Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[O-:24]I(=O)(=O)=O.[Na+].CC(O)C.Cl>CC(C)=O.O.[Ru]=O>[C:19]([O:18][C:17]([NH:16][C@H:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[C:2]([OH:24])=[O:1])=[O:23])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CCc1ccc(C(F)(F)F)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of (R)-tert-butyl 1-hydroxy-4-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (LXX) (41.3 g; 0.124 mol) in 60% aqueous acetone was added solid sodium (meta)periodate (266 g; 1.24 mol) followed by ruthenium(II) oxide hydrate (1.65 g; 12.4 mmol). The greenish suspension was stirred for 3 h before adding propan-2-ol (500 mL) and stirring for an additional 30 min. The resulting suspension was filtered through Celite, and the filtrate was concentrated under vacuum to give a brown foam. To the brown foam was added 1 N HCl to pH 1 which was followed by extraction with EtOAc. The organic layer was washed with brine and dried with MgSO4. The crude residue was then purified on a silica gel column (10:1 hexane:EtOAc) to obtain (2R)-2-[(tert-butoxycarbonyl)amino]-4-[4-(trifluoromethyl)phenyl]butanoic acid (LXXI) (18 g; 51.8 mmol, 42% yield). 1H NMR (CDCl3) δ ppm 1.46 (brs, 9H), 1.93-2.30 (m, 2H), 2.68-2.87 (m, 2H), 4.12-4.47 (m, 1H), 5.04-5.23 (m, 1H), 7.30 (d, J=8, 2H), 7.55 (d, J=8, 2H); ESIMS found for C16H20F3NO4 m/z 348.3 (M+H).
Reaction SMILES: Br[C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li:20])CCC>CCCCCCC>[Li:20][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Brc1cccc2c1ccc1ccccc12
Solvent: CCCCCCC
Product: [Li]c1cccc2c1ccc1ccccc12

Procedure:
2.1 Grams (8.3 mmols) of a 1-bromophenanthrene was dissolved in 43 ml of heptane, and to which was added 5.3 ml (1.6 mols/l, 8.5 mmols) of butyllithium to obtain a 1-lithiophenanthrene, which was, then, cooled down to −5° C. 1.6 Grams (5.2 mmols) of the 3.9-dimethoxy-5-hydroxybenzo[c]fluorene-7-one was added thereto, and the mixture was stirred for one hour. Then, THF was added thereto at a temperature of not higher than 0° C., and the mixture was stirred at this temperature for 2 hours. The conversion was 40%. The mixture was continuously stirred for another 20 hours, but the conversion remained to be 40%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F-:10].[K+]>COCCOCCOCCOCCOC.C1OCCOCCOCCOCCOCCOC1>[F:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(Cl)n1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: COCCOCCOCCOCCOC
Agent: [K+]
Product: CSc1nccc(F)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 35.7 g (0.22 mol) of 4-chloro-2-methylthiopyrimidine (Aldrich Chemical Co., Milwaukee, Wis., USA) in 135 mL of tetraglyme was added 18-crown-6 (1.33 g) and potassium fluoride (Anhydrous, Aldrich Chemical Co., Milwaukee, Wis., USA, 80 g). The mixture was heated at 150° C. with stirring for 16 hours. The mixture was then cooled and distilled under reduced pressure to give 20 g (62%) of 4-fluoro-2-methylthiopyrimidine as a liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[CH3:16][S-:17].[Na+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]2[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]=1[CH2:2][S:17][CH3:16]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1c(C)oc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (200 mg) and sodium thiomethoxide (68 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2-methyl-3-methylthiomethyl-7-nitrobenzo[b]furan (144 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[F:24])=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>COCCOC.C(O)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[F:24])=[CH:12][C:11]=1[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:28])[CH:34]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1Br
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1-c1cccc(N)c1
Temperature: 130 °C

Procedure:
To a solution of {1-[2-bromo-4-(3-fluoro-pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1094 μmol) and 3-aminophenylboronic acid (2 eq) in a mixture of DME/ethanol/1N Na2CO3: 1/1/1 (10 ml) was added Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 130° C. for 1.5 hours. The reaction mixture was cooled to RT and diluted with water and citric acid and extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:34]([C:42]5[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=5)[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: COc1ccc(-c2c(-c3ccccc3)c(Cl)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)c(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc3ccccc23)cc1
Yield: 42.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (60 mg, 0.23 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-phenyl-4-(4-methoxyphenyl)quinoline (95 mg, 0.27 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography ethyl acetate eluent) to give 56 mg (43%) of the title compound as an off white solid. mp 239°-242° FDMS: m/e=570. α[D]589 =+45.00 (c=1.40, chloroform).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[NH2:18][C:19]1[C:20]([CH3:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[CH2:16]([NH:15][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[C:6]([N:8]=1)=[N:7][C:2]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[CH:3][N:4]=2)=[O:14])[CH3:17]
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Reactant: Cc1ccccc1N
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1ccc2ncc(Nc3ccccc3C)nc2n1
Temperature: 100 °C

