Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[N:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To the mixture of 2,6-dichloro-nicotinic acid (4.7 g, 22 mmol) and acetone (22 ml), potassium carbonate (4.6 g, 33 mmol) and dimethylsulfate (2.4 ml, 24 mmol) were sequentially added at room temperature, and the obtained reaction mixture was stirred at room temperature for 16 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Dichloromethane was added to the obtained residue, followed by washing with a saturated sodium bicarbonate aqueous solution. The obtained organic layer was dried using anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography (heptane:ethyl acetate=10:1 to 1:1), thereby obtaining the entitled compound (4.0 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=C)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:31])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reaction time: 0.05 h

Procedure:
OsO4 (15 mg, 0.06 mmol) was added to a stirred mixture of 1-[(2-methylphenyl)sulfonyl]-4-vinyl-1H-indole (300 mg, 1.01 mmol; Intermediate 15) and 2,6-lutidine (235 μl, 2.02 mmol) in dioxane (24 mL). The mixture turned from colorless to black in 3 minutes. Sodium periodate (0.865 g, 4.04 mmol) in water (8 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 1.40 h and extracted with 2M aqueous HCl (25 mL) and DCM (2×25 mL). The organic layers were combined, dried, filtered and concentrated to give the title compound (358 mg, 118%, still some dioxane according to HNMR) as a black gum. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([CH3:16])[CH2:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13].[CH2:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:13][O:12][Si:11]([O:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:16]
Reactant: C=CCCCC
Reactant: CO[SiH](CC(C)c1cc(C)ccc1C)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC[Si](CC(C)c1cc(C)ccc1C)(OC)OC
Yield: 59.5 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 12.7 g (0.049 mole) of 3-(2,5-dimethylphenyl)-1,1-dimethoxy-1-silabutane, 13.1 g (0.15 mole) of 1-hexene, and 90 μl of 1% chloroplatinic acid in isopropanol were placed under the dry nitrogen atmosphere. The reactor was refluxed for 3 hours. Vacuum distillation of the reaction products gave 9.4 g (bp, 131°-3° C./0.6 mmHg) of 4,4-dimethoxy-2-(2,5-dimethylphenyl)-4-siladecane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:37]1[CH:41]=[C:40]([CH2:42]O)[CH:39]=[N:38]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:42][C:40]1[CH:41]=[N:37][NH:38][CH:39]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Reactant: COc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 48.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.98 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole (1.83 g) as starting materials, 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.74 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:32])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[Ni].C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1CCN(Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CCN(Cc2ccc(CCC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Reaction time: 1 h

Procedure:
A reaction mixture of 80 mg (0.18 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-[4-(4-methylpiperidin-1-ylmethyl)phenyl]acrylamide and 20 mg of Raney nickel in 15 mL of ethyl acetate and 15 mL of methanol is hydrogenated for 1 hour at 50 psi and ambient temperature. The catalyst is filtered off, the filtrate is evaporated to dryness and stirred with diisopropylether. Yield: 40 mg (49.7% of theory); melting point: 150° C.-151° C.; C28H31ClN2O (M=447.02); calc.: molecular ion peak (M+H)+: 447/449; found: molecular ion peak (M+H)+: 447/449; Rf value: 0.5 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH:13]=O.[C:15]([OH:25])(=O)[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:3]([CH:13]=[CH:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]3[O:25][C:3]4[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=4[CH:1]=3)=[CH:23][CH:22]=2)=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C)c(C=O)cc1C(=O)O
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: COc1cc(C)c(C=Cc2ccc(-c3cc4ccccc4o3)cc2)cc1C(=O)O

Procedure:
When an equivalent amount of the anil derivative of 4-methyl-6-methoxyisophthalaldehydic acid is substituted for the anil derivative of terephthalaldehydic acid in the procedure described in Example 2 above, there is obtained as the product 2-[4-(6-methyl-4-methoxy-3-carboxystyryl)phenyl]benzofuran.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:17][CH2:16][C:10]3([C:14](=[O:15])[NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:18][C:19]([F:30])([F:29])[CH:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[OH:21]>>[CH:1]1([S:4]([N:7]2[CH2:17][CH2:16][C:10]3([C:14](=[O:15])[N:13]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]([OH:21])[C:19]([F:29])([F:30])[F:18])=[CH:23][CH:24]=4)[CH2:12][CH2:11]3)[CH2:9][CH2:8]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C1NCCC12CCN(S(=O)(=O)C1CC1)CC2
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)C1CC1)CC2

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(cyclopropylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. White solid. MS (ESI): 433.14 MH+).
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH:29]([CH3:31])[CH3:30]>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:4](=[O:10])[NH:5][CH:6]([CH:7]([CH3:9])[CH3:8])[C:2]=1[OH:1])=[C:23]2[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)c1c[nH]c2ccc(F)cc12
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: O=Cc1ccccc1
Product: CC(C)c1c(C(C2=C(O)C(C(C)C)NC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with benzaldehyde and 5-fluoro-3-isopropyl-1H-indole to give 3-[(5-fluoro-3-isopropyl-1H-indol-2-yl)-phenyl-methyl]-4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one as a orange solid. MS: 405.2 ([M−H]−).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:31].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:43]4[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH2:41][CH2:42]4)=[CH:13][CH:12]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2Cl)C3)cc1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3Cl)C4)cc2)CC1
Product: Cl

