Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH2:40]([NH2:46])[CH:41]1[O:45][CH2:44][CH2:43][CH2:42]1.N1CCOCC1.[N-]=C=O>C1COCC1>[O:45]1[CH2:44][CH2:43][CH2:42][CH:41]1[CH2:40][NH:46][C:36]([C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([C:23]3[CH:22]=[C:21]([N:15]4[C:14](=[O:39])[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=5)[C:16]4=[O:20])[CH:26]=[CH:25][CH:24]=3)[O:28][C:29]=2[CH:35]=1)=[O:37]
Reactant: NCC1CCCO1
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccc(C(=O)NCC5CCCO5)cc4o3)c1)C2=O
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) in THF (1 ml) was added to a solution of tetrahydrofurfurylamine (14 mg, 0.14 mmol) in THF (1 ml) containing polymer bound morpholine (2.5 mmol g−1, 72 mg). After shaking overnight, polymer bound isocyanate (2.0 mmol g−1, 90 mg) was added and the reaction shaken for 4 h. The reaction was filtered and the solvent removed under reduced pressure. The residue was suspended in dioxane and palladium on carbon was added (spatula tip). The reaction vessel was purged with hydrogen and stirred at room temperature overnight. The reaction was filtered through celite and the filtrate concentrated to give the title compound (27 mg, 59%). 1H NMR (DMSO) δ 8.74(t, 1H), 8.44(dd, 1H), 8.37(m, 2H), 8.31–8.27(m, 3H), 8.12(d, 1H), 7.97(dd, 1H), 7.90(d, 1H), 7.85–7.76(m, 1H), 4.00(m, 2H), 3.79(m, 1H), 3.65(m, 2H), 1.98–1.77(4H, m). MS 510.2 m/z (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:13].[Br:14]CC(C1C=C(C)C=CN=1)=O>>[BrH:14].[Br:13][CH2:2][C:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: CCCc1ccnc(C(C)=O)c1
Agent: Br
Product: CCCc1ccnc(C(=O)CBr)c1

Procedure:
The title compound was prepared from 2-acetyl-4-propylpyridine according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[Li])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([N:22]([CH2:39][CH3:40])[C:23]([C:25]1[C:26]([O:37][CH3:38])=[N:27][CH:28]=[CH:29][C:30]=1[C:31](N(OC)C)=[O:32])=[O:24])[CH3:21]>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:31]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([O:37][CH3:38])[C:25]=2[C:23]([N:22]([CH2:20][CH3:21])[CH2:39][CH3:40])=[O:24])=[O:32])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)C(=O)c1c(C(=O)N(C)OC)ccnc1OC
Reactant: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1
Product: CCN(CC)C(=O)c1c(C(=O)c2cc3cnccc3n2S(=O)(=O)c2ccccc2)ccnc1OC

Procedure:
This compound was prepared according to the method described in Example 14c starting from 1-benzenesulfonyl 2-lithio 5-aza indole and 3-diethylaminocarbonyl 2-methoxy 4-(N-methoxy N-methylaminocarbonyl) pyridine.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[F:52][B-](F)(F)F>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[F:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: FC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (100 mg, 0.18 mmol) and DBU (44 μL, 0.28 mmol) in dichloromethane (0.5 mL) is added diethylaminodifluorosulfinium tetrafluoroborate (68 mg, 0.28 mmol) at room temperature and under nitrogen. After 90 min of stirring, the reaction mixture is quenched at room temperature with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture is extracted twice using dichloromethane. The organic phases are combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents are evaporated to provide 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl fluoride (96 mg, 96%, β:α anomers in a 1.1:1 ratio respectively) as a foam. 1H NMR (CDCl3, 300 MHz) δ 7.47-7.15 (m, 20H), 5.61 (dd, 2JH-F=53.2 Hz, 3JH-H=2.3 Hz, 0.48H, α-anomer), 5.31 (dd, 2JH-F=51.8 Hz, 3JH-H=6.4 Hz, 0.52H, β-anomer), 5.07-4.48 (m, 8H), 4.11-3.54 (m, 6H); 19F NMR (CDCl3, 282 MHz) δ −138.0 (dd, 1JF-H=53.4 Hz, 2JF-H=10.6 Hz, β-F), −149.44 (dd, 1JF-H=54.4 Hz, 2JF-H=25.8 Hz, α-F); 13C NMR (CDCl3, 75 MHz) δ 138.5, 138.3, 138.1, 137.9, 137.5, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8, 112.8 (d, 1JC-F=215.2 Hz, β-anomer), 108.6 (d, 1JC-F=228.7 Hz, α-anomer), 83.6, 83.4, 81.7, 81.5, 81.4, 79.5, 79.2, 77.5, 77.1, 77.0, 77.7, 75.9, 75.5, 75.2, 75.0, 74.9, 74.8, 74.5, 73.6, 73.5, 72.7, 68.4, 67.8.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][S:4](=[O:7])([OH:6])=[O:5].Cl.[CH2:12](O)CCC.C(OCC)(=O)C.C(O)(=O)C.O>O1CCOCC1.CO>[CH3:12][O:9][C:8](=[O:10])[C@H:2]([CH2:3][S:4](=[O:6])([OH:7])=[O:5])[NH2:1]
Reactant: CCCCO
Reactant: N[C@@H](CS(=O)(=O)O)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)CS(=O)(=O)O
Reaction time: 96 h

