Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[S:21][CH2:20][CH2:19][C:18]2=[O:27].Cl>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[S:21][CH2:20][CH:19]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[C:18]2=[O:27]
Reactant: COc1cc2c(cc1OC)C(=O)CCS2
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)C(C(=O)C(F)(F)F)CS2
Temperature: 25 °C
Reaction time: 87.5 h
Yield: 64.9 %

Procedure:
Ethyl trifluoroacetate (0.84 g, 5.9 mmol) was dissolved in tetrahydrofuran (20 mL), and treated with 25% sodium methoxide (1.68 g, 7.8 mmol). To the stirred solution was added 6,7-dimethoxythiochroman-4-one from Step 2 (1.12 g, 5.0 mmol). The reaction was stirred at room temperature for 87.5 hours, treated with 3N HCl (25 mL) and filtered to give an orange solid (1.04 g, 65%): mp 148°-151° C.; 1H NMR (CDCl3) 300 MHz 16.05 (s, 1H), 7.48 (s, 1H) 6.78 (s, 1H) 3.94 (s, 3H) 3.92 (s, 3H) 3.83 (s, 2H); 19F NMR (CDCl3) 300 MHz -71.06 (s). Mass spectrum: M+H=321.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5]1
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
cis-2,6-Dimethylmorpholine (2.0 g) was dissolved in acetonitrile (70 ml). Ethyl bromoacetate (2.5 ml) and potassium carbonate (3.1 g) were added and the mixture was heated with stirring at 60° C. for 12 hours. The solvent was evaporated and then ethyl acetate was added to the residue. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.9 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:27](=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([CH3:27])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 80 °C
Reaction time: 13 h
Yield: 82 %

Procedure:
To a solution of (3aR*,10aS*)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one (2.93 g, 10 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% liquid paraffin dispersion, 0.41 g, 10 mmol) and methyl iodide (1.3 mL, 21 mmol). The mixture was stirred for 13 hours at 80° C. To the reaction mixture were added water and, then, a saturated aqueous solution of sodium hydrogencarbonate. The mixture was subjected extraction with ethyl acetate three times. Organic layers were combined and washed with water and, then, with a saturated aqueous solution of sodium hydrogencarbonate, which was dried over sodium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified by silica-gel column chromatography (hexane-ethyl acetate 10:1) to give 2.52 g (yield 82%) of the titled compound. The sample for analytical experiment was prepared by recrystallization from methanol. m.p. 123°-125° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>ClC(Cl)Cl>[Cl:2][CH2:3][CH2:4][NH:5][C:18]([C:14]1[O:13][CH:17]=[CH:16][CH:15]=1)=[O:19]
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCCl)c1ccco1
Reaction time: 8 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 87 parts of 2-chloroethanamine hydrochloride and 300 parts of trichloromethane are added 224.2 parts of N,N-diethylethanamine, there is added dropwise, during a 1.50 hours period, a solution of 96 parts of 2-furancarbonyl chloride in 300 parts of trichloromethane at a temperature below 5° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, with a diluted hydrochloric acid solution and again twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 2% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 95 parts of N-(2-chloroethyl)-2-furancarboxamide as a residue.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[S:10][C:9]([C:11]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]5[N:20]([C:22]([C:25]6[S:26][CH:27]=[CH:28][N:29]=6)=[CH:23][N:24]=5)[CH:21]=4)=[CH:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:12]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[ClH:49].O>O1CCCC1.CO>[ClH:49].[ClH:49].[NH:1]1[C:5]([C:6]2[S:10][C:9]([C:11]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]5[N:20]([C:22]([C:25]6[S:26][CH:27]=[CH:28][N:29]=6)=[CH:23][N:24]=5)[CH:21]=4)=[CH:14][NH:13][N:12]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5nccs5)n4c3)c(-c3ccc(-c4nnn[nH]4)s3)n2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: c1csc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(-c5nnn[nH]5)s4)cn23)n1
Reaction time: 3 h

