Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:6][CH:5]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].Cl>CN(C)C=O.O>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:6][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: O=C1NC(=O)C(CCc2ccc(O)cc2)S1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
Oily sodium hydride (60%, 0.10 g) was added to a solution of 5-[2-(4-hydroxyphenyl)ethyl]-2,4-thiazolidinedione (0.30 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 15 minutes. Then, 4-chloromethyl-5-methyl-2-phenyloxazole (0.29 g) was added, and the mixture was stirred at 90 to 100° C. for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-chloroform (1:9, v/v) gave 5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-2,4-thiazolidinedione (0.30 g, 59%). This product was recrystallized from dichloromethane-isopropyl ether. Colorless needles. mp: 146-147° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[C:19]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])=[C:18]1[C:13]([C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[CH:16]=[CH:17]1)=[N:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Br[CH2:37][CH2:38][CH2:39][OH:40].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.C(=O)([O-])O.[Na+]>C(#N)C>[OH:40][CH2:39][CH2:38][CH2:37][C:11]1[N:12]=[C:13]2[C:18](=[C:19]3[C:10]=1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:22]([O:23][CH3:24])[CH:21]=[CH:20]3)[CH:17]=[CH:16][C:15]1[CH:25]=[CH:26][CH:27]=[CH:28][C:14]2=1
Reactant: OCCCBr
Reactant: COc1ccc2c(cnc3c4ccccc4ccc23)c1OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc2c(c(CCCO)nc3c4ccccc4ccc23)c1OCc1ccccc1
Temperature: 80 °C

Procedure:
7-Benzyloxy-8-methoxy-benzo[c]phenanthridine (prepared by the process described in Japanese Patent KOKAI No. 5-208959, 284 mg, 0.78 mmol) was suspended in acetonitrile (10 mL), and trifluoroacetic acid (60 μL, 0.78 mmol), 3-bromo-1-propanol (71 μL, 0.79 mmol) and tris(trimethylsilyl)silane (481 μL, 1.56 mmol) were added to the suspension. The mixture was stirred at 80° C. on an oil bath. After the suspension was dissolved, azobis(isobutyronitrile) (256 mg, 1.56 mmol) was added to the solution followed by heating under reflux. An hour later, the reaction mixture was allowed to cool to room temperature, and then a saturated sodium hydrogencarbonate aqueous solution (60 mL) was added thereto followed by extraction with methylene chloride. After the organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was passed through a silica gel column (eluted with 1% methanol-methylene chloride). The main fractions were collected and concentrated in vacuo to give 6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine as a crude product (purity 50%, 142 mg, yield 21%) in a yellow brown dry mass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]C)[C:5]2=[O:21].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:5]2=[O:21]
Reactant: COc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccccc2O)coc2cc(O)c(Cl)cc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 58.4 %

Procedure:
To a stirred solution of 6-chloro-7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one (2.5 gm, 8.3 mmol) in dry CH2Cl2 (25 ml) at −80° C. was added BBr3 (1.6 ml in DCM, 16.6 mmol). The reaction mixture was then stirred for 1 hour at −80° C. and 12 hours at room temperature. The reaction was then quenched with ice-cooled water. The reaction mixture was then extracted with CH2Cl2 and the organic layer was separated, washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography using hexane-chloroform as the eluent to give 6-chloro-7-hydroxy-3-(2-hydroxy-phenyl)-chromen-4-one (1.4 gm, 60%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH:11]([CH3:13])[CH3:12]>>[C:10]([C:15](=[CH:21][NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(C)C
Reactant: Nc1ccccc1CO
Product: CCOC(=O)C(=CNc1ccccc1CO)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
2-Aminobenzyl alcohol (12.32 g, 0.1 mol) was dissolved in ethyl 2-isobutyryl-3-ethoxyacrylate (23.57 g, 0.11 mol), stirred for 2 hours at room temperature then warmed briefly to boiling. Cooling and trituration with petroleum ether gave ethyl 2-isobutyryl-3-(2-(hydroxymethyl)phenylamino)acrylate (22.29 g, 77%) as a mixture of E/Z isomers, m.p. 72°-84°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Br[C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[N:15][N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:17]=1.BrC1C=NN(C2CCCCO2)C=1[N+]([O-])=O.COCCOC.O>C(=O)([O-])[O-].[K+].[K+].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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[C:14]([N+:24]([O-:26])=[O:25])=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:17]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
Reactant: OB(O)c1cc(Cl)ccc1O
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: O=[N+]([O-])c1c(Br)cnn1C1CCCCO1
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(Cl)ccc1O
Temperature: 80 °C

