Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:41]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[NH2:41][C:10]1[CH:11]=[C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
Acetic acid (R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethyl ester in a mixture of THF and toluene is stirred under hydrogen in the presence of PtO2 at room temperature for 15 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo. ES+MS m/e 549 (MH+)
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]#[N:17])[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:12]2[CH3:22])=[CH:7][CH:6]=1)C.O.[OH-].[Li+].Cl>C(O)C.O>[CH2:18]([C:13]1[C:14]([C:16]#[N:17])=[CH:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:23])=[O:3])=[CH:10][CH:9]=2)[C:12]=1[CH3:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(C#N)cn(-c2ccc(C(=O)OCC)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1c(C#N)cn(-c2ccc(C(=O)O)cc2)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A suspension of 4-(3-butyl-4-cyano-2-methylpyrrole-1-yl)benzoic acid ethyl ester (0.030 g) and lithium hydroxide mono hydrate (0.041 g) in ethanol (2 mL) and water (1 mL) was stirred at 50° C. for 2 hours. To this reaction mixture was added 1 mol/L hydrochloric acid (5 mL), and this mixture was stirred at room temperature for 30 minutes. This reaction mixture was extracted with ethyl acetate, and this organic layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.027 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][O:26][C:27]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: COc1cccc(C(=O)Cl)c1OC
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1OC
Yield: 54.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100 mg, 0.315 mmol) obtained in Example 1, (3), and 2,3-dimethoxybenzoyl chloride (0.473 mmol), the title compound (83 mg, yield 55%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][OH:14]>>[OH:14][N:13]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)c1cccc(O)c1
Reactant: NO
Product: O=C(O)C(=NO)c1cccc(O)c1
Reaction time: 0.42 h

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and 1 N-methanol solution of hydroxylamine (45 ml.) were refluxed with stirring for 25 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1 N-aqueous solution of sodium hydroxide (70 ml.). An aqueous solution was washed with ether, acidified with dil. hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with an activated charcoal. The solvent was distilled off to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (2.9 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](Cl)[C:12]=3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1.[OH:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17]([N:28]4[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][OH:22])[CH2:26][CH2:27]4)[C:12]=3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1nc(Cl)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCC(CCO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g), 4-(2-hydroxyethyl)piperidine (3.2 g), N,N-diisopropylethylamine (3.2 g) in ethanol (15 mL) was heated at reflux for 5.5 hours. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=2:1) to obtain 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol as a white solid (6.41 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:29][C@H:30]2[O:32][CH2:31]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:29][C@@H:30]2[CH2:31][O:32]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
4-Benzyloxyphenol (15.00 g, 74.91 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added to a solution of sodium hydride (60% dispersion in oil) (2.88 g, 74.9 mmol) in N,N-dimethylformamide (50 mL). The solution was stirred for 30 minutes and (S)-(+)-glycidyl 4-methylbenzenesulfonate (17.12, 75.0 mmol) was added. The mixture was heated to 80° C. for 2 hours. The solvent was removed and the residue partitioned between diethyl ether and water. The organic phase was washed with brine-and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo. To yield the title compound as a white solid (13.6 g, 53.3 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][CH2:24][C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1nccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2nccs2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-thiazolyl)pentanoate (1.5 eq., prepared in Synthetic Example 24) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(thiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 198 to 199° C./DMF, wherein the product was purified through flash column chromatography and recrystallization.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].N1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S(Cl)(Cl)=O.[CH2:29](OCC)C>>[C:20]1([O:5][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH3:15])[CH:29]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOCC
