Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SiH](CC)(CC)CC.[CH2:8]([O:10][C:11](=[O:40])[C:12]([NH:36][C:37](=[O:39])[CH3:38])([CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:24]=2)[C:19]1=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:8]([O:10][C:11](=[O:40])[C:12]([NH:36][C:37](=[O:39])[CH3:38])([CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:24]=2)[CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]
Reactant: CCCCCCCCc1ccc2c(c1)CC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc2c(c1)CC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of Et3SiH (1.014 g, 8.704 mmol) in CH2Cl2 (8 mL) was added 4 (0.213 g, 0.465 mmol) in CH2Cl2 (1.5 mL) dropwise at room temp under N2. TiCl4 (0.354 g, 1.858 mmol) was then added and the reaction left to stir at room temp over night. The reaction was then poured slowly over ice and extracted with CH2Cl2, the organic layer was then dried and concentrated. The product was then purified with silica gel chromatography eluding with 70% hexanes-30% EtOAc. The reaction provided 5 (0.149 g, 0.336 mmol, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[C:38]2[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(c2ccc(C#N)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 20.5 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol), 4-cyanophenylboronic acid (127.7 mg, 869 μmol; 4 eq.), copper(II) acetate (158 mg, 869 μmol; 4 eq.) and 4 Å molecular sieve (500 mg) were initially charged in dichloromethane (5 ml), pyridine (281 μl; 16 eq.) and triethylamine (121 μl; 4 eq.) were added and the mixture was subsequently stirred at RT for 4 days. The reaction mixture was then filtered through kieselguhr which was then repeatedly washed with methanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (25 mg, 19.5% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:7][C:8]1[N:9]=[C:10]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1nccs1
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2nccs2)n1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 1.37 g (9.26 mmol) of 2-aminothiazole, 0.74 g (7.39 mmol) of 2,6-dichloropyridine, 387 mg (0.621 mmol) of (S)-(−)-2,2′-(bisdiphenylphosphino)-1,1′-binaphthyl, 322 mg (0.311 mmol) of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 2.77 g (8.50 mmol) of cesium carbonate and 10 ml of toluene was heated under reflux for 1 hour and 30 minutes, cooled to room temperature and diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography to give 990 mg (4.68 mmol) of the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:25])=[C:5]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([Br:23])[CH:14]=1)[C:6]([OH:8])=[O:7].[CH3:26]O>>[Cl:2][C:3]1[C:4]([CH3:25])=[C:5]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([Br:23])[CH:14]=1)[C:6]([O:8][CH3:26])=[O:7]
Reactant: Cc1c(C(=O)O)cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c(Cl)c1C
Temperature: 20 °C
Reaction time: 22 h

Procedure:
HCl gas was bubbled through a solution of 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoic acid (375 mg, 0.86 mmol) in MeOH (20 mL) for 5 min. Upon stirring at 20° C. for 22 hr, HPLC analysis revealed esterification was complete. After removal of the solvent under vacuum and dissolution of the residue in EtOAc, the EtOAc layer was washed 2× with H2O then with brine prior to drying over MgSO4. Removal of the volatiles yielded 391 mg of crude methyl 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoate as a brown solid which was not further purified.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@@:9]12[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C@@H:21]([OH:27])[CH2:20][CH2:19]4)[CH2:16][CH:15]=[C:14]1[CH2:13][C@@H:12]([OH:28])[CH:11]=[CH:10]2.[CH2:29](COC)OC.C(I)I>CCOCC.[Cu].[Zn]>[CH2:29]1[C@@H:11]2[C@H:12]([OH:28])[CH2:13][C:14]3[C@:9]([CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)([C@H:10]12)[C@@H:26]1[C@H:17]([C@H:18]2[C@@:22]([CH2:24][CH2:25]1)([CH3:23])[C@@H:21]([OH:27])[CH2:20][CH2:19]2)[CH2:16][CH:15]=3
Reactant: COCCOC
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)C=C[C@@]43COC3CCCCO3)[C@@H]1CC[C@@H]2O
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: ICI
