Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[CH:20][C:15]([C:16](=O)[CH2:17]Br)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][CH:17]=[C:16]([C:15]2[CH:20]=[CH:21][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: NC(=O)c1sccc1Cl
Product: FC(F)(F)c1ccc(-c2coc(-c3sccc3Cl)n2)cc1
Temperature: 150 °C
Yield: 6 %

Procedure:
3-Chloro-thiophene-2-carboxamide (0.145 g, 0.898 mmol) and 4-trifluoromethyl-phenacyl bromide (0.200 g, 0.749 mmol) were placed in a sealed tube and heated at 150° C. for 4 h. The reaction mixture was quenched with ethyl acetate and the residue was purified by column chromatography (gradient 100:1, 20:1 hexane:dichloromethane). The product was further purified by preparative-TLC (100:1, hexane:dichloromethane) to yield 0.0148 g (5.0%) of the title compound as a white solid. 1H NMR (Acetone-d6): 8.58 (s, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.71 (t, 3H), 7.10 (d, J=5.1 Hz, 1H), 7.08 (d, J=5.7 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH3:11][C@H:12]([CH2:28][CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1.O>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]([O:20][Si:2]([CH3:4])([CH3:3])[CH3:1])([C@H:12]([CH3:11])[CH:28]=[CH2:29])[CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC[C@@H](C)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@@H](C)[C@@](Cn1cncn1)(O[Si](C)(C)C)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 114.7 %

Procedure:
2.47 ml (19.4 mmole) of trimethylsilyl chloride and 1.7 g (24.3 mmole) of imidazole were added to a solution of 900 mg (3.24 mmole) of (2R*,3R*)-3-methyl-2-(4-chlorophenyl) -(1H-1,2,4-triazol-1-yl)-2-pentanol in 20 ml of N,N-dimethylformamide, and then the mixture was stirred at 50° C. for 4 hours. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure to give 1.3 g of the title compound in the form of a crude oil.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([SH:11])[CH3:10].[NH2:12][C:13]1[N:21]=[C:20](Cl)[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Na+].O>[NH2:12][C:13]1[N:21]=[C:20]([S:11][CH:9]([CH3:10])[CH3:8])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)S
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol 60% in mineral oil) were added 2-propanethiol (1.0 ml, 11 mmol) and 6-amino-9-benzyl-2-chloropurine (160 mg, 0.62 mmol) in order. The mixture was stirred under heating at 100° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (112 mg, yield 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1)([O-:3])=[O:2].CO[C:16](OC)([CH3:18])[CH3:17]>CC(C)=O.S(=O)(=O)(O)O>[CH3:17][C:16]1([CH3:18])[O:13][C@@H:10]([CH2:9][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:11][O:12]1
Reactant: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
A solution of (S)-3-(3-nitro-pyrazol-1-yl)propane-1,2-diol (1.00 g, 5.35 mmol) in acetone (10 mL) was treated with concentrated sulfuric acid (5 drops) and 2,2-dimethoxypropane (3.34 g, 32.09 mmol). The reaction mixture was stirred for 5 h at room temperature. Upon completion of the reaction the mixture was concentrated at reduced pressure and then diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 80% ethyl acetate/hexanes) to afford 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (0.70 g, 58%) as a yellow oil: LR-ES-MS m/z calculated for C9H13N3O4 [M]+ 227, observed 228 [M+H]+.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]O)[CH2:17][CH2:16]1>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:22][CH2:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCC1CCNCC1
Product: c1ccc(C(OCCC2CCNCC2)c2ccccc2)cc1
Yield: 94 %

Procedure:
Using benzhydrol and 4-piperidineethanol, the procedure of Reference Example 23 was otherwise repeated to provide the title compound. Yield 94%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH2:16])=[S:15])[CH2:3][S:2]1.[CH3:17]I>CC(C)=O>[CH3:17][S:15][C:14](=[NH:16])[NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:1][S:2][CH2:3]1
Reactant: NC(=S)Nc1ccccc1N1CCOSC1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccccc1N1CCOSC1