Reactant: CC(=CC(=O)O)CCC=C(C)CCC(C)=C(C)C
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(=CC(=O)Oc1ccccc1)CCC=C(C)CCC(C)=C(C)C
Reaction time: 1.25 h

Procedure:
To 10 g. of 3,7,10,11-tetramethyl-2,6,10-dodecatrienoic acid and 3.8 ml. of absolute pyridine in 80 ml. of absolute diethyl ether, 5.4 ml. of thionyl chloride were added dropwise under cooling. The reaction mixture was continually stirred for 75 minutes at 0°-2°C. Thereafter, the resulting mixture was filtered with precipitated pyridine hydrochloride and the filtrate was evaporated under vacuum. After evaporation, the residue was mixed into 20 ml. of absolute benzene. To this reaction mixture there was added dropwise 3.9 g. of phenol and 3.8 ml. of absolute pyridine in 170 ml. of absolute benzene. This addition was carried out dropwise. The resulting reaction mixture was continually stirred at room temperature for 2 hours. After this period, the reaction mixture was poured over dilute ice-cold hydrochloric acid and exhaustively extracted with benzene. The combined benzene extracts were diluted with an aqueous sodium bicarbonate solution. After this, the dilute extract is washed with a saturated sodium chloride solution and dried over sodium sulfate and evaporated. By chromatography on Kieselgel with hexane/diethyl ether (95:5 parts by volume) there is obtained pure 3,7,10,11-tetramethyl-2,6,10,-dodecatrienoic acid phenyl ester; b.p. 135°-140°C./0.001 mmHg (bulb tube distillation).
Reaction SMILES: [F:1][C:2]([F:31])([C:27]([F:30])([F:29])[F:28])[C:3]([F:26])([F:25])[C:4]([P:7]([C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=[O:11])[O:8]CC)([F:6])[F:5].[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[F:31][C:2]([F:1])([C:27]([F:28])([F:29])[F:30])[C:3]([F:25])([F:26])[C:4]([P:7]([C:12]([F:24])([F:23])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=[O:8])[O-:11])([F:6])[F:5].[CH2:36]([N+:35]1[CH:27]=[CH:2][N:33]([CH3:32])[CH:34]=1)[CH3:37]
Reactant: Cn1ccnc1
Reactant: CCOP(=O)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CC[n+]1ccn(C)c1
Product: O=P([O-])(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 41 h
Yield: 95 %

Procedure:
Ethyl bis(nonafluorobutyl)phosphinate, (C4F9)2P(O)OC2H5, (3.834 g; 7.2 mmol) is slowly added to cooled (0° C.) N-methylimidazole (0.458 g; 5.6 mmol) in a 25 ml glass flask. An exothermic reaction and two orange phases are observed. After a few minutes, a green-coloured, more highly viscous solution forms. This is stirred at 0° C. for 2.5 h and at room temperature for 41 h. 1-Ethyl-3-methylimidazolium bis(nonafluorobutyl)phosphinate, [EMIM][(C4F9)2P(O)O], (3.233 g; 5.3 mmol) can be isolated as a highly viscous, green liquid in a yield of 95% and a purity of 95% by purification in vacuo (10−3 mbar) at room temperature to 50° C.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1[N:55]=[C:54]([CH:56]2[CH2:60][CH2:59][CH2:58][NH:57]2)[O:53][N:52]=1>>[C:28]([C:32]1[N:33]=[C:34]([N:57]2[CH2:58][CH2:59][CH2:60][CH:56]2[C:54]2[O:53][N:52]=[C:51]([CH3:50])[N:55]=2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: Cc1noc(C2CCCN2)n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: Cc1noc(C2CCCN2c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methyl-5-(pyrrolidin-2-yl)-1,2,4-oxadiazole. MS(m/e): 453.4
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1[C:19](=[O:20])[CH2:18]CC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[O-]CC.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)C>[CH2:19]([O:20][CH:12]1[C:13]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][CH2:10][O:11]1)[CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cccc2c1COCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1OCOc2cccc([N+](=O)[O-])c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred solution of 5-nitro4H-1,3-benzodioxine (10.0 g, 55.203 mmol) in carbon tetrachloride (70 mL) were added N-bromosuccinimide (10.808 g, 60.723 mmol) and 2,2′-azobisisobutyronitrile (0.906 g, 5.520 mmol). The mixture was stirred at 100° C. for 2 hrs. After cooled to room temperature, a solution of sodium ethoxide (4.884 g, 71.764 mmol) in ethanol (70 mL) was added to the mixture, and the stirring was continued at room temperature for 3 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give 4-ethoxy-5-nitro-4H-1,3-benzodioxine as a pale yellow oil (10.8 g, yield; 87%).
