Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:23]([CH3:25])=[CH2:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH:9]([C@H:8]1[O:11][C:23]([CH3:25])([CH3:24])[N:12]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH2:10]
Reactant: C=C(C)OC
Reactant: C=C[C@@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C[C@H]1OC(C)(C)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 38 %

Procedure:
32 mg (0.12 mmol) of (1S,2R)-1-phenyl-1-benzoylamino-2-hydroxy-3-butene, in suspension in 0.64 cm3 of anhydrous toluene, are put, under an argon atmosphere, in a 10 cm3 single-necked, round-bottomed flask equipped with a magnetic stirrer system and a reflux condenser. 226 μl (173 mg, 2.4 mmol) of 2-methoxypropene, 6.0 mg (0.024 mmol) of pyridinium p-toluenesulphonate and 8 grains of 4 Å molecular sieve are then added. The resulting reaction mixture is allowed to react at a temperature in the region of 15° C. for 2.5 hours and is then heated at 100° C. for 2 hours. After cooling to a temperature in the region of 15° C., the reaction mixture is diluted in 40 cm3 of dichloromethane. The organic phase is washed once with 5 cm3 of a saturated sodium bicarbonate solution, 3 times with 5 cm3 of water and once with a saturated aqueous sodium chloride solution and is then dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting a first time with an ethyl ether/dichloromethane (2/98 by volume) mixture and then a second time with an ethyl acetate/hexane (10/90 by volume) mixture. There are thus obtained, with a yield of 38%, 14 mg (0.0456 mmol) of (4S,5R)-5-vinyl-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine, the characteristics of which are the following:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17][CH2:18]Br>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:18][CH2:17][O:16][CH3:15]
Reactant: COCCBr
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccccc1I

Procedure:
To a mixture of 2-iodophenol (5.00 g, 22.7 mmol) and potassium carbonate (4.71 g, 34.1 mmol) in ACN (7 ml) was added 2-bromoethyl methyl ether (3.79 g, 27.3 mmol).
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]2[O:23][CH2:22]2)=[CH:19][CH:18]=1.[H-].[Na+].FC(F)(F)C([O-])=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:22][CH:21]([C:20]3[CH:24]=[CH:25][C:17]([CH3:16])=[CH:18][CH:19]=3)[OH:23])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: O=C([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 17.9 %

Procedure:
Preparation of the title compound was carried out according to General Method 6. 2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (400 mg, 2.0 mmol), 4-methylstyrene oxide (2.01 g, 15 mmol) and NaH (240 mg, 6 mmol) were heated in DMF (6 mL) at 120° C. for 16 h to obtain 120 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([N:22]=[CH:23][C:24]=3B3OC(C)(C)C(C)(C)O3)[CH:21]=2)=[CH:12][CH:11]=1.Cl[C:35]1[CH:40]=[C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])[CH:38]=[CH:37][N:36]=1.N#N>O.O1CCOCC1>[CH2:45]([NH:44][C:42]([NH:41][C:39]1[CH:38]=[CH:37][N:36]=[C:35]([C:24]2[CH:23]=[N:22][N:20]3[CH:21]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=4)[CH:17]=[N:18][C:19]=23)[CH:40]=1)=[O:43])[CH3:46]
Reactant: CCNC(=O)Nc1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cnn3cc(-c4ccc(F)cc4)cnc23)OC1(C)C
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccnc(-c2cnn3cc(-c4ccc(F)cc4)cnc23)c1
Temperature: 90 °C
Yield: 18.6 %

Procedure:
A solution of K3PO4 (640 mg, 3 mmol) in H2O (2 ml) was added to a stirred mixture of 6-(4-fluoro-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine (330 mg, 0.97 mmol) and 1-(2-chloro-pyridin-4-yl)-3-ethyl-urea (procedure U4, 420 mg, 2.1 mmol) in dioxane (8 ml) at RT under N2. The mixture was deoxygenated by evacuate/fill N2 (×2), PdCl2dppf (40 mg, 0.05 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 90° C. for 18 h. After cooling to RT the reaction was partitioned between CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2 (×1). The combined extracts were dried, then evaporated. The residue was purified by preparative HPLC to give the title compound (68 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20](F)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 95.2 %

