Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28](OC)[O:29]C)[CH:20]=2)[CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[CH2:2]([O:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28]=[O:29])[CH:20]=2)[CH:13]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(OC)c1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
12 N HCl (33 mL) and water (66 mL) were added to a mixture of [3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.14 mol) in THF (400 mL) and the reaction mixture was stirred for 48 hours at room temperature. The mixture was diluted with H2O (500 mL) and extracted 2 times with diisopropyl ether. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The resulting product was removed with a spatula and dried under vacuum to yield the title compound as a residue.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.O1CCOCC1.Cl.[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C=O)C.Cl.C(Cl)Cl>[N:24]1([C:14]([C:11]2[CH:10]=[CH:9][C:8]([Br:7])=[CH:13][N:12]=2)=[O:16])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cn1)N1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
Oxalyl chloride (11.5 mL, 130 mmol) then DMF (2 drops) were added to a mixture of 5-bromopyridine-2-carboxylic acid (CAS no. 30766-11-1) (12.6 g, 62.4 mmol) in 4M HCl in dioxane (15.6 mL, 74.9 mmol) and DCM (300 mL). The mixture was stirred at ambient temperature for 18 hours. The volatiles were removed under reduced pressure and azeotroped with toluene. The residue was dissolved in DCM (300 mL). Azetidine hydrochloride (6.14 g, 65.5 mmol) then triethylamine (24 mL, 187 mmol) were added and the mixture stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure and ethyl acetate (400 mL) added to the residue. The resulting mixture was washed with water (100 mL), filtered, washed with 1M citric acid solution (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of 0-40% ethyl acetate in isohexane to afford the product (8.8 g, 65%). m/z 242 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[CH:24]=[CH:25][C:26]6[N:30]=[C:29]([C@@H:31]7[CH2:35][CH2:34][CH2:33][N:32]7[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:28][C:27]=6[CH:43]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)O1.Br[C:46]1[NH:50][C:49]([C@@H:51]2[CH2:55][CH2:54][CH2:53][N:52]2[C:56](=[O:66])[C@@H:57]([NH:61][C:62](=[O:65])[O:63][CH3:64])[CH:58]([CH3:60])[CH3:59])=[N:48][CH:47]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[CH3:64][O:63][C:62]([NH:61][C@@H:57]([CH:58]([CH3:60])[CH3:59])[C:56]([N:52]1[CH2:53][CH2:54][CH2:55][C@H:51]1[C:49]1[NH:50][C:46]([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[CH:24]=[CH:25][C:26]6[N:30]=[C:29]([C@@H:31]7[CH2:35][CH2:34][CH2:33][N:32]7[C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[NH:28][C:27]=6[CH:43]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:47][N:48]=1)=[O:66])=[O:65]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(B5OC(C)(C)C(C)(C)O5)ccc3-4)cc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
A mixture of (S)-tert-butyl 2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (590 mg, 1.0 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (492 mg, 1.3 mmol), PdCl2(dppf) (37 mg, 0.05 mmol), 2M aqueous potassium phosphate solution (1.5 mL, 3.0 mmol), and dimethoxyethane (5 mL) was degassed with a stream of argon for twenty minutes. The reaction was heated to 90° C. After one hour, the reaction was cooled to room temperature and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was added. The reaction was heated to 90° C. After three hours, the reaction was cooled to room temperature and more PdCl2(dppf) (37 mg, 0.05 mmol) was added. The reaction was heated to 80° C. After 16 hours, the reaction was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The resulting residue was purified by flash column chromatography to yield (S)-tert-butyl 2-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (30 mg, 4%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[C:19](Cl)[CH:18]=[C:17](Cl)[CH:16]=2)=[C:6]1[C:23]([O-:25])=[O:24].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Cl.FC(F)(F)OC1C=CC(CBr)=CC=1>>[Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([O:34][CH3:33])[CH:36]=3)=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:23]([OH:25])=[O:24]