Reaction SMILES: C(O[C@@H:6]1[O:20][C@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@H:7]1[O:8][C:9](=[O:12])[CH2:10][CH3:11])(=O)CC.[C:33]1([OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:9]([O:8][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[O:20][C@H:6]1[O:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: Oc1ccccc1
Reactant: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](Oc2ccccc2)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Reaction time: 8 h
Yield: 75.7 %

Procedure:
1,2,3,5,6-Penta-O-propanoyl-β-D-glucofuranose (1.0 g, 2.2 mmol) and phenol (0.41 g, 4.3 mmol) were dissolved in CH2Cl2 (10 mL) and boron trifluoride diethyl etherate (134 μL, 1.1 mmol) was added dropwise. The solution was left at room temperature overnight by which time the reaction was complete by TLC. The reaction mixture was washed with saturated aqueous NaHCO3 (30 mL), water, dried (MgSO4) and concentrated in vacuo. Flash silica chromatography of the residue, eluting with 15% ethyl acetate in petroleum ether, gave phenyl 2,3,5,6-tetra-O-propanoyl-β-D-glucofuranoside as a colourless syrup (0.8 g, 77%); δH (CDCl3) 7.29 (2H, dd, J 7.4 and 8.4, 3′-and 5′-H), 7.02 (1H, t, J 7.4, 4′-H), 7.01 (2H, d, J 8.4, 2′- and 6′-H), 5.63 (1H, s, 1-H), 5.46 (1H, d, J 5.0, 3-H), 5.31 (1H, ddd, J 9.4, 4.6 and 2.4, 5-H), 5.27 (1H, s, 2-H), 4.62 (1H, dd, J 9.4 and 5.0, 4-H), 4.54 (1H, dd, J 12.3 and 2.4, 6a-H), 4.09 (1H, dd, J 12.3 and 4.6, 6b-H), 2.42 (2H, q, J 7.5, CH2), 2.39 (2H, q, J 7.5, CH2), 2.33 (2H, q, J 7.5, CH2), 2.25 (2H, q, J 7.5, CH2), 1.17 (3H, t, J 7.5, CH3), 1.15 (3H, t, J 7.5, CH3), 1.13 (3H, t, J 7.5, CH3), 1.08 (3H, t, J 7.5, CH3); δC (CDCl3) 174.3, 173.3, 173.3, 173.0 (4×C═O), 156.6 (1′-C), 130.0 (3′- and 5′-C), 122.9 (4′-C), 116.9 (2′- and 6′-C), 104.6 (1-C), 80.7 (2-C), 79.7 (4-C), 73.6 (3-C), 68.9 (5-C), 63.2 (6-C), 27.8, 27.8, 27.8, 27.7 (4×CH2), 9.4, 9.2, 9.2, 9.1 (4×CH3).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16](N(CC)CC)C.[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32]N[CH2:30][CH2:29]1)=[O:27])[CH3:24]>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH:16]2[CH2:32][CH2:33][N:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH2:29][CH2:30]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(C2CCN(C(=O)OCC)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate (10.0 g, 46.91 mmol) prepared in the Step 1-1-1 was dissolved in ethanol (100 ml). To the solution, triethylamine was added and then ethoxycarbonylpiperazine (49.26 mmol) was added, and the mixture was stirred at a room temperature for 18 hours. After the mixture was concentrated, ethyl acetate was added thereto. The resulting mixture was washed with a saturated sodium bicarbonate solution and a saturated saline solution in order. The washed product was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1-1:1) to give the title compound (17.4 g, quantitative) as a yellowish-brown oily substance.
