Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:19]4[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=4)[S:18][C:11]=23)[CH:6]=[CH:5][C:4]=1[NH2:25].S1C=CN=C1C1SC2C(=NC=CC=2OC2C=CC(N[C:48]([NH:50][C:51](=[O:59])[CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[S:49])=CC=2F)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:19]4[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=4)[S:18][C:11]=23)[CH:6]=[CH:5][C:4]=1[NH:25][C:48]([NH:50][C:51](=[O:59])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[S:49]
Reactant: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1N
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1NC(=S)NC(=O)Cc1ccccc1
Yield: 48 %

Procedure:
Starting from compound 216 and following the procedure described above for the synthesis of compound 13a (scheme 2, step 5, example 12), title compound 217 was obtained in 48% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (1H, s), 11.59 (1H, s), 8.45 (1H, d, J=5.48 Hz), 7.91 (1H, d, J=8.80 Hz), 7.85 (1H, s), 7.41 (1H, s), 7.24-6.98 (8H, m), 6.66 (1H, d, J=5.67 Hz), 3.99 (3H, s), 3.78 (3H, s), 3.59 (2H, s). MS (m/z) 530.2 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]([F:23])=[C:21]3[C:17]([C:18]([NH2:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:22]([F:23])=[C:21]3[C:17]([C:18]([NH2:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A suspension of 3 g of tert-butyl[4-(3-amino-7-fluoro-1H-indazol-6-yl)phenyl]carbamate in 60 mL of dichloromethane is admixed at ambient temperature with 6 mL of trifluoroacetic acid. The reaction mixture is stirred at ambient temperature for 18 h and concentrated to dryness under reduced pressure. The solid obtained is taken up in ethyl acetate and the solution is treated with 4N aqueous sodium hydroxide solution and then decanted. The organic phase is subsequently washed with distilled water, then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The yellow solid obtained (2.08 g) is chromatographed on a silica column (eluent: ethyl acetate). Evaporation to dryness under reduced pressure of the fractions containing the expected product gives 1.88 g of 6-(4-aminophenyl)-7-fluoro-1H-indazol-3-ylamine in the form of a yellow solid, whose characteristics are as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1[CH2:16][O:17][C:18](=[O:27])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1[CH2:16][O:17][C:18](=[O:27])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CCC/C=C\CN1C(=O)CC[C@@H]1COC(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CC[C@@H]1COC(=O)NCc1ccccc1
Reaction time: 3.5 h
Yield: 84.5 %

Procedure:
Palladium on carbon (10 mol %, 7 mg) was added to a solution of alkene 21 (39 mg, 0.10 mmol) in MeOH (2.5 mL). The flask was evacuated and refilled with hydrogen (3×), and the reaction mixture was stirred vigorously under a balloon of hydrogen for 3.5 h. The mixture was then filtered through celite, washing with MeOH (5 mL) and the filtrate was concentrated in vacuo to afford 33 mg (85%) of the title compound (23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:18]([C:19]=2[CH2:20][CH:21]=1)[CH2:17][CH2:16][C@@:13]1([CH2:14][CH3:15])[C@H:9]3[CH:10]=[CH:11][C@@H:12]1[OH:22].C(O)(C)(C)C>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:18]([C:19]=2[CH2:20][CH:21]=1)[CH2:17][CH2:16][C@@:13]1([CH2:14][CH3:15])[C@H:9]3[CH:10]=[CH:11][C:12]1=[O:22]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1C=C[C@@H]2O)CC(OC)=CC4
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1C=CC2=O)CC(OC)=CC4

Procedure:
4.7 g of 3-methoxy-18-methyl-2,5(10),15-estratrien-17β-ol is refluxed for 18 hours in 250 ml of chloroform and 35 ml of t-butanol with 10 g of manganese dioxide. The product is suctioned off over Celite, rewashed with chloroform and concentrated under reduced pressure. After chromatographic purification on silica gel with hexane/ethyl acetate, 4.1 g of pure 3-methoxy-18-methyl-2,5(10),15-estratrien-17-one with a melting point of 89°-91° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11]Cl.[H-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COCCl
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cccnc1Br
Temperature: -20 °C

