Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH:15]([OH:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH:15]([OH:17])[CH3:16])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: CC(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)Cn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 80 °C

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (40.0 g; 147 mmol) in DMF (200 ml) was added over 15 minutes to a suspension of NaH (6.5 g, 162 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (320 ml) with stirring and under an inert atmosphere. After stirring for 35 minutes, a solution of 1-bromo-2-propanol (26.8 ml; 221 mmol) in DMF (80 ml) was added dropwise. The reaction mixture was heated at 80° C. for 2 hours and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (480 ml, 2/1) was added. The organic phase was extracted with DCM (2×160 ml). The combined organic phases were washed with water (3×400 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The 1-(3,5-dibromo-4-nitropyrazol-1-yl)-propan-2-ol was obtained as a white solid (23.3 g; 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11](OC)=[C:10](OC)[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=CC=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1C2C(=CC=CC=2)C=CC=1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]2[C:10](=[CH:24][CH:23]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (2.6 mL, 20 mmol), aluminum chloride (2.9 g, 22 mmol) and 2-naphthoyl chloride (3.9 g, 20 mmol) with a reaction time of 4 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 4.52 g (77%) of the product as a white solid: mp 120-121.5° C.; 1H NMR (CDCl3) δ 8.24 (s, 1 H), 8.03-7.84 (m, 4 H), 7.68-7.40 (m, 4 H), 7.00-6.87 (m, 1 H), 3.97 (s, 3 H), 3.95 (s, 3 H); 13C NMR (CDCl3) δ 195.5, 153.0, 149.0, 135.5, 134.9, 132.2, 131.0, 130.4, 129.2, 128.1, 128.0, 127.8, 126.7, 125.9, 125.4, 112.2, 109.8, 56.1, 56.0; Anal. Calcd for C19H16O3. Theoretical: C, 78.06; H, 5.52. Found: C, 77.73; H, 5.69.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.C(N1C=CN=C1)CCC.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:29][CH:28]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[N:3]=[CH:4][C:5]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCn1ccnc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(F)nc2)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (900 mg, 4.03 mmol), anhydrous copper acetate (550 mg, 3.03 mmol), 1-butylimidazole (175 mg, 1.41 mmol), N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (418 mg, 2.02 mmol) and pyridine (0.326 ml, 4.03 mmol) were admixed with 25 ml of toluene, and stirred at 100° C. for 15 h, under argon. The reaction mixture was filtered and the filtrate was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 394 mg (32%), M+H+: 303.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:12]1([Li])C=CC=CC=1.[C:19](=[O:21])=[O:20]>CCOCC>[CH3:12][O:20][C:19]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:21]
Reactant: O=C=O
Reactant: [Li]c1ccccc1
Reactant: Cc1cnc2c(c1)CCCC2
Solvent: CCOCC
Product: COC(=O)C1CCCc2cc(C)cnc21

Procedure:
A 3-necked flask is charged with 3-methyl-5,6,7,8-tetrahydroquinoline (45 g. 0.29 moles) and ether (400 ml). Phenyl lithium solution (330 ml. of a 1 molar solution 0.3 moles in ether is added to the stirred solution at a rate to give gentle reflux. Reflux is maintained for 2 hours. After cooling in an ice-bath CO2 is bubbled through the resulting red solution of 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline till no further colour change. The mixture is further treated with methanolic HCl as described in Example 24 of copending U.S. Ser. No. 460,265 to give methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=1.CC1(C)C(C)(C)OB([C:77]2[CH:82]=[CH:81][C:80]([OH:83])=[CH:79][CH:78]=2)O1>>[OH:83][C:80]1[CH:81]=[CH:82][C:77]([C:61]2[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=2)=[CH:78][CH:79]=1
Reactant: N#Cc1ncccc1Cl
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: N#Cc1ncccc1-c1ccc(O)cc1

