Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>ClCCl>[CH3:16][C:14]1[N:15]=[C:6]2[C:5]3[NH:4][C@H:3]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@@H:2]([O:1][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:11](=[O:12])[C:10]=3[CH:9]=[CH:8][N:7]2[CH:13]=1
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)C3=O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](OC(=O)C(C)(C)C)C3=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a of 0° C. cooled solution of 10.5 g (35.8 mmol) (8R,9R)-8-hydroxy-2-methyl-9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridin-7-one in dichloromethane (110 ml) is added 5.70 ml (41.2 mmol) triethylamine, 0.22 g (1.80 mmol) dimethylaminopyridine and 5.10 ml (41.2 mmol) pivaloyl chloride dissolved in dichloromethane (10 ml). The reaction is stirred for 2 h at 0° C. and warmed up to 25° C. and stirred for further 24 h. Afterwards 5.70 ml (41.2 mmol) triethylamine, 0.22 g (1.80 mmol) dimethylaminopyridine and 5.10 ml (41.2 mmol) pivaloyl chloride are added to this mixture and it is stirred for 18 h at 25° C. Subsequently the reaction is quenching by adding of water (100 ml). The organic layer is separated, washed with ammonia solution, washed with water two times, dried over sodium sulphate and evaporated in vacuo. The crude product is crystallised from 2-propanol to provide 12.1 g (32.06 mmol/90%) of the title compound as a colourless solid with a melting point of 145–147° C. (2-propanol).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[N:27][CH:28]=1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][N:27]=3)[CH2:34][CH2:33]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCC(N)CC2)nc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)nc1
Temperature: 120 °C
Yield: 43.5 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (97 mg, 0.324 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 1-(5-Methylpyridin-2-yl)piperidin-4-amine dihydrochloride (86 mg, 0.327 mmol) was added followed by TEA (33 g, 0.324 mmol). The reaction mixture was heated in a microwave reactor for at 120° C. for 25 mins. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3-solution and water. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (64 mg, 43.5%). 1H NMR (500 MHz, CDCl3): δ 1.33-1.41 (m, 2H), 1.71-1.74 (m, 1H), 2.17 (s, 3H), 2.38-2.43 (m, 2H), 3.08-3.15 (m, 1H), 3.95-3.99 (m, 2H), 5.23 (d, 1H), 6.51 (d, 1H), 7.26 (dd, 1H), 7.43-7.45 (m, 3H), 7.53-7.55 (m, 2H), 7.96 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 17.51, 27.84, 32.05, 44.64, 50.68, 61.78, 107.10, 107.50, 122.63, 125.39, 128.91, 130.11, 131.90, 134.20, 138.65, 147.86, 157.77, 159.91; Mass Spectrum: M+H+ 455.0.
Reaction SMILES: C(OC(N[CH:12]1[NH:16][C@H:15]([CH3:17])[C:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[O:13]1)=O)C1C=CC=CC=1.[OH2:27].Cl>O1CCCC1>[CH2:14]([O:27][C:12]([NH:16][C@H:15]([CH3:17])[C:14]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=[O:18])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H]1NC(NC(=O)OCc2ccccc2)OC1(O)c1ccc(F)cc1F
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(F)cc1F
Yield: 92 %

Procedure:
In tetrahydrofuran (35 mL) was dissolved (4R)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (6.98 g) prepared in Example 16, and water (25 mL) and conc. hydrochloric acid (10 mL) were added. The mixture was processed as described in Example 13 to give the title compound (5.87 g) as pale yellow syrup in a yield of 92%.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOP(=O)(OCC)c1cccc(-c2cccc(C)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1cccc(-c2cccc(CBr)c2)c1
Temperature: 25 °C

Procedure:
To the compound of Step 2 (0.122 g, 0.400 mmol) in CCl4 (5 mL) were added NBS (0.050 g, 0.480 mle) and a catalytic amount of benzoyl peroxide. The reaction mixture was refluxed under light for 2 h. The reaction was cooled to room temperature, filtered and evaporated. The title compound was obtained after purification by flash chromatography. (0.150 g).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]1([C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[N:27]=[CH:28][N:29]([C:2]3[CH:11]=[C:10]4[C:5]([NH:6][C:7](=[O:16])[C:8]5[N:9]4[C:12](=[O:15])[NH:13][N:14]=5)=[CH:4][C:3]=3[N+:17]([O-:19])=[O:18])[CH:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Reactant: c1ccc(-c2c[nH]cn2)cc1
Product: O=c1[nH]c2cc([N+](=O)[O-])c(-n3cnc(-c4ccccc4)c3)cc2n2c(=O)[nH]nc12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and 4-phenylimidazole by a method analogous to the method described in example 11. M.p. 365° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:36]2([C:41]([F:44])([F:43])[F:42])[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:30][C:31]([O:33]CC)=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:36]2([C:41]([F:43])([F:44])[F:42])[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:30][C:31]([OH:33])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C(F)(F)F)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1(C(F)(F)F)CCCC1
Temperature: 25 °C