Procedure:
50 g of 2-bromo-3-hydroxypyridine was suspended in 200 ml of tetrahydrofuran, to which 33 ml of chloromethyl methyl ether was added. The mixture was cooled to −20° C. and 17 g of 60% oily sodium hydride was portionwise added while stirring. After the addition of sodium hydride, the refrigerant was removed and the mixture was stirred at room temperature for 3.5 hours. In an ice bath, ice water was portionwise added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (10–15% ethyl acetate/hexane), to give 35 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:23][C:24]1[N:25]=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.C(N(CC)CC)C.ClCCl>C(O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:25]2[C:24](=[O:23])[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[CH:26]2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cc2ccccc2cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-n2cc3ccccc3cc2=O)cc1)C(=O)O
Reaction time: 48 h

Procedure:
The mixture of 98 mg of (2S)-2-[(t-butoxycarbonyl)amino]-3-[4-(dihydroxyboranyl)phenyl]propionic acid, 46 mg of 3-hydroxyisoquinoline, 43 mg of copper acetate (II), 175 μl of triethylamine and 10 ml of dichloromethane was stirred for two days and diluted with ethanol. After Celite filtration, the filtering solvent was concentrated and the obtained residue was diluted with ethyl acetate. After extraction by an aqueous solution of 1N sodium hydroxide, the water phase was acidified by hydrochloric acid. The organic phase was extracted with ethyl acetate. The residue was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate to remove the solvent. The obtained residue was split by HPLC to obtain the objective compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[C:12]2=[O:31])[CH2:9][CH2:8][C@@H:7]([NH:32]C(=O)OC(C)(C)C)[CH2:6]1)(=[O:3])[CH3:2].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[NH2:32][C@H:7]1[CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[C:12]2=[O:31])[CH2:9][CH2:8]1.[C:42]([OH:44])([C:41]([F:46])([F:45])[F:40])=[O:43]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirring solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexylcarbamate (1.65 g, 3 mmol) in dichloromethane (8 mL) was charged with trifluoroacetic acid (4 mL). The reaction was stirred for 1 h at room temperature and concentrated in vacuo. The residue was dissolved in a mixture of 1 mL of methanol and 5 mL of dichloromethane. The resulting solution was added dropwise to 80 mL of t-butylmethylether with stirring. The solid formed was collected with filtration and dried to give the title compound as its TFA salt (1.75 g, 86%). LC/MS found [M+H]+=451. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.82 (1H, s), 8.77 (1H, s), 8.20-8.27 (1H, m), 7.95 (1H, d, J=8.65 Hz), 5.32 (1H, t, J=9.92 Hz), 4.36 (1H, t, J=4.07 Hz), 4.16-4.23 (1H, m), 3.87 (1H, t, J=9.16 Hz), 3.70-3.79 (1H, m), 3.39 (1H, s), 2.54-2.67 (1H, m), 2.32-2.45 (1H, m), 2.08-2.23 (2H, m), 1.88-2.04 (6H, m), 1.73-1.87 (1H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]([C:18]2[C:19]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=3[CH:37]=2)[CH:13]=[CH:14][C:15]=1[O:16]C.B(Br)(Br)Br.O>ClCCl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[O:25][C:21]3[CH:20]=[C:19]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:40])=[O:41])[C:18]([C:12]4[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([C:2]5[NH:1][C:9]6[C:4]([CH:3]=5)=[CH:5][CH:6]=[CH:7][CH:8]=6)[CH:11]=4)=[CH:37][C:22]=3[C:23]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:27][CH:28]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(-c4cc5ccccc5[nH]4)c3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5ccccc5[nH]4)c3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.1 %