Procedure:
55 mg 1-(3-chlor-pyrido[2,3-b]pyrazine-6-yl)-3-ethyl-urea (0.22 mmol), 60 mg o-toluidine (0.56 mmol), 33 mg sodium-tert.-butylate(0.33 mmol), 29 mg tris(dibenzalacetone)palladium(0) (0.03 mmol) and 78 mg 2-(dicyclohexylphosphanyl)biphenyl (0.22 mmol) were presented in 1.5 ml predried toluene in a microwave reaction vessel under nitrogen as protective gas. The reaction mass was heated in the microwave at 100° C. (100 watt) for 30 minutes. Then the volatile components were removed in vacuum and the raw product was cleaned using column chromatography on silica gel (solvent dichloromethane/methanol). A yellow solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N)nc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
2-Amino-5-bromopyridine (15 g) was dissolved in a mixed solvent of N,N-dimethylformamide (hereinafter referred to as “DMF”; 60 ml) and N,N-diisopropylethylamine (60 ml). Ethyl acrylate (12 ml), palladium acetate (980 mg), and tris(2-methylphenyl)phosphine (10.5 g) were added thereto in a nitrogen atmosphere, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was filtered through Celite and separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized with N-hexane to obtain Compound 1a (15.5 g, 89%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25]Br)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([NH2:37])(=S)[CH3:35].O.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:37]/[C:34](/[CH3:35])=[CH:25]\[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:27]
Reactant: CC(N)=S
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
To a solution (44 ml) of 6-bromo-3-(2-bromoacetyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (4.41 g) in DMF was added thioacetamide (1.1 g) and the mixture was stirred at 70° C. for 24 hrs. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were washed with methanol and recrystallized (ethyl acetate) to give the title compound (1.31 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.CN([CH:48]=[O:49])C.C(N(CC)CC)C.[CH3:57][OH:58]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:43]=[CH:44][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:57]([O:49][CH3:48])=[O:58])[C:11]=12
Reactant: CO
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: CCN(CC)CC
Product: COC(=O)c1nn(Cc2ccc(OC)cc2)c2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a suspension of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (1.0 g, 1.42 mmol; prepared as in Example 7, Step B) in 1:2 DMF:MeOH (60 mL) was added triethylamine (0.434 ml, 3.11 mmol) and 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.116 g, 0.142 mmol). The mixture was purged with N2(g) and CO(g) and then held under balloon pressure CO(g). The mixture was heated at 70° C. and stirred overnight (18 hours). The heat was removed and the excess solvent was evaporated. Diethyl ether (100 mL) was added and the resulting solid removed by filtration to afford the desired product as white solid. Yield (735 mg, 81%). LRMS (APCI pos) m/e 639.1 (M+H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:25]([OH:27])=O)[NH:17]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:28]1([S:34]([Cl:37])(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[ClH:37].[NH2:17][C@H:16]([C:25](=[O:27])[N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:34]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)(=[O:36])=[O:35]
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: Cl
Product: N[C@@H](CCCCNS(=O)(=O)C1CCCCC1)C(=O)N1CCCC1

Procedure:
Starting from (S)-N6-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-lysine, cyclohexanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [P:1]([Br:4])(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1>N1C=CC=CC=1>[Br:2][P:1]([Br:4])[C:10]1[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][C:9]=1[O:13][CH3:14]
Reactant: BrP(Br)Br
Reactant: COc1cccc(OC)c1
Solvent: c1ccncc1
Product: COc1ccc(P(Br)Br)c(OC)c1