Procedure:
To a solution of racemic ethyl 3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-(trifluoromethyl)cyclopentyl)propanoate, 197a, (0.080 g, 0.120 mmol) in THF (10 mL) was added lithium hydroxide (2 mL of 2N solution). The reaction was refluxed for 3 hours and cooled to room temperature. The non aqueous solvent was removed under reduced pressure and the aqueous layer was adjusted to pH 4. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phases concentrated in vacuo to afford 16 mg of the desired product as a pale yellow solid: 1H NMR (300 MHz, d6-DMSO) δ 8.51 (s, H), 8.25-7.97 (m, 2 H), 7.58-7.42 (m, 2 H), 7.12 (d, J=7.5 Hz, H), 4.35 (m, H), 2.85 (m, 2 H) and 1.27-0.70 (m, 8 H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.55 minutes (M+H) 456.45.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:17]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>CCO>[C:1]1([C:7]2[C:8]([CH:17]([NH2:19])[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1nc2cccnc2cc1-c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CC(N)c1nc2cccnc2cc1-c1ccccc1
Yield: 115.3 %

Procedure:
2-(1-(3-Phenyl-1,5-naphthyridin-2-yl)ethyl)isoindoline-1,3-dione (120 mg, 0.32 mmol) was suspended in EtOH (2 mL) and treated with NH2NH2 (0.2 mL) at 70° C. for 30 min and worked up to give a colorless oil (92 mg, 96%). LC-MS (ESI) m/z 250 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Br:7][C:8]1[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[C:10](I)[CH:9]=1>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.[Cu]I.C(N(CC)CC)C>[Br:7][C:8]1[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[C:10]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=1
Reactant: Nc1cc(F)c(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (44 mL) followed by trimethylsilylacetylene (0.737 mL, 5.32 mmol) were added dropwise to a suspension of 4-bromo-5-fluoro-2-iodoaniline (1.4 g, 4.43 mmol), Pd(PPh3)2Cl2 (0.156 g, 0.222 mmol), and CuI (0.042 g, 0.222 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred for 2 h. The reaction was concentrated, diluted with Et2O, and filtered through Celite. The filtrate was washed with brine, dried (Na2SO4), filtered and concentrated. Chromatography over silica eluting with 2-8% EtOAc/hexanes afforded the desired product as a yellow oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][CH2:12][N:13]([CH2:20][C:21]([O:23]CC)=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][CH2:12][N:13]([CH2:20][C:21]([OH:23])=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2
Reactant: CCOC(=O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
0.5 ml of 1M sodium hydroxide solution were added to a solution of 113 mg (0.28 mmol) of ethyl (E)-2-[5-(3,4-dichlorostyryl)-2,3-dihydro-1,4-benzodiazepin-1-yl]acetate in 3 ml of ethanol and the mixture left at room temperature for 1.5 hours. The solvent was removed by evaporation and the residue dissolved in water and washed with diethyl ether. The aqueous layer was acidified with acetic acid and a red gum separated out. The gum was dissolved in a small amount of ethanol and diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness to give 88 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepine-1-acetic acid as a red solid. MS: m/e 374.9 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([OH:10])[C@H:6]([OH:11])[C@@H:5]([O:12][CH3:13])[O:4]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:9][C@H:8]1[C@H:7]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:6]([O:11][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:5]([O:12][CH3:13])[O:4][C@@H:3]1[CH2:2][O:1][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of (2R,3S,4S,5S,6S)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triol (15.0 g, 77.2 mmol, 1.0 equiv., commercially available Sigma Aldrich) in dry DMF (250 mL) was added sodium hydride (14.8 g, 309 mmol, 4.0 equiv) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 minutes and then benzylbromide (38 mL, 309 mmol, 4.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with MeOH (50 mL) at 0° C. and concentrated in vacuo. Ice cold water (80 mL) was added, the mixture was extracted with EtOAc (2×250 mL), and the combined organic layers were washed with saturated NaHCO3 solution (3×60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was purified by silica gel chromatography, eluting with 20% EtOAc in petroleum ether to afford (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran as a pale yellow oil (28 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.47-7.24 (m, 18H), 7.25-7.15 (m, 2H), 4.92 (d, J=10.8 Hz, 1H), 4.79 (dd, J=17.2, 2.2 Hz, 3H), 4.70 (d, J=12.1 Hz, 1H), 4.67-4.50 (m, 4H), 4.01 (t, J=9.1 Hz, 1H), 3.92 (dd, J=9.3, 3.1 Hz, 1H), 3.86-3.72 (m, 4H), 3.36 (s, 3H). ESI (M+H2O) 572.0, calc for C35H38O6 554.3.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH:37][CH2:38][CH2:39][OH:40])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:48].C1(OC)C=CC=CC=1>CCOC(C)=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH:37][CH2:38][CH2:39][OH:40])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:48]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCO

Procedure:
Boc-Tyr-DAla-Phe-Met-NHCH2CH2OH (2.0 g) was treated with HCl, anisole, EtOAc as in Step B to give H-Tyr-DAla-Phe-Met-NHCH2CH2OH.HCl which was chromatographed on Amberlite XAD-2 as in Step E to give 1.23 g (64%) of H-Tyr-DAla-Phe-Met-NHCH2CH2OH.HOAc, m.p. 200°-203° C., [α]D26 =10.21° (c, 1.01 in methanol).
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[C:7]([O:26][CH3:27])=[CH:8][C:9]([O:24][CH3:25])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:15]=[CH:14][CH:13]=2)[CH:11]=1)(=[O:5])=[O:4]>CO>[NH2:1][S:3]([C:6]1[C:7]([O:26][CH3:27])=[CH:8][C:9]([O:24][CH3:25])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:15]=[CH:14][CH:13]=2)[CH:11]=1)(=[O:5])=[O:4]
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1ccnn1-c1ccccc1Cl
Reactant: N
Solvent: CO
Product: COc1cc(OC)c(S(N)(=O)=O)cc1-c1ccnn1-c1ccccc1Cl
Reaction time: 8 h

Procedure:
8.2 20 ml of a 32% ammonia solution are added at room temperature to a solution of 413.3 mg of “B2” in 5 ml of dry methanol. The mixture is stirred overnight, approximately half of the solvent is removed, the precipitated crystals are separated off and washed with water, giving 230 mg of 5-(5-aminosulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole (“C1”) and, as by-product, 5-(5-hydroxysulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole (“C2”).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:3]1[C:2](=[O:11])[NH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc2c([nH]1)CCCC2
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2c(cc1[N+](=O)[O-])CCCC2
Temperature: 5 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
5,6,7,8-Tetrahydro-2(1H)-quinolinone (0.134 mol) was added portionwise at 5° C. to sulfuric acid (200 ml). Then HNO3 (0.235 mol) was added portionwise while the temperature was kept below 10° C. The mixture was stirred at 5° C. for 1 hour, poured out carefully into a small amount of ice water and stirred at 0° C. for 10 min. The precipitate was filtered off and dried, yielding 14.2 g (55%) of 5,6,7,8-tetrahydro-3-nitro-2(1H)-quinolinone (intermediate 8)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([OH:25])=[C:6]([C:8]2([CH2:23]O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[O:25][CH2:23][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:6]=2[CH:7]=1
Reactant: CCCCCN1C(=O)C(CO)(c2cc(Cl)c(F)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc(F)c(Cl)cc32)c2ccccc21
Yield: 80 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(5-chloro-4-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 80% yield; mp 74-76° C.; 1H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m, 1H), 7.18-7.02 (m, 2H), 6.94 (d, 1H), 6.77 (d, 1H), 6.69 (d, 1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.87-3.64 (m, 2H), 1.82-1.65 (m, 2H), 1.47-1.28 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.5, 160.6, 157.4, 142.6, 133.9, 131.8, 129.5, 124.6, 124.1, 123.5, 113.1, 109.0, 100.0, 81.2, 57.5, 40.6, 29.2, 27.2, 22.5, 14.1; MS (ES+) m/z 360 (M+1).
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[F:13][C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1.Cl>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([CH:3]2[C:2](=[O:1])[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=3)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C=Nc1cccc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 40 ml of tetrahydrofurane is added dropwise, at 10° to 20°, to a stirred suspension of 1.93 g of a 50% strength sodium hydride/mineral oil suspension in 50 ml of tetrahydrofurane. The mixture is stirred for a further 30 minutes at room temperature and 5.5 g of 3-fluoro-phenyl isocyanate are then added slowly dropwise, an exothermic reaction taking place. The reaction mixture is then stirred for a further one hour at room temperature and for one hour at 40° and is poured into a mixture of 500 ml of ice water and 50 ml of 2 N hydrochloric acid and the precipitate, which at first is oily but immediately crystallises, is filtered off and recrystallised from acetone/petroleum ether. N-(3-Fluorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide with a melting point of 169°-171° is obtained.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.C[O-].[Na+].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1>C(#N)C>[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21]2([C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:10][O:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 162 ml (2.2 moles) of dimethyl sulphide in 400 ml of absolute acetonitrile was added to a solution of 189 ml (2.0 moles) of dimethyl sulphate in 1,200 ml of absolute acetonitrile at room temperature. The reaction mixture was stirred overnight at room temperature. 118.8 g (2.2 moles) of sodium methylate were then added. The mixture was stirred for 30 minutes and a solution of 272 g (1.2 moles) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 600 ml of absolute acetonitrile was then added dropwise in the course of 30 minutes. The reaction mixture was subsequently stirred overnight. It was then concentrated, the residue was partitioned between water and ethyl acetate, the organic phase was separated off, washed twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated and the residue was distilled in vacuo. 242.4 g (84% of theory) of 2-(4-chlorophenoxymethyl)-2-tert.-butyl-oxirane of boiling point 115°-22° C./0.003 mm Hg column and of melting point 50°-52° C. were obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH:28]([O:43][CH2:44][O:45][CH3:46])[CH2:29][N:30]1[C:35](=[O:36])[CH:34]=[N:33][C:32]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[N:40][C:31]1=2)(C(C)(C)C)(C)C>O1CCCC1.ClCCl>[OH:26][CH2:27][CH:28]([O:43][CH2:44][O:45][CH3:46])[CH2:29][N:30]1[C:35](=[O:36])[CH:34]=[N:33][C:32]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[N:40][C:31]1=2
Reactant: COCOC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)cnc2ccc(OC)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCOC(CO)Cn1c(=O)cnc2ccc(OC)nc21
Reaction time: 15 h
Yield: 87 %

