Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([NH:18][C@@H:19]2[C:37](=[O:38])[N:21]3[C:22]([C:34]([OH:36])=[O:35])=[C:23]([CH:26]([S:28][C:29]4[NH:33][N:32]=[N:31][N:30]=4)[CH3:27])[CH2:24][S:25][C@H:20]23)=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[N+]=[N-])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCOCC1>[C:39]1([CH:45]([O:35][C:34]([C:22]2[N:21]3[C:37](=[O:38])[C@@H:19]([NH:18][C:16](=[O:17])[CH2:15][C:13]4[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=4)[C@H:20]3[S:25][CH2:24][C:23]=2[CH:26]([S:28][C:29]2[NH:30][N:31]=[N:32][N:33]=2)[CH3:27])=[O:36])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The product, containing 7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid, is dissolved in 30 ml of dioxane, 1.5 g of diphenyldiazomethane are added to the solution and the mixture is stirred for 12 hours at room temperature and then concentrated. After crystallisation from a mixture of methyl acetate and diethyl ether, the residue gives 7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]([O:11][C:12](=[O:32])[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].C([BH3-])#N.[Na+].C(O)(=O)C>CO.O>[C:7]([O:11][C:12]([CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=1)[CH2:21][NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:32])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)COc1cc(C=O)cc(OCC(=O)OC(C)(C)C)c1
Reactant: NCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cc(CNCCC(=O)O)cc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
Beta-alanine (0.5 g, 5.68 mmol) was dissolved in methanol (20 mL). (3-Tert-Butoxycarbonylmethoxy-5-formylphenoxy)acetic acid tert-butyl ester (2.08 g, 5.58 mmol) was dissolved in methanol (2 mL) and added. The mixture was heated to reflux for 1 hour and allowed to cool to room temperature. Sodium cyanoborohydride (282 mg, 4.54 mmol) was added and the mixture stirred at room temperature, after 1 hour acetic acid was added (2 mL) and the mixture was stirred for an additional hour before being poured into water (50 mL) and stirred overnight. The water phase was washed with ethyl acetate (2×50 mL). The organic phase was dried (Na2SO4) and solvent removed in vacuo to yield the crude product. The crude product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:8]1([C:13](=[O:16])[NH:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([N:7]([C:8]3([C:13](=[O:16])[NH:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:6][CH2:5][C:4]([OH:34])=[O:3])(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A solution of 7.48 g (15.1 mmol) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution was treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture was stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase was separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture was stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase was separated and washed with water. The ethyl acetate solution was slowly treated with 150 mL of hexanes at ambient temperature causing solids to precipitate, and stirred overnight. Filtration yielded 5.01 g of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid as a white solid (71% yield from 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].S(=O)(=O)(O)O.[CH3:27]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH3:27])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CO
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 2-[(4-amino-3-nitrophenyl)carbonyl]benzoic acid (4.60 g, 16.00 mmol) in methanol (300 mL) in the presence of catalytic amount of cc. sulfuric acid was heated to reflux for 18 h. The solution was cooled to room temperature and the solvent was evaporated. The yellow precipitate formed was collected by filtration, washed with water and dried in vacuo to provide methyl 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (4.8 g, quantitative). MS (EI) for C15H12N2O5: 301 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].C(OC(=O)[NH:21][OH:22])(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C(#N)C.CCOC(C)=O.O>[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][O:22][NH2:21]
Reactant: CC(C)(C)OC(=O)NO
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CON)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.4 %