Procedure:
(R)-(+)-3-(Dimethylamino)pyrrolidine (0.111 mL, 0.87 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 mL, 0.87 mmol) in DMA (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated and further purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (353 mg, 96%) as an orange foam; 1H NMR: 1.78-1.91 (1H, m), 2.16-2.27 (7H, m), 2.70-2.85 (1H, m), 3.12-3.29 (3H, m), 3.41-3.55 (1H, m), 3.89 (3H, s), 6.57 (1H, s), 6.95 (1H, t), 7.17 (1H, t), 7.46 (1H, d), 8.09 (1H, s), 8.24 (1H, br s), 8.37 (1H, s), 8.50 (1H, d), 8.54 (1H, s), 11.88 (1H, s); m/z: ES+ MH+ 508.5.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](/[CH:15]=[CH:16]/OC(=O)C1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]([C:15]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2][O:1][CH:16]=1)=[O:14]
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: COC(=O)/C=C/OC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1conc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a mixture of (E)- and/or (Z)—N-hydroxy-benzenecarboximidoyl chloride (12.0 g, 77 mmol) and 4-nitro-benzoic-acid (E)-2-methoxycarbonyl-vinyl ester (9.7 g, 39 mmol) in dichloromethane (200 mL) was added triethylamine (20.9 mL, 150 mml) and the resulting solution stirred overnight at room temperature. The mixture was then diluted with dichloromethane (500 mL) and the organic extract removed and washed with water, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (3.1 g, 40%) which was obtained as a light yellow oil. MS: m/e=204.2 [M+H]+.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[N:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(Br)(Br)[Br:26]>>[Br:26][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[N:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: BrC(Br)Br
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1N
Product: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1Br

Procedure:
5-Amino-4-ethoxycarbonyl-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole, was treated with bromoform in a similar manner to Example 11, to give ethyl 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole-4-carboxylate. This was then reduced with zirconium borohydride to give [5-bromo-1-(4-trifluoromethyl-2nitrophenyl)-1H-pyrazol-4-yl]methanol, which was oxidised in a similar manner to that described in Example 4, to give 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole-4-carboxaldehyde, which was converted, as described in Example 1, to 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-4-[(2-amino-1,2-dicyanoethenylimino)-methyl]-1H-pyrazole, mp 195°-198°, which was cyclised to give 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-4-(4,5-dicyano-1H-imidazol-2-yl)-1H-pyrazole, m.p. 86°-90°. (compound 34)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)=[O:20]>C(O)(C)C>[ClH:1].[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:12][C:13](=[O:15])[CH3:14])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)c1cccc(N)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cccc(C(C)=O)c3)c2cc1OC(C)=O
Product: Cl
Yield: 83.3 %

Procedure:
A solution (200 mL) of acetic acid 4-chloro-7-methoxy-6-quinazolinyl ester [described in U.S. Pat. Nos. 5,770,599 and 5,770,603] (3.74 g, 14.8 mmol) and 3-aminoacetophenone (2.0 g, 14.8 mmol) in isopropanol was heated under reflux for 5 hrs. After allowing to stand to cool, the precipitate was collected by filtration to give acetic acid 4-(3-acetylphenylamino)-7-methoxy-6-quinazolinyl ester hydrochloride (4.78 g, yield as monohydrochloride 83%). To a solution (100 mL) of this compound (3.0 g, 7.74 mmol) in methanol was added 28% aqueous ammonia (2 mL), and the mixture was stirred at room temperature for 4 hrs and then refluxed. The produced precipitate was collected by filtration and dried under reduced pressure to give 1-[3-(6-hydroxy-7-methoxy-4-quinazolinylamino)phenyl]ethanone (2.07 g, 87%). 2) A solution (20 mL) of 1-[3-(6-hydroxy-7-methoxy-4-quinazolinylamino)phenyl]ethanone (870 mg, 2.8 mmol) and pyridine (0.34 mL, 4.2 mmol) in acetonitrile was stirred on an ice bath and trifluoromethanesulfonic acid anhydride (0.57 mL, 3.4 mmol) was added dropwise. The reaction solution was gradually warmed up to room temperature and, after stirring at room temperature for 2 hrs, the mixture was concentrated. Aqueous sodium hydrogen carbonate was added to the residue and the mixture was stirred at room temperature for 30 min. The product was filtered and dried under reduced pressure to give the title compound 6a (1.20 g, 98%).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]1(=[O:22])[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]1.C([O-])(=O)C.[NH4+:27]>C(O)C>[CH2:3]([C:4]1[NH:27][C:17]2[CH2:18][CH2:19][CH2:20][C:15](=[O:22])[C:16]=2[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=1)[CH:2]([CH3:14])[CH3:1]
Reactant: CC(C)CC(=O)C=Cc1ccccc1
Reactant: O=C1CCCC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC(C)CC1=CC(c2ccccc2)C2=C(CCCC2=O)N1
Yield: 19.6 %