Procedure:
A mixture of 1 g of L-cysteic acid, 8 ml of 4 N hydrochloric acid in dioxane and 30 ml dry methanol was placed in a bottle. The bottle was capped and stored for approximately 96 hours at room temperature. Thin layer chromatography of the clear solution [Analtech silica gel plates, n-butanol:ethyl acetate:acetic acid:water (1:1:1:1), chlorine/potassium iodide-starch reagent (Stewart J. M. and Young J. D. in Solid Phase Peptide Synthesis, Pierce Chemical Company, PP.120 (1984)] indicated greater than 95 % conversion of cysteic acid to the ester. Solvents were removed under vacuum to get 1.05 g of a sticky solid. Mass spec analysis gave the m/z for the major M+1 ion as 184.3. Fragmentation of this ion gave the M+1 ion of 123.9, which represents the loss of one of the carboxymethyl groups. The solids were used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]=C)=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:11]([CH:12]=[O:24])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(F)cc2ncccc2c1F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c(F)cc2ncccc2c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5,7-Difluoro-6-vinyl-quinoline (iv) (614 mg, 3.21 mmol) was dissolved in dioxane (1.7 mL) and water (0.6 mL). 2,6-lutidine (0.761 mL, 6.42 mmol), sodium periodate (2.75 g, 12.85 mmol) and osmium tetroxide (653 mg, 0.064 mmol) were added to the previous solution. The RM was stirred at rt for 15 min. A precipitate was formed. Water was added to the RM and it was extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by MPLC with Hexane and EtOAc to give the title compound as a white solid (tR 1.2 min (conditions 2), MH+=244, 1H-NMR in DMSO-d6: 10.36 (s, 1H); 9.15 (s, 1H); 8.65 (d, 1H); 7.79 (d, 1H); 7.69 (dd, 1H)).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.024 g, 24%). MP: 69-79° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.50 (s, 1H), 8.55 (d, 1H, J=8.3 Hz), 8.15 (s, 1H), 7.98 (s, 1H), 7.93 (d, 1H, J=7.8 Hz), 7.63-7.57 (m, 1H), 7.50 (s, 1H), 7.29-7.23 (m, 1H), 6.64 (s, 1H), 3.87 (s, 3H), 3.31-3.20 (m, 1H), 2.90-2.68 (m, 10H), 1.69 (t, 3H, J=18.7 Hz), 1.32 (d, 6H, J=6.8 Hz). MS: 580.48 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][C:19]=3[O:21][CH3:22])[N:14]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]2=[O:32])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:16]([O:23][CH3:24])=[C:15]2[C:20]=1[C:12]1([C:3]3[C:2](=[CH:11][C:6]4[O:7][CH2:8][CH2:9][O:10][C:5]=4[CH:4]=3)[O:1][CH2:33]1)[C:13](=[O:32])[N:14]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31]
Reactant: COCCOCCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(OC)ccc(OC)c21
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(OC)ccc(OC)c21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 4′,7′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (24%): mp 109-110° C.; 1H NMR (300 MHz, CDCl3) δ6.80 (d, J=9.0 Hz, 1H), 6.47 (d, J=9.0 Hz, 1H), 6.39 (s, 1H), 6.24 (s, 1H), 4.76 (ABq, 2H), 4.26-4.03 (m, 6H), 3.81 (s, 3H), 3.77-3.69 (m, 2H), 3.64-3.59 (m, 2H), 3.59 (s, 3H), 3.49-3.43 (m, 2H), 3.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.4, 155.6, 150.4, 144.1, 139.7, 137.6, 131.0, 120.2, 119.5, 113.4, 111.1, 106.1, 98.7, 71.9, 69.8, 68.8, 64.5, 63.8, 59.0, 57.5, 56.4, 56.0, 41.2; MS (ES+) m/z 457.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH3:11])[C:7]([N+:12]([O-])=O)=[CH:6][CH:5]=1)[CH3:2]>O1CCOCC1.[Pd]>[NH2:12][C:7]1[C:8]([NH:10][CH3:11])=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCOc1ccc([N+](=O)[O-])c(NC)n1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOc1ccc(N)c(NC)n1
Yield: 100.1 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 4.95 g of 6-ethoxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 96) were hydrogenated in 100 ml of 1,4-dioxane in the presence of 1.00 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.20 g of the title compound having Rf=0.57(on silica gel thin layer chromatography using ethyl acetate as the developing solvent) were obtained.
Reaction SMILES: [CH3:1][C@@H:2]([CH:7](C(O)=O)[C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCCC[C@@H](C)C(C(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCC[C@@H](C)CC(=O)O
Temperature: 125 °C

