2][CH:3]=4)[O:10][CH2:9][CH2:8][CH2:7]5)=[C:14]([CH:30]=[O:31])[C:15]([CH3:29])=[N:16][C:17]2=3)[CH2:27][CH2:28]1
Reactant: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1-c1cc(Cl)c2c(c1C)CCCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: ClCl
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(c3c(n2C2CC2)CCCC3)c(-c2ccc3c(c2C)CCCO3)c1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
An ice cold solution of ethyl 4-(8-chloro-5-methylchroman-6-yl)-9-cyclopropyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (348 mg, 0.726 mmol) in tetrahydrofuran (THF) (7 mL) was treated slowly with LAH (1M in THF) (2.179 mL, 2.179 mmol), and then stirred at rt for 18 hours. LCMS indicated mixture of chlorinated and dechlorinated product. Continued adding LAH (total 11 mL over 1 day) until all the chlorine had been reduced. The reaction was cooled to 0° C., treated slowly with 501 uL H2O, followed by 501 uL 15% aq. NaOH and 3×501 uL H2O. The mixture was stirred at rt for 1 hour, filtered, washed with EtOAc, and then concentrated to give crude alcohol as beige solid. The intermediate was suspended in dichloromethane (DCM) (7.00 mL), treated with PCC (235 mg, 1.090 mmol), and stirred at rt for 4.5 hours. The mixture was treated with additional PCC (108 mg), Celite™ (350 mg), DCM (3 mL), and stirred over the weekend. The mixture was filtered through a short pad of Celite™ washed with large amount of EtOAc, and then concentrated. Purification with column chromatography (0-70% EtOAc/Hexane) gave 9-cyclopropyl-2-methyl-4-(5-methylchroman-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carbaldehyde (112.5 mg, 0.281 mmol, 38.7% yield) as off white powder, LCMS (m/z) ES+=401 (M+1), NMR was mixed.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].ClCC[I:31]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:31])[N:8]2[CH2:11][CH3:12])=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:3]=1
Reactant: ClCCI
Reactant: CCn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(I)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To (S)-4-(2-chloro-9-ethyl-9H-purin-6-yl)-3-methylmorpholine (465.0 mg, 1.65 mmol) in anhydrous THF (6.7 mL) at −78° C. under N2 was added freshly prepared lithium diisopropylamide in THF (2.0 eq). The reaction was stirred at −78° C. under N2 for 2 hours, and 1-chloro-2-iodoethane (1.01 g, 5.78 mmol, 3.5 eq.) was added. The reaction mixture was then stirred at RT for 3 days and then quenched with saturated aqueous sodium ammonium chloride solution at 0° C. Volatile solvent was then evaporated in vacuo, and the crude was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in hexane) to give the desired compound as a foam (610.0 mg, 90.7%). 1H NMR (CDCl3, 400 MHz) δ ppm 5.28 (broad s, 2H), 4.17 (q, J=7.4 Hz, 2H), 4.00 (dd, J=11.3, 3.4 Hz, 1H), 3.75 (m, 2H), 3.59 (m, 1H), 3.48 (broad s, 1H), 1.37 (m, 6H); LC-MS m/z (method B2)=408 [M+H]+, RT=2.06 min.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH3:12])[CH:8]=[CH:9][CH:10]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27].CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15]2)[CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc([C@@H](C)N[C@H]2CCNC2)c1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cccc([C@@H](C)N[C@H]2CCN(c3ccccc3C(F)(F)F)C2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To a suspension of 146.6 mg of (S)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride, 112.5 mg of 1-bromo-2-trifluoromethylbenzene, 22.5 mg of palladium acetate, and 62.3 mg of BINAP (2,2′-bis(diphenylphosphino-1,1′-binaphthyl)) in 5 ml of toluene was added 336 mg of sodium tert-butoxide, and the mixture was stirred at 80° C. for 16 hours. To the reaction mixture was added a saturated sodium bicarbonate solution, the mixture was stirred and then the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate-97:3→80:20) to obtain 78.9 mg of (R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(2-trifluoromethylphenyl)pyrrolidin-3-yl]amine. (2) In 10 ml of chloroform was dissolved 78.9 mg of (R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(2-trifluoromethylphenyl)pyrrolidin-3-yl]amine, and 1 ml solution of 4M hydrochloric acid in a dioxane was added to the mixture and the resulting mixture was stirred. The reaction mixture was evaporated, and diethyl ether was added to the residue, and the precipitates were collected by filtration and washed with diethyl ether to obtain 66.7 mg of (R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(2-trifluoromethylphenyl)pyrrolidin-3-yl]amine dihydrochloride (the following Table A1, Example 1.001).