Procedure:
The title compound 58A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 3-chloropicolinonitrile and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively. ESI (+)/LC/MS: 197 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].N1C=NC=N1.[OH-:12].[Na+].O[C:15]1([Cl:25])[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][CH:16]1[CH2:17][CH2:18]Cl>O.CS(C)=O>[OH:12][CH:17]([C:16]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=1[Cl:25])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: [OH-]
Reactant: c1nc[nH]n1
Reactant: OC1(Cl)C=C(Cl)C=CC1CCCl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a dimethyl sulfoxide solution (50 ml) of sodium 1,2,4-triazole, generated from 3.25 g (0.047 m) of 1H-1,2,4-triazole, and 1.9 g (0.047 m) of sodium hydroxide, is added 10 g (0.045 m) of 2-hydroxy-2,4-dichlorophenethyl chloride dropwise at 110° under nitrogen. The reaction is stirred at 110° for 11/2 hours. The reaction mixture is poured into water and extracted with methylene chloride. The combined organic extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 8 g of product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=C(C#N)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-:17].[Na+].Cl.[CH3:20][CH2:21][OH:22]>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:20]([C:21]([OH:17])=[O:22])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CCO
Reactant: CC(C)(C)c1ccc2nc(C#N)ccc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc2nc(C(=O)O)ccc2c1

Procedure:
A solution of 6-tert-butylquinoline-2-carbonitrile (295 mg, 1.40 mmol) and 2M-aqueous sodium hydroxide (3 ml) in EtOH (4.5 ml) was stirred for 4 hours at reflux. The mixture was diluted with water (10 ml), neutralized by 2M-aqueous hydrochloride and extracted with EtOAc (30 ml). The organic layer was dried over sodium sulfate, filtrated, and concentrated in vacuo to furnish the title compound (313 mg, quant.) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH2:14]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH3:15]>>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([N:16]([CH2:14][CH3:15])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: CCNc1cccc2ccccc12
Agent: Cl
Product: CCc1cccc(N(C)C(=N)N(CC)c2cccc3ccccc23)c1
Reaction time: 14 h
Yield: 71 %

Procedure:
In a 5 ml round bottom flask was placed N-(3-ethylphenyl)-N-methylcyanamide (626 mg, 3.91 mmol), N-ethyl-N-(1-naphthyl)amine hydrochloride (859 mg, 4.15 mmol) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath and allowed to stir under N2 for 14 h. The resultant brown glass was dissolved in methanol (6 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (25 ml) and extracted with CHCl3 (5×20 ml) to yield a brownish green oil (920 mg). A TLC of this oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/EtOH 20:1 (TLC Rf =0.064, CHCl3 :EtOH, 1:1) to afford a pale greenish viscous oil, 460 mg (35.5%). IR (neat) 3484, 3394 (--NH), 1635 (--C=NH). 1H-NMR (CDCl3) δ1.00 (t, 3H, J=7.5), 1.14 (t, 3H, J=6.6), 2.32 (q, 2H, J=7.5), 2.91 (s, 3H), 3.72 (q, 2H, J=6.6), 5.62 (s, 1H), 6.34-7.73 (m, 11H, H-aromat). 13C-NMR (CDCl3) CN3, 162.2; Ar, 145.9, 144.0, 140.3, 133.7, 130.3, 127.9, 127.5, 125.5, 125.1, 125.0, 124.5, 124.4, 122.7, 122.6, 122.4, 120.4; NCH2, 46.2; NCH3, 39.1; CH2, 27.9; CH3, 14.8; CH3, 12.5. Mass Spec. m/e calcd for C22H25N3, 331.2048, Found, 331.2046.
Reaction SMILES: [C:1]([O:10]CC(CO)O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N:16]([CH2:23][CH2:24][OH:25])([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19].C(OC)(=O)C1C(=CC=CC=1)O.C[O-].[Na+]>>[C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N:16]([CH2:23][CH2:24][OH:25])([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19]
Reactant: O=C(OCC(O)CO)c1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: COC(=O)c1ccccc1O
Solvent: OCCN(CCO)CCO
Product: O=C(O)c1ccccc1O

Procedure:
Triethanolamine salicylate was prepared by the method described in Example 1 for the preparation of glycerol salicylate except that the reactants were triethanolamine (32.9 g; 0.22 moles), methyl salicylate (67.1 g; 0.44 moles) and sodium methoxide (0.82 g; 0.015 moles). The final methyl salicylate level was 20.0%.
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=[O:2].O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([OH:3])=[O:2]
Reactant: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 7) (13 mg) was dissolved in a 2:2:1 mixture of tetrahydrofuran, methanol, and water (5 mL). Lithium hydroxide monohydrate (3 mg) was added, and the resulting mixture was stirred at room temperature for 2 h. Addition of 1.0 M aqueous hydrochloric acid (10 mL) was followed by extraction with ethyl acetate (20 mL twice). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to provide the title compound (12 mg). HPLC/MS [M+H]+, 398.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].CC(C)([O-])C.[K+].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C)C=O>[NH2:7][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([C:12]([F:15])([F:14])[F:13])=[C:2]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)[CH:8]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(C=O)cc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 74.5 %

