Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]=1[O:18][CH3:19])[CH:13]=[O:14].S(=O)(=O)(O)O>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]=1[O:18][CH3:19])[CH:13]([OH:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)cc([N+](=O)[O-])c1OC
Reaction time: 2 h

Procedure:
25 ml of 2M phenyl lithium solution (in benzene/ether (7:3)) are added dropwise within 15 minutes to 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 150 ml of tetrahydrofuran and the mixture is stirred at 0° for 1 hour and at 20° for 2 hours. The mixture is subsequently treated with 150 ml of 2N sulfuric acid and extracted three times with 150 ml of ether. The combined ether phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is chromato graphed on 180 g of silica gel with methylene chloride. There is obtained 3,4-dimethoxy-5-nitrobenzhydrol as an amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)C1C=CC=CC=1.IC.N1CCOCC1>CN(C)C=O>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH3:1])[CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: OC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Solvent: CI
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CN1CCC(O)(c2cccc(Cl)c2F)C1

Procedure:
Preparation according to Example 34: (+)-1-benzyl-3-(3-chloro-2-fluorophenyl)-pyrrolidin-3-ol (0.93 g, 3.05 mmol) and iodomethane (1 mL, 15.9 mmol), dimethyl formamid (3 mL), morpholine (2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.289 g. [α]D=+25.9° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 123-125° C.; MS m/z (relative intensity, 70 eV) 229 (M+, 7), 157 (8), 129 (6), 58 (29), 57 (bp).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCC(O)CCCC
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(CCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 10 g (0.08 moles) of 4-hydroxy-1-octyne [1. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g (0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively with ice cold 2% hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Column chromatography of the residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25μ (triphenylmethoxy group).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1>>[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])[CH:22]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cccc(C)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and m-toluoyl chloride, there is obtained ethyl N-(m-toluoyl)-5,7-dihydro-6H-dibenz[c,e]azepin-6-carboximidate m.p. 102°-105° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:24])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 99.1 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid (300 mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol) and EDC.HCl (320 mg, 1.70 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum and the residue was subjected to flash silica gel column chromatography eluting with methanol/CH2Cl2 (1:99, v/v) to give the desired amide 18 as a white solid (360 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.88 (d, 2H), 7.15 (m, 31), 7.35 (m, 7H), 7.58 (d, 2H), 8.25 (s, 1H). m/7/z (ESI): 433 [C26H28N2O4+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:31]3[CH:30]=[CH:29][C:28]4[O:23][CH2:24][CH2:25][O:26][C:27]=4[CH:32]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCOCc1ccc2c(c1)OCCO2
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOCc2ccc3c(c2)OCCO3)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-((1,4-benzodioxan-6-yl)-methoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-((1,4-benzodioxan-6-yl)-methoxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH:13]=[CH:12]3)(=[O:3])[CH3:2].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>ClCCl.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:27][CH:26]=[CH2:25])(=[O:3])[CH3:2]
Reactant: C=CC[Si](C)(C)C
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reaction time: 0.08 h