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[C:13]1[C:14]2[NH:21][CH:20]=[C:19]([C:22](O)=[O:23])[C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:5]4[C:6]5[O:10][CH2:9][O:8][C:7]=5[CH:11]=[CH:12][C:4]=4[O:3][CH2:1][CH3:2])[C:14]=3[NH:21][CH:20]=2)=[O:23])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A69) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>C1(C)C(C)=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH:16][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(O)cc2)c1
Temperature: 160 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxyphenylacetic acid (20.0 g, 131 mmol) and 3,5-dimethylaniline (15.9 g, 131 mmol) in xylene (100 mL) was stirred for three days at 160° C. with a Dean Stark trap. The mixture was cooled to room temperature and filtered. The solid product obtained was washed with hexane (200 mL), 10% sodium bicarbonate solution (250 mL), water (200 mL), 10% hydrochloric acid (200 mL), and then water (200 mL). The beige solid was air dried to yield 27.7 g, 82.7%. mp 183-185° C.
Reaction SMILES: [CH:1]1([C:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH3:8])[CH2:3][CH2:2]1.[Mg]>CO.C(O)C>[CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:5]=[CH:6][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(=CC=C(c1ccc(Cl)cc1)C1CC1)c1ccc(F)c(Oc2ccccc2)c1
Agent: [Mg]
Solvent: CCO
Solvent: CO
Product: CC(C=CC(c1ccc(Cl)cc1)C1CC1)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.7 %

Procedure:
A mixture of 0.40 gram (0.01 mole) of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)-1,3-pentadiene and 2.43 grams (0.1 mole) of magnesium in 25 ml of methanol and 5 ml of ethanol was vigorously stirred for about 18 hours at ambient temperature. After this time the reaction was quenched with aqueous 3N hydrochloric acid, and the reaction mixture was extracted with two 25 ml portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.23 gram of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)-2-pentene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>CN(C)C=O>[CH2:24]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 92.5 %

Procedure:
3.3 g (10 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred with 5.06 g (50 mmol) of dipropylamine in 20 ml of N,N-dimethylformamide at room temperature for 4 hours. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. There were obtained 3.65 g (92%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 130°-132°, which was converted into the hydrochloride of m.p. 213°-215°.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(=O)(O)[O-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[C:11]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CC(O)CN1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1

Procedure:
26.5 g. (0.02 mole) of 4-hydroxy-L-proline and 32.8 ml. (0.23 mole) of benzyl chloroformate are reacted in 200 ml. of water and 100 ml. of acetone in the presence of 20 g. (0.02 mole) of potassium bicarbonate and 69.2 g. (0.50 mole) of potassium carbonate and worked up with 90 ml. of concentrated hydrochloric acid as described in Can.J. Biochem. & Physiol. 37, 584 (1959) to obtain N-carbobenzyloxy-4-hydroxy-L-proline. This product is reacted with cyclohexylamine to form the cyclohexylamine salt yield 69 g., m.p. 193°-195°. The salt (34 g.) is neutralized with N-hydrochloric acid to obtain 27 g. of free acid as a colorless glass [α]D26 -70°, (c, 1% in chloroform).