Procedure:
A solution of tetrabutyl ammonium fluoride in 1M tetrahydrofuran (3.22 ml, 3.22 mmol) was added to a solution of 4-[3-{[tert-Butyl(dimethyl)silyl]oxy}-2-(methoxymethoxy)propyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.02 g, 2.48 mmol) in tetrahydrofuran (15 ml) under cooling on ice and the mixture was stirred for 15 hours. The reaction solution was diluted with dichloromethane and washed with saturated sodium bicarbonate water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 637 mg (87%) of the title compound in the form of an orange oily product.
Reaction SMILES: [P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])(N)(=[O:3])[OH:2].[P:25](=[O:29])([OH:28])([OH:27])[OH:26]>N1C=CC=CC=1>[P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])([O:27][P:25]([OH:29])([OH:28])=[O:26])(=[O:3])[OH:2]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(N)(=O)O)[C@H]2O)c(=O)[nH]1
Reactant: O=P(O)(O)O
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)OP(=O)(O)O)[C@H]2O)c(=O)[nH]1
Reaction time: 96 h

Procedure:
A mixture of 0.35 millimoles of the guanosine-3'-monophosphoramidate and 1.5 millimoles of inorganic phosphoric acid was dissolved in 2.0 ml of dried pyridine, the solution was left to stand at room temperature for a period of 3 or 4 days, the undissolved matter was filtered off, and the filtrate was concentrated under vacuum to remove the pyridine. The residue was dissolved in 25 ml of an aqueous solution that contained 1 g of sodium acetate, the solution was adjusted to a pH of 7.0 with sodium hydroxide, and washed five times with ether twice the volume of the solution to remove the guanidium salt. The solution was then passed through a column of Dowex 2 (Cl- type: manufactured by Dow Chemical Co.) to remove the unreacted guanosine-3'-monophosphoramidate. The solution was treated with lithium hydroxide to bring its pH to 6.5, concentrated under vacuum, the residue was dissolved in 25 ml of methanol, to which was added 200 ml of acetone to precipitate the crystal of a lithium salt of guanosine-3'-diphosphate. The crystal was passed through a column of Dowex 50 (H+ type) for desalting. The eluate was collected, concentrated under vacuum, and the residue was lyophilized to give guanosine-3'-diphosphate.