Procedure:
A solution of PBr3 (2.5 g, 9.2 mm) in 15 mL of pyridine was treated with 1,3-dimethoxybenzene (2.5 g, 18.1 mm) over a period of 5 min. The resulting mixture was then refluxed for 4 h. to give the crude 1-dibromophosphino-2,4dimethoxybenzene (31P NMR: δ159.2 ppm). This compound was used directly for the next step without further purification. Next, polymer-supported secondary amines from Example 1 (10.0 g, 1.1 mmol/g, 11.0 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was stirred at room temperature overnight before the solution was filtered off. The resin was washed with THF (50 mL), hexane (3×50 mL), CH2Cl2 (4×50 mL), and hexane (2×50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported 2-P(Br)-1,5-(MeO)2-C6H3. 31P NMR (122 MHz, CDCl3): δ153.8 ppm.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:10]=[C:9]([CH3:25])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:11]1[C:12]([CH2:13][OH:14])=[C:7]([O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:8]=[C:9]([CH3:25])[N:10]=1
Reactant: CCC(CC)Oc1cc(C)nc(Nc2ccc(Cl)cc2Cl)c1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2ccc(Cl)cc2Cl)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-6-methyl-2-(2,4-dichloro-phenylamino)-nicotinic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux overnight. The mixture was quenched with dilute HCl and stirred for 30 min, adjusted pH to 7.5–8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a golden oil. After silica gel column chromatography, the title compound was obtained as a golden oil. 1H NMR(CDCl3) d 8.44(d,1H), 8.18(s,1H), 7.32(d,1H), 7.179d,1H), 6.28(s,1H), 4.82(s,2H), 4.21(m,1H), 2.42(s,3H), 1.6–1.8(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH3:37])[N:10]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22]C)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[C:9](=[O:24])[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:7]1=[O:36].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:5][C:6]1([CH3:37])[N:10]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[C:9](=[O:24])[N:8]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:29][CH:30]=2)[C:7]1=[O:36]
Reactant: COc1ccc2nccc(CN3C(=O)N(c4ccc(OC(F)(F)F)cc4)C(=O)C3(C)C)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc2ccc(O)cc12
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
6 ml of a 1M solution of boron tribromide in CH2Cl2 are added to a solution of 0.26 g of 5,5-dimethyl-1-(6-methoxyquinolin-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 40 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 0° C. The reaction medium is stirred at a temperature in the region of 20° C. for 16 hours. 5 ml of methanol are added dropwise. After stirring for 30 minutes at this temperature, 50 ml of water, 30 ml of CH2Cl2 and 10 ml of saturated NaHCO3 are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The beige-colored foam obtained is purified by flash chromatography (SiO2, EtOAc as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 0.17 g of 5,5-dimethyl-1-(6-hydroxyquinoline-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: ClC1[CH:15]=[CH:14][C:13]([C@H:16]2[C@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:20]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:19]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:17]2)=[CH:12][C:3]=1[CH2:4][C:5]1[NH:10][CH2:9][C:8](=O)[NH:7][N:6]=1.C(C1C(=O)C([Cl:65])=C(Cl)C(=O)C=1C#N)#N.CCOCC.[CH2:74]([Cl:76])Cl>O>[Cl:65][C:8]1[N:7]=[N:6][C:5]([CH2:4][C:3]2[CH:12]=[C:13]([C@H:16]3[C@H:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:20]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@H:19]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:17]3)[CH:14]=[CH:15][C:74]=2[Cl:76])=[N:10][CH:9]=1
Reactant: ClCCl
Reactant: O=C1CNC(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)=NN1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: O
Product: Clc1cnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Reaction time: 3 h
Yield: 35 %

Procedure:
The 3-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (compound 55, 826 mg, 1.11 mmol) in a mixture of CH2Cl2 (20 ml) and water (2 ml) treated with DDQ (504 mg, 2.22 mmol) at 0° C. After 3 hours, Et2O and water were added to the reaction mixture. Normal work-up with CH2Cl2 and drying with MgSO4 generated crude title compound. Without further purification, it was reacted with POCl3 (2 ml) in toluene (20 ml) under refluxed condition. After reaction complete, the resulting solution was poured into iced water (50 ml). After work-up with CH2Cl2, organic layer was evaporated under reduced pressure. The residue was purified with use of column chromatography (Hexane/EtOAc=½) to provide title compound (296 mg, 35% overall yield) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10](NC)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:31][CH2:30][CH2:29][CH:25]([C:26](O)=[O:27])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O.O[N:34]1[C:38]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[CH2:31][CH2:30][CH2:29][CH:25]([C:26]([NH:34][CH2:38][C:10]2[S:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH3:13])=[O:27])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: On1nnc2ccccc21
Reactant: CNc1sc(-c2ccc(Cl)cc2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.8 %

Procedure:
2-(4-Chlorophenyl)-4-methylthiazol-5-yl methylamine (477 mg, 2.00 mmol), 1-tert-butoxycarbonyl nipecotic acid (459 mg, 2.00 mmol) and 1-hydroxybenzotriazole monohydrate (368 mg, 2.40 mmol) were dissolved in N,N-dimethylformamide (10 mL). While this mixture was chilled in an ice bath, 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (460 mg, 2.40 mmol) and N-methylmorpholine (0.484 mL, 4.40 mmol) were added. The mixture was then stirred at room temperature for 6 hours. Subsequently, 5% aqueous citric acid was added and the mixture was extracted with ethyl acetate. The extract washed sequentially with a saturated aqueous sodium bicarbonate solution and brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 916 mg (100%) of the desired compound as a colorless powder.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CN1CCC(N)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCN(C)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-methylpiperidin-4-amine via General Procedure E to give 4.6 mg of 284 following reverse phase purification. MS (Q1) 476.3 (M)+