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)[NH:3]1.C([Li])CCC.[C:16](#N)[C:17]1C=C[CH:20]=[CH:19][CH:18]=1.C1C[O:27]CC1>>[CH3:9][C:4]1[NH:3][C:2]([C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:6](=[O:27])[CH:5]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: C1CCOC1
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Product: Cc1cc(=O)cc(-c2ccccc2)[nH]1
Temperature: -56 °C

Procedure:
To a −78° C. cooled solution of 2,2,6,6-tetramethylpiperidine (157 g) in THF (830 mL) was added n-butyllithium (1.6 M in hexane, 697 mL) over 45 min. After 25 min stirring at −78° C. a solution of intermediate 1.4 (63 g) in THF (200 mL) was added to the mixture over 25 min, followed by a solution of benzonitrile (47.9 mL) in THF (200 mL) over 30 min. The cooling bath was removed and the mixture was allowed to warm to −56° C. over 1.5 h. HCl (32%, 186.5 g) was added, followed by water (400 mL) and THF (200 mL). The phases were separated. The org. phase was washed with water and HCl (32%, 150 mL) was added, followed by water (200 mL). The phases were separated and the aq. phase was evaporated off. The residue was taken up in toluene and evaporated to dryness to afford 249 g of the desired compound with 13% purity. No further purification was performed.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=2[C:5](=[O:31])[NH:4][C:3]1=[O:32].CS(O[CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:6]=2[C:5](=[O:31])[N:4]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])[C:3]1=[O:32]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Reactant: CS(=O)(=O)OCCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCC(F)(F)F)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 1.06 mmol, intermediate 12, step 2) in DMF (6 mL) was added 3,3,3-trifluoropropyl methanesulfonate (305 mg, 1.59 mmol) followed by potassium carbonate (439 mg, 3.17 mmol). The reaction was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate and extracted with brine. The organic phase was dried and concentrated to give 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (510 mg, 84.6% yield) as yellow syrup. LCMS retention time 2.275 min; LCMS MH+ 569.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12]O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].S(Cl)([Cl:16])=O.C1COCC1>ClC(Cl)C>[Cl:16][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)C1CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)C1CCN(CCCl)CC1
Temperature: 74 °C
Yield: 59.3 %

Procedure:
A mixture of 2-(4-(methylsulfonyl)piperidin-1-yl)ethanol (620 mg, 2.99 mmol) and thionyl chloride (1.092 mL, 14.95 mmol) in dichloroethane (5 mL) was heated up at 74° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to provide the crude, to the crude was added THF (10 mL), the grey precipitate was observed and collected. The solid was dried under vacuum for 20 hour to provide the desired product as grey solid (400 mg, 59%). LCMS: m/e 226.1 (M+H)+, 1.00 min (method 6).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CS(C)=O.Cl.[NH2:38][OH:39]>C(N(CC)CC)C>[OH:39][NH:38][C:29](=[NH:30])[CH2:28][CH:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: NO
Reactant: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N=C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)NO
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of (4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile (0.15 g, 0.34 mmol, 1.0 equiv) in 4 Ml DMSO was added hydroxylamine hydrochloride (0.12 g, 1.7 mmol, 5.0 equiv) and triethylamine (0.25 Ml, 1.8 mmol, 5.2 equiv). The yellow solution was heated to 120° C. using microwave heating for 10 min. Additional portions of hydroxylamine hydrochloride and triethylamine were added, and the reaction was allowed to stir overnight at 75° C. The reaction was partitioned between EtOAc and water, and the organic extracts were washed with saturated NaHCO3 followed by brine. The organic layer was then dried over sodium sulphate, filtered, and concentrated in vacuo to afford the title compound which was used without further purification: (M+H)+ 471.2.