Procedure:
60 mg 6-{3-[5-(1H-tetrazol-5-yl)-thiophen-2-yl]-1-trityl-1H-pyrazol-4-yl}-3-thiazol-2-yl-imidazo[1,2-a]-pyridine obtained in Example 441 was dissolved in 8.0 mL solvent mixture of tetrahydrofuran and methanol (1:1), then 3.0 mL of 5 N hydrochloric acid was added thereto, and the mixture was left at room temperature for 3 hours. Water was poured into the reaction solution, and the precipitated crystals were collected by filtration and washed with diethyl ether, to give 14.5 mg of the title compound as pale pink crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH:51]2[CH2:53][CH2:52]2)=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:45][C:46]2[S:47][C:48]([CH:51]3[CH2:53][CH2:52]3)=[N:49][N:50]=2)=[O:43])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Nc1nnc(C2CC2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C5CC5)s4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.9 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-cyclopropyl-1,3,4-thiadiazole (55 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 42 mg of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][C:15]([NH2:23])([CH2:16]3)[CH2:14]1)[CH2:20]2.[O:24]1CC[CH2:26][CH2:25]1>CN(C)C=O>[C:1]([NH:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][C:15]([NH:23][C:25](=[O:24])[CH3:26])([CH2:16]3)[CH2:14]1)[CH2:20]2)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: NC12CC3CC(C1)CC(N)(C3)C2
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC12CC3CC(C1)CC(NC(C)=O)(C3)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 22 mmole of acetyl chloride and 24 mmole of triethylamine were dissolved in 2 ml of tetrahydrofurane (THF). To the resultant solution, 10 ml of solution containing 10 mmole of 1,3-diaminoadamantane obtained by the method of Example 65 in N,N-dimethylformamide (DMF) was added and then stirred for 3 hours at 40° C. As a result, the conversion of 1,3-diaminoadamantane was 99%, and 1,3-bis(acetylamino)adamantane (yield 95%) was formed.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35]
Reactant: CC(C)CCc1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a solution of 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethyl)phenoxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (30 mg, 0.060 mmol) in THF (4 mL) and water (4 mL)) was added LiOH.H2O (5.10 mg, 0.12 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13 mg, 45.9% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.58 (s, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 4.50 (t, J=5.2 Hz, 1H), 4.09-3.93 (m, 2H), 3.58 (s, 3H), 3.48 (q, J=6.3 Hz, 2H), 3.19-3.06 (m, 2H), 1.75 (dd, J=14.0, 6.8 Hz, 2H), 1.51 (dd, J=13.0, 6.6 Hz, 1H), 1.29 (dd, J=15.3, 7.2 Hz, 2H), 0.79 (d, J=6.6 Hz, 6H). LCMS: MH+ 466 and TR=3.373 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:4][CH:3]=1.[CH:15](=O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17][CH3:18]
Reactant: Nc1cccc(-c2ccc(Cl)cc2)c1
Reactant: CCCC=O
Product: CCCCNc1cccc(-c2ccc(Cl)cc2)c1
Yield: 82.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4′-chlorobiphenyl-3-amine (ChemBridge, 285 mg, 1.40 mmol) and butyraldehyde (125 μL, 1.40 mmol) were converted to the title compound (300 mg, 74%). 1H NMR (CDCl3) δ 7.73-7.62 (m, 2H), 7.57-7.44 (m, 3H), 7.43-7.34 (m, 2H), 7.29-7.19 (m, 1H), 3.04-2.96 (m, 2H), 1.67-1.59 (m, 2H), 1.47 (dd, J=15.1, 7.4 Hz, 2H), 0.99 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 260.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([NH:21][C:22](=[O:24])C)[CH:19]=[CH:20][C:13]=2[NH:12][C:11](=[O:25])[CH2:10]1.CO.O=S(Cl)Cl.[CH2:33]([N:40]=C=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO.Cl>[CH2:33]([NH:40][C:22](=[O:24])[NH:21][C:18]1[CH:19]=[CH:20][C:13]2[NH:12][C:11](=[O:25])[CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:26])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)CCCCCN1CC(=O)Nc2ccc(NC(C)=O)cc2C1=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: O=C(O)CCCCCN1CC(=O)Nc2ccc(NC(=O)NCc3ccccc3)cc2C1=O
Reaction time: 18 h
Yield: 19.5 %

