Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(=O)oc1CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 1.5 g of benzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was concentrated under reduced pressure to give 2.3 g of the captioned compound as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccnc1Oc1cccc(C=C2CCNCC2)c1

Procedure:
tert-Butyl 4-(3-(3-methylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (3.9 g, 10 mmol) from Step 4 was dissolved in CH2Cl2 (50 mL) and treated with HCl in dioxane (20 mL, 4.0 M, 80 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (3.6 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>ClC(Cl)C>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(N3CCc4ccccc4C3)CC2)cc1

Procedure:
1,2,3,4-Tetrahydroisoquinoline (700 mg, 5.3 mmol), acetic acid (3.2 g, 5.3 mmol), sodium triacetoxyborohydride (2.2 g, 11 mmol) and benzylpiperidone (1.0 g, 5.3 mmol) were stirred at room temperature for 3.5 hours in dichloroethane (7 ml). The reaction solution was alkalified by adding sodium hydroxide aqueous solution, the reaction product was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 900 mg (3.0 mmol, 56% in yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:4][CH2:5][O:6][CH3:7].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([NH:24][C:25](=[O:26])[NH:1][C:2]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=2[O:4][CH2:5][O:6][CH3:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCOc1c(N)cc(OC)cc1C(C)(C)C
Solvent: C1CCOC1
Product: COCOc1c(NC(=O)Nc2ccccc2)cc(OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A tetrahydrofuran (THF) (20 ml) containing 2.4 g of (2-amino-4-methoxy-6-tert-butylphenoxy)methoxymethane and 1.09 ml of phenyl isocyanate was stirred at room temperature for 3 hours, and then the solvent was removed under reduced pressure. The obtained residue was crystallized from hexane, and recrystallized from an ethyl acetate-hexane mixed solution to give 2.3 g of [2-(3-phenylureido)-4-methoxy-6-tert-butylphenoxy]methoxymethane (yield: 64%, melting point: 121°-123° C., IR: 3300, 1650 cm31 1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:22])[CH:2]=[CH2:3].[H][H]>C(O)C.Cl.[Pd]>[CH2:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:22])[CH2:2][CH3:3]
Reactant: C=CCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Yield: 94 %

Procedure:
The product from Example 134, step (ii) (0.74 g) in ethanol (25 ml) and 1N hydrochloric acid (2.5 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium charcoal (0.15 g) until uptake of hydrogen was complete. Catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated. The residue was triturated with a mixture of ethyl acetate (25 ml) and saturated sodium bicarbonate solution (25 ml) and the insoluble solid was filtered and washed with water and ethyl acetate. The aqueous layer of the filtrate was extracted twice with dichloromethane and the combined organic extracts evaporated. The residue was combined with the ethyl acetate-insoluble material and treated with boiling ethanol (40 ml), unsoluble material being removed by filtration. Evaportion of the filtrate gave 2-n-propyl-4-[4-(4-pyridyl)piperazin-1-yl]phenol (0.7 g) as a solid NMR (d6DMSO) δ8.84-8.68(1H,m), 8.18(2H,d), 6.82(2H,m), 6.7(3H,m), 4.1(1H,m), 3.42(4H,t), 3.17(3H,s), 3.05(4H,t), 2.48(DMSO), 1.55(2H,m), 0.89(3H,t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11](OC)OC)=[CH:5][CH:4]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:9][CH:10]=[CH:11][C:7]=2[CH:8]=1
Reactant: COc1ccc(OCC(OC)OC)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2occc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a suspension of polyphosphoric acid (38.3 g) in toluene (400 ml) was added 4-methoxy-(2,2-dimethoxy)ethoxybenzene (38.0 g), and the mixture was stirred at 100° C. overnight and cooled. To the mixture was added water, and the mixture was separated. The organic layer was washed with 1N sodium hydroxide solution and then washed with saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give brown oil of 5-methoxybenzofuran (6.5 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH2:42][CH2:41][CH:40]=1)(=O)=O>C(OCC)C>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:43]4[C:44]([CH3:46])([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]=4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)OC1(C)C
Reactant: CC1(C)CCCC=C1OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Product: CC1(C)CCCC=C1c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Yield: 71.4 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 10, Step B (0.350 g, 0.780 mmol) and 6,6-dimethyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.222 g, 0.858 mmol) were reacted by the procedure described in Example 1, Step F. The crude product was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane to afford a clear oil. The oil was dissolved in diethyl ether and precipitated with petroleum ether to afford a white solid (0.240 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[C:21]([C:22]([OH:24])=O)=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:22]([C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[N:14]=3)[NH:19][CH:20]=2)=[O:24])[CH2:27]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)O)c3n2)cc(OC)c1OC
Reactant: NC1CCCOC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)NC4CCCOC4)c3n2)cc(OC)c1OC