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)[C@H]5C[C@H]5[C@@]43COC3CCCCO3)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
To a stirred solution of 19-tetrahydropyranyloxy-1,5-androstadiene-3β,17β-diol in a mixture of dry ether and glyme is added zinc-copper couple and methylene iodide. This reaction mixture is refluxed for four hours, cooled to room temperature, diluted with ether and filtered. The ether filtrate is washed with an aqueous sodium chloride solution, washed with water, and dried over anhydrous magnesium sulfate. The ether is removed under reduced pressure and the residue which remains is crystallized from an acetone-hexane solution to yield 1β,2β-methylene-19-tetrahydropyranyloxy-5-androstene-3β,17β-diol.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[S:16][C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]=2[OH:17])[CH:9]=1.IC>CN(C)C=O.O>[Cl:7][C:8]1[S:16][C:15]2[C:14](=[O:17])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:11]([CH3:1])[C:10]=2[CH:9]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)sc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2cc(Cl)sc2c1=O
Reaction time: 18 h

Procedure:
Potassium carbonate (0.56 g) was added to a stirred solution of ethyl 2-chloro-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (1.1 g) in dry dimethylformamide (100 ml) at ambient temperature. After 5 minutes iodomethane (0.3 ml) was added to the mixture and stirring was continued for 18 hours. The mixture was stirred at 60° for 2 hours and then evaporated to dryness to give a residue which was dissolved in water (80 ml). The aqueous solution was extracted with dichloromethane (3×150 ml) and the combined extracts dried over anhydrous sodium sulphate and evaporated to give the novel compound ethyl 2-chloro-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p. 168°-171°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(Br)nc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of the product of step (iii) (200 g, 0.86 mol) in MeOH (500 mL) was added 5 N—NaOH (500 mL) slowly. The resulting mixture was stirred at 50° C. for 3 hours. MeOH was removed under a reduced pressure and water (300 mL) added to the reaction mixture. The solution was acidified to pH 3 with 6N—HCl. The solution was extracted with EtOAc and washed with water. The combined organic extract was dried over Na2SO4, filtered and evaporated to dryness to afford the subtitle compound (iv) as a brown yellow solid (180 g).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.CO.Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27]>N1C=CC=CC=1.O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=[N:24][NH:25][C:26]([NH2:28])=[O:27])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CC(C=NNC(N)=O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
To a solution of 0.288 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2 -yl)propanal in 3 ml. of methanol is added a solution of 0.111 g. of semicarbazide hydrochloride in 0.5 ml. of water, followed by 1 drop of pyridine. The mixture is refluxed briefly and then poured into water. The product is extracted with ethyl acetate and the extract washed, dried and evaporated to afford, upon crystallization from ethyl acetate/hexane, 2-(5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)propanal semicarbazone.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4](/[CH:17]=[CH:18]/[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[N:6]=1.[Na].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(NCCS([O-])(=O)=O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>P([O-])([O-])([O-])=O.O>[CH3:1][C:2]1[S:3][C:4](/[CH:17]=[CH:18]/[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[N:6]=1
Reactant: CCCCCC(=O)/C=C/c1sc(C)nc1CCCCCCC(=O)OC
Agent: C[C@H](CCC(=O)NCCS(=O)(=O)[O-])[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CCCCCC(=O)/C=C/c1sc(C)nc1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