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzyl chloride (1.00 g, 4.6 mmol) and tert-butyl-N-hydroxycarbamate (0.62 g, 4.6 mmol) in acetonitrile (20 ml) was added Cs2CO3 (4.51 g, 13.8 mmol). The reaction mixture was stirred at room temperature for 24 hours. Water was added and the products extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by chromatography on silica using a gradient of EtOAc in petroleum ether (0-40%, v/v) affording 411 mg of Boc-protected O-(3,4,5-trimethoxy-benzyl)-hydroxylamine. This intermediate (383 mg/1.22 mmol) was treated with 37% hydrochloric acid (2.5 ml) in EtOAc (7.5 ml) for 30 min. at room temperature. The mixture was concentrated under reduced pressure and diethyl ether was added. The resulting precipitated material was isolated by filtration and dried under high vacuum affording the title compound (211 mg) as white shiny crystals.
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:7])=[CH:4][C:3]=1[F:22].N([O-])=O.[Na+].[S:27](=[O:29])=[O:28].[ClH:30]>O.CC(O)=O.O.O.[Cu](Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2([CH2:9][NH:8][C:6]([C:5]3[CH:20]=[CH:21][C:2]([S:27]([Cl:30])(=[O:29])=[O:28])=[C:3]([F:22])[CH:4]=3)=[O:7])[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: Cl
Reactant: O=S=O
Reactant: Nc1ccc(C(=O)NCC2(c3ccc(Cl)cc3)CC2)cc1F
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCC1(c2ccc(Cl)cc2)CC1)c1ccc(S(=O)(=O)Cl)c(F)c1
Reaction time: 0.33 h

Procedure:
4-Amino-N-{[1-(4-chlorophenyl)cyclopropyl]methyl}-3-fluorobenzamide (Preparation 92, 338 mg, 1.06 mmol) in 6 M of HCl in water (2 mL) was cooled at −5° C. Sodium nitrite (80.5 mg, 1.17 mmol) in water (0.4 mL, 20 mmol) was added slowly. After 20 minutes, sulfur dioxide in AcOH (8:25, sulfur dioxide:AcOH, 3 mL) and copper(II)chloride dihydrate (0.18 g, 1.1 mmol) were added to the reaction mixture. Vigorous gas evolution occurred. After 2 hours, the reaction was poured onto ice and water. The resulting solid was collected by filtration, washed with water, and dried to afford a tan powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]1[CH2:41]C[CH2:39][CH:38](O)[CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH2:35]2)=[CH:18][CH:17]=1
Reactant: CN1CCCC(O)C1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCN(C)C4)cc3)c2cc1OC
Yield: 35.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-methyl-3-piperidinol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (26 mg, yield 28%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH2:63])[CH2:40][C@H:41]([OH:62])[C@@H:42]([NH:50][C:51](=[O:61])[C@H:52]([CH:58]([CH3:60])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1>CN(C=O)C>[CH3:59][CH:58]([C@H:52]([NH:53][C:54]([O:56][CH3:57])=[O:55])[C:51]([NH:50][C@H:42]([C@@H:41]([OH:62])[CH2:40][N:39]([NH:63][C:10]([C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:11])[CH2:38][C:35]1[CH:34]=[CH:33][C:32]([C:28]2[S:27][CH:31]=[CH:30][N:29]=2)=[CH:37][CH:36]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:61])[CH3:60]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7, 140 mg (0.80 mmol) of N-methoxycarbonyl-(L)-valine, 288 mg (1.5 mmol) of EDC and 135 mg (1.0 mmol) of HOBT in 2.2 ml of DMF and 418 μl (3.0 mmol) of TEA are reacted with 0.5 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane in 4.5 ml of DMF to form the title compound: m.p: 207-210° C.; HPLC20-100 : tRet =13.8; FAB MS (M+H)+ =683.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19]([O:21]C)=[O:20])[CH:12]=[C:13]([Cl:15])[N:14]=1)C1C=CC=CC=1.O.CO.Cl>C1COCC1>[Cl:15][C:13]1[N:14]=[C:9]([O:8][CH3:1])[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19]([OH:21])=[O:20])[CH:12]=1
Reactant: COC(=O)c1cnn2cc(Cl)nc(OCc3ccccc3)c12
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(Cl)cn2ncc(C(=O)O)c12
Reaction time: 5 h