Procedure:
(5-chloro-2-hydroxyphenyl)boronic acid (16.10 g, 93.38 mmol) and 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole or 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 869, 22.95 g, 83.12 mmol) in 1,2-dimethoxyethane (300 mL, 3000 mmol) and 2 M of potassium carbonate in water (116 mL, 2.10E2 mmol) was added tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol). The solution was sparged 3 times with Ar and heated at 80° C. for 4 hours. Additional (5-chloro-2-hydroxyphenyl)boronic acid (2.866 g, 16.62 mmol) was added to the reaction. The reaction was heated at 80° C. for another 18 hours. The cooled reaction was poured into a separatory funnel and the phases separated. The aqueous phase was washed two times with dichloromethane (250 mL). The combined organic phase was washed with brine then dried over anhydrous magnesium sulfate and treated with activated carbon. The mixture was filtered through diatomacious earth and the filtrate evaporated to a residue. The crude product was separated into two portions and each purified by column chromatography (80 g silica gel column, hexanes to 20% ethyl acetate gradient elution). Product fractions were combined and evaporated to give a thick oil which formed a waxy solid upon standing. The solid was triturated with hexanes and filtered to give 17.71 g of tan powder after vacuum drying.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[Br:11][C:12]1[CH:23]=[CH:22][C:15]2[CH:16]=[C:17](C(O)=O)[S:18][C:14]=2[CH:13]=1>[Cu].CCOCC>[Br:11][C:12]1[CH:23]=[CH:22][C:15]2[CH:16]=[CH:17][S:18][C:14]=2[CH:13]=1
Reactant: O=C(O)c1cc2ccc(Br)cc2s1
Agent: [Cu]
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: Brc1ccc2ccsc2c1
Temperature: 220 °C

Procedure:
To quinoline (45 ml) were added 6-bromobenzothiophene -2-carboxylic acid (14 g) and copper powder (874 mg), followed by stirring under heat at an oil temperature of 220° C. for 2 hours. After the reaction mixture was allowed to cool down, ether was added and the copper powder was filtered off. The filtrate was washed with a 1N aqueous solution of hydrochloric acid, then with a 1N aqueous solution of sodium hydroxide and finally with saturated aqueous NaCl solution, followed by drying over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane), whereby the title compound (5.56 g) was obtained as a pale yellow solid. In addition, the raw material (3.15 g) was recovered.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[Na+].O1CCOCC1.[CH3:30][O:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[CH3:30][O:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(CNc2ccc(S(=O)(=O)Nc3nccs3)c(F)c2)c(OC)c1
Temperature: 100 °C
Yield: 79.3 %

Procedure:
Into a vial was added the 4-bromo-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (2.60 g, 0.00771 mol), sodium tert-butoxide (1.78 g, 0.0185 mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.27 g, 0.00046 mol), tris(dibenzylideneacetone)dipalladium(0) (0.14 g, 0.00015 mol) and 1,4-dioxane (24.1 mL, 0.308 mol). Argon was bubbled for 15 minutes. 2,4-Dimethoxybenzylamine (1.40 mL, 0.00925 mol) was added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature then filtered over Celite. The filtrate was concentrated to give the crude product that was purified via automated flash chromatography (silica gel, 50% EtOAc in hexanes to 100% EtOAc) to give the product as a yellow solid (2.59 g, 79.3%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([N:18]3[CH2:23][CH2:22][N:21](C(=O)C)[CH2:20][CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:27][CH2:28][Cl:29])[CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[ClH:29].[CH:27]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:17])=[C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)=[CH2:28]
Reactant: CCOC(=O)c1cn(CCCl)c2cc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 88.7 %

Procedure:
A mixture of the 1-(2-chloroethyl)-6-fluoro-7-(4-acetyl-1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (65 mg) (0.153 millimole), NaOH (0.10 g), H2O (1 ml), and ethanol (1 ml) was heated at 95°-100° C. for 4 hours under stirring. After cooling, the reaction mixture was acidified with hydrochloric acid, and evaporated under vacuum. The residue was recrystallized from a mixture of water and ethanol to obtain 48 mg of 1-vinyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CBr
Reactant: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Temperature: 0 °C