Procedure:
At room temperature, 60 g of [(R)-1-methylpentyl]-malonic acid (0.318 mol) were dissolved in 120 ml of xylene in a three-neck flask with internal thermometer, condenser and stirrer. The mixture was heated to 125° C. for 5 h. After cooling to 25° C., the mixture was admixed with 200 ml of 2N sodium hydroxide solution. After phase separation, the aqueous phase was admixed with 200 ml of ether and, with cooling, with 180 ml of 15% by weight hydrochloric acid. After phase separation, the aqueous phase was extracted twice with 100 ml of ether. The combined organic phases were washed with 50 ml of water and then dried over sodium sulfate. After solvent had been distilled off, (R)-3-methylheptanoic acid was distilled and obtained in a yield of 35.5 g (77% of theory) with >99% ee and >99% chemical purity (b.p.: 67-68° C. at 0.45 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([CH:8](C(OC)=O)[C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.[Cl-].[Li+]>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: COC(=O)Cc1ncc(Br)cc1[N+](=O)[O-]

Procedure:
Prepared according to procedure H using dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (35 g, 105 mmol), lithium chloride (22.27 g, 525 mmol) and water (50 mL) and heating at reflux for 24 h. After purification methyl 2-(5-bromo-3-nitropyridin-2-yl)acetate was obtained as brown oil. Mass Spectrum (ESI) m/e=275 [(M+1) (79Br)] and 277 [(M+1) (81Br)].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][CH2:32][OH:33].C(N(CC)CC)C.[ClH:41]>CC#N>[ClH:41].[ClH:41].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:31][CH2:32][OH:33])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: OCCI
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CCO)CC2
Yield: 27 %

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol), 2-iodoethanol (17 μL, 36 mg, 0.21 mmol) and triethylamine (105 μL, 0.82 mmol) were dissolved in MeCN (2 mL) and heated to reflux for 3 h. The mixture was then concentrated and purified by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) providing the free base. This was converted to the HCl salt (2 N HCl/Et2O) providing the title compound (22 mg, 27%) as a yellow solid: mp 162-168° C.; 1H NMR (500 MHz, CD3OD) δ 7.63 (dd, J=7.6, 2.0 Hz, 2H), 7.51-7.50 (m, 3H) 7.46-7.43 (m, 2H), 7.41-7.38 (m, 1H), 7.09 (dd, J=8.3, 1.7 Hz, 1H), 6.36 (dd, J=7.6, 2.7 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.82 (d, 1H, partially masked by solvent), 4.520 (d, J=14.3 Hz, 1H), 4.06-4.02 (m, 3H), 3.77 (s, 3H), 3.70-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.33-3.31 (m, 2H, partially masked by solvent); ESI MS m/z 430 [M+H]+; HPLC (Method B) 95.1% (AUC), tR=12.4 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:22])([N:16]3C[CH2:20][S:19][CH2:18][CH2:17]3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])=[CH:4][CH2:3]1.OO.CCOC(C)=O>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([NH:16][CH2:17][CH2:18][S:19][CH3:20])[CH3:22])[CH:11]=[CH:10][C:9]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)N3CCSCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: OO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSCCNC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-methyl-1-thiomorpholin-4-yl-ethyl)-phenyl]-amide (as prepared in Example 14, step (e), 38.0 mg, 0.0820 mmol) in 0.5 mL of DCM at RT was added titanium (IV) isopropoxide (24.0 μL, 0.0820 mmol). The mixture was cooled to 0° C. and H2O2 (18 μL, 0.16 mmol, 30 wt % in H2O) was added. After stirring at 0° C. for 0.5 h and at −20° C. for 16 h, the mixture was treated with EtOAc (50 mL) and washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (15-25% EtOAc/DCM) to afford the title compound (33 mg, 80%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.6 Hz), 7.99 (s, 1H), 7.49 (dd, 1H, J=8.6, 2.3 Hz), 7.37 (d, 1H, J=2.3 Hz), 5.74 (m, 1H), 2.91-3.07 (m, 8H), 2.31 (m, 2H), 2.08 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.42 (s, 6H), 1.09 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H33N5O3S, 494.2 (M−H). found 494.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:12])[CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].CO[C:22](OC)([CH3:24])[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C@@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH:10]=[CH2:11])[O:12][C:22]1([CH3:24])[CH3:23])=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(C)(C)OC
Reactant: C=C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 82.5 °C
Reaction time: 2.5 h