Procedure:
A mixture of 1-(2-thiamorpholinophenyl)thiourea (12.6 g), methyl iodide (7.1 g) and acetone (60 ml) was heated at 90°-95° C. for 21/2 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-thiamorpholinophenyl)-2-thiopseudourea hydroidide (m.p. 176°-177° C.).
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.O>[N:20]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19])=[N+:21]=[N-:22]
Reactant: O=C1C(Cl)CCc2ccccc2N1c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCc2ccccc2N(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A suspension of 5.0 g (0.0184 mole) of 3-chloro-1-phenyl-2,3,4,5-tetrahydro-1-benzoazepin-2(1H)-one and 1.8 g (0.0277 mole) of sodium azide suspended in 50 ml of dimethylformamide was stirred at a bath temperature of 80° C. overnight. Next, to the mixture was added 1.0 g (0.0154 mole) of sodium azide, and the mixture was stirred for 8 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried, and the solvent was removed under reduced pressure to obtain a residue. The residue was recrystallized from ethyl acetate to obtain 3.58 g of the title compound as colorless crystals.
Reaction SMILES: CC(C)C[N:4]1[C:8]2=[C:9]3[N:19]=[CH:18][N:17]=[C:10]3[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[N:7]2N=N1.[H][H]>[Pt]=O.FC(F)(F)C(O)=O.Cl>[CH3:10][CH:11]([CH3:12])[CH2:16][N:17]1[C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:16]=3[N:7]=[C:8]([NH2:4])[C:9]=2[N:19]=[CH:18]1
Reactant: [H][H]
Reactant: CC(C)Cn1nnn2c3ncccc3c3ncnc-3c12
Agent: O=[Pt]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)CCCN3

Procedure:
Platinum oxide catalyst was added to a solution of 1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure for 5 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with water and sodium bicarbonate. The resulting precipitate was isolated by filtration. The solid was dissolved in 1N hydrochloric acid and charcoal filtered. The filtrate was treated with 10% sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethyl acetate/methanol. The recrystallized material was dissolved in dichloromethane/methanol and placed on a silica gel column. The column was eluted with 10% methanol in ethyl acetate. The eluant was concentrated under vacuum and the residue was recrystallized from methanol/water to provide 0.9 g of 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine as a solid, m.p. 231-233° C. Analysis: Calculated for C13H19N5: %C, 63.65; %H, 7.81; %N, 28.55. Found: %C, 62.99; %H, 7.74; %N, 28.33.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:14]4[O:22][CH:21]=[CH:20][C:15]=4[CH:16]=[N:17][C:18]=3[NH2:19])=[N:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:14]5[O:22][CH:21]=[CH:20][C:15]=5[CH:16]=[N:17][C:18]=4[NH2:19])=[N:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3nnc(COc4c(N)ncc5ccoc45)n3n2)cn1

Procedure:
A mixture of 7-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]furo[3,2-c]pyridin-6-amine (15.0 mg, 0.047 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.7 mg, 0.095 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (19.6 mg, 0.142 mmol) and 4:1 dioxane:water (2 mL) was microwaved at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z 363.06 (100) [MH+]. HPLC: tR=1.89 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>ClCCl.C(C1C(C)=CC=C(O)C=1C(C)(C)C)(C)(C)C>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: C=C(C)C(=O)Cl
Agent: Cc1ccc(O)c(C(C)(C)C)c1C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCC[Si](OC)(OC)OC
Reaction time: 1 h
Yield: 71.6 %