To a suspension of 912 mg of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 = CH3) in 20 ml of 0.2 M phosphate buffer of pH 7.5, 90 mg of the lipase enzyme specified in Example 5, 9 mg of the sodium salt of taurocholic acid nd 0.9 ml of a 10 % solution of gum arabic were added. The mixture was then shaken at 25° C in a screening shaker desk at 260 revolutions/minute and an amplitude of 2 cm for 24 hours. Then the reaction mixture was diluted with 50 ml of water, acidified with citric acid and extracted with 3 × 40 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated in vacuo. The obtained 1.03 g of evaporation residue were purified by preparative thin layer chromatography in the way specified in Example 6. Thus, 645 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole Ib, R1 = CH3) were obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:43][C:33]1[CH:38]=[CH:37][C:36]([S:39]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCc1c(OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 15.6 g (50.0 mmole) of [(2S)-8-allyl-7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol in 100 mL of methylene chloride was added 26.3 mL (0.15 mole) of N,N-diisopropylethylamine, 0.63 g (5 mmole) of 4-dimethyl-aminopyridine and 14.25 g (75.0 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant. Combination of the product fractions and concentration in vacuum gave 18.0 g (77%) of the (R)-enantiomer of the title compound as a white solid, m.p. 76-77° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][N:7]=1.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][P:15]([CH2:2][C:3]1[O:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][N:7]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)c1cnc(CCl)o1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ncc(C(C)(C)C)o1)OCC
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution of 2-(chloromethyl)-5-t-butyloxazole (8.00 g, 46.1 mmol) in triethylphosphite (15.3 g, 92.0 mmol) was heated at 120° C. for 18 hours. After cooling the mixture to room temperature, toluene (30 mL) was added and the solution was concentrated in vacuo with a bath temperature of 70° C. This procedure was repeated three times and the resulting brown oil was dried in vacuo at 90° C. for 30 minutes to give (5-t-butyl-oxazol-2-ylmethyl)-phosphonic acid diethyl ester (12.4 g, 98%, C12H22NO4P, MS m/e 276 (M+H)+) as a red-orange liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH2:13]([OH:16])[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OCCO
Reactant: COC(=O)c1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(C2OCCO2)c1

Procedure:
A stirred solution of methyl 3-formylbenzoate (10.0 g., 61 mmol), ethylene glycol (5.0 ml, 91 mmol) and p-toluene sulphonic acid (10 mb) in toluene (100 ml) was refluxed under a Dean and Stark water trap for 4 hours. The cooled solution was washed with sodium bicarbonate solution, dried and evaporated to a pale oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]1.C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:37][CH2:36][CH:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CN1CCC(CN)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CN1CCC(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), C-(1-Methyl-piperidin-4-yl)-methylamine (184 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 135 mg of 118 (yield=37%). 1H NMR (CDCl3, 400 MHz) δ: 8.49 (s, 1H), 8.01 (s, 1H), 7.48-7.45 (m, 1H), 7.08-6.98 (m, 3H), 6.88 (s, 1H), 6.24-6.00 (m, 1H), 4.16-4.12 (m, 2H), 3.42-2.84 (m, 4H), 3.02-2.96 (m, 2H), 2.55 (s, 3H), 2.38-2.32 (m, 2H), 1.82-1.80 (m, 1H), 1.76-1.70 (m, 2H), 1.68-1.59 (m, 2H). LC-MS (ESI): m/z=509 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>F[B-](F)(F)F.[H+].O>[N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2)=[N+:19]=[N-:20]
Reactant: Nc1cc2nc(O)c(O)nc2cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 757.6 %

Procedure:
A solution of 2 g (g,6 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxaline in 40 ml 50% fluoroboric acid was added 100 ml water, filtered and then ice-cooled. A solution of 0,68 g (9,9 mmol) sodium nitrite in 20 ml water was added, and after stirring at 0° C. for 15 min. 0,68 g (1,0 mmol) sodium azide dissolved in 20 ml water was added. Stirring was continued at 25° C. for 2 h. The precipitate was filtered off and washed with water to give 1,8 g (80%) 6-azido-7-chloro-2,3-dihydroxyquinoxaline. IR (KBr): 2100 cm-1 (N3). NMR (DMSO-d6): 11.7 (2H, broad s), 7.03 (1H,s), 6.g3 (1H,s).