Reactant: COc1cccc(CCl)c1
Reactant: O=C([O-])c1c(-c2cc(Cl)cc(Cl)c2)c2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2
Agent: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cccc(COc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2cc3c(cc2Cl)OCO3)c1

Procedure:
Following the procedure of Example 26(c)-26(d), except substituting ethyl 1-(2-chloro-4,5-methylenedioxybenzyl)-5-hydroxy-3-phenylindole-2-carboxylate for 1-(2-chloro-4,5-methylenedioxybenzyl)-3-(3,5-dichlorophenyl)-5-hydroxyindole-2-carboxylate and 3-methoxybenzyl chloride for 4-trifluoromethoxybenzyl bromide in step (c), the title compound was prepared as a white solid (64% overall). MS (MH+): 542.4
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:17].[C:18](=[O:20])=[O:19].[Cl-].[Na+]>CN(C)C=O.O.CN(C)C=O.O>[C:11]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])[C:18]([O-:20])=[O:19])([CH3:14])([CH3:13])[CH3:12].[Na+:17]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(C(=O)[O-])cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of dimethylformamide/water is distilled from a solution of 206 g (1 mol) of 2,6-di-tert.-butylphenol and 80 g of a 50% strength aqueous sodium hydroxide solution in 500 ml of dimethylformamide at boiling point 30°-50° C./approx. 20 mm Hg until the water content in the last sample of the distillate is approx. 1.5%. After releasing the vacuum with nitrogen, carbon dioxide gas is passed into the reaction solution, with vigorous stirring, in the course of which the temperature of the solution rises to approx 85° C. After 11/2 hours at this temperature, the reaction mixture is cooled to 60° C. and 450 ml of a 20% strength sodium chloride solution are added under carbon dioxide gas. The resulting clear reaction solution is thereafter cooled, whereupon crystallisation starts at room temperature and is completed by stirring for 0.5 hours at 0°-5° C. Filtration, successive washing with 200 ml of 20% strength sodium chloride solution and 200 ml of n-hexane and drying the crystals to constant weight in vacuo at 40° C. yields colourless sodium 3,5-di-tert.-butyl-4-hydroxy-benzoate, containing water of crystallisation; when this substance is dissolved in 500 ml of water and precipitated with concentrated hydrochloric acid, it yields 189 g (yield, 77% of theory) of 3,5-di-tert.-butyl-4-hydroxybenzoic acid of melting point 215° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:20]=[CH:21]C=1O)=[O:16].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[F:6])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1cc(F)ccc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 15 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 4 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 16.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:21][CH2:20]3)[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[CH:28][C:29]=1[C:30]([F:33])([F:32])[F:31].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:20][CH2:21]3)[C:14]=2[NH:18][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[CH:28][C:29]([C:30]([F:31])([F:32])[F:33])=[C:24]([F:23])[CH:25]=2)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C3CC3)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Temperature: 40 °C

Procedure:
A reaction vial was charged with (R)-2-(5-amino-6-cyclopropyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (23.0 mg, 0.0000766 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (26 mg, 0.00011 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (73 mg, 0.00019 mol), N,N-diisopropylethylamine (33 μL, 0.00019 mol) and methylene chloride (2 mL, 0.03 mol) and the reaction stirred at 40° C. over night. The solvent was removed and the residue purified by flash chromatography (0-70% ethylacetate) to obtain the product as light yellow solid. MS m/z=505.3 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.Cl[P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(OCC)C>[C:23]1([P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
