Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][CH2:8][C:9]1[N:10]([CH2:22][C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH3:6].C(N(CC)CC)C>ClCCl>[C:1]([N:26]1[CH2:27][CH2:28][C:23]([CH2:22][N:10]2[C:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=[C:9]2[CH2:8][O:7][CH2:5][CH3:6])([OH:29])[CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(C)=O)CC1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Acetyl chloride (0.57 mL, 8.1 mmol) was added to a suspension of 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (2.50 g, 7.34 mmol) and triethylamine (1.50 mL, 11.0 mmol) in dichloromethane (37 mL) at rt. The resulting solution was stirred for 1 h. The solution was diluted with dichloromethane (100 mL) and washed with water (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The combined aqueous layers were back-extracted with dichloromethane (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to a brown foam. Purification by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) provided 1-acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol as a white foam (1.8 g, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.308 g, 0.74 mmol) in absolute ethanol (5 ml) was added hydrazine (47 μl, 1.48 mmol). The reaction was stirred at 80° C. for 4 h and then at room temperature for another 12 h. The precipitate formed was filtered off and the filtrate concentrated in vacuo. To the oily residue was added dichloromethane (15 ml) and the precipitate formed was filtered off. The filtrate was concentrated in vacuo to give 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester 0.19 g (90%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[NH2:11].CN(C)[C:14]1[O:15][C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[N:11]1[C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:19][C:14]1=[O:15]
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: Nn1ncc2c(Cl)cccc21
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-n1ncc2c(Cl)cccc21
Reaction time: 4 h
Yield: 83.5 %

Procedure:
The crude 168A (1.15 g, 6.88 mmol assumed) is dissolved in glacial acetic acid (15 mL) and 2-dimethylamino4-trifluoromethyl-[1,3]oxazin-6-one (1.43 g, 6.88 mmol) is added. The mixture was stirred for 4 h under reflux, after which the acetic acid iss removed in vacuo. The residue is dissolved in ethyl acetate, washed with saturated sodium carbonate solution and water, and is subsequently dried over sodium sulfate. The crude product (1.9 g) is obtained after removal of the drying agent by filtration and evaporation of the solvent. The product (100 mg) is purified by flash chromatography (ethyl acetate/petrol ether 3/7).
Reaction SMILES: [CH2:1]([CH:8]([C:17](=[O:36])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][Si](C(C)(C)C)(C)C)=[C:22]([O:34][CH3:35])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([CH:8]([C:17](=[O:36])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/C(=O)C(Cc2ccccc2)C(=O)c2ccccc2)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(/C=C/C(=O)C(Cc2ccccc2)C(=O)c2ccccc2)ccc1O
Temperature: 25 °C
Yield: 84.6 %

Procedure:
(E)-2-Benzyl-5-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-1-phenylpent-4-ene-1,3-dione (204 mg, 0.41 mmol) was dissolved in anhydrous THF (5 ml) and stirred at room temperature under a nitrogen atmosphere. TBAF (0.14 ml, 0.49 mmol) was added (yellow/green solution goes deep red colour) and the mixture was stirred overnight at room temperature. After this time the solvents were removed in vacuo to leave a residue which was purified on silica gel column using dichloromethane/diethyl ether (1:0 to 10:1) to give (E)-2-benzyl-5-(4-hydroxy-3-methoxyphenyl)-1-phenylpent-4-ene-1,3-dione (134 mg, 85%) as a light green foam: 1H NMR (400 MHz, CDCl3) δ 3.34 (1H, dd, J=14.0, 7.2 Hz, CH2), 3.50 (1H, dd, J=14.0, 7.2 Hz, CH2), 3.92 (3H, s, OCH3), 4.95 (1H, t, J=7.2 Hz, H-2), 5.96 (1H, brs, OH), 6.68 (1H, d, J=16.0 Hz, H-4), 6.90 (1H, d, J=8.0 Hz, H-5′), 6.95 (1H, d, J=2.0 Hz, H-2′), 7.04 (1H, dd, J=8.0, 2.0 Hz, H-6′), 7.16-7.28 (5H, m, 5×ArH), 7.44 (2H, brt, J=8.0 Hz, 2×H-5″, H-3″, H-6), 7.53 (1H, d, J=16.0 Hz, H-5), 7.52-7.57 (1H, m, H-4″), 7.96-7.98 (2H, m, H-2″, H-6″) ppm.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)C=[CH:7][CH:8]=1.CO.C(O)(=[O:21])C>C(OCC)(=O)C>[CH:13]1[C:14]2[C:9](=[CH:5][CH:4]=[C:3]([CH2:8][CH:7]=[O:21])[CH:2]=2)[CH:10]=[CH:11][N:12]=1
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=CCc1ccc2ccncc2c1
Temperature: 2.5 °C