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(2-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and 1-(2-methoxyethyl)piperazine was used instead of piperidine to afford 6-(2-chlorophenyl)-N-(4-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine hydrochloride. 1H-NMR 400 MHz (CDCl3) δ 8.43 (d, J=7.4, 1H), 8.11 (s, 1H), 7.63 (d, J=7.4 Hz, 2H), 7.44-7.39 (m, 3H), 7.40 (s, 1H), 7.21 (d, J=6.6 Hz, 2H), 7.15-7.12 (m, 1H), 7.02 (d, J=7.8, 2H), 6.73 (d, J=6.2, 1H), 4.85 (m, 1H), 3.35 (s, 3H), 3.55 (t, J=5.4, 2H), 3.18-3.13 (m, 3H), 2.66-2.61 (m, 11H). LCMS m/e 554 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:17][F:18])([CH2:15][F:16])[CH:3]1[OH:19].Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](OC)=[O:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[F:18][CH2:17][C:4]1([CH2:15][F:16])[C@@H:3]([OH:19])[C@H:2]([N:1]2[CH2:21][C:22]3[C:23](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:24]2=[O:25])[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: NC1c2cc([N+](=O)[O-])ccc2OC(CF)(CF)C1O
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2CN1[C@@H]1c2cc([N+](=O)[O-])ccc2OC(CF)(CF)[C@H]1O
Temperature: 80 °C
Reaction time: 6 h
Yield: 42.2 %

Procedure:
A mixture of 0.25 g of 4-amino-2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran-3-ol, 0.22 g of methyl 2-bromomethylbenzoate, 0.40 g of potassium carbonate, 0.09 g of potassium iodide and 5 ml of acetonitrile was stirred at 75-85° C. for 6 hours. Water was added thereto and the mixture was extracted with a mixed solvent of ethyl acetate and ether. After the organic layer was washed with 1N hydrochloric acid and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, AcOEt:hexane=1:1) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 0.15 g of trans-2,2-bisfluoromethyl-3,4-dihydro-4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-6-nitro-2H-1-benzopyran-3-ol represented by the following formula having a melting point of 285-288° C.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH:20]1([CH2:29][NH2:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[CH:20]1([CH2:29][NH:30][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A mixture of 3.0 g of 6-chloropurine riboside, 2.0 g of 1-indanylmethylamine as prepared in Example A hereinafter and 3.18 g of triethylamine are refluxed in 75 ml of absolute ethanol under nitrogen for 24 hours. The reaction is cooled to room temperature, precipitated nucleoside is filtered, washed with ethanol and dried affording 2.78 g (67%) of N6 -[2,3-dihydro-1H-inden-1-yl]methyl-adenosine having a melting point of 137°-139° C. Anals. calcd. for C20H23N5O4 ; Found: C=60.44; H=5.83; N=17.62 C=60.81; H=5.70; N=17.35.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.O[C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18]C=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.[I-].[Na+].[OH-].[Na+]>O.C1(C)C=CC=CC=1.CO>[OH:2][CH2:3][CH2:4][O:5][C:1]1[CH:18]=[CH:19][C:14]([C:12]([C:11]2[CH:20]=[CH:21][CH:8]=[CH:9][CH:10]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(OCCO)cc1
Temperature: 88 °C