Procedure:
2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (tetrahydro-pyran-3-yl)-amide was prepared starting from 2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid and tetrahydro-pyran-3-ylamine hydrochloride following the general procedures described in these Examples but with triethylamine and DMAP added. MP 191-192° C., M+H 413.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C1C(=O)N([I:18])C(=O)C1>CC#N.O>[I:18][C:4]1[NH:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)c(I)[nH]1
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2, 1.72 g, 11.46 mmol) in CH3CN (25 mL). NIS (3.87 g, 17.20 mmol) was added to the reaction. The reaction mixture was stirred overnight at 85. The reaction mixture diluted with 50 mL of H2O and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 2×20 mL of Na2S2O3(sat.) and 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 4.32 g (crude) of the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>C(#N)C>[CH2:26]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH:25]=[CH2:24]
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and allyl bromide (0.16 ml, 2.0 mmol). Yield: 0.42 g (80%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 224-226° C. MS m/z (relative intensity, 70 eV) 287 (M+, 70), 286 (90), 260 (bp), 258 (53), 82 (95).
Reaction SMILES: C(O)(=O)C.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:36])([C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]=1[O:28][CH2:29][O:30][CH3:31])[CH2:23]N)[CH3:19]>C1(C)C=CC=CC=1>[CH3:35][C:32]([C:26]1[CH:25]=[C:22]([CH2:23][NH:16][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([S:6][CH3:5])=[CH:12][CH:11]=2)=[O:15])[CH:21]=[C:20]([C:18]([CH3:36])([CH3:19])[CH3:17])[C:27]=1[O:28][CH2:29][O:30][CH3:31])([CH3:33])[CH3:34]
Reactant: CSc1ccc(NC(N)=O)cc1
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2ccc(SC)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
Acetic acid (1.08 g; 18 mmol), 4.5 g (24.7 mmol) of the compound of Example 5 and 5.0 g (18 mmol) of the compound of Example 1 were dissolved in 180 ml of toluene. The resulting solution was heated to reflux, stirred at that temperature for 4 hours and then cooled to room temperature. The cooled solution was washed with a IN hydrochloric acid solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. The washed solution was then filtered to remove any solid particulates which had formed and the liltrate was concentrated to dryness to provide a residue. This residue was purified by column chromatography using a 20-40% ethyl acetate in hexane gradient as eluent. Fractions containing the above titled compound were combined and then concentrated to dryness to provide 3.14 g of title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](OC2C=CC=CC=2)=[N:19][C:20]#[N:21])=[CH:13][CH:12]=1>COCCOC>[C:20]([N:19]=[C:18]([O:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[NH:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:21]
Reactant: CN(C)c1ncccc1N
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: COCCOC
Product: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1