Procedure:
1.75 g (0.0077 mol) of 4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine, 30 ml of methanol, 1.15 ml of glacial acetic acid and 0.73 g of anhydrous ethyl acetate are mixed. The mixture is cooled to 0-5° C. and 1.14 g of 7-isoquinolylacetaldehyde (as obtained according to the Preparation) and, with care, 1.1 g (0.0175 mol) of sodium cyanoborohydride are added thereto. The mixture is stirred at 0-5° C. for 1.5 hours and subsequently at ambient temperature overnight. 7 ml of concentrated hydrochloric acid are added, the mixture is stirred for 10 minutes, the solvent is evaporated under reduced pressure and the residue is taken up in an ethyl acetate/dilute NH4OH mixture. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated. The residue is purified on a column of silica gel, elution being carried out with an ethyl acetate/methanol=9/1 mixture. The title compound is obtained. The dihydrochloride is prepared using a solution of isopropanol saturated with hydrochloric acid. 1.1 g of product are obtained.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>ClCCl.O>[N:26]([CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCc1cc2ccccc2cn1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCCc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a ice-bath cooled solution of 3-(2-hydroxyethyl)isoquinoline (Description 111; 4.85 g, 28 mmol) and triethylamine (5.07 ml, 36.4 mmol) in anhydrous dichloromethane (100 ml) was added slowly methanesulfonyl chloride (2.49 ml, 32.2 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water (200 ml), sat NaCl (100 ml), dried over Na2SO4, filtered and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (100 ml) and sodium azide (2.00 g, 30.8 mmol) added and the resulting mixture stirred at room temperature for 4 days. The mixture was poured into water (400 ml), and extracted with EtOAc (3×100 ml). The combined EtOAc layers were washed with water (3×200 ml), saturated aqueous NaCl (100 ml), dried over Na2SO4, filtered and evaporated to give the title compound (5.6 g, 100%).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=O)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]>CO.C(O)(=O)C>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][CH2:14][C@@H:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Sodium cyanoborohydride (2.0 g, 0.03 mole) was added portionwise (one hour) to a solution of the known compound 2(S)-t-butoxycarbonylamino-3-methylbutyraldehyde (5.8 g, 0.029 mole) and phenylalanine methyl ester hydrochloride (6.1 g, 0.028 mole) in methanol (150 ml) and acetic acid (1.5 ml). The clear reaction mixture was stirred at room temperature under argon for 2 hours and concentrated in vacuo. The residue was cooled in an ice bath, neutralized with saturated NaHCO3 and extracted (3×) with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated to give a pale yellow residue, which was purified by column chromatography on silica gel using 20% ethyl acetate-hexane. The title compound (8.4 g) was obtained as a pale yellow oil.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.C[O-:25].[Na+].Cl>CO.O>[O:25]=[C:3]1[NH:8][C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]=2[N:5]=[N:4]1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1ccccc1-c1nc2[nH]c(=O)nnc2c(=O)[nH]1
Yield: 92.4 %

Procedure:
A stirred mixture of 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (0.5 g) and sodium methoxide (prepared from sodium, 0.17 g. and methanol) in methanol (50 ml) was heated under reflux for 3 hours. The cooled reaction mixture was evaporated under reduced pressure to afford a yellow solid which was dissolved in water and acidified with 2 Normal hydrochloric acid to yield a yellow solid (420 mg) which was recrystallized from dimethylformamide to afford the title compound, 0.16 g, m.p. 296-299° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]3[S:47][C:48]([CH3:51])=[CH:49][CH:50]=3)=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.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>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](/[C:40]2[CH:41]=[CH:42][C:43]([C:46]3[S:47][C:48]([CH3:51])=[CH:49][CH:50]=3)=[CH:44][CH:45]=2)\[C:20]2[CH:21]=[CH:22][C:17]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:18][CH:19]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(-c3ccc(C)s3)cc2)cc1C
Reactant: C#CCN1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc(-c3ccc(C)s3)cc2)cc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Propargylpyrrolidine (168 mg, 1.54 mmol) and diisopropylamine (0.27 mL, 1.93 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(5-methylthiophen-2-yl)phenyl]allyloxy]-2-methylphenoxy]acetate (235 mg, 0.385 mmol; prepared as described in example 17) in tetrahydrofuran (5 mL). The mixture was degassed and copper(I) iodide (15 mg, 0.079 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (27 mg, 0.038 mmol) were added. The reaction mixture was stirred at ambient temperature for 2.5 h and subsequently evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2+0.5% of triethylamine) yielding methyl (E)-[2-methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-allyloxy]phenoxy]acetate as brownish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P(Cl)(Cl)[Cl:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([Cl:26])[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Nc2nc(O)cc(-c3ccccc3)n2)cc1Cl
Product: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl

Procedure:
Chlorination of 2-(3-chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-4-ol (1.5 g, 4.1 mmol) with POCl3 (10 mL) as explained above, afforded (3-chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[S:13])[NH:11][N:12]=2)[O:5][C:6]=1[CH3:7].Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([S:13][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)oc1C
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1cc(-c2nc(SCc3ccccn3)n[nH]2)oc1C
Yield: 27 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a) and 2-(bromomethyl)pyridine hydrobromide. Yield 27%. 1H NMR (500 MHz, dMSO): δ 1.98 (s, 3H), 2.28 (s, 3H), 4.37 (s, 2H), 6.76 (s, 1H), 7.3 (m,1H), 7.45 (d, 1H), 7.75 (t, 1H), 8.6 (s, 1H). MS(M+H, 287).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:66]=[CH:67][CH:68]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47]O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:42]=1)=[O:38])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:69]>O1CCOCC1>[OH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:66]=[CH:67][CH:68]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][Cl:69])[CH:42]=1)=[O:38]
Reactant: Cl
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cccc(CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)c4)n3Cc3cccc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12
Solvent: C1COCCO1
Product: Cc1nnc2ccc3c(cc(C(=O)OCc4cccc(CCl)c4)n3Cc3cccc(CO)c3)n12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
3-({[tert-Butyl(diphenyl)silyl]oxy}methyl)benzyl 6-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (0.890 g, 0.954 mmol, from Step 5) was dissolved in 1,4-dioxane (20 mL) and 4.0 M solution of HCl in dioxane (20 mL, 80 mmol) was added. The reaction was stirred for 1 h at 110° C. Three additional portions of 4.0 M HCl in dioxane (10 mL, 40 mmol) were added periodically over the course of 6.5 hours at 110° C. After the third addition, the reaction mixture was heated at 110° C. in a sealed vessel for 48 hours. When the reaction was complete, the dioxane was evaporated and the residue was neutralized by the addition of saturated NaHCO3 solution. The product was extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-10% MeOH/DCM was used to isolate 3-(chloromethyl)benzyl 6-[3-(hydroxymethyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate, which was used in the displacement reaction that follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1.C(O[C:25](=[O:27])[CH3:26])(=O)C.[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([N:1]([C:25](=[O:27])[CH3:26])[C:2]1[CH:3]=[C:4]([N:20]([C:9](=[O:10])[CH3:11])[C:7](=[O:8])[CH3:6])[C:5]2[O:10][CH:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1)(=[O:30])[CH3:29]
Reactant: Nc1cc(N)c2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Cl
Product: CC(=O)N(C(C)=O)c1cc2c(c(N(C(C)=O)C(C)=O)c1)OC(C(Cl)(Cl)Cl)OC2C(Cl)(Cl)Cl