Procedure:
A mixture of ethylene carbonate (14.26 g), xylenes (1.19 g) and 4-hydroxybenzophenone (30.41 g) was heated to 88° C. Sodium iodide (1615 mg) was added. Heating was continued until the temperature of the mixture reached 169° C. The melt was cooled to 110° C. and methanol (12.76 g), sodium hydroxide (50% aqueous solution; 4.01 g), toluene (42.51 g) and water (28.88 g) were added. The lower layer was separated (‘cut’) and discarded. Toluene (18.1 g) was added and the solvents were evaporated by heating to the boiling point of 111° C. 4-(2-Hydroxyethoxy)benzophenone was isolated by crystallisation and filtration at 17° C. resulted in 34.1 g (92%) of beige crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O.C(OCC)(=O)C>[CH2:16]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)NC(=O)NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To the stirred solution of 5,5-dimethylhydantoin (7 g, 54.7 mmole) in dry acetone (150 mL) under nitrogen were added potassium carbonate (10.6 g, 76.8 mmole) and benzylbromide (11.2 g, 65.9 mmole) at room temperature. The reaction mixture was refluxed for 20 hr. The reaction mixture was cooled to room temperature and the solid was filtered off by suction filtration. The titrate was concentrated on a rotary evaporator to give a residue. The residue was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and evaporated to give 10.9 g (yield=91.3 %) of 3-benzyl-5,5-dimethylhydantoin as a white solid, mp=101°-104° C. This intermediate was subjected to the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.[N+:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])#[C-:20].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:9][CH:20]=[N:19][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[N:3][CH:2]=1
Reactant: O=C(O)c1ccncn1
Reactant: [C-]#[N+]CC(=O)OC
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ncoc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of pyrimidine-4-carboxylic acid (261 mg, 2.00 mmol) and DIPEA (0.52 mL, 2.96 mmol) in DMF (8 mL) was added methyl isocyanoacetate (0.28 mL, 2.93 mmol) at rt. The resulting yellow solution was stirred at rt for 5 min and cooled to 0° C. DPPA (0.54 mL, 2.43 mmol) was then added and the resulting solution was stirred at 0° C. for 1 h and at rt for 30 min. Aq. sat. NaHCO3-solution was added and the mixture extracted with EtOAc (4×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by FC (hept/EtOAc 9:1 to 100% EtOAc) yielded methyl 5-(pyrimidin-4-yl)oxazole-4-carboxylate. LC-MS conditions A: tR=0.68 min, [M+H]+=206.43.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([OH:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)(=[O:24])=[O:23].[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C.ClCCl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[O:33][CH2:34][CH2:35][CH2:36][OH:37])(=[O:23])=[O:24]
Reactant: OCCCO
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
Tri-n-butylphosphine (8.4 mL, 34 mmol) was added dropwise over 5 min to 3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (4.97 g, 16.9 mmol, as prepared in the preceding step), 1,3-propanediol (12 mL, 170 mmol) and 1,1'-(azodicarbonyl)dipiperidine (8.54 g, 33.8 mmol) in anhydrous tetrahydrofuran (75 mL) at 0° C. under a nitrogen atmosphere. Dichloromethane (75 mL) was added mid-way through the tri-n-butylphosphine addition to aid stirring. The slurry was stirred at ambient temperature for 1 h, then the mixture was cooled to 0° C. and more 1,1'-(azodicarbonyl)dipiperidine (4.27 g, 16.9 mmol) and tri-n-butylphosphine (4.2 mL, 16.9 mmol) were added. The reaction was stirred overnight at ambient temperature. Diethyl ether (200 mL) was added and the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (25% ethyl acetate in hexane to 60% ethyl acetate in hexane, then 2% acetone in dichloromethane to 7% acetone in dichloromethane in two separate chromatographic separations) to give the title compound (3.79 g, 64%) as a gold oil. 1H-NMR (300 MHz, CDCl3) δ 7.82 (dd, 1 H, J=1.7, 7.9 Hz),7.61 (ddd, 1 H, J=1.8, 7.5, 8.4 Hz),7.08 (d, 1 H, J=8.4 Hz), 7.01 (ddd, 1 H, J=1, 7.5, 7.9 Hz), 6.58 (br s, 1 H), 6.51 (br s, 1 H), 6.46 (t, 1 H, J=2.1 Hz), 4.02 (s, 3 H), 4.00 (t, 2 H, J=6.0Hz), 3.81 (m, 2 H), 2.24 (s, 3 H), 1.98 (pentet, 2 H, J=6.0 Hz), 1.72 (t, 1 H, J=5.0 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20O6S: 375.1 (M+Na). Found: 375.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[OH:37][C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:39](=[O:40])[C:38]([OH:37])([CH3:43])[CH3:42])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C(C)(C)O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.8 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.20 mmol), 2-hydroxyisobutyric acid (24 mg, 0.23 mmol), HATU (85 mg, 0.22 mmol) and DIPEA (40 μL, 0.23 mmol) in DCM (2 mL) was allowed to stir at r.t. for 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-3%) affording 741 as a white solid (55 mg, 46%). LCMS (method I): RT 2.89 min, [M+H]+ 576.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-8.02 (1 H, m), 7.76-7.75 (1 H, m), 7.33-7.22 (2 H, m), 4.40-4.20 (5 H, m), 3.92 (3 H, s), 3.88-3.83 (5 H, m), 3.63 (2 H, s), 3.53 (2 H, s), 3.36 (2 H, q, J=7.48 Hz), 2.59-2.53 (2 H, m), 1.50 (6 H, s), 1.45 (3 H, t, J=7.48 Hz), 1.23 (6 H, s)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=3)[C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl.O1CCOCC1>O.CCOCC>[C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=3)[C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1cccc(C(=O)OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1cccc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 19 h
Yield: 32.6 %

Procedure:
A mixture of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methoxycarbonylphenyl ester (0.037 mmol; 25 mg), aqueous 6M HCl (0.5 mL) and 1,4-dioxane (0.1 mL) is stirred at 100° C. for 19 hours. The mixture is cooled to ambient temperature, then diluted with water and Et2O. The product is extracted three times with Et2O. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-carboxy-phenyl ester (8.0 mg, 33%); ESI-MS m/z: 663 [M+1]+, Retention time 2.14 min (condition A).