Procedure:
According to the procedure of Example 5, Step 3, 3-amino-2-dimethylaminopyridine (1.41 g, 0.0108 mol) was allowed to react with diphenylcyanocarbonimidate (2.45 g, 0.0108 mol) in ethylene glycol dimethyl ether (20 ml), under nitrogen for 18 hours. The reaction mixture was concentrated and the residue chromatographed on silica gel with mixtures of MeOH--CHCl3 containing from 0 to 5% MeOH. The product amounted to 3.23 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[C:4]([S:11][CH3:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:22][C:23]1([CH3:33])[O:27][C:26](=[CH:28][C:29](Cl)=[O:30])[C:25](=[O:32])[O:24]1>C(Cl)Cl>[CH3:22][C:23]1([CH3:33])[O:27][C:26](=[CH:28][C:29]([N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=2[S:11][CH3:12])[CH3:8])=[O:30])[C:25](=[O:32])[O:24]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CNCc1ccc(F)cc1SC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(F)ccc1CN(C)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of (4-fluoro-2-methylsulfanyl-benzyl)-methyl-amine (1.3 g) and diisopropylethylamine (1.74 mL, 10 mmol) in CH2Cl2 (60 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (1.1 g, 6 mmol). After 1 h, the reaction mixture was concentrated and the resulting residue was taken up in ether (100 mL), washed with 1N HCl (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a viscous yellow oil. Flash chromatography on a silica gel column with 3:2 hexanes/EtOAc followed by 2:3 hexanes/EtOAc gave the desired product as a 1:1 mixture of E and Z isomers 1.8123 g, 89% yield). 1HNMR (500 MHz, CDCl3) δ: 7.17 (0.5H, dd, J=8.54, 6.11 Hz), 7.00 (0.5H, dd, J=8.55, 5.8 Hz), 6.94–6.89 (1H, m), 6.83–6.77 (1H, m), 6.17 (0.5H, s), 6.04 (0.5H, s), 4.68 (1H, s), 4.51 (1H, s), 2.98 (1.5H, s), 2.97 (1.5H, s), 2.48 (1.5H, s), 2.45 (1.5H, s), 1.72 (3H, s), 1.67 (3H, s). MS calcd for C16H19FNO4S (M+H): 340.1. found: 340.3.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][CH:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>CN1CCCC1=O>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:26]2[CH2:27][CH2:28][CH:24]([CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: c1ccc(CCC2CCNC2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)CCNC(=O)c1ccc(N2CCC(CCc3ccccc3)C2)nn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide (20 mg, 0.088 mmol) and 3-(2-phenylethyl)pyrrolidine (23 mg, 0.13 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was added Et3N (25 μL, 0.18 mmol) at room temperature. The mixture was stirred at 120° C. overnight. The reaction was then concentrated and the residue purified using a semi-prep HPLC/MS to give the title compound. MS (+ESI) m/z 367 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]3[O:15]C(C)(C)[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O>FC(F)(F)C(O)=O>[C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:17])[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(Cl)cc4F)ncnc31)O[C@@H]2c1nnc(C(C)(C)C)o1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(Cl)cc5F)ncnc43)[C@H](O)[C@@H]2O)o1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
9-{(3aR,4R,6S,6aR)-6-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-N-(4-chloro-2-fluorophenyl)-9H -purin-6-amine (2.35 g) was dissolved in trifluoroacetic acid (20 ml) and water (2 ml) with ice bath cooling, and the mixture allowed to stand at 4° C. for 17 h. The mixture was poured slowly into ice cold saturated aqueous sodium bicarbonate (400 ml) and extracted with ethyl acetate (3×200 ml). The organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a buff solid (2.30 g).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[OH-].[Na+]>>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]([C:14]2[NH:13][CH:17]=[CH:16][CH:15]=2)[C:17]2[NH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: c1cc[nH]c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Following a general procedure,8 a solution of 4-tert-butylbenzaldehyde (16.2 g, 100 mmol) in pyrrole (694 mL, 10.0 mol) at room temperature under argon was treated with InCl3 (2.21 g, 10.0 mmol) for 1.5 h. Powdered NaOH (12.0 g, 300 mmol) was added. After stirring for 1 h, the mixture was suction filtered and excess pyrrole was removed under high vacuum. The residue was treated with hexanes (3×100 mL) to facilitate removal of traces of pyrrole. The resulting solid was recrystallized [EtOH/H2O (6:1)], affording a grayish white solid (21.6 g, 79%): mp 155-157° C.; 1H NMR δ 1.31 (s, 9H), 5.45 (s, 1H), 5.94-5.96 (m, 2H), 6.15-6.17 (m, 2H), 6.68-6.70 (m, 2H), 7.13-7.16 (m, 2H), 7.32-7.35 (m, 2H), 7.89-7.95 (br, 2H); 13C NMR δ 31.5, 34.6, 43.6, 107.2, 108.5, 117.2, 125.7, 128.2, 132.9, 139.1, 149.9; FAB-MS obsd 278.1788, calcd 278.1783 (C19H22N2). Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.82; H, 7.96; N, 10.05. The data (1H NMR, mp, elemental analysis) are consistent with those obtained from samples prepared via earlier routes.2
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:31](=[O:35])[C:32]([NH2:34])=[O:33])=[C:9]([CH2:28][CH2:29][CH3:30])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].CO>[NH2:34][C:32](=[O:33])[C:31]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:36])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]=1[CH2:28][CH2:29][CH3:30])=[O:35]
Reactant: CCCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccccc1
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
A mixture of 440 mg (0.9 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 5 mL of 1N NaOH and 15 mL of MeOH was stirred for 0.75 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl to pH 2-3 and extracted with EtOAc. The EtOAc solution was dried (MgSO4) and evaporated to give 374 mg (88% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[OH:10][CH:11]([CH3:15])[C:12](=O)[CH3:13]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH:12]([CH3:13])[C:11](=[O:10])[CH3:15]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)C(C)O
Solvent: c1ccccc1
Product: CC(=O)C(C)Nc1c(C)cccc1C
Yield: 94.4 %