Procedure:
In a three-necked round bottom flask equipped with mechanical stirring and nitrogen inlet was placed methyl bromacetate (7.82 mL, 82.6 mmol) and a suspension of N4-benzyloxycarbonyl-cytosine (9, 21 g, 82.6 mmol) and potassium carbonate (11.4 g, 82.6 mmol) in dry DMF (900 mL). The mixture was stirred vigorously overnight, filtered, and evaporated to dryness, in vacuo. Water (300 mL) and 4 N hydrochloric acid (10 mL) were added, the mixture was stirred for 15 minutes at 0° C., filtered, and washed with water (2×75 mL). The isolated precipitate was treated with water (120 mL), 2N sodium hydroxide (60 mL), stirred for 30 minutes, filtered, cooled to 0° C., and 4 N hydrochloric acid (35 mL) was added. The title compound was isolated by filtration, washed thoroughly with water, recrystallized from methanol (1000 mL) and washed thoroughly with ether. This afforded 7.70 g (31%) of pure title compound. The mother liquor from recrystallization was reduced to a volume of 200 mL and cooled to 0° C. This afforded an additional 2.30 g of a material that was pure by tlc but had a reddish color. M.p. 266-274° C. Anal. for C14H13N3O5. Found(calc.); C, 55.41(55.45); H, 4.23(4.32); N, 14.04(13.86). 1H-NMR (90 MHz; DMSO-d6): 8.02 ppm (d,J=7.32 Hz, 1H, H-6); 7.39 (s, 5H, Ph); 7.01 (d, J=7.32 Hz, 1H, H-5); 5.19 (s, 2H, PhCH2—); 4.52 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([C@@H:14]([CH2:23][O:24]S(C2C=CC(C)=CC=2)(=O)=O)[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[C@@H:10]1OS(C1C=CC(C)=CC=1)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[CH2:16]([O:15][C@H:14]1[C@@H:13]2[C@@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([C@H:11]([N:35]3[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[O:12]2)[O:24][CH2:23]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](OCc2ccccc2)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cn([C@@H]2O[C@H]3[C@@H](OCc4ccccc4)[C@@H]2OC[C@H]3OCc2ccccc2)c(=O)[nH]c1=O

Procedure:
To a stirred solution of nucleoside 17 (0.63 g, 0.81 mmol) in a mixture of ethanol and H2O (40 cm3, 1:1, v/v) at room temperature was added an aqueous solution of sodium hydroxide (1M, 7 cm3). The resulting mixture was heated under reflux for 16 h and then neutralised by addition of dilute hydrochloric acid (10 cm3). The volume of the mixture was reduced to 50% and extraction was performed using dichloromethane (50 cm3×3). The combined organic phase was dried (Na 2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1,v/v) as eluent to give nucleoside 18 as a white solid material (0.40 g, 93%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: C([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)CCC.[H]1[BH2][H][BH2]1.Cl.O>C1COCC1>[CH2:6]([C:12]1[CH:11]=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[CH2:6][NH2:5])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cc(Cl)ccc1CN
Temperature: 0 °C
Yield: 164.6 %

Procedure:
A solution of N-butyl-4-chlorobenzamide (2.26 g; 0.011 mol) in dry THF (25 ml) was added slowly to an ice-cooled solution of 1.0M B2H6 --THF complex (45 ml; 0.045 tool) under a nitrogen blanket. When addition was complete, the mixture was stirred and heated to reflux for 3 hours, cooled and decomposed by dropwise addition of 1:1 conc aq HCl-water (10 ml). The mixture was then evaporated on a rotary evaporator at 60° for 1/2 hour to decompose the boron-amine complexes. The residue was taken up in water, strongly basified with aq NaOH and extracted with CH2Cl2 (3×25 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give n-butyl-4-chlorobenzenemethanamine (1.79 g) as an oil. The oil was converted to the hydrochloride salt of the title compound (1.98 g) by crystallising from ethanolic HCl and ethyl acetate, mp 250°-252° after melting and resolidifying at 203°-207° .
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH2:13][CH2:12][C:9]2([O:11][CH2:10]2)[CH:8]([C:14]2([CH3:22])[CH:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[O:15]2)[CH:7]1[O:23][CH3:24])([OH:3])=O.C(N(CC)CC)C.C(C(Cl)=O)(C)(C)C.[CH2:39]([NH2:42])[CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][O:23][CH:7]1[CH:6]([O:5][CH2:4][C:1](=[O:3])[NH:42][CH2:39][CH2:40][CH3:41])[CH2:13][CH2:12][C:9]2([O:11][CH2:10]2)[CH:8]1[C:14]1([CH3:22])[CH:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[O:15]1
Reactant: CCCN
Reactant: COC1C(OCC(=O)O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)COC1CCC2(CO2)C(C2(C)OC2CC=C(C)C)C1OC
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a mixture of 6-carboxymethoxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]-octane (9.0 mg), triethylamine (2.5 mg), and 4-dimethylaminopyridine (0.6 mg) in dichloromethane (1 ml) was added dropwise tert-butylcarbonyl chloride (3.5 mg) under ice cooling. The mixture was stirred for half an hour at ambient temperature and propylamine (2.9 mg) was added. After stirred for 2 hours at the same temperature, the solution was washed with water, aqueous HCl solution, saturated aqueous NaHCO3 solution, and brine successively. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (diethyl ether-ethyl acetate =1-1) to give 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-propylcarbamoylmethoxy-1-oxaspiro[2,5]octane (7.6 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
6-Amino-9-benzyl-2-pentoxypurine (95 mg, 0.305 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated and dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (78 mg, yield 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[OH-:16].[Na+].O.Cl>O1CCOCC1>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([OH:16])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1nc(O)nc(NCCC)n1
Temperature: 140 °C
Yield: 74.8 %