Procedure:
To a solution of 5-(3-(1H-indol-2-yl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 g, 0.16 mmol) in dichloromethane (2 mL) was added dropwise BBr3 (0.2 mL) at 0° C., Then warmed up to room temperature and stirred for 5 hours. Water was added, extracted with dichloromethane and washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using Prep-TLC to provide the product of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(1H-indol-2-yl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 31%). 1H-NMR (CDCl3, 400 MHz) δ 9.30 (s, 1H), 8.75 (s, 1H), 7.79˜8.30 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.37 (d, J=1.6 Hz, 1H), 6.91˜7.19 (m, 7H), 6.65 (d, J=1.2 Hz, 1H), 6.01 (d, J=4.4 Hz, 1H), 2.95 (d, J=4.8 Hz, 3H), 2.61 (s, 3H), 2.43 (s, 3H). MS (M+H)+: 584.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[C:4]([CH3:20])[CH:3]=1.[C:21](=[N:34][NH2:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:21](=[N:34][NH:35][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[C:4]([CH3:20])[CH:3]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)NCCN1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(NN=C(c2ccccc2)c2ccccc2)ccc1S(=O)(=O)NCCN1CCOCC1
Temperature: 85 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
To a degassed solution of 4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene-sulfonamide (939 mg, 2.58 mmol), benzophenone hydrazone (558 mg, 2.84 mmol, 1.1 eq), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (75 mg, 0.13 mmol, 0.05 eq) in anhydrous toluene (13 mL, 0.2M) was added sodium tert-butoxide (596 mg, 6.20 mmol, 2.4 eq) followed by palladium(II) acetate (29 mg, 0.13 mmol, 0.05 eq), and the reaction mixture was stirred at 85° C. under nitrogen for 17 h. The reaction mixture was cooled to room temperature and was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. Purification by MPLC (75% EtOAc/hexane) afforded the title compound (1.00 g, 80%) as a white solid. 1H-NMR (DMSO-d6) δ 9.25 (s, 1H), 7.64 to 7.52 (m, 4H), 7.44 to 7.41 (m, 2H), 7.35 to 7.26 (m, 5H), 7.16 to 7.13 (m, 3H), 3.45 (t, J=4.8 Hz, 4H), 2.79 (q, J=6.3 Hz, 2H), 2.47 (s, 3H), 2.21 to 2.15 (m, 6H); MS LC-MS [M+H]+=479, RT=3.15 min.
Reaction SMILES: [ClH:1].[Cl-].[NH2:3][C:4]1[C:9]([CH2:10][N+:11]2[CH:12]=[C:13]3[S:20][CH:19]=[CH:18][C:14]3=[CH:15][C:16]=2C)=[CH:8][N:7]=[C:6]([CH2:21][CH3:22])[N:5]=1.Cl.[Cl-].N[C:26]1C(C[N+]2C=C3SC=CC3=CC=2)=CN=C(C)N=1.Br.NC1C(CBr)=CN=C(CC)N=1.CC1C=C2C=CSC2=CN=1.Br.NC1C(CBr)=CN=C(C)N=1.S1C2=CN=CC=C2C=C1>>[ClH:1].[Cl-:1].[NH2:3][C:4]1[C:9]([CH2:10][N+:11]2[C:12]([CH3:26])=[C:13]3[S:20][CH:19]=[CH:18][C:14]3=[CH:15][CH:16]=2)=[CH:8][N:7]=[C:6]([CH2:21][CH3:22])[N:5]=1
Reactant: Cc1ncc(C[n+]2ccc3ccsc3c2)c(N)n1
Reactant: CCc1ncc(C[n+]2cc3sccc3cc2C)c(N)n1
Agent: Br
Agent: CCc1ncc(CBr)c(N)n1
Agent: Cc1cc2ccsc2cn1
Product: CCc1ncc(C[n+]2ccc3ccsc3c2C)c(N)n1

Procedure:
The compounds, 6-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-5-methylthieno[2,3-c]pyridinium chloride hydrochloride and 6-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-thieno[2,3-c]pyridinium chloride hydrochloride can be prepared following the above reaction, using the reactants 4-amino-2-ethyl-5-pyrimidinyl-methyl bromide hydrobromide with 5-methylthieno[2,3-c]pyridine or 4-amino-2-methyl-5-pyrimidinyl-methyl bromide hydrobromide with thieno[2,3-c]-pyridine, respectively.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.CS(O)(=O)=O.B(OC)(OC)OC>ClCCl>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 9 h