Procedure:
methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (5.35) (894 mg, 2.81 mmol) was suspended in THF (7.5 mL), water (2.5 mL), and MeOH (2.5 mL). After stifling at 30° C. for 5 h, HPLC demonstrated one primary product. The reaction mixture was acidified with aqueous HCl and was partitioned between water, EtOAc and 2-Me-THF. The phases were separated and the aqueous phase was extracted 3 times with a mixture of EtOAc and 2-Me-THF. The combined organic phase was concentrated to afford crude 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine-3-carboxylic acid that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C8H7ClN3O3: 228.0; found: 228.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][C:10]([CH3:15])=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5])[CH3:2].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[C:13]2[C:8](=[N:9][C:10]([CH3:15])=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(C)nc2c1-c1cccnc1OC
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cccnc2OC)c2nc(C)ccc2n1Cc1ccccc1F
Temperature: 25 °C
Yield: 96.9 %

Procedure:
3-(2-Methoxy-pyridin-3-yl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester B3 (0.2 g, 0.64 mmol) was diluted with DMF (4 mL). To the resulting solution was added 2-fluorobenzyl chloride (0.14 g, 0.96 mmol) and cesium carbonate (0.312 g, 0.96 mmol) and the resulting suspension was allowed to stir at room temperature. After 24 hours the reaction mixture was then diluted with ethyl acetate (50 mL) and water (20 mL) and the layers were separated. The organic layer was sequentially washed with aqueous saturated sodium bicarbonate solution (10 mL), water (10 mL) and saturated brine (10 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue obtained was purified using flash chromatography to provide 1-(2-Fluoro-benzyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester B4 (0.26 g) MS: 420.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].Cl.[CH3:14][NH2:15]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH3:14])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(N)c(OC)c1

Procedure:
4-Amino-3-methoxy-N-methylbenzamide was prepared by the procedure described in Example 7 using 4-amino-3-methoxybenzoic acid and methylamine hydrochloride.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[C:11]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][N:27]=[CH:26]5)[CH:21]=3)[NH:16][CH:15]=2)=[O:13])=[C:10]([F:32])[CH:9]=[CH:8][C:7]=1[NH:33][S:34]([C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[F:44])(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.C(OCC)(=O)C.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>[CH3:1][NH:2][C:3]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([C:20]3[CH:21]=[C:22]4[C:14]([C:12](=[O:13])[C:11]5[C:10]([F:32])=[CH:9][CH:8]=[C:7]([NH:33][S:34]([C:37]6[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=6[F:44])(=[O:36])=[O:35])[C:6]=5[F:5])=[CH:15][NH:16][C:17]4=[N:18][CH:19]=3)=[CH:31][CH:30]=2)[CH:26]=[N:27]1)=[O:4]
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(-c3ccc4[nH]ncc4c3)cc12
Reactant: CN=C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)n1ncc2cc(-c3cnc4[nH]cc(C(=O)c5c(F)ccc(NS(=O)(=O)c6cc(F)ccc6F)c5F)c4c3)ccc21
Temperature: 140 °C
Yield: 72.5 %

Procedure:
Into a reaction flask, methyl isocyanate (6.5 mg, 0.11 mmol) is combined with N-{2,4-difluoro-3-[5-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-0002, 22 mg, 0.031 mmol), tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 0.0019 mmol), potassium carbonate (1.0 mL, 1.0 M in water) and 3 mL of acetonitrile. The reaction is heated at 140° C. for 50 minutes in a microwave, then diluted with water and ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, then brine and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-0003, 14 mg, 72%). MS (ESI) [M+H+]+=623.
Reaction SMILES: [H][H].[NH3:3].[CH2:4]([O:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C)[C@@H:24]([O:25]C(=O)C)[C@H:19]2[O:20]C(=O)C)=[C:11](Cl)[N:10]=1)[CH2:5][CH2:6][CH3:7]>>[CH2:4]([O:8][C:9]1[N:10]=[C:11]([NH2:3])[C:12]2[N:13]=[CH:14][N:15]([C:16]=2[N:17]=1)[C@@H:18]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:24]([OH:25])[C@H:19]1[OH:20])[CH2:5][CH2:6][CH3:7]
Reactant: N
Reactant: [H][H]
Reactant: CCCCOc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Product: CCCCOc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 30 %