1.00 g (3.89 mmol) of 6-bromo-2-pivaloylaminopyridine from example 14.2.1 was dissolved in 10 ml of diethyl ether and admixed at 0° C. with 3.64 ml (8.00 mmol) of (iso-C3H7)MgBr (2.2M in Et2O). The suspension was stirred at 0° C. for 18 h and then admixed with 0.7 ml (0.86 g, 3.89 mmol) of chlorodiphenylphosphine. The mixture was allowed to warm to ambient temperature overnight and was then hydrolyzed by adding 10 ml of dist. H2O. The resulting phases were separated and the aqueous phase was extracted twice with 50 ml each time of ethyl acetate. The organic phases were combined and dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was filtered together with dichloromethane through a short silica gel column (2×10 cm) and the solvent was removed under reduced pressure. The resulting oil was crystallized by digesting with petroleum ether/diethyl ether (40/60). The crystals were filtered off and washed with petroleum ether/diethyl ether (40/60). 0.38 g (1.05 mmol, 27.0%) of 6-(diphenylphosphino)-2-pivaloylaminopyridine was obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13](OC)([O:16]C)[CH2:14]Br.[H-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:14][C:13](=[O:16])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2cccc(Br)c2)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-bromophenylacetonitrile (7.55 g, 38.5 mmol) and 1,3-dibromo-2,2-dimethyoxypropane (10.09 g, 38.5 mmol) in dry DMSO (100 ml) was added in two portions sodium hydride (3.23 g of 60% dispersion in oil, 81 mmol) while the mixture was cooled in a water bath. The mixture was stirred at RT for 10 minutes, and heated at 60° C. in an oil bath for 6 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and the solvent removed. The residual red oil was eluted through a short pad of silica, eluent 10% EtOAc/Hexane. The resulting ketal was dissolved in acetone (100 ml) and 1N aqueous HCl (10 ml) and heated at reflux for 6 hours under a nitrogen atmosphere. The solvent was removed and the residue was neutralized by treatment with aqueous NaHCO3 and extracted with EtOAc. The solvent was removed and the residue was chromatographed (SiO2, eluent 10% EtOAc in hexane) to give a yellow oil which solidified on drying under vacuum.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[C:18]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:7]1[CH3:32])C.[OH-].[K+]>C1COCC1.O>[C:26]1([S:23]([C:18]2[C:17]([CH2:16][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=4)[N:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]=3[CH3:32])=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of [3-(2-benzenesulfonyl-pyridin-3-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid ethyl ester (1.20 g, 2.56 mmol) in THF (26 ml) was added a solution of potassium hydroxide (0.43 g, 7.68 mmol) in water (9 ml). The resulting solution was stirred at room temperature for 3.5 h. THF was removed in vacuo and the remaining aqueous layer was acidified with aqueous HO (0.1 M, 2.5 ml). The product was collected by filtration, washed with water and dried in vacuo to afford 1.12 g (100%) of the title compound (LCMS RT=4.58 min, M+-H 437.2).
Reaction SMILES: [O:1]([CH2:8][C@H:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:11][C@H:9]([CH3:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)COc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](COc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
(R)-1-phenoxy-2-propylamine (4.3 g, 23 mmol) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (11.2 g, 18 mmol) in dioxan (150 ml) in the presence of diisopropylethylamine (5.3 g, 41 mmol). The reaction mixture was stirred at room temperature for 18 h, heated at 50° C. for 4 h, and stirred at room temperature for 60 h before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro- N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam (4.2 g, 64%), 1H NMR (DMSO-d6)δ 1.31 (3H, d, --CH3), 3.52-3.59 (1H, m, H-5'a), 3.63-3.72 (1H, m, H-5'b), 3.92-3.99 and 4.10-4.21 (4H, 2 m, H-3', H-4' and --CH2 --), 4.52 (1H, dd, H-2'), 4.65 (1H, m, --CH3C H--), 5.07 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.84 (1H, d, H-1 '), 6.88-7.02 (3H, m, Ar--H), 7.24-7.33 (2H, dd, Ar--H), 8.32-8.45 (2H, s & m, H-8 and N--H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:37][CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:39][C:40]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[C:42]([F:55])[C:41]=1[OH:56]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:44]5[CH:43]=[C:42]([F:55])[C:41]([OH:56])=[C:40]([Cl:39])[CH:45]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:37][CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(Cl)nc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 103.5 %