Procedure:
A solution of 5-chloro-2-nitro-4-(trifluoromethyl)aniline (0.240 g, 1.00 mmol), potassium t-butoxide (0.135 g, 1.2 mmol), and 4-hydroxybenzaldehyde (0.147 g, 1.2 mmol) in dimethylformamide (5 mL) was heated to 80 degrees Centigrade for 6 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were then washed once in brine and then dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 30%-40% ethyl acetate/hexanes eluted the product to give 0.243 g of 4-{[5-amino-4-nitro-2-(trifluoromethyl)phenyl]oxy}benzaldehyde as an yellowish solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[F:10])#[N:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:11])=[CH:5][C:4]=1[F:10])#[N:2]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-cyano-3-fluorotoluene, as described above in Step C, (5.0 g, 37.0 mmol) in carbon tetrachloride (300 mL) was added N-bromosuccinimide (7.57 g, 42.6 mmol) and 2,2′-azobisisobutyronitrile (610 mg, 3.7 mmol). The reaction mixture was heated to reflux under argon for 24 hrs, then cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane −4% to 7% EtOAc, to yield the titled product as a yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:35]5[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=5)=[CH:3][C:4]([C:25]([F:27])([F:26])[F:28])=[CH:5][C:6]=4[N:7]=3)[CH2:16][CH2:15]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncc(Cl)cc4Cl)CC3)[nH]c2c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncc(Cl)cc5Cl)CC4)[nH]c23)c1

Procedure:
The reaction of 4-bromo-2-[4-(3,5-dichloropyridin-2-yl)piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (99 mg, 0.2 mmol, Example 9) and 3-trifluoromethylphenylboronic acid (48 mg, 0.25 mmol, Aldrich) under the conditions of Example 10 gave the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 560 (M+1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[C:7]([CH3:12])[N:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[C:22]2[CH:21]=[CH:20][C:19]([C:33]3[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=3)=[C:18]([F:17])[CH:23]=2)[N:10]=1
Reactant: Cc1cc(N)nc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Cc1cc(N)nc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 2-(2-bromophenoxy)-6-methylpyrimidin-4-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H17FN6O, 388.15; m/z found, 389.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=1.2, 2H), 7.53 (t, J=8.2, 1H), 7.49-7.44 (m, 1H), 7.41-7.36 (m, 1H), 7.34 (s, 1H), 7.33-7.30 (m, 1H), 7.29-7.25 (m, 1H), 7.12 (d, J=8.0, 1H), 6.85 (s, 2H), 6.82 (s, 2H), 5.94 (s, 1H), 2.04 (s, 3H).
Reaction SMILES: [N+](C1N(C)C(C2N3N=C(N=C[O:21][CH2:22][CH3:23])C=CC3=NN=2)=NC=1)([O-])=O.C(CN)O.[N+:28]([C:31]1[N:35]([CH3:36])[C:34]([C:37]2[N:41]3[N:42]=[C:43]([N:46]=[CH:47][NH:48]CCO)[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)=[N:33][CH:32]=1)([O-:30])=[O:29]>C(O)(C)C.O1CCOCC1>[N+:28]([C:31]1[N:35]([CH3:36])[C:34]([C:37]2[N:41]3[N:42]=[C:43]([N:46]=[C:47]([CH2:23][CH2:22][OH:21])[NH2:48])[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)=[N:33][CH:32]=1)([O-:30])=[O:29]
Reactant: CCOC=Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=CNCCO)nn12
Solvent: NCCO
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=C(N)CCO)nn12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1.2 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-ethoxymethyleneamino-s-triazolo[4,3-b]pyridazine was dissolved in 13 ml. isopropanol-dioxan mixture (7:3), 1 ml. ethanolamine was added thereto at 20° C., while stirring, and stirring was then continued for 30 minutes. The precipitated crystals were filtered off with suction, washed with isopropanol and water and dried for 2 hours at 120° C. in a vacuum. There was obtained 1.07 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-(β-hydroxyethylaminomethyleneamino)-s-triazolo[4,3-b]pyridazine, which has a melting point of 191° - 192° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([O:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC(O)CO
Solvent: c1ccncc1
Product: OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mmol of the glycerol derivative obtained in (b) in 10 ml of pyridine were reacted at room temperature overnight with 101 mmol of trityl chloride. The pyridine was removed under reduced pressure and the residue was taken up in 100 ml of ether. The solution was filtered, the ether was removed and the residue was treated with 10 ml of pyridine, 1 ml of water and 1 g of potassium bicarbonate and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and moisture residues were removed with toluene. The residue was taken up in toluene and chromatographed on silica gel with ether/pyridine (99:1). There was obtained (RS)-1-O-[3RS,7R,11R)-3,7,11,15-tetramethylhexadecyl]-3-O-tritylglycerol as an oil.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:23])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([S:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:24]([O:27][NH2:28])[C:25]#[CH:26]>O1CCCC1>[OH:12][C:11]1[CH2:10][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([S:21][CH3:22])=[O:20])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:23])[C:6]=1[C:1](=[N:28][O:27][CH2:24][C:25]#[CH:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(C(=O)SC)cc2)CC1=O
Reactant: C#CCON
Solvent: C1CCOC1
Product: C#CCON=C(CCC)C1=C(O)CC(c2ccc(C(=O)SC)cc2)CC1=O
Reaction time: 15 h