Procedure:
To a solution of 17β-acetoxy-4,6-androstadien-3-one 1 (2.0 g, 6.1 mmol) in dry dichloromethane (130 ml) was added titanium tetrachloride (5.36 g, 3.1 ml, 28 mmol) at -70° C. The reaction mixture was allowed to stir for 5 min. Then, a solution of allyltrimethylsilane (4.0 g, 5.6 ml, 35 mmol) in dry dichloromethane (10 ml) was added over a period of 10 min and the resulting solution stirred during 1 hour at -70° C. followed by 1 hour at -20° C. Afterwards, the solution was diluted with 150 ml of ether and was washed with water (6×100 ml), dried, filtrated and concentrated to yield the crude 17β-acetoxy-7α-allyl-4-androsten-3-one which was immediately hydrolyzed.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:35][CH2:34]4)=[CH:41][CH:40]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
2.64 (192 mg, 0.581 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (355 mg, 1.16 mmol), K3PO4 (400 mg, 1.9 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (21 mg, 0.029 mmol) were taken up in 1,4-dioxane (10 mL) and water (1 mL). The stirred reaction mixture was heated to 100° C. for 1.5 h and was then cooled and partitioned between EtOAc (30 mL), water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-12.5% MeOH in DCM) to provide tert-butyl 4-(4-(3-(difluoromethyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H35F2N6O4: 557.3; found: 557.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=1)=[C:9]([OH:29])[C:8]2=[O:30])(=[O:3])[CH3:2].C1(=O)[O:36][C:34](=[O:35])[CH2:33]C1>Cl.C(O)(=O)C.O.N1C=CC=CC=1>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[O:11][C:12]3[C:7]([C:8](=[O:30])[C:9]=2[OH:29])=[CH:6][C:5]([NH:4][C:1]([CH2:2][CH2:33][C:34]([OH:36])=[O:35])=[O:3])=[CH:14][CH:13]=3)=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(OCc4ccccc4)cc3)c(O)c(=O)c2c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
A mixture of the protected flavonol (11) (600 mg, 1.49 mmol) in aqueous HCl (36%, 38 mL) and acetic acid (38 mL) was heated under reflux for 2 h. The mixture was then cooled on ice and diluted with water. The resulting suspension was centrifuged and the collected solid washed with water, then freeze-dried to afford the salt as a crude yellow solid (457 mg). A mixture of the crude yellow product and succinic anhydride (179 mg, 1.79 mmol) in pyridine was stirred at room temperature for 4 h. Water (1 mL) was added and the mixture was acidified with 2 M HCl. The mixture was left to stand at room temperature for 30 min, and the resulting suspension was centrifuged and the collected solid was washed with water, freeze-dried and recrystallised from DMF/water to afford the succinamic acid (2) as a brown powder (211 mg, 38.2%), m.p. 256-257° C. Anal. Calcd. for C19H16NO7.½H2O: C, 60.32; H, 4.26; N, 3.70. Found: C, 59.99; H, 4.53; N, 3.90. 1H NMR (399.7 MHz, d6-DMSO) δ 2.55-2.60 (m, 4H, CH2CH2); 6.93 (app. d, 2H, J=9.2 Hz, H3′,5′); 7.69 (d, 1H, J7,8 8.8 Hz, H8); 7.85 (dd, 1H, J5,7 2.8, J7,8 8.8 Hz, H7); 8.09 (app. d, 2H, J=9.2 Hz, H2′,6′); 8.43 (d, 1H, J5, 7 2.8 Hz, H5); 9.33 (s, 1H, NH); 10.11, 10.31 (2 br s, 2×1H, 2×OH); 12.21 (br s, 1H, CO2H). 13C NMR (100.5 MHz, d6-DMSO) δ 25.16, 28.78 (2C, CH2CH2); 31.06, 67.05, 112.65, 115.46, 118.80, 121.45, 122.06, 125.11, 129.55, 135.80, 137.57, 146.01, 150.38, 159.11 (14C, Ar); 170.40, 172.33, 173.86 (3C, 3×C═O).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1O

Procedure:
0.75 g of 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 12 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(3-hydroxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 205°-207° C. is obtained.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].[NH4+:18].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][C:13]3=[N:12][C:4]=1[C:5]([NH2:18])=[N:6]2
Reactant: [NH4+]
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)OCC3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2OCC1
Reaction time: 0.08 h

Procedure:
A solution of 8,9-dihydroisoxazolo[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.0499 g, 0.220 mmol) in dichloromethane from the previous step was treated with 1.5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.046 g, 0.242 mmol) was carefully added. Rapid stirring was continued for 5 minutes. The reaction mixture was then diluted with more dichloromethane, washed successively with dilute aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography (SiO2, 0-15% CMA/CHCl3) gave 0.015 g of 8,9-dihydroisoxazolo[2′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a brown solid, mp greater than 300° C.
Reaction SMILES: [C:1]([CH:4]([CH:11]([C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[CH2:12][C:13](=[O:25])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])(=O)[CH3:2].S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH:11]2[CH2:12][C:13](=[O:25])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)[C:1]([CH3:2])=[C:4]2[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])=[CH:31][CH:30]=1)#[N:33]
Reactant: C=CCOC(=O)C(C(C)=O)C(CC(=O)Nc1cccc(C(F)(F)F)c1)c1ccc(C#N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
To a solution of allyl 2-acetyl-3-(4-cyanophenyl)-5-oxo-5-{[3-(trifluoromethyl)-phenyl]amino}pentanoate (Example 53A) (12.60 g, 27.49 mmol) in 400 ml ethanol are added Amberlyst-15 (12.60 g) and magnesium sulphate (25.20 g, 209.4 mmol). The reaction mixture is stirred at reflux temperature overnight and then cooled to room temperature. The solids are removed by filtration using a pad of kieselgur. The solvent is removed in vacuo and the crude material is purified by column chromatography on silica gel (eluent dichloromethane).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[N:6]=[C:5]1Cl)[CH:2]=[CH2:3].[CH3:20][N:21]([CH3:30])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[CH:24][N:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:13][C:12]1[C:7]2[N:6]=[C:5]([NH:29][C:25]3[C:26]([CH3:28])=[CH:27][C:22]([N:21]([CH3:30])[CH3:20])=[N:23][CH:24]=3)[N:4]([CH2:1][CH:2]=[CH2:3])[C:8]=2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=1
Reactant: Cc1cc(N(C)C)ncc1N
Reactant: C=CCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 26 %