Procedure:
5-Methyl-1-phenyl-1-hexen-3-one (5.05 g), 1,3-cyclohexanedione (3.31 g) and ammonium acetate (4.91 g) were combined in 200 mL of ethanol and allowed to reflux for 7 hours. The mixture was evaporated and the residue was purified by chromatography, with ethyl acetate as the eluent, to provide the title compound as a white solid (1.48 g); mp 182°-184° C.; MS: 281 (M); NMR: 0.79 (d,3, J=5.5, CH3), 0.85 (d,3, J=5.5, CH3), 1.73-1.93 (m,5, CH2, CH2, CH), 2.13 (m,2, CH2), 2.42 (m,2, CH2), 4.38 (d,1, J=4.9, CH), 4.58 (d,1, J=5.0, CH), 7.03-7.23 (m,5, Ar), 8.30 (s,1, NH). Analysis for C19H23NO: Calculated C, 81.80; H, 8.24 ; N, 4.98; Found: C, 80.91; H, 8.21; N, 5.00.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([NH:14][C:15](=[O:21])[C:16]([O:18]CC)=[O:17])=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[C:24]([O:26]CC)=[O:25].C(Cl)(Cl)Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([NH:14][C:15](=[O:21])[C:16]([OH:18])=[O:17])=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)C(=O)Nc1cc(NC(=O)C(=O)OCC)c(Cl)c(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C(=O)Nc1cc(NC(=O)C(=O)O)c(Cl)c(-c2ccccc2)c1

Procedure:
To a solution of 5.0 g (0.014 mole) of diethyl N,N'-(4-Chloro-5-phenyl-m-phenylene)dioxamate in 125 ml. of chloroform in a separatory funnel is added 29 ml. of 1 M sodium hydroxide solution. Water is added to the mixture until the solid that forms on shaking redissolves. The mixture is allowed to stand with occasional shaking for fifteen minutes. The aqueous layer is drawn off, filtered and the filtrate acidified by the addition of 1N hydrochloric acid. The precipitate that forms is removed by filtration. There is obtained 3.89 g. of material melting above 310°.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1F)[C:17]([OH:19])=[O:18].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[C:1]12([CH2:11][O:12][C:22]3[C:21]([F:24])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:25])[C:14]=3[Cl:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F
Reaction time: 0.5 h
Yield: 150.9 %

