Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:50])[CH:30]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]([S:35]CC3C=CC(OC)=CC=3)[NH:32]2)=[CH:27][C:26]=1[F:51]>>[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:50])[C:30]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:31]([SH:35])[NH:32]2)=[CH:27][C:26]=1[F:51]
Reactant: CCOC(=O)C1C(=O)c2cc(F)c(Cl)cc2NC1SCc1ccc(OC)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(S)[nH]c2cc(Cl)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
To 1.7 ml (0.01896mol) of trifluoromethane sulfonic acid were added 2.06 mol (0.0189 mol) of anisole and 8.8 ml (0.11378 mol) of trifluoroacetic acid and the mixture was cooled at 0° C. in an ice-sodium chloride bath. With stirring, 2.0 grams (0.0047 mol) of ethyl 7-chloro-6-fluoro-2-(4-methoxybenzylthio)-4-oxo-dihydroquinoline-3-carboxylate was added thereto and the mixture was stirred for about twenty minutes. Then trifluoroacetic acid and anisole were evaporated therefrom under reduced pressure and 15 grams of ice water was added to the residue. Yellow crystals appeared immediately. The crystals were collected by filtration, washed with water, dried, and recrystallized from dimethyl formamide and ether to give ethyl 7-chloro-6-fluoro-2-mercapto-4-oxo-1,4-dihydroquinoline-3-carboxylate. Yellow crystals. Yield 1.4 grams (98 percent). Melting point 221° to 223° C. (decomposition). Elementary analysis calculated as C12H19ClFNO3S: C 47.-7, H 3.01, N 4.64; Found: C 47.81, H 3.25, N 4.81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:13](=[O:15])[C:12]3[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][S:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(SCc2cccc([N+](=O)[O-])c2C(=O)O)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2c(c1)SCc1cccc([N+](=O)[O-])c1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
In methylene chloride (30 ml) was suspended 2-(3-methoxyphenylthiomethyl)-6-nitrobenzoic acid obtained in Reference Example 17 (0.92 g, 2.88 mmol), and trifluoroacetic anhydride (0.81 ml, 5.76 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was ice-cooled, and boron trifluoride etherate (0.13 ml, 1.06 mmol) was added thereto, followed by reaction for one hour. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give 3-methoxy-10-nitro-6,11-dihydrodibenzo[b,e]thiepin-11-one (0.40 g, 46%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.3 %

Procedure:
To a solution of N-(t-butyloxycarbonyl)-3-nitrobenzylamine (13.8 g, 54.7 mmol) in dimethylformamide (200 mL) was added tin(II) chloride dihydrate (74.1 g, 328 mmol) and the reaction was stirred at room temperature for 48 hours. The dimethylformamide was removed under vacuum. The residue was resuspended in dichloromethane (300 ml), washed with brine (200 mL), filtered through a celite pad, and the solvent removed to provide 12.2 g of the title compound. (100%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19])[CH:6]=1)[CH3:3].[CH3:23][NH2:24]>C(O)C>[N+:18]([CH:17]=[C:16]([NH:24][CH3:23])[NH:15][CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1)([O-:20])=[O:19]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1cc(CN(C)C)ccn1
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1cc(CN(C)C)ccn1
Reaction time: 36 h

Procedure:
A solution of 1-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-1-methylthio-2-nitroethylene (0.85 g) in 16% methylamine in ethanol (40 ml) was allowed to stand at ambient temperature for 36 hours. The solvent was removed in vacuo and the product was purified by chromatography on a silica gel column eluted with 15% methanol/chloroform followed by recrystallisation from acetonitrile to give 1-nitro-2-methylamino-2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]ethylene (0.32 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][O:21][CH3:22].C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:19][CH2:20][O:21][CH3:22])[CH:6]=[O:7]
Reactant: COCCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 3-methoxy-4-hydroxybenzaldehyde (8.0 g) in DMF (60 mL) was added K2CO3 (8.0 g) and 1-chloro-2-methoxyethane (5.1 g). The resulting mixture was stirred at 80° C. overnight. After reaction finished, ethyl acetate (200 mL) was added, and washed with 2 N aqueous HCl solution, brine, dried over Na2SO4, filtered, concentrated. The residue was washed with petrol ether to give 3-methoxy-4-(2-methoxyethoxy)benzaldehyde (10 g) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 9.86 (s, 1H); 7.45-7.41 (m, 2H); 7.01 (d, J=8.0, 1H); 4.27-4.25 (m, 2H); 3.93 (s, 3H); 3.85-3.82 (m, 2H); 3.46 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1cc(I)c(NCC(F)(F)F)cn1
Product: Cc1cc(-c2ccccc2Cl)c(NCC(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-6-methyl-N-(2,2,2-trifluoroethyl)pyridin-3-amine and 2-chlorophenylboronic acid after a reaction time of 15.5 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (71%). MS (ESI): m/z=301.07 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:8]=1)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]N)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:25][CH:24]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(O)c2)ccc1=O
Product: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1ccc(F)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-hydroxyphenyl)-1H-pyridazin-4-one (A-17) and 4-fluoro-phenylhydrazine according to the method described for example 43. MS: M=349.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=O.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:4](=[O:6])[C:3]([O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[CH:18][CH:17]=1)#[N:14]
Reactant: COC(C)(C(=O)O)c1ccccc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C)(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(RS)-2-Methoxy-2-phenyl-propionic acid was reacted with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-phenyl-propionamide. Off-white, waxy solid. MS 295.0 ([M+H]+)
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:15]2[N:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)[N:17]([CH3:18])[C:16]=2[C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:25][CH2:26]2)=[O:20])=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCc1cccc(-c2nc(-c3ccc(F)cc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 0.275 g (0.50 mmol) of [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) and 0.140 g (1.0 mmol) of 4-fluorophenyl boronic acid in 10 ml of DMF was added drop by drop 2.50 ml of tribasic potassium phosphate (2 M in water), followed by 0.029 g (0.025 mmol) of tetrakis-(triphenylphosphine)-palladium. This reaction mixture was stirred at 80° C. for two hours and subsequently cooled down to RT, then poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.20 g (76%) of the title compound as light yellow oil. MS: 517.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CCO.CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(N)cc3)CC2)CC1