Procedure:
A mixture of 6,8-diamino-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1 g.), acetic anhydride (25 ml.) and acetyl chloride (2 ml.) was heated on the steam bath for 10 hours. After cooling, the reaction mixture was evaporated to dryness under reduced pressure, and the residue was triturated with aqueous ethanol. The solid product thus obtained was crystallised from ethanol to give 6,8-bis(diacetylamino)-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 182°-183° C.
Reaction SMILES: [F:1][C:2]1([F:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[Cl-].[NH4+]>CO.[Zn]>[F:15][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(F)(F)CCO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc2c(c1)C(F)(F)CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
Dissolve 4,4-difluoro-6-nitro-chromane (2.5 g, 11.6 mmol) in methanol (100 mL), add zinc powder (2.5 g, 34.8 mmol), then add dropwise a 15.5% aqueous solution of ammonium chloride (40 mL, 139 mmol), stir at room temperature for 5 hrs. Filter off the solid, add water (50 mL) to the filtrate, extract with EtOAc (50 mL×2). Combine the organic layers, wash with brine (50 mL×2), dry over anhydrous Na2SO4. Concentrate under reduced pressure to get a crude residue. Purification by chromatography (silica gel, EtOAc:PE=1:3) affords the title compound (1.8 g, 83.7%). MS: (M+1): 186.2.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][N:26]2C(=O)C3=CC=CC=C3C2=O)[O:22][C@@H:21]([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNN>C(Cl)Cl>[NH2:26][O:25][CH2:24][C@H:23]1[O:22][C@@H:21]([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[CH2:20][C@@H:19]1[O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Agent: CNN
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a stirred solution of 3′-O-(t-butyldiphenylsilyl)-5′-O-phthalimidothymidine (10 g, 16 mmol) in dry CH2Cl2 (100 ml) was added methylhydrazine (1.3 ml, 24 mmol) under argon at room temperature and solution stirred for 12 h. The solution was cooled (0° C.) and filtered. The white residue was washed with CH2Cl2 (2×25 ml) and combined filtrates were evaporated to furnish gummy residue. The residue on purification by silica gel column chromatography (elution with CH2Cl2:MeOH, 98:2, v/v) furnished 7.03 g (89%) of 5′-O-amino-3′-O-(t-butyldiphenylsilyl)thymidine that crystallized from CH2Cl2/MeOH mp 141-143° C. 1H NMR (DMSO-d6) δ 11.29 (s, 1, NH), 7.42-7.62 (m, 11, TBDPhH, C6 H), 6.25 (dd, 1, H1′, J1′,2′=8.4 Hz, J1′,2′=6.3 Hz), 6.02 (s, 2, NH2), 4.35 (m, 1, H4′), 4.04 (m, 1, H3′), 3.34-3.51 (m, 2, H5′,5″) 2.04 (m, 2, H2′, 2″), 1.73 (s, 3, CH3), 1.03 (s, 9, C(CH3)3). Anal. Calcd. for C26H33O5N3Si: C, 63.00; H, 6.71; N, 8.48. Found: C, 62.85; H, 6.67; N, 8.32.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>O.CN(C)C=O>[CH2:27]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CC(C)Oc1ccc(Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(OC(C)C)cc2)cc1
Reaction time: 0.4 h
Yield: 69 %

Procedure:
To a mixture of 1.23 g of 4-(4-isopropoxyphenoxy)phenol, 1.4 g of potassium carbonate and 10 ml of N,N-dimethylformamide, 0.65 ml of allyl bromide was added dropwise at room temperature with stirring. After 24 minutes, the reaction solution was poured into water, and acidified by adding 10% hydrochloric acid. The solution was extracted with 50 ml of diethyl ether, washed in turn with 10% hydrochloric acid, an aqueous 10% sodium hydroxide and a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.98 g of 4-(4-isopropoxyphenoxy)phenyl allyl ether (yield, 69%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:25]#[N:26]>C1(C)C=CC=CC=1>[CH2:3]1[O:4][C:5]2([CH2:10][CH2:9][N:8]([C:22]3[CH:23]=[C:24]([C:25]#[N:26])[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:7][CH2:6]2)[O:1][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc(C#N)cc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C#N)cc1N1CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.47 g, 10.28 mmol), sodium bis(trimethylsilyl)amide (1 N in THF, 12 ml), and PdCl2(p(o-tolyl)3)2 [2 mol % catalyst prepared from bis(acetonitrile) Pd(II) chloride(53 mg, 0.206 mmol) and tri(o-tolyl)phosphine (125 mg, 0.52 mmol)] were added to a solution of 3-bromo-4-methoxybenzonitrile (1.82 g, 8.58 mmol) in toluene (40 ml). The reaction was stirred for 5 hours at 100° C. The reaction was concentrated in vacuo, diluted with water, and extracted with methylene chloride. The organic extract was concentrated in vacuo, and the residue purified by chromatography on silica gel using hexane/ethyl acetate (80/20) as the eluent to give 1-(5-cyano-2-methoxyphenyl)-4-piperidone ethylene ketal (900 mg, 38%). This ketal was dissolved in dioxane (15 ml) and HCl (6 N, 2.2 ml) and stirred at 100° C. for 2 h. The solution was cooled, quenched with saturated aqueous NaHCO3. The mixture was extracted with methylene chloride, concentrated in vacuo, and purified by chromatography on silica gel using hexane/ethyl acetate (80/20) as the eluent to give 1-(5-cyano-2-methoxyphenyl)-4-piperidone (125 mg, 19%).