Procedure:
80 mg (0.22 mmol) 6-(7-acetylamino-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-hexanoic acid methyl ester was dissolved in 1 ml MeOH/HCl (freshly prepared from 10 ml MeOH and 1 ml SOCl2). The solution was stirred for 18 h and concentrated in vacuo. The residue was taken up in 2 ml of THF/MeOH (1: 1) and 0.5 ml 1N aqueous NaOH was added. After stirring for 16 h at 22° C. the mixture was neutralised by addition of solid carbon dioxide, and the solvents were evaporated. The residue was taken up in DMF (2.5 ml) and 0.032 ml benzylisocyanate (0.26 mmol) was added. The mixture was shaken at 45° C. over night and evaporated. The crude product was purified by preparative HPLC to give 6-[7-(3-benzyl-ureido) -2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-hexanoic acid (19 mg, 0.043 mmol): MS (ISN) 437(M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].[OH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:21][C:22]1[CH:27]=[C:26]([C:15]2[C:14]3[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: OB(O)c1cccc(O)c1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from 4-chloro-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester and 3-hydroxyphenylboronic acid according to the procedure of Example 1. MS (ES) m/z 359.9.
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].[CH:28](=[C:35]1[C:43]2[C:42](Cl)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:28](=[C:35]1[C:43]2[C:42]([N:25]3[CH2:24][CH2:23][CH:22]([C:14]4[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=[C:12]([C:7]5[CH:8]=[CH:9][C:10]([F:11])=[C:5]([Cl:4])[CH:6]=5)[N:13]=4)[CH2:27][CH2:26]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(c2ncnc3c2C(=Cc2ccccc2)C(=O)N3)CC1

Procedure:
Combine {2-[4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-dimethyl-amine tris hydrochloride (0.5 g; 0.0013 mol; 1.0 equiv); 5-benzylidene-4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.33 g; 0.0013 mol; 1.0 equiv); DIPEA (1.7 mL 0.0098 mol; 7.6 equiv); 2-propanol (10 mL) and microwave at 100° C. for 30 min. Cool and concentrate in vacuo. Dilute with saturated sodium bicarbonate solution and extract with DCM. Wash organic layer with water and brine and dry over anhydrous sodium sulfate. Concentrate the crude compound and purify by reverse phase HPLC to give the title compound as a mixture of E and Z isomers (0.09 g; 12.2%). MS (ES+): m/z=572 (M+H)
Reaction SMILES: N1C=C2C(N=CN2)=NC=1.[O:10]([CH3:20])[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].O=C[C@@H]([C@@H]([C@@H](CO)O)O)O.CC1C(=O)NC(=O)N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C=1.[Si:49](Cl)([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[Si:49]([CH:18]([OH:19])[C@H:16]1[O:17][C@@H:11]([O:10][CH3:20])[C@H:12]([OH:13])[C@@H:14]1[OH:15])([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: c1ncc2[nH]cnc2n1
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O