Procedure:
A vial was charged with 6-chloro-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (XXXIV) (800 mg, 3.48 mmol), NaOH (696 mg, 17.40 mmol), water (3 mL) and 1,4-dioxane (3 mL). The reaction mixture was heated at 140° C. for 30 min under microwave irradiation. The mixture was acidified with 1N HCl to pH 5, precipitate were filtered, washed with water. The product was dissolved in 50% trifluoroacetic acid (30 mL), the indissoluble residue was filtered off. The filtrate was neutralized with saturated NaHCO3 solution, the formed precipitate was filtered, washed with water, acetone and dried to give 550 mg (75%) of 4,6-bis(propylamino)-1,3,5-triazin-2-ol (CLXXVIII). 400 MHz 1H NMR (DMSO-d6+CF3COOD, ppm) 3.18-3.34 (4H, m), 1.45-1.59 (4H, m), 0.86 (6H, t). ESI-MS (m/z): 212 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14]([O:18]C=C)[CH2:15]CC.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)(=[O:18])[CH3:15]
Reactant: COC(=O)c1ccc(Br)cc1OC
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)=O)cc1OC
Temperature: 122 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
A flask was charged with methyl 4-bromo-2-methoxybenzoate (250 mg, 1.020 mmol), vinyl butyl ether (131 μl, 1.020 mmol), potassium carbonate (169 mg, 1.224 mmol), 1,3-(bis(diphenylphosophine)propane (25.2 mg, 0.061 mmol) and palladium (II) acetate (6.87 mg, 0.031 mmol). The flask was sealed and 3 evacuation/argon purges were performed. DMF (4554 μl) and Water (546 μl) were added and the reaction was heated in a microwave at 122° C. for 75 minutes. Additional vinyl butyl ether (131 μl, 1.020 mmol) was added and the reaction was heated an additional 30 minutes in a MW at 122° C. Once complete the reaction was stirred overnight at 100° C. with conventional heating. The reaction was then cooled. HCl (5%, 8 mL) was added and the mixture was stirred for 30 minutes and then diluted with ethyl acetate and transferred to a separatory funnel. The organic layer was washed with aqueous saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-acetyl-2-methoxybenzoate (54.4 mg, 0.261 mmol, 25.6% yield). MS ESI: [M+H]+ m/z 200.1. 1H NMR (600 MHz, DMSO-d6) δ 7.70 (d, J=7.9, 1H), 7.57 (dd, J=1.1, 7.9, 1H), 7.53 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 2.49-2.44 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]3[NH:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]([O:26]C)=[O:25])[CH2:18]3)=[CH:11][CH:10]=2)=[N:7][CH:8]=1)#[N:2].N>[Ni].CO>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]3[NH:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]([OH:26])=[O:25])[CH2:18]3)=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C#N)cn3)cc2)NC1=O
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(-c2ccc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3)cc2)nc1

Procedure:
Prepared from (3S,5S)-5-[[4-(5-cyano-2-pyridyl)phenyl]oxymethyl]-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone by saponification analogously to Example 13 and subsequent hydrogenation with Raney nickel in methanol/conc. aqueous ammonia.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[O:8])[N:6]=1.[Br:33]N1C(=O)CCC1=O>>[Br:33][C:18]1[O:17][C:16]([CH2:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:8])=[N:20][C:19]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)co2)c(-c2ccccc2)s1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)c(Br)o2)c(-c2ccccc2)s1
Yield: 69.1 %

Procedure:
The title compound (0.075 g) was prepared by treating the compound of example 168 (0.093 g) with N-bromosuccinimide (0.037 g) according to the method of example 164.