Procedure:
A suspension of the product of Example 12.29, Step 1 above (640 mg; 1.643 mmol) in an EtOH/EtOAc mixture (15 mL; 1:2 vol. ratio) was hydrogenated (35 psi) in the presence 10% Pd/C catalyst (150 mg) for 1 hr. The mixture was filtered through Celite and evaporated to afford the title compound as a gray solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[CH:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:28]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[N+:29]=[N-:30]>O1CCCC1.[Cu]I>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[N:30]=[N:29][N:28]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:17]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCCc1ccc(F)cc1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.8 %

Procedure:
To a solution of N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide (0.10 g, 0.39 mmol) in tetrahydrofuran (5 mL) was added copper(I) iodide (0.002 g, 0.008 mmol), N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) and 1-(2-azidoethyl)-4-fluorobenzene (0.077 g, 0.47 mmol). The reaction mixture was stirred at ambient temperature for 17 hours then concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:1) to afford the title compound as a white solid (0.090 g, 55%): mp 181-182° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.38-7.24 (m, 5H), 7.09-6.99 (m, 2H), 6.95-6.85 (m, 2H), 6.23 (t, J=5.6 Hz, 1H), 4.61-4.56 (m, 4H), 3.20 (t, J=7.1 Hz, 2H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 161.6, 157.9, 156.7, 142.5, 137.8, 132.2, 130.1, 128.8, 127.8, 127.7, 124.8, 121.8, 115.9, 52.0, 44.2, 35.7, 17.3; MS (ES+) m/z 422.3 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)[N:6]=[C:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:4]=1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)(C)[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[C:16]([C:5]1[CH:4]=[C:3]([NH2:2])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][SiH:29]([C:26]([CH3:28])([CH3:27])[CH3:25])[CH3:30])[CH:9]=2)[N:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CO)c2)n1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[SiH](OCc1cccc(-n2nc(C(C)(C)C)cc2N)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of [3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl]methanol hydrochloride salt (2.0 g, 7.1 mmol) in DMF (20 mL) was added imidazole (2.7 g, 39 mmol) and TBSCl (2.1 g, 14 mmol), which was stirred at RT for 8 h. The reaction mixture was quenched with water and extracted with EtOAc (3×). Organic extracts were washed with NaHCO3, H2O and 10% LiCl solution. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to yield 3-t-butyl-1-(3-[(t-butylmethylsilyloxy)methyl]phenyl}-1H-pyrazol-5-amine in 36% yield (for three steps): 1H-NMR (CDCl3): δ 7.3-7.6 (m, 4H), 5.54 (s, 1H), 4.80 (s, 2H), 1.34 (s, 9H), 0.97 (s, 9H), 0.13 (s, 6H); MS (EI) m/z: 360 (M+H+).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:7][C@@H:6]([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:5]1)=[N+:2]=[N-:3]>C(O)(=O)C>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Yield: 68.8 %

Procedure:
A mixture of 3'-azido-5'-O-trityl-2',3'-dideoxyuridine (63 g, 0.132 mol) and 300 ml of acetic acid (80%) was heated at 95°-100° C. for two hours. The reaction mixture was cooled in an ice-bath and the solid separated was filtered off. The filtrate was evaporated to dryness. The residue was dissolved in a methanol-chloroform mixture and concentrated to a syrup. The residue was purified by flash vacuum chromatography over a silica gel column eluting sequentially with chloroform-methanol (70:1), chloroform-methanol (50:1) and finally chloroform-methanol (30:1), to yield 23 g (70%) of 3'-azido-2',3'-dideoxyuridine.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(ON=O)CC(C)C.[I:20]CI>>[I:20][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: ICI
Reactant: Nc1cccc2ncccc12
Agent: CC(C)CCON=O
Product: Ic1cccc2ncccc12
Temperature: 80 °C

