Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([C@@H:16]([CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([O:8][C:9](=[O:41])[N:10]([C@@H:16]([CH2:36][CH2:37][CH2:38][CH:39]=[O:40])[CH2:17][O:18][Si:19]([C:32]([CH3:33])([CH3:34])[CH3:35])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCCC=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of the material from Step 6 (3.27 g, 5.68 mmol) in dichloromethane (57 mL) were added 4-methylmorpholine N-oxide (0.8 g, 6.81 mmol), and activated 4 Å molecular sieves. After stirring at room temperature for 10 minutes, TPAP (0.1 g, 0.28 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 3 hours, and then filtered through a silica gel plug. The filtrate was concentrated in vacuo to afford the title compound which was used directly at Step 8.
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)C)CC1>>[ClH:43].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:54])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cc(Cl)ccc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117, see example 72) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([Cl:24])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[C:7]([Cl:24])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(Cl)c1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
To a solution of 71 (1.75 g; 4.5 mmol) in tetrahydrofuran (25 mL) was added aqueous sodium hydroxide (20 mL; 6M) and then heated at 70° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and then acidified to pH 2 with concentrated hydrochloric acid. The organic solvent was removed under reduced pressure and the resulting aqueous solution was extracted with chloroform (3×20 mL). The organic extracts were combined and successively washed with water and aqueous saturated sodium chloride, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as an off-white solid (1.57 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].Br.Br.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: N#CCCCCl
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 80 %

Procedure:
A mixture of 11.5 parts of 4-chlorobutanenitrile, 48.5 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 30 parts of sodium carbonate and 270 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 2.2 parts (80%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinebutanenitrile; mp. 130.5° C. (intermediate 94).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]([C:15]=1[OH:16])=[CH:9][CH:10]=[CH:11][C:12](=[O:14])[N:13]=2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([C:15]=1[OH:16])=[CH:9][CH:10]=[CH:11][C:12](=[O:14])[N:13]=2
Reactant: O=c1cccc2c(O)c([N+](=O)[O-])ccc2n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc2nc(=O)cccc2c1O
Yield: 66.2 %