Procedure:
A mixture of 1-allyl-2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazole (1.19 g, 4.00 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (1.21 g, 8.00 mmol) and p-toluenesulfonic acid monohydrate (760 mg, 4.00 mmol) in 1-methyl-2-pyrrolidinone (12 mL) was irradiated by microwave at 180° C. for 1 hr. After cooling, the mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (430 mg, 1.04 mmol, 26%) as a colorless solid.
Reaction SMILES: C([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29]C(=O)OC(C)(C)C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH:38]([C:41]1[O:42][C:43](=[O:57])[C:44]2[C:49]([C:50]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][CH3:40].[H-].[Na+]>CN(C=O)C>[N:24]1[C:25]([NH:29][CH:38]([C:41]2[O:42][C:43](=[O:57])[C:44]3[C:49]([C:50]=2[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:39][CH3:40])=[C:26]2[C:21]([NH:20][CH:28]=[N:27]2)=[N:22][CH:23]=1
Reactant: CCC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Nc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 2.4 %

Procedure:
The title compound was made in a similar way as that of the compound of example 21, from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (167 mg, 0.350 mmol), 3-(1-bromopropyl)-4-phenyl-1H-isochromen-1-one (intermediate C20, 100 mg, 0.291 mmol) and 50% dispersion in mineral oil NaH (21 mg, 0.870 mmol) in DMF at 55° C. The crude was purified via reverse phase chromatography with a column stacking of two Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) and further purified by Preparative HPLC (method 1) to give the title compound (2.8 mg, 2.4%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])[C:4]=2[CH2:3]1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1Br)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(OCC)(=O)C.O>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:8]2[CH2:7][CH2:6][N:5]3[C:10](=[CH:11][C:12]4[CH2:13][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=43)[C:9]2=[O:14])=[CH:23][C:24]([F:28])=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 56.3 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 110e (740 mg, 3.6 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101j (2.4 g, 7.2 mmol) and cesium carbonate (2.6 g, 7.9 mmol) in 1,4-dioxane (36 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (250 mg, 0.43 mmol) and tris(dibenzylideneacetone) dipalladium(0) (260 mg, 0.29 mmol) were added, and the reaction mixture was heated to 100° C. for 16 h. After this time, H2O (50 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of 100% hexanes-100% Ethyl acetate to afford a 56% yield (910 mg) of 110f.
Reaction SMILES: [CH2:1]([C:8]1([C:23]([O-])=O)[C:12](=[O:13])[N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:10](=[O:22])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl:27][C:28]1[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@:8]1([C:23]2[NH:35][C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[CH:32][C:31]=3[N:34]=2)[NH:9][C:10](=[O:22])[N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)NC(Cc2ccccc2)(C(=O)[O-])C1=O
Reactant: Nc1ccc(Cl)cc1N
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C(=O)N[C@](Cc2ccccc2)(c2nc3ccc(Cl)cc3[nH]2)C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To the product from Step D (200 mg, 0.581 mmol), 4-chlorobenzene-1,2-diamine (91 mg, 0.639 mmol) in N,N-dimethylformamide (2.5 ml) was added N,N-diisopropylethylamine (0.152 mL, 0.871 mmol) and O-(7-azabensotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (265 mg, 0.697 mmol) sequentially. The reaction mixture was stirred for 16 h, diluted with ethyl acetate (50 mL), washed with water (2×10 mL), saturated aqueous brine (1×10 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. LC/MS 463.0 (M+1). The crude residue was dissolved in acetic acid (5 ml) and heated at 80° C. for 1 h. The mixture was cooled and the solvent removed in vacuo. The residue was purified by column chromatography (silica gel 40 g column) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give a mixture of diastereomers as a brown amorphous solid. The isomers were separated via chiral HPLC (ChiralPak AS-H; 40% 2:1 methanol:acetonitrile/carbon dioxide) to afford the first eluting isomer (5R)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (1.9 minutes) and the second eluting isomer (5S)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (2.97 minutes) as colorless amorphous solids. LC/MS 445.0 (M+1). IC50 value=C rating
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33](O)=[O:34])=[N:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:26]3[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:24][N:25]=3)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1noc2ccccc12
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3noc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with benzo[d]isoxazole-3-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=477.1.