Procedure:
To a solution of 1-adamantylmethanol (309 mg) and 3-chloro-2,4,5-trifluoro-benzoic acid (391 mg) in DMSO (5.6 mL) at 14° C. (bath) was added potassium tert-butoxide (458 mg) gradually. The mixture was stirred at that temp for 30 min. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the product was obtained as white solid (1.00 g).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Reactant: CC[C@H](N)C(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (1.25 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.25 mL, 14.4 eq, 1.44 mmol) followed by (3S)-3-amino-2-methyl-pentan-2-ol (40 mg, 3.2 eq, 34 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 6.5 mg (16%). 1H-NMR (d-CDCl3, 250 MHz): 1.00 (t, 3H, J=7.42 Hz, —NHCH(CH2CH3)C(CH3)2OH), 1.22 & 1.31 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.70-1.90 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 3.66-3.81 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.56-4.73 (m, 1H, —CH(CH3)2), 4.78-5.01 (m, 2H, —HNCH2-Pyr), 7.20-7.45 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.48-7.69 (m, 1H, Pyr-H), 7.77 (d, 1H, J=7.74 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 366 (30), 324 (85), 286 (40), 242 (65), 192 (63), 176 (70). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2494.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22].O>O1CCCC1>[N:23]1([C:21]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:22])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=NC(=O)n1ccnc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
2.0 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6carboximidate and 1.83 g of 1,1'-carbonyldiimidazole are stirred at room temperature for 5 hours in 20 ml of tetrahydrofuran. The reaction mixture is poured into water and extracted twice with ethyl acetate. The extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on silica gel with n-hexane/acetone (1:4) as the eluent, and there is obtained ethyl N-(1-imidazolylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6 carboximidate, m,p. 134°-137° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH:17]=2)=[C:13]([OH:15])[CH:14]=1)C1C=CC=CC=1.O1CCCC1.C(O)C>ClCCl.[Pd]>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=3[OH:15])[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: Oc1cc(OCc2ccccc2)ccc1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A flask equipped with magnetic stirrer was charged with 5-(benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol (14.5 g, 42.8 mmol) and tetrahydrofuran (50 ml) and ethanol (100 ml) and palladium (4.54 g, 10% on activated carbon) were added sequentially. The reaction vessel was then evacuated, placed under a hydrogen atmosphere and stirred vigorously for 24 hr. The reaction mixture was filtered through a celite plug, washing with ethyl acetate. The filtrate was concentrated in vacuo to give an off white solid. The crude solid was slurried in dichloromethane (200 ml), affording the title compound (10.2 g, 95%) as a white solid. m/z(ES+) 251(M+H+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])(C(C)(C)C)(C)C.[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:31]([S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@H:29]1[CH2:53]I)=[O:27])[CH:23]=[CH2:24].C(OCC)(=O)C>O1CCCC1>[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:31]([S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@H:29]1[CH2:53][CH:18]1[CH2:19][CH2:20][NH:16][C:17]1=[O:21])=[O:27])[CH:23]=[CH2:24]
Reactant: CC(C)(C)[Si](C)(C)N1CCCC1=O
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1CCNC1=O
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
Lithium diisopropylamide (2.1M tetrahydrofuran solution, 6.45 ml, 13.5 mmol) was dropwise added to a solution of N-tert-butyldimethylsilyl-2-oxopyrrolidine (1.80 g, 9.03 mmol) in tetrahydrofuran (150 ml) at -78° C., and the mixture was stirred at the same temperature for 15 minutes. Then, a solution of (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (2.57 g, 4.5 mmol) in tetrahydrofuran (18 ml) was dropwise added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into a mixture of ethyl acetate (150 ml) and a 10% ammonium chloride aqueous solution (50 ml) for liquid separation. The organic layer was washed sequentially with a 10% sodium dihydrogen phosphate aqueous solution (100 ml) and a saturated sodium chloride aqueous solution (100 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (12 ml) and methanol (3 ml), and 6N hydrochloric acid (3 ml) was added thereto under cooling with ice. The mixture was stirred for 1 hour. Ethyl acetate (50 ml) was added to the reaction solution, and the organic layer was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution (30 ml) and a saturated sodium chloride aqueous solution (30 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel flash column chromatography (Wakogel™ C-300, 40 ml, ethyl acetate-n-hexane 3:1) to obtain (2R,4S)-N-allyloxycarbonyl-2-(2-oxopyrrolidin-3-ylmethyl)-4-tritylthiopyrrolidine (880 mg, yield: 37%).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][CH:5](OC)[O:6]C.[NH2:12][CH:13]=[CH:14][CH:15]=O.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CCOCC.C([O-])(=O)C.[NH2+]1CCCCC1>[CH3:1][O:2][CH:3]=[CH:4][CH:5]=[O:6].[N:12]1[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(CC(OC)OC)OC
Reactant: NC=CC=O
Reactant: O=C1CCCCC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC=CC=O
Product: c1cnc2c(c1)CCCC2
Yield: 35 %

Procedure:
3-Methoxyacrolein was prepared from 1,1,3,3-tetramethoxypropane (Helv. Chim. Acta 1959, 42, 851) and converted to 3-aminoacrolein according to the method of Brietmaier and Gasenmann (Chem. Ber. 1971, 104, 665-7). 5,6,7,8-Tetrahydroquinoline was prepared from 3-aminoacrolein as described by Brietmaier and Bayer (Tet. Letts 1970, 38, 3291). A mixture of 3-aminoacrolein (7.3 gm, 0.1 m) and cyclohexanone (12 gm., 0.12m) was treated with triethylamine (5 ml.) and piperidinium acetate (0.1 gr) and the mixture heated in an oil bath at 120° for 24 hours. The cooled reaction mixture was dissolved in ether (100 ml.), washed with water and 2N HCl (2 × 20 ml.) and the acid washings combined, made basic with sodium carbonate and extracted with ether. The combined extracts were dried, evaporated and the residue distilled to give the title compound as a pale yellow oil (4.5 gm, 35%) b.p. 100°/15 mm.