Procedure:
A compound having a structure of the above formula was prepared where the substituents R1 and R2 are hydrogen and R3 is n-butyl (—CH2CH2CH2CH3). The compound (C14H21N5O5) was prepared by reaction of ammonia with 2-butyloxy-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 5) as described in Example 2, Step E. The final product was isolated in 30% yield as a solid with a melting point of 145-146° C. 1H-NMR (DMSO-d6): δ 0.9 (t, 3H); 1.37 (m, 2H, J=8); 1.65 (m, 2H, J=8); 3.66 (m, 2H); 3.97 (m, 1H); 4.18 (m, 3H); 4.57 (m, 1H), 4.95 (d, 1H, J=6); 5.23 (m, 2H); 5.78 (d, 1H, J=6); 6.9 (bs, 2H); 7.94 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](OC1C=CC(OCCCBr)=CC=1)C1C=CC=CC=1.CNC>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Reactant: CNCCCOc1ccc(OCc2ccccc2)cc1
Agent: CNC
Product: CN(C)CCCOc1ccc(OCc2ccccc2)cc1

Procedure:
In the manner described above for the preparation of 1-benzyloxy-4-(3-methylaminopropoxy)benzene, 1-benzyloxy-4-(3-bromopropyloxy)benzene was reacted with dimethylamine to give 1-benzyloxy-4-(3-dimethylaminopropoxy)benzene. The product was isolated as its hydrochloride salt and crystallization from isopropanol gave the purified hydrochloride salt of 1-benzyloxy-4-(3-dimethylaminopropoxy)benzene, mp 183°-185°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+]>CO.[Cu]>[Br:1][C:2]1[CH:7]=[C:6]([O:10][CH3:9])[CH:5]=[N:4][CH:3]=1
Reactant: C[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1cncc(Br)c1
Temperature: 150 °C
Yield: 59.2 %

Procedure:
A mixture of 3,5-dibromopyridine (20.00 g, 84.42 mmol), sodium methoxide (11.40 g, 211.06 mmol), and copper powder (1 g, 5% by weight of 3,5-dibromopyridine) in dry methanol was heated in a sealed glass tube at 150° C. for 14 h. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4×200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1:9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing 9.40 g (59.5%) of a colorless oil, which tended to crystallize upon cooling.
Reaction SMILES: [C:1]1(/[C:7](/[C:31]#[C:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:8]\[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:30])[C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>N1C2C(=CC=CC=2)C=CC=1.CO>[C:1]1(/[C:7](/[CH:31]=[CH:32]\[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:8]/[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:30])[C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)/C=C(/C#Cc3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Reactant: [H][H]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: COc1cc(C(=O)N2CCN(C(=O)/C=C(\C=C/c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Reaction time: 15 h
Yield: 61 %

Procedure:
0.025 g of 10% w/w palladium-on-barium sulfate and two drops of quinoline were added to 5 ml of a methanol solution containing 0.250 g of 1-[(E)-3,5-diphenylpent-2-en-4-ynoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine (prepared as described in Example 58). Hydrogen gas was introduced into the reaction mixture at room temperature and at atmospheric pressure. The reaction mixture was then shaken for 15 hours, after which the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was subjected to moderate pressure liquid chromatography using a Lobar B column. 0.153 g of the title compound was obtained as a powder from those fractions eluted with mixtures of methylene chloride and ethyl acetate ranging from 3:2 to 1:3 by volume.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].Cl>C1(C)C=CC=CC=1>[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([CH:18]=[CH:17][C:13]=1[C:14](=[O:15])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:21]#[N:22]
Reactant: N#Cc1ccc(C(=O)Cl)c(CCl)c1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 4-fluoro phenylmagnesium bromide (0.73 M in THF, 170 ml) was added to a cooled solution of 2-chloromethyl-4-cyano-benzoyl chloride (25.0 g) in toluene (200 ml) so that the temperature did not raise above 0° C. The mixture was stirred at 0° C. for 2 hours. An aqueous solution of HCl (250 ml) was added and stirring continued for 0.5 hours. The phases were separated and the aqueous phase was extracted with toluene (200 ml). The combined organic phases were washed with saturated NaHCO3 solution (200 ml) and water (100 ml). The solvents were evaporated in vacuo to give a brownish oil (29.0 g, 90%). Spectral and analytical data were in accordance with the example above.