Procedure:
7 g of the resulting 7-nitro-6-hydroxybenzazepin-2-one was dispersed in 50 ml of water, and to the dispersion was slowly added 30 g of sodium hydrosulfite while heating on a steam bath. After refluxing, the reaction mixture was cooled and the precipitated crystals were collected by filtration and dried to obtain 4 g of 7-amino-6-hydroxybenzazepin-2-one.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=3)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CCc3ccc(Cl)cc3)Cc3ccc(C(=O)OC)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(CCc3ccc(Cl)cc3)Cc3ccc(C(=O)O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a solution of methyl 4-({{4-[(4-butylphenyl)ethynyl]benzyl}[2-(4-chlorophenyl)-ethyl]amino}methyl)benzoate (980 mg, 1.78 mmol) in MeOH (15 mL) was added an aqueous solution of NaOH (4.5 mL, 1N) and the resulting mixture was stirred at rt for 12 hrs. An aqueous solution of HCl (1N) was added and the resulting mixture was extracted with Et2O. The combined organic layers were dried over MgSO4 and evaporated to give 929 mg of 4-({{4-[(4-butylphenyl)ethynyl]benzyl}[2-(4-chlorophenyl)ethyl]amino}-methyl)benzoic acid as a colorless oil. This product was dissolved in Et2O (30 mL) and a solution of HCl in dioxane (2 mL, 4N) was added. The precipitate was filtered, washed with Et2O and dried under vacuum to give 985 mg (97%) of the title compound as a white powder. HPLC, Rt: 4.7 min (purity: 98.9%). M−(ESI): 534.3; M+(ESI): 536,2. 1H NMR (DMSO-d6) δ: 13.4 (brs, 1M), 11.3 (brs, 1H), 8.35-7.28 (m, 16H), 4.82-4.45 (m, 2H), 3.96-4.58 (m, 6H), 2.81 (t, J=7.9 Hz, 2H), 1.84-1.68 (m, 2H), 1.60-1.41 (m, 2H), 1.10 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]([Cl:11])[C:5]([CH3:10])([CH3:9])[C:6](=[O:8])[CH3:7].[Br:13]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]([Cl:11])[C:5]([CH3:9])([CH3:10])[C:6](=[O:8])[CH2:7][Br:13]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)C(Cl)C=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)CBr)C(Cl)C=C(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.475 g (0.05 mol) of 1,1,3-trichloro-4,4-dimethyl-1-hexen-5-one are dissolved in 150 ml of chloroform, and 8 g (0.05 mol) of bromine are added without cooling. The mixture is stirred for 3 hours at room temperature, and hydrogen bromide and solvent are distilled off in vacuo; the final residues are removed in a high vacuum. 15.5 g are obtained of crude 1,1,3-trichloro-6-bromo-4,4-dimethyl-1-hexen-5-one, the structure of which is confirmed by the 1H-NMR spectrum. It is used directly in the next stage:
Reaction SMILES: FC(F)(F)C(O)=O.IC[C:10]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:39])[C@H:24]([CH:36]([CH3:38])[CH3:37])[NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>ClCCl>[CH2:29]([O:28][C:26]([NH:25][C@H:24]([C:23]([O:22][CH2:21][CH2:20][O:19][C:17]1[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=1)=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOc1ccc(C(=O)O)c(CI)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxybenzyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate (10.2 g, 19.04 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred 3 hours at room temperature. The solution was evaporated under reduced pressure and co-evaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 6.9 g=87%. The product may be activated and esterified direct to a drug or converted to iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid as described above, that is by treatment with a base, chloroiodomethane, separation and then treatment with NaI.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Mg].II.[CH3:12][O:13][C:14](=[O:28])[C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[CH3:12][O:13][C:14](=[O:28])[C@H:15]([NH:16][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:18][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1)=[O:20]
Reactant: COC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cccc(Br)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCC(=O)c1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of 1-bromo-3-fluorobenzene (0.79 g, 4.5 mmol) and magnesium turnings (0.12 g, 5.0 mmol) in anhydrous THF (8 mL) was added a small piece of iodine. The mixture was heated at reflux for 2 hr and no magnesium turnings left. The solution was cooled to 0° C. and transferred into a stirred solution of N-Boc-D-pyroglutamic acid methyl ester (0.80 g, 3.3 mmol) in anhydrous THF (4 mL) at −40° C. under argon atmosphere. After stirring at −40° C. for 1 hr and then at 0° C. for 1 hr, the reaction was quenched with 8 mL of 1:1 HOAc/MeOH and the mixture diluted with Et2O (40 mL). The organic layers were washed with water and brine, dried (Na2SO4) and concentrated under vacuum. Purification by silica gel chromatography (10–20% EtOAc/hexanes) gave 0.57 g (51%) of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.82 (1H, d), 7.75 (1H, d), 7.56 (1H, q), 7.38 (1H, t), 5.30 (1H, br.d), 4.50 (1H, br.s), 3.87 (3H, s), 3.20 (2H, m), 2.45 (1H, m), 2.20 (1H, m), 1.54 (9H, s).
Reaction SMILES: [N+](C1C=C(N)C(=CC=1)C(O)=O)([O-])=O.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1.[CH3:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[CH3:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH:32][C:15]1[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Reactant: Cc1cccc(N)c1
Agent: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Product: Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials, 4-nitroanthranilic acid was converted into 4-chloro-7-nitroquinazoline. Using an analogous procedure to that described in Example 1 except that the reactants were stirred together at ambient temperature for 20 minutes, 4-chloro-7-nitroquinazoline was reacted with 3-methylaniline to give 4-(3'-methylanilino)-7-nitroquinazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7](CC1CCN(CC3C=CC=CC=3)CC1)[CH2:6]2.COC1C=C2C(=CC=1OC)C(=O)CC2.[N:43]1[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45][CH:44]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:49]([C:46]1[CH:45]=[CH:44][N:43]=[CH:48][CH:47]=1)[C:6]2=[CH2:7]
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Reactant: O=Cc1ccncc1
Agent: COc1cc2c(cc1OC)C(=O)CC2
Product: C=C1c2cc(OC)c(OC)cc2C(=O)C1c1ccncc1

Procedure:
In a preferred embodiment, the present invention relates to an improved and convenient process for the preparation of 2,3-dihydro-5,6-dimethoxy-2[[1-(phenyl methyl)-4-piperidinyl]methyl]-1H-inden-1-one (Donepezil) of the formula (I), which involves a reaction of 5,6-dimethoxy indanone of the formula (II) with pyridine-4-carboxaldehyde of the formula (III) in the presence of an organic solvent to afford 5,6 dimethoxy-2-(pyridin-4-yl)-methylene indan-1-one of the formula (IV). The compound of the formula (IV) is hydrogenated under palladium carbon catalyst in the presence of acetic acid in methanol to afford the acetate salt of the formula (V), which is in situ converted to the key intermediate 5,6-dimethoxy-2-piperidin-4-yl-methyl indan-1-one of the formula (VI). Further reaction of the formula (VI) with benzyl bromide in a solvent in the presence of base yields donepezil of the formula (I) in an overall yield of 83%. The relevant synthetic scheme may be schematically depicted as follows:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:26])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C)C=O.O>[CH:35]1([CH2:34][N:23]2[CH2:22][CH2:21][CH:20]([O:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[C:10](=[O:26])[CH2:11][CH2:12]4)[CH2:25][CH2:24]2)[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OC3CCN(CC4CC4)CC3)ccc2N1c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
A suspension of 1-(4-fluorophenyl)-6-(piperidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one hydrochloride prepared in Example 7-(3) (0.30 g), potassium carbonate (0.55 g) and (bromomethyl)cyclopropane (0.32 g) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1) and preparative TLC (on a single plate of 2 mm thickness, developing solvent: chloroform/methanol=9/1) to give the titled compound (0.11 g, 35%) as a colorless amorphous substance.
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Cl:37][C:38]1[N:47]=[CH:46][CH:45]=[CH:44][C:39]=1[C:40]([NH:42][CH3:43])=[O:41].Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>O.C(O)(C)C.CN1C(=O)CCC1>[ClH:37].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:47]=[CH:46][C:45]([Cl:1])=[CH:44][C:39]=4[C:40]([NH:42][CH3:43])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: CNC(=O)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1cc(Cl)cnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 100 °C
Yield: 4.7 %