Procedure:
Following general procedure II, (S)-tert-butyl(1-(5-((6-chloro-3-(cyclobutanecarbonyl)-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (110 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82 mg, 0.30 mmol) to afford the product (134 mg) which was carried forward without any purification: ESI MS m/z 647 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([N+:16]([O-])=O)=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl>CCO>[NH2:16][C:9]1[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2c(Cl)cc(C(F)(F)F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(C(F)(F)F)cc(Cl)c2[nH]c(=O)c(=O)[nH]c12
Temperature: 75 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A mixture of 5-chloro-8-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (25 mg, 0.08 mmol), SnCl2 ·2 H2O (97 mg, 0.34 mmol) and EtOH (3 mL) was heated at 75° C. with stirring for 12 h. Work-up as above gave 21 mg (93%) of the title compound as a yellow powder. Mp>360° C. 1H NMR (DMSO-d6) 11.441 (s, 1H), 11.324 (s, 1H), 7.241 (s, 1H), 5.916 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][CH3:19])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCNc1ccc(CC2CCN(C(C)=O)CC2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN(Cc1ccccc1)c1ccc(CC2CCN(C(C)=O)CC2)cc1

Procedure:
In 30 ml of ethanol was dissolved 3.13 g of the 1-acetyl-4-[4-(ethylamino)benzyl]piperidine (Compound No. 8) prepared in Example 16, followed by addition of 3.31 g of potassium carbonate and 1.43 ml of benzyl bromide. The mixture was refluxed for 2 hours and the insolubles were filtered off. The solvent was then distilled off and the remaining oil was purified by silica gel column chromatography (eluent: ethyl acetate) to give 3.8 g of the title compound as a colorless oil.
Reaction SMILES: N[C:2]1[N:7]=[C:6](O)[C:5]([N+]([O-])=O)=[C:4]([NH:12][C:13](CC)(CC)[C:14](=[N:17]O)CO)[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N1C2C(=NC=CN=2)C=NC1>[OH-].[Na+]>[N:3]1[C:4]2[NH:12][CH2:13][CH:14]=[N:17][C:5]=2[CH:6]=[N:7][CH:2]=1
Reactant: CCC(CC)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(CO)=NO
Agent: C1=NCNc2nccnc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: C1=Nc2cncnc2NC1
Yield: 70.3 %

Procedure:
2-Amino-4-hydroxy-6-(3-hydroxy-2-hydroxyimino-1-spirocyclohexylpropylamino)-5-nitropyrimidine (II) (500 mg) was dissolved in the minimum of 0.1M sodium hydroxide by warming on the steam bath. Sodium dithionite was added portionwise until an almost colourless solution was obtained. On cooling the dihydropteridine separated and was filtered off and purified by dissolving in 2M HCl and reprecipitated by the addition of 0.88 ammonia to pH8. On standing the dihydropteridine (I) (150 mg; yield 38%) was obtained as a pale yellow crystalline solid, m.p. >300 (decomp.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]=[O:12].C(N(C(C)C)CC)(C)C.C(OCC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]=[O:12])(=[O:4])=[O:3]
Reactant: O=Cc1ccc(OCc2ccccc2)c(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
Methanesulfonyl chloride (2.50 g) was added to a stirred solution of 3-(hydroxymethyl)-4-phenylmethoxybenzaldehyde (4.00 g) in dichloromethane (50 ml) at 0° C. To this solution was then added diisopropylethylamine (8.1 ml) over approx. 2 minutes. After stirring for a further 5 minutes the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with dilute hydrochloric acid, dried over sodium sulfate, filtered and concentrated under reduced pressure to give pale straw coloured oil. Addition of diethyl ether caused the product to crystallize. This material was collected and washed with more diethyl ether to give 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (4.51 g) as off-white crystals. 1H NMR (CDCl3) δ 9.78 (s, 1H, CHO); 5.22 (s, 2H); 5.10 (s, 2H); 2.83 (s, 3H). TLC (silica gel): Rf=0.4 (dichloromethane:diethyl ether, 24:1).