Reaction SMILES: [Na].Br[CH2:3]/[CH:4]=[CH:5]/[CH:6]=[CH2:7].[CH3:8][O:9][CH2:10][CH2:11][OH:12]>>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH:7]=[CH:6]/[CH:5]=[CH:4]/[CH3:3]
Reactant: COCCO
Reactant: C=C/C=C/CBr
Agent: [Na]
Product: C/C=C/C=COCCOC
Reaction time: 8 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, to a stirred solution of sodium (0.53 g, 23 mmol) in 2-methoxyethanol (50 mL) at room temperature was added 5-bromo-(3E)-1,3-pentadiene (3.38 g, 23 mmol). The mixture was stirred overnight and then refluxed for three more hours. Excess 2-methoxyethanol was removed by distillation. Water was added to the cooled reaction mixture, which was then extracted with diethyl ether. The diethyl ether solution was dried over MgSO4, then stripped off at reduced pressure. Distillation at 87-88° C., 31 mmHg (water aspirator) yielded 2.46 g (75%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N:5]([CH2:15][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:6][CH2:7][CH2:8][CH3:9])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: CCCCNc1cccc(Br)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Yield: 57.8 %

Procedure:
To a solution of 3-bromo-N-butyl-2-methylaniline (700 mg, 2.89 mmol) in dry acetonitrile (75 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (830 mg, 2.89 mmol) and N,N-diisopropylethylamine (331 μL, 1.9 mmol). The resultant mixture was heated at 80° C. for 3 h. The reaction mixture was cooled and the solvents removed in vacuo, diluted with water (50 mL) and extracted with CH2Cl2 (2×100 mL). The organic solution was dried (Na2SO4) and the solvents removed in vacuo. Purification by SPE (silica, 20 g) eluted with 100:2 to 100:5 cylclohexane:EtOAc afforded the title compound as a colourless oil (749 mg).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([O:11][CH2:12][CH:13]([O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH:18]C(OCC2C=CC=CC=2)=O)=[O:10])[O:5][C@@H:4]([N:53]2[C:63]3[N:62]=[C:60]([NH2:61])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]2)[CH2:3]1>CO.C(OCC)(=O)C.C(O)(=O)C.[Pd]>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([O:11][CH2:12][CH:13]([O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH2:18])=[O:10])[O:5][C@@H:4]([N:53]2[C:63]3[N:62]=[C:60]([NH2:61])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]2)[CH2:3]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)COC(=O)[C@@H](N)C(C)C
Reaction time: 2 h

Procedure:
2′,3′-dideoxy-3′-fluoro-5′-O-[1-(N-CBz-L-valyloxy)-2-stearoyloxy-3-propyloxy carbonyl]guanosine (190 mg), was dissolved in a mixed solvent of methanol (6 ml), ethyl acetate (2 ml) and acetic acid (1 ml). To the solution was added palladium black (30 mg), and the reaction mixture was kept under hydrogen for 2 h. It was then filtered and the filtrate was evaporated and the titled product was isolated by silica gel column. 110 mg.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:16]=[C:17](SC)[NH:18][C:19]([O:21]C(C)(C)C)=[O:20])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][NH2:39]>CC(O)=O>[Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:38]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[Cl:31])[N:39]=[C:17]([NH:18][C:19](=[O:20])[OH:21])[N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CSC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Nc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
CH3COOH (50 ml) was added to a mixture of methyl N′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate, from Example 569, (1.0 g, 2.08 mmol) and (2-chlorophenyl)hydrazine hydrochloride (0.74 g, 4.16 mmol). The resulting mixture was stirred at 120° C. overnight. The reaction mixture was concentrated and purified by silica gel chromatography (Hexanes:EtOAc, 3:1-1:1) to give 5-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-ylcarbamic acid (630 mg, 60%). 1H NMR (DMSO, 400 MHz) δ 10.60 (s, 1H), 7.76 (s, 1H), 7.70-7.6 8 (m, 1H), 7.63-7.60 (m, 2H), 7.52-7.52 (m, 1H), 7.48-7.46 (m, 1H), 7.18 (s, 1H), 7.10-7.07 (m, 1H), 5.45 (s, 1H), 4.42 (s, 4H)