Procedure:
77.4 g 3-(amino)propyltrimethoxysilane, 43.7 g triethylamine and 25 mg di-tert-butyl-p-cresol were dissolved in 500 ml dichloromethane under argon. 45.1 g methacryloyl chloride was slowly added dropwise within 1 h at −5° C., after which stirring was continued for a further 1 h at 0° C. The precipitated hydrochloride was filtered off and washed again with dichloromethane. The volatile components were removed at 40° C. under reduced pressure on the rotary evaporator. A yellow liquid with separated solid (hydrochloride) remained. The precipitation of the hydrochloride was completed by adding 150 ml diethyl ether, the precipitate was filtered off and the filtrate concentrated to small volume by introducing dry air at 40° C. on the rotary evaporator. The brownish liquid was freed from the remaining volatile components at 4 Pa (4×10−2 mbar) and the crude product (104.2 g) was distilled at a pressure of 0.06 Pa (6×10−4 mbar). The product had a boiling point of 123-125° C. 76.4 g product was obtained as a yellowish clear liquid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:9][CH2:10][S:11](Br)(=[O:13])=[O:12]>C(Cl)Cl>[Br:9][CH2:10][S:11]([CH:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Br)CBr
Reactant: C=C1CCCCCC1
Solvent: ClCCl
Product: O=S(=O)(C=C1CCCCCC1)CBr
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of methylenecycloheptane (3.3 g) and bromomethanesulfonyl bromide (7.14 g) in methylene chloride (10 mL) was irradiated at -20° C. with an ultraviolet lamp for 1 hour. Evaporation of the solvent gave a solid which was washed with pentane. This solid (9.7 g) was dissolved in methylene chloride (150 mL), chilled in ice and treated dropwise with a solution of triethylamine (3.3 g) in methylene chloride (20 mL). The reaction mixture was stirred for 0.5 hours, washed with dilute HCl and water. The organic layer was separated, dried over anhydrous magnesium sulfate and the methylene chloride removed in vacuo to give oily bromomethanesulfonylmethylene cycloheptane (7.0 g, 96% yield) which was characterized by IR and NMR spectroscopy.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[C:12]([CH2:33][CH3:34])=[CH:13][C:14]4[C:26](=[O:27])[C:25]5[C:24]6[C:19](=[CH:20][C:21]([C:28]#[N:29])=[CH:22][CH:23]=6)[NH:18][C:17]=5[C:16]([CH3:31])([CH3:30])[C:15]=4[CH:32]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:33]([C:12]1[C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:32][C:15]2[C:16]([CH3:31])([CH3:30])[C:17]3[NH:18][C:19]4[C:24]([C:25]=3[C:26](=[O:27])[C:14]=2[CH:13]=1)=[CH:23][CH:22]=[C:21]([C:28]#[N:29])[CH:20]=4)[CH3:34]
Reactant: CCc1cc2c(cc1N1CCC3(CC1)OCCO3)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reaction time: 17 h
Yield: 64 %

Procedure:
8-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, which had been prepared in Example 809, was dissolved in THF (10 ml), added with 5 N hydrochloric acid (50 ml), and the mixture was stirred for 17 hrs. The reaction mixture was neutralized with 5 N aqueous solution of sodium hydroxide and diluted with ethyl acetate (200 ml). The organic layer was washed with 10% brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (2.9 g, two step yield 64%).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[CH:15]=[CH:14][C:13]3[C:17]4[C:22]([CH:23]=[CH:24][C:12]=3[C:11]=2[NH:10][C:9]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=[CH:19][CH:18]=4>C(Cl)Cl.CCCCCC>[CH3:5][N:10]1[C:11]2[C:12]3[CH:24]=[CH:23][C:22]4[C:17]([C:13]=3[CH:14]=[CH:15][C:16]=2[CH:8]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:19]=[CH:20][CH:21]=4
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2[nH]1
Reactant: COS(=O)(=O)OC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2n1C
Yield: 74.5 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-naphth[1,2-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 74.5% yield of ethyl 3-methyl-3H-naphth[1,2-g]indol-2-carboxylate, mp 136°-138°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC[C@@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC[C@@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
2-{[(1R)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.05 g, 16.54 mmol) was dissolved in chloroform (30 ml) and cooled to 0° C. To this solution N-bromosuccinimide (3.24 g, 18.19 mmol) was added portionwise keeping the temperature below 2° C. This gave a dark green solution which was stirred at 0° C. for 30 minutes before allowing to warm to room temperature and stirring for 6 hours. The reaction mixture was washed with water (2×50 ml) and the layers separated using hydrophobic frit. The organic layer was concentrated to give a dark brown gum which was dissolved in dichloromethane and purified by chromatography silica (100 g) using a 0-50% gradient of ethyl acetate-cyclohexane over 60 mins on a Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (5.23 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:48][CH:49]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:50]1[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=1>C(OCC)(=O)C>[OH:1][C:2]1[C:7]([C:8]([NH:48][CH:49]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:50]2[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cn1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h, (1 g, 4.6 mmol) in ethyl acetate (20 ml) was added HATU (1.75 g, 4.6 mmol), Et3N (465 mg, 4.6 mmol) and diethyl {5-[amino(phenyl)methyl]pyridin-2-yl}phosphonate (4-g) (1.47 g, 4.6 mmol). The resulting mixture was stirred at room temperature for 2 hour. Then it was filtered before diluted with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography to provide the product, 4-1, (360 mg, 15%). 1H NMR (CD3OD, 300 MHz,): δ 10.56 (m, 1H), 8.66 (m, 3H), 8.37 (m, 1H), 7.83 (m, 3H), 7.52 (m, 1H), 7.23 (m, 5H), 6.33 (m, 1H), 4.09 (m, 4H), 1.30 (m, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:34]1[CH2:35][CH2:36][CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:32][CH2:33]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Temperature: 25 °C
Yield: 60.75 %