Procedure:
(1S,2S)-(2-hydroxy-1-phenyl-but-3-enyl)-carbamic acid tert-butyl ester (160 grams, 0.608 mole) was dissolved in toluene (1600 mL). Dimethoxypropane (745 mL, 6.08 mole) was added at temperature in the range of 20-40° C. followed by addition of pyridinium p-toluene sulphonate (2.3 grams, 0.00912 mole). The mixture was heated to 80-85° C., and stirred at the same temperature for about 2-3 hours. The reaction mixture was cooled to 45° C., neutralized with pyridine (3 mL), and concentrated under reduced pressure to get the semi-solid compound (4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC([O-])(C)C.[Na+].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(N2CCOCC2)cc1
Yield: 77 %

Procedure:
According to General Procedure B, a mixture of 4-chloro trifluoromethylbenzene (67 μL, 0.50 mmol), morpholine (52 μL, 0.60 mmol), NaOt-Bu (67 mg, 0.70 mmol), Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol) and 12f (8 mg, 0.02 mmol) in PhMe (2.5 mL) was heated, cooled and filtered. Evaporation of the solvent under reduced pressure and column chromatography of the pre-adsorbed crude material (20% Et2O in hexane, silica gel) gave 52a (89 mg, 77%) as off-white crystals. 1H NMR (300 MHz, CDCl3) δ 7.50 (d, 2H, J=8.7 Hz), 6.92 (d, 2H, J=8.7 Hz), 3.87 (t, 4H, J=4.8 Hz), 3.24 (t, 4H, J=5.1 Hz); 13C NMR (75.5 MHz, CDCl3) δ 153.3, 126.4 (q, J=3 Hz), 124.6 (q, J=271 Hz), 120.9 (q, J=33 Hz) 114.3, 66.6, 48.1.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+].[OH:29][S:30]([OH:33])(=[O:32])=[O:31]>C(O)(C)C>[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[OH:32][S:30]([OH:33])(=[O:31])=[O:29]
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 159.7 %

Procedure:
A mixture of N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (10 g, 28 mmol), isopropanol (100 ml) and 10% solution of NaOH (16.8 ml, 42 mmol) was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and washed several times with 25% solution of NaOH (10 ml). The wet organic layer was neutralized to pH 7.0-7.5 with 17% hydrochloric acid and it was concentrated to dryness under vacuum. The residue was taken in isopropanol (100 ml) and the salts were filtered off. To the filtrate, H2SO4 96% (0.78 ml, 14.0 mmol) was added dropwise. This mixture was cooled to 0-5° C. and the precipitated was filtered and dried under vacuum at 40° C. to afford 15.0 g (80%) of abacavir hemisulfate as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[Br:1][C:2]1[C:3]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(N)cc(C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-2-iodo-5-(trifluoromethyl)aniline (5.21 g), ethynyl(trimethyl)silane (2.21 mL), triethylamine (100 mL), dichlorobis(triphenylphosphine)palladium(II) (1.00 g) and copper(I) iodide (0.271 g) was stirred overnight at 80° C. under nitrogen atmosphere. The solvent was evaporated under reduced pressure, to the residue was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.70 g).