Procedure:
To 10 ml of dichloromethane were added 1.41 g of 7-ACA, 5.1 ml of methanesulfonic acid and 1.07 ml of trimethyl borate. The reaction was conducted at 0° C. for 9 hours. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.70 g. The yield of the desired product was 55%.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:26])[C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4].[CH3:35][N:36](C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:26])[C:14]([C:35]#[N:36])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CC1c2ccc(OS(=O)(=O)C(F)(F)F)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCCOC(=O)CC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-5-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 17; 837 mg, 1.64 mmol) in N,N-dimethylformamide (6 ml) was degassed under vacuum for 15 min. Tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.164 mmol) and zinc cyanide (251 mg, 2.13 mmol) were then added and the resulting orange mixture stirred at 100° C. for 4 h. The mixture was cooled to room temperature and insoluble material filtered off and washed with ethyl acetate. The mother liquors were concentrated in vacuo and the residue dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate and the aqueous phase further extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound (600 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][NH:13][CH2:12]2)[O:8][N:7]=1.C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=3)[CH2:14][N:13]([C:36]([O:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:37])[CH2:12]2)[O:8][N:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCOc1noc(C2CNCC(c3ccc(CC(F)(F)F)cc3)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 32 mg (0.08 mmol) of the compound from Example 66A in dichloromethane (1.0 ml) was admixed with 0.04 ml (29 mg, 0.29 mmol) of triethylamine and then, at 0° C., 17 mg (0.08 mmol) of 4-nitrophenyl chloroformate were added. The mixture was stirred at 0° C. for 2 h, then warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 50.5 mg (79% of theory, purity 70%)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[Cl:14].[N-:16]=[N+:17]=[N-:18].[Na+].O>CS(C)=O>[N:16]([CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[Cl:14])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1nc(Cl)c2ncn(CCCCl)c2n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCn1cnc2c(Cl)nc(N)nc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
N9-(3-Chloropropyl)-2-amino-6-chlorpurine (21, 2.56 g, 10.40 mmol) and sodium azide (811 mg, 12.48 mmol) are dissolved in 25 mL DMSO and stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture is poured into 150 mL of water and extracted with CH2Cl2. The combined organic phases are washed with water, dried over MgSO4 and evaporated in vacuo. The residue is purified by flash column chromatography (dichloromethane/methanol 50:1 to 10:1) to yield the title compound as a colorless solid (650 mg, 2.57 mmol, 24%). 1H-NMR (400 MHz, DMSO-d6): δ=8.12 (s, 1H, H-8), 6.89 (s, 2H, NH2), 4.10 (t, J=6.8, 2H, CH2), 3.38 (t, J=6.8, 2H, CH2), 2.05 (m, 2H, CH2) ppm. MS (ESI) m/z 253.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O.[BH4-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(CO)cc1[N+](=O)[O-]
Yield: 86.8 %

Procedure:
A solution of 4-methyl-3-nitrobenzoylchloride (5.5 g) in dioxane (30 mL) was added dropwise to a solution of water (30 mL), dioxane (30 mL) and sodium borohydride (2.5 g) under ice cooling. The reaction solution was refluxed for one hour, and after cooling, the solution was filtered through Celite. Water was added to the filtrate, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of (4-methyl-3-nitrophenyl)methanol (4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2].Br[CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([O:17][CH2:19][CH2:20][CH2:21][Cl:22])[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(=O)c2ccc(OCCCCl)cc2o1
Yield: 72.4 %

Procedure:
A mixture of 23.4 g (0.1 mole) of 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. The mixture was cooled and filtered through Celite®. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and recrystallized from 2-propanol to yield 22.5 g (73%) of white solid, m.p. 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: Ic1ccccc1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccccc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and iodobenzene.