Procedure:
A suspension of 10 g (0.07 mol) of 5- aminoquinoline, 94 ml (0.7 mol) of isoamylnitrite and 100 ml of diiodomethane was heated at 80° C. for 2 hours. The reaction mixture was evaporated under reduced pressure at 60°-70° C. The residue was slurried with diethyl ether, decanted and the filtrate was evaporated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluting with 3:1 hexane-ethyl acetate to yield 2.81 g of 5-iodoquinoline. 1H-NMR (CDC13, 300MHz) δ 7.42(d, 1H, J=7.7 Hz); 7.48 (dd, 1H, J=4.3 Hz); 8.1 (m, 2H,); 8.38 (d, 1H, J=8.5 Hz); 8.88 (m, 1H,). Mass spec. m/e=255=p. ##STR27## 2.18 g (0.022 mol) of triethylamine were added to a suspension of 2.75 g (0.011 mol) of 5-iodoquinoline in acetonitrile (24 ml) and the solution formed on warming. The solution was allowed to cool briefly. To the solution were added 50 mg of triphenylphosphine, 50 mg of palladium(II) acetate and 3.1 ml (0.022 mol) of 3,3- zdiethoxy-1-propyne (propiolaldehyde diethylacetal). The reaction was heated at 80° C. for 1.5 hours. The reaction was poured into water and extracted with hexane. The hexane was removed under reduced pressure and the residue was chromatographed on a silica gel column and eluted with 1% methanol-dichloromethane to yield 1.44 g of 5-quinoline-[l- propiolaldehyde diethyl acetal]. 1H-NMR (CDC13, 300MHz) 6 1.3 (t, 6H, J=7.2 Hz); 3.73 (m, 2H,); 3.88 (m, 2H); 5.62 (s, 1H,); 7.48 (dd, IH, J=8.5 and 4.2 Hz); 7.66 (d, 1H, J=7.4 Hz); 7.76 (d, 1H, J=7.2Hz); 8.1 (d, 1H, J=8.5Hz); 8.6 (d, 1H, J=8.5Hz); 8.94 (m, 1H). Mass spec. m/e=255=p. ##STR28##
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[CH:10]=[O:25]
Reactant: C=C(C#N)C1CC(C)(C)CC1C
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C=O)C1CC(C)(C)CC1C
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)acrylonitrile 5 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and is then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].C([Li])CCC.CCCCCC.Cl[CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>O1CCCC1.CCOCC>[CH3:1][N:2]([CH3:9])[C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1
Reactant: CC(=O)CC(=O)N(C)C
Reactant: ClCc1ccsc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(=O)CCc1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
N,N-Dimethyl acetoacetamide (46.8 g; 0.363 mole) was converted to its dianion by treatment with 80% sodium hydride (11.8 g; 0.393 mole) in dry tetrahydrofuran (350 ml) under nitrogen, at 20° C. The resulting suspension was diluted with dry ether (1 L) and stirred mechanically for 15 minutes at 0° C. before a solution of n-butyl lithium in hexane (227 ml; 1.6 M; 0.363 mole) was added dropwise. To the now clear mixture was then added 3-chloromethyl thiophene (38 g; 0.287 mole) in dry tetrahydrofuran (50 ml), again dropwise, and the reaction allowed to warm up to room temperature. After the solution had stood at room temperature overnight the solvents were removed on a rotary evaporator and the residue acidified with dilute HCl in the presence of ethyl acetate (200 ml). The organic layer was separated off and the aqueous layer extracted once again with ethyl acetate (200 ml). The combined organic layers were dried (anhydrous MgSO4), and evaporated to give an oil which was purified on a short silica gel column using chloroform as eluant affording the product as a red-brown oil (48.5 g; 75%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1
Reactant: BrBr
Reactant: OCc1coc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1coc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a stirring solution of 912 mg (3.48 mmol, 1.2 equiv) of triphenylphosphine in 5 mL of CCl4 at 0° C. is added 165 μL (3.19 mmol, 1.1 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 430 mg (2.90 mmol) of 3-hydroxymethylbenzofuran, prepared as in Intermediate 19, in 5 mL of CCl4 is added over 2 min. The resulting solution is stirred 1.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 20/1 as eluent afforded 500 mg of the title compound as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ7.71 (m, 2H), 7.50 (m, 1H), 7.37 (m, 2H), 4.62 (s, 2H); Rf =0.67 in hexane/EtOAc 5/1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[C:20]([CH3:23])[C:19]([F:24])=[C:18]([NH2:25])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:26])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[C:20]([CH3:23])[C:19]([F:24])=[C:18]([NH2:25])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:26])[CH2:30][CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.6 %

Procedure:
506 mg (1.40 mmol) of the above 2-(4-acetylamino-3-fluorophenyl)-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide under argon atmosphere, 60 mg (1.5 mmol) of sodium hydride (60% oil dispersion) and 0.28 mL (2.8 mmol) of 1-iodopropane were added thereto under ice-cooling and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 315 mg of 2-[4-[N-acetyl-N-(1-propyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (yield: 56%).