Procedure:
The compound 2 (0.31 g, 0.8 mmol), 4-phenylpiperidine (0.2 g, 1.2 mmol) and K2CO3 (0.166 g, 1.2 mmol) were added to 50 mL CH3CN, and the solution was refluxed under argon atmosphere for 16 h. After cooling to room temperature, the solvent was evaporated to dryness. Purification was carried out on a silica gel TLC plate that was developed in 4% methanolic NH3 (7 M NH3 in methanol)/96% CH2Cl2. The product was obtained as pale yellow oil (60.75%). 1H NMR (CDCl3) δ 8.489 (dd, 1H, Ar), 7.624 (ddd, 1H, Ar), 7.572 (d, 1H, Ar), 7.497 (dd, 1H, Ar), 7.290 (t, 2H, Ar), 7.203 (m, 4H, Ar), 7.106 (m, 1H, Ar), 6.936 (ddd, 1H, Ar), 6.836 (d, 1H, Ar), 3.792 (s, 3H, —OCH3), 3.763 (s, 2H, —CH2—), 3.667 (s, 2H, —CH2—), 3.063 (m, 2H, —CH2—), 2.486 (t, 3H, —CH—CH2—), 2.336 (s(br), 2H, —CH2—), 2.041 (s(br), 2H, —CH2—), 1.836 (s(br), 4H, —CH2—CH2—), 1.543 (m, 4H, —CH2—CH2—), 1.300 (m, 2H, —CH2—), 1.238 (m, 2H, —CH2—). Mass Spect.=471.68 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]#[N:21])=[CH:4][N:3]=1.CS(O)(=O)=[O:24]>>[NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:16])[F:17])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]([NH2:21])=[O:24])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)O
Reactant: Cn1c2cc(C(F)(F)F)ccc2c2c(N)ncc(C#N)c21
Product: Cn1c2cc(C(F)(F)F)ccc2c2c(N)ncc(C(N)=O)c21
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A suspension of the product of Step 3 in a 1:1 (mass/mass) mixture of PPA/CH3SO3H (0.034 M) was stirred for 90 min at 120° C. The resulting mixture was then added to ice-cold saturated NaHCO3 solution, stirring until all the reagent was consumed and the pH was 7-8. The crude material was collected by filtration, and was purified by preparative TLC, eluting with 1:20 MeOH:EtOAc to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>O1CCOCC1>[C:30]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22])(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: N#Cc1ccc(N=Nc2ccc(OCCO)c(C#N)c2)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1C#N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
5.8 g (4-(2-hydroxyethyloxy)-3,4′-dicyanoazobenzene are dissolved in 15 ml dioxane at 65° C.; 2.4 g triethylamine are added. A solution of 3.1 g methacrylic acid chloride in 3 ml dioxane is added and the reaction mixture is stirred at 65° C. for 2 h and then introduced into 350 ml ice-water. The precipitate is filtered off with suction and dried. Purification is carried out by chromatography on silica gel in toluene/THF (½). The yield of 4-(2-methacryloyloxyethyloxy)-3,4′-dicyanoazobenzene is 5.9 g. M.p.=110° C.; max=352 nm (DMF).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[I-:12].[K+].C(OCC)(=O)C>C(O)(=O)C>[Cl:8][C:7]1[C:2]([I:12])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: [I-]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(I)c(Cl)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 2,3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100° C. for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 mL) added. The organic phase was separated and washed with water (2×100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g).