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[C:23]([S:27]/[C:28](/[O:31][Si](C)(C)C)=[CH:29]/[CH3:30])([CH3:26])([CH3:25])[CH3:24].[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[O:38].Cl.CO>C1(C)C=CC=CC=1>[C:23]([S:27][C:28](=[O:31])[CH:29]([CH3:30])[CH:37]([OH:38])[C:36]([O:40][CH3:41])=[O:39])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)C=O
Reactant: C/C=C(\O[Si](C)(C)C)SC(C)(C)C
Agent: Cl
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(O)C(C)C(=O)SC(C)(C)C
Temperature: 0 °C
Yield: 80 %

Procedure:
An (S)-binaphthol-dichlorotitanium complex solution was prepared in the same manner as the preparation of the (R)-binaphthol-dichlorotitanium complex solution in Example 1 except that (S)-binaphthol was used in place of (R)-binaphthol. 0.5 ml (0.1 mmol) of the (S)-binaphtholdichlorotitanium complex solution were cooled to 0° C., and 218 mg (1 mmol) of (E)-1-t-butylthio-1-trimethylsilyloxy-1-propene (93% E) and subsequently 88 mg (1 mmol) of freshly distilled methyl glyoxylate and 0.5 ml of toluene were added thereto, followed by allowing the mixture to react at 0° C. for 2 hours. The resulting mixture was poured into 10% hydrochloric acid-methanol cooled at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/1 by volume) to obtain mg of methyl 4-t-butylthio-2-hydroxy-3-methyl-4-oxobutyrate in a yield of 80% (16% syn, 84% ee; 84% anti, 93% ee).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([S:11][CH3:12])[S:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([S:11]([CH3:12])=[O:38])[S:8][C:6]=2[N:7]=1
Reactant: CSc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To an ice cooled suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-methylthio-thiazolo[5,4-d]pyrimidine (90 mg, 0.2 mmol) in dichloromethane (5 ml) was added mCPBA (125 mg, 0.5 mmol). The resulting mixture was stirred at 0° C. for 2 h. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (65 mg, 70%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N(CC)CC)C.[NH2:26][OH:27].Cl.NO.[OH-].[K+]>C1COCC1>[OH:27][NH:26][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NO
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)NO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A solution of 4-phenylbutyric acid (10.0 g, 60.9 mmol) in anhydrous THF (180 mL) was added ethyl chloroformate (7.0 mL, 73.1 mmol) and triethylamine (11.1 mL, 79.2 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min. The solid was filtered off. The filtrate was added to a freshly prepared methanolic hydroxylamine solution (63.0 mL, prepared by adding 6.34 g or 91.4 mmol of hydroxylamine hydrochloride to 30.0 mL of a stirred methanolic solution containing 5.13 g or 91.4 mmol of KOH at 0° C. for 15 min). The resulting mixture was stirred at room temperature for 30 min and evaporated in vacuo. The residue was purified by chromatography to give Compound 1 (6.4 g, 58%): mp>300° C.; NMR (400 MHz in CDCl3): δ 1.98 (m, 2H, PhCH2—CH2—CH2CONHOH), 2.13 (t, 2H, Ph-CH2—CH2CH2CONHOH), 2.64 (t, 2H, PhCH2CH2—CH2—CONHOH), 7.15 (d, 2H, Ar—H), 7.20 (t, 2H, Ar—H), 7.28 (m, 1H, Ar—H), 8.20 (br, 1H, NH).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3ccccc3n2)c1
Yield: 33.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (139 mg, yield: 33.5%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:38])([F:37])[F:36]>C(O)C>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:12]3[NH:13][CH:14]=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:10](=[O:17])[N:11]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CSc1nc(=O)c(Cc2ccc(C)nc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: Cc1ccc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 49 %

Procedure:
5-(6-methyl-pyridin-3-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.202 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (100 mg, 0.317 mmol, 1.57 eq) were heated in a sealed vial at 130° C. in 300 μl of absolute ethanol for 20 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/20% MeOH in DCM solvent system (gradient 5-40% of 20% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting crude was purified once more under the same conditions. Solvent from the gathered fractions of appropriate composition was evaporated the resulting oil was triturated with cyclohexane and diethyl ether to afford 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-(6-methyl-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (51 mg, yield=46.54%, purity=95%). MS: [M+H]+=515.34. 1H NMR (300 MHz; CDCl3) δ/ppm 2.48 (s, 3H), 2.87 (t, J=7.23 Hz, 2H), 3.57 (s, 2H), 3.52-3.62 (m, 4H), 5.55 (br.s., 1H), 6.93 (d, J=8.23 Hz, 2H), 6.98-7.06 (m, 2H), 7.21 (d, J=8.23 Hz, 1H), 7.28 (d, J=2.84 Hz, 1H), 7.36-7.43 (m, 2H), 7.60 (br.s., 1H), 8.39 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.CO.C1COCC1.CO.[CH3:26][C:27]1[C:28]([C:32]2[C:41]3[N:40]=[CH:39][CH:38]=[N:37][C:36]=3[C:35]([C:42](O)=[O:43])=[CH:34][CH:33]=2)=[CH:29][S:30][CH:31]=1>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:42]([C:35]3[C:36]4[N:37]=[CH:38][CH:39]=[N:40][C:41]=4[C:32]([C:28]4[C:27]([CH3:26])=[CH:31][S:30][CH:29]=4)=[CH:33][CH:34]=3)=[O:43])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Reactant: Cc1cscc1-c1ccc(C(=O)O)c2nccnc12
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cscc1-c1ccc(C(=O)Nc2nc(CN3CCN(C)CC3)c[nH]2)c2nccnc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 16 h at 60° C., using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid (Example 67) in Step 14.1. Title compound: ESI-MS: 448.0 [M+H]+; tR=3.00 min (System 1); TLC: Rf=0.14 (DCM/MeOH, 9:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][O:39][CH3:40])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:41].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][O:39][CH3:40])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:41][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)CC4=O)c(OC)cc23)c2c1OCO2
Yield: 75.9 %

Procedure:
This was prepared by the method described in example 4 using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (200 mg, 0.55 mmol), 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (145 mg, 0.60 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.15 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using ethyl acetate as eluent. There was thus obtained the title compound (237 mg, 76%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.05 (quintet, 2H), 2.20 (s, 3H), 2.58 (t, 2H), 2.92 (s, 2H), 3.33 (t, 2H), 3.36 (s, 3H), 3.48 (t, 2H), 3.94 (s, 3H), 4.13 (t, 2H), 4.37 (s, 2H), 6.15 (s, 2H), 7.15 (s, 2H), 7.82 (s, 1H), 8.34 (s, 1H), 9.51 (s, 1H); Mass Spectrum: M+H+ 568/570.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[CH3:39][O:40][C:41]1[CH:60]=[CH:59][C:44]([CH2:45][C@H:46]([CH2:50][C:51]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)=[O:52])[C:47]([OH:49])=O)=[CH:43][CH:42]=1>>[CH2:26]([NH:25][C:23](=[O:24])[C@H:22]([CH3:30])[CH2:21][C@H:20]([OH:31])[C@@H:19]([NH:18][C:16](=[O:17])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:47](=[O:49])[C@H:46]([CH2:45][C:44]1[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[CH:60][CH:59]=1)[CH2:50][C:51]([N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:52])[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)O)cc1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccc(OC)cc1
Yield: 59.2 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 200 mg (0.36 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-N-butyl-6-cyclohexyl-4-hydroxy-2-methylhexanamide [prepared as described in Example 6(a)] and 110 mg (0.36 mmole) of 2(R)-(4-methoxybenzyl)-3-(morpholinocarbonyl)propionic acid, to afford 158 mg of the title compound as a white powder, melting at 130°-132° C.