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (70 mg, 0.29 mmol, Compound C of Example 1) and 2-chloro-N-methylnicotinamide (59 mg, 0.29 mmol) were suspended in 3:1 isopropanol-NMP (2.9 mL). 4N HCl in 1,4-dioxane (0.22 mL, 0.86 mmol) was added and the reaction was heated to 100° C. for 168 h. The reaction was diluted with 30 mL of H2O and then basified with sat. aq. NaHCO3 soln. (5 mL). The aqueous layer was extracted EtOAc (3×10 mL). The combined organic layers were washed with 10% LiCl (15 mL), dried (MgSO4) and concentrated. The crude product was purified by preparative (RP) HPLC chromatography (YMC S5 ODS, 30×75 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA, 40 mL/min). The fractions containing the desired product were combined and concentrated. The product residue was dissolved in MeOH (2 mL) and acidified with 4N HCl in 1,4-dioxane (0.10 mL). Concentration afford the desired product as a brown solid (3.3 mg, >99% HPLC purity). 1H NMR (CD3OD) δ 8.33 (d, 1H, J=2.54 Hz), 8.31 (d, 1H, J=7.12 Hz), 8.17 (dd, 1H, J=13.48, 2.29 Hz), 8.09 (d, 1H, J=2.03 Hz), 7.56 (d, 1H, J=3.56 Hz), 7.33-7.43 (m, 2H), 6.91 (d, 1H, J=6.61 Hz), 6.68 (d, 1H, J=3.56 Hz), 2.93 (s, 3H); MS(ESI+) m/z 412.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31]C1C=CC=CC=1N=C=O.Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:31])[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1Cl

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2-chlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 223°-227° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH2:15]([O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>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].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]3[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=3[CH:12]=2)=[CH:21][CH:20]=1)[CH3:16]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCc1cc(N)cc2c1OCC2(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Yield: 76.9 %

Procedure:
Following general procedure E and using 5-amino-3,3-dimethyl-7-ethyl-2,3-dihydrobenzofuran (Compound 12, 0.22 g, 1.15 mmol), ethyl-4-iodo-benzoate (0.318 g, 115 mmol), cesium carbonate (0.525 g, 1.61 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol), (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.040 g, 0.064 mmol) in 5 mL of anhydrous toluene, the title compound (0.3 g, 77%) was obtained as a deep yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, 2H, J=8.8 Hz), 6.79 (m, 4H), 5.92 (br s, 1H), 4.32 (q, 2H, J=7.2 Hz), 4.25 (s, 2H), 2.59 (q, 2H, J=7.5 Hz), 1.36 (t, 3H, J=7.2 Hz), 1.33 (s, 6H), 1.21 (t, 3H, J=7.5 Hz).
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[OH-].[Na+]>C1COCC1.C(O)C.O>[C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@H:23]1[OH:36])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn([C@H]2C[C@@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
In a 50-ml one-necked flask with lateral stopcock, 5′-O-tritylthymidine and triethylamine are placed in THF at t=0° C. under inert gas and stirring. Mesyl chloride is added dropwise from a syringe. The initially colorless solution becomes faintly yellow and cloudy. The reaction solution is allowed to warm up to room temperature within 30 minutes under stirring. Instead of the spot corresponding to starting material (Rf=0.29), a spot corresponding to the mesylated compound (Rf=0.45) is evident in TLC (V(MeOH):V(CH2Cl2)=1:19). At this point, 5 ml each of water, ethanol and 1 M sodium hydroxide solution are added to the reaction solution, which is stirred for 1 hour under reflux. In the TLC control test (V(MeOH):(VCH2Cl2)=1:19), exclusively the spot corresponding to the anhydro compound (Rf=0.15) is visible. Thereafter 3.4 ml of 10 M sodium hydroxide solution is added and the mixture stirred for 30 minutes under reflux. Two phases can form during this step. Instead of a spot corresponding to the anhydro compound (Rf=0.15), the product spot (Rf=0.33) is now evident on the TLC plate (V(MeOH):V(CH2Cl2)=1:19). The reaction solution is mixed with about 6 g of silica gel 60, and the solvent mixture is distilled off in the rotary evaporator. Subsequent column chromatography under flash conditions (silica gel 60; Ø=2.9 cm; h=32 cm; V(MeOH):V(CH2Cl2)=1:19+0.1% of triethylamine; 8.5 ml/min) yields the product, 1-(5-O-trityl-2-deoxy-β-D-lyxofuranosyl)thymine.