Procedure:
A solution of 484.8 g (4 mols) 2,6-dimethylaniline and 422.8 g (4.8 mols) 3-hydroxy-2-butanone in 1200 ml benzene was heated under reflux for 21 hours in a reaction vessel equipped with a Dean-Stark trap. The reaction mixture was then cooled, washed with four 600-ml portions of water, slurried with silica gel, filtered and evaporated under reduced pressure to give 722 g of 3-(2,6-dimethylphenylamino)-2-butanone, as an orange oil. The infrared spectrum of the product showed strong carbonyl absorption at 6.3 microns.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][C:14]31[CH:12]([CH2:13]3)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:17][NH:16][CH2:15][C:14]31[CH:12]([CH2:13]3)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CCC3CC31CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCC3CC31CNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 10% palladium-carbon catalyst (47.6 mg, 50 wt %) was added to a solution of 6-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azatricyclo[4.3.0.01,3]nonane (derived from optical isomer A) (95.2 mg, 0.255 mmol) in methanol (2.55 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature for one hour. A 10% palladium-carbon catalyst (28.6 mg, 30 wt %) was added. After the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature for one hour. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give 56.0 mg of the title compound as a black oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[S:30])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(S(=O)(=O)N2CCCC2=S)cc1
Yield: 50.5 %

Procedure:
A mixture comprising 9 g of 1-[4-(diethylamino)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 2 of the European Patent published under No. 0,033,578, and 6.15 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in 180 cm3 of toluene is heated to reflux for 1 hour. The mixture is allowed to return to room temperature and is evaporated to dryness, the residue is taken up in 200 cm3 of chloroform and the resulting mixture is dried, filtered on celite and evaporated to dryness. 3.6 g of crude product (m.p. 170°-180° C.) are recovered, which product is chromatographed on silica (eluant: ethyl acetate/n-hexane, 2:1) and the residue is then crystallized in ethanol. 2.4 g of expected product are obtained. M.p. 183°-184° C.