Procedure:
The triple substitution of adenosine, i.e., at 5'-, 2-, and N6 -positions, can be carried out by a synthetic strategy in which a 5'-uronamide sugar moiety is condensed with a purine moiety, such as a substituted adenosine derivative. The key sugar intermediate, N-methyl 1-O-acetyl-2,3-dibenzoyl-β-D-ribofuronamide, was synthesized starting from methyl β-D-ribofuranoside, which is commercially available or can be synthesized from D-ribose (Baker et al., J. Org. Chem., 26, 4605-4609 (1961)), in 8 steps. The primary alcohol of β-D-ribofuranoside can be selectively protected with tert-butyldiphenylsilyl chloride (Chaudhary et al., Tet. Lett., 20(2), 99-102 (1979)) to provide 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside, and other alcohols can be followed with benzoyl protection to provide 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside, the desilylation of which with TBAF/THF will give 1-O-methyl 2,3-dibenzoyl-β-D-ribofuranoside. The 5'-position of 1-O-methyl 2,3-dibenzoyl-β-D-ribofuranoside can be oxidized using ruthenium tetroxide (Singh et al., Tet. Lett., 33(17), 2307-2310 (1992)) to yield 1-O-methyl-2,3-dibenzoyl-β-D-ribofuronic acid which can be purified after methylation on a silica gel column chromatography. Methylamide at 5-position can be introduced by nucleophilic displacement of methyl 1-O-methyl-2,3-dibenzoyl-β-D-ribofuronate with methylamine in THF and benzoyl reprotection of resulting 2,3-diol to yield the sugar intermediate N-methyl 1-O-acetyl-2,3-dibenzoyl-β-D-ribofuronamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(C)ccc1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of 2-chloro-5-methyl-benzoic acid (3.0 g, 17.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 10 ml, 20 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 1 hour, methanol (20 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 2-chloro-5-methyl-benzoate (3.2 g, 100% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[NH:18][C:17]2[CH:19]=[C:20]3[C:25](=[CH:26][C:16]=2[N:15]=1)[CH:24]=[CH:23][CH:22]=[CH:21]3>C(Cl)Cl>[CH3:12][S:13]([C:14]1[NH:15][C:16]2[CH:26]=[C:25]3[C:20](=[CH:19][C:17]=2[N:18]=1)[CH:21]=[CH:22][CH:23]=[CH:24]3)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2cc3ccccc3cc2[nH]1
Solvent: ClCCl
Product: CS(=O)c1nc2cc3ccccc3cc2[nH]1
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
A solution of 4.2 g of m-chloroperbenzoic acid in 100 ml of methylenechloride was added dropwise at 0°-5° to 4.3 g of 2-(methylthio)-1H-naphth[2,3-d]imidazole in 500 ml of methylenechloride. The reaction solution was stirred for 90 minutes at 0°, washed twice with aqueous potassium bicarbonate solution and once with saturated sodium chloride solution, dried over magnesium sulphate, and concentrated by evaporation on a rotary evaporator. Crystallisation from acetonitrile gave 2.3 g of 2-(methylsulphinyl)-1H-naphth[2,3-d]imidazole having a m.p. of 194°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:10]([CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:13]([O-:15])=[O:14])=O.Cl.[C:25]1(C)C=CC=C[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7]/[CH:10]=[C:12](/[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)\[C:13]([O:15][CH2:25][CH3:26])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccccc1
Reactant: COc1ccc(C(C=O)C(=O)[O-])cc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 74 %

Procedure:
A solution of 4-methoxyaniline (1.47 g, 11.94 mmol) and ethyl ∀-formyl-4-methoxyphenylacetate (2.92 g, 1.1 eq) in toluene (25 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (15 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: CH2Cl2) to give 2.89 g (74%) of compound 22 (Z isomer) in the form of a yellow solid which crystallizes from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:16][CH:15]3[CH:13]([CH:14]3[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(CC)CC.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][N:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[CH:3]=[C:4]([C:9]([N:11]3[CH2:16][CH:15]4[CH:13]([CH:14]4[C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[CH2:12]3)=[O:10])[CH:5]=[CH:6][C:7]=2[CH3:8])=[O:38])=[CH:35][N:34]=1
Reactant: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(N)c4)CC32)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(NC(=O)c5ccc(Cl)nc5)c4)CC32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a solution of (3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone (150 mg, 0.47 mmol) and Et3N (0.25 mL, 1.8 mmol) in CH2Cl2 (4 mL) at 0° C. was added 6-chloronicotinoyl chloride (106 mg, 0.6 mmol). The ice bath was removed after the addition. The reaction mixture was stirred at room temperature for 1.5 h and then purified by flash column chromatography with EtOAc in hexane (60%, then 100%) to give the title compound as a white foam (0.172 g, 80% yield). MS [M+H]+: 462, 464.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)(=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=C(C(=O)O)c2ccccc2)cc1
Temperature: 90 °C

Procedure:
A mixture of 4-methoxybenzaldehyde (30.0 g, 0.22 mol), phenylacetic acid (31.5 g, 0.23 mol), and triethylamine (31 ml) in acetic anhydride (75 ml) was heated at 90° C. for 5 hours. After cooling, 18 ml of water was dropped carefully during 15 min. Then, potassium carbonate (243 g) in water (1800 ml) was dropped and the solution was heated at 60° C. for 1 hour. After cooling, the solution was extracted with dichloro-methane. When the aqueous phase was acidified (pH 6-7), the product was precipitated. After stirring at 0° C., the product was filtered and dried.