Procedure:
Into 20 ml of tetrahydrofuran was dissolved 2 g of 2-butyryl-3-hydroxy-5-[4-(methylthio)carbonylphenyl]-2-cyclohexen-1-one and to the solution was added 0.7 g of propargyloxyamine. The mixture was kept for 15 hours at room temperature and the solvent was distilled off from it under reduced pressure. Then, the residue was recrystallized with mixture solvent of benzene-ligroin and 1.6 g of colorless desired crystals having a melting point of 95°-96° C. were obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[Na].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[I-].[Na+]>CC(C)=O>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4])[C:15](=[O:16])[CH3:17])[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Yield: 98.4 %

Procedure:
A mixture of 2-chloro-1-(4-fluoro-phenyl)-ethanone (4.83 g, 28.0 mmol), ethyl acetoacetate sodium salt (4.26 g, 28.0 mmol) and sodium iodide (420 mg, 2.80 mmol) in acetone (50 mL) was refluxed for 1 h; then the solvents were evaporated, the residue was partitioned between EtOAc and 1 M HCl aqueous solution, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, to give a brown liquid, the title product (7.334 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=8.1-7.9 (m, 2H), 7.2-7.1 (m, 2H), 4.22 (q, 2H, J=6.8 Hz), 4.2-4.0 (m, 1H), 3.8-3.4 (m, 2H), 2.44 (s, 3H), 1.30 (t, 3H, J=6.8 Hz).
Reaction SMILES: C(OC(=O)[N:7]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)[CH2:8][CH2:9][CH2:10][N:11]([C:13]1[S:17][N:16]=[C:15]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:14]=1)[CH3:12])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]3[S:17][N:16]=[C:15]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[N:14]=3)[CH3:12])=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Yield: 99.5 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-{3-[(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester (10.6 g, 22.4 mmol) in TFA/DCM (50%, 70 mL) was stirred at room temperature for 30 min. The solvent was evaporated and a saturated solution of potassium carbonate (50 mL) was added to make it basic (pH 9). The solution was extracted with ethyl acetate (2×200 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave 8.30 g (99%) of N′-benzo[1,3]dioxol-5-ylmethyl-N-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N-methyl-propane-1,3-diamine as a colorless oil. [M+H]+ 373.26; 1H-NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.63 (s, 1H), 7.07 (s, 1H), 6.79 (s, 1H), 6.72 (s, 2H), 5.92 (s, 2H), 3.67 (s, 3H), 3.60 (br s, 1H), 3.10 (br s, 2H), 2.66 (t, 2H), 2.0 (br s, 2H), 1.87 (q, 2H); 13C-NMR (100 MHz, CD3OD) δ 184.3, 156.7, 147.7, 146.6, 136.4, 133.8, 129.9, 121.2, 117.1, 108.6, 108.1, 100.9, 53.7, 45.7, 27.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (66) (147 mg, 0.52 mmol), 1-methyl-piperazine (1.5 eq., 87 μL) and acetic acid (1.05 eq., 32 μL) in 1,2-dichloroethane (3 mL) was added sodium triacetoxyborohydride (1.1 eq., 121 mg) and then stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated solution of sodium hydrogen carbonate, brine, separated and dried (MgSO4). The crude product was evaporated in vacuo and purified by chromatography to give the title compound 72 as an off-white crystalline solid (51 mg, 45%).