Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C([C:28]1([O:39][C:40]2(CC=C)C(Cl)=C(Cl)C(Cl)=[C:42](Cl)[CH:41]2Cl)[C:33]([Cl:34])=[C:32]([Cl:35])[C:31]([Cl:36])=[C:30]([Cl:37])[CH:29]1[Cl:38])C=C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:34][C:33]1[C:28]([O:39][CH2:40][CH2:41][CH2:42][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[C:29]([Cl:38])[C:30]([Cl:37])=[C:31]([Cl:36])[C:32]=1[Cl:35]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCC1(OC2(CC=C)C(Cl)=C(Cl)C(Cl)=C(Cl)C2Cl)C(Cl)=C(Cl)C(Cl)=C(Cl)C1Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCO[Si](CCCOc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)(OCC)OCC
Temperature: 90 °C

Procedure:
27.0 parts of triethoxysilane, 0.05 parts phenothiazine, and 250 ppm hexachloroplatinic acid were charged to a three-neck 100 ml round bottom flask equipped with a magnetic stirrer, thermometer, addition funnel, and water condenser with a nitrogen by-pass. 18.4 parts of allylpentachlorophenyl ether prepared as described above was then added to the dropping funnel. Flask contents were heated to 80° C. at which point the allylpentachlorophenyl ether was added dropwise keeping the exotherm below 100° C. by regulation of the addition rate. After the addition was completed (ca. 15 minutes) the total flask contents were heated at 90° C. for 30 minutes then cooled to room temperature. The flask contents were then evaporated under reduced pressure at 60° C. to yield a liquid which was subsequently vacuum distilled through a six-inch heated vigreux column at 1.0 mm Hg. 13.0 parts of 3-(pentachlorophenoxy)propyltriethoxysilane with a boiling point of 216°-245° C. at 1.0 mm Hg was obtained. The product was identified by gas chromatography, infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(O)C>[N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Solvent: CCO
Product: CCOC(=O)c1ccc([N+](=O)[O-])o1

Procedure:
To a solution of 39 g. of 5-nitro-2-furancarboxylic acid in 200 ml. of ethanol is added 2 ml. of p-toluenesulfonic acid. The reaction is heated for 48 hours. The reaction mixture is evaporated and methylene chloride is added to the residue. The solution is extracted with 10% sodium bicarbonate and dried over anhydrous sodium sulfate. The solution is concentrated and then filtered through Magnesol. The product is obtained by recrystallization from methylene chloride and hexane.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O>O1CCOCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][C:19]=3[C:10]=2[CH:9]=1
Reactant: CN1CCCCC1=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid (3.5 mL) was added to a solution of 4-chlorophenylhydrazine hydrochloride (2.0 g, 11.2 mmol) in dioxane (50 mL), and stirred for 5 min. at RT. N-methyl piperidone (0.76-1.4 equiv.) was added and the mixture was heated at 80° C. for 2 h. After reaction completion as determined by thin layer chromatography (TLC), the reaction mixture was concentrated to approximately 20 mL under reduced pressure and basified to pH 10 using a 10% aqueous KOH solution. The reaction product was extracted with EtOAc (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator to obtain the product (1.3 g) as a brown solid. 1H NMR (CDCl3, freebase) δ (ppm): 7.40 (s, 1H), 7.20-7.10 (d, 1H), 7.10-7.00 (d, 1H), 3.60 (s, 2H), 2.90 (s, 4H), 2.60 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].[CH3:18][NH:19][CH3:20]>CCOCC>[CH3:18][N:19]([CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4])[CH3:20]
Reactant: CNC
Reactant: CCCCCCCCCCCCOC(=O)CCl
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(=O)CN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Dodecyl chloroacetate (5.5 g, 0.021 mol) was dissolved in 20 ml of ether and the resultant solution was cooled in an ice-bath. Dimethylamine (40 ml, 0.1 M in ether) was added to the cooled solution of dodecyl chloroacetate. The reaction mixture was stirred at room temperature for two hours, then filtered through a filter paper to remove the white solid which formed. The filtrate was concentrated to give a liquid product which was chromatographed through a column of silica gel (60-200 mesh) using ethyl acetate as the eluent. The purity of the fractions was checked by thin layer chromatography. The pure fractions were combined and the solvent was removed by a rotary evaporator under reduced pressure to afford 5.8 g (100% yield) of dodecyl (N,N-dimethylamino)acetate. 1HNMR(CCl4) δ0.83(3H, t, CH3); 1.20[20 H, s, broad, --(CH2)10 ]; 2.23[6H, s, (CH3)2N--]; 3.0 (2H, s, --CH2 --N); 3.93 (2H, t, J=6 Hz, --OCH2 --) νmax (film): 2940,2870,2790 (CH); 1760, 1740(C=O); 1200, 1170 (--C--O--C) cm-1. m/e 271; C16H33NO2 requires 271.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:36]([O:38][CH2:39][CH2:40][CH2:41]C)=[O:37]>ClCCl>[CH2:33]([O:32][CH2:31][C:20]1[N:21]([CH2:22][C:23]([CH3:25])([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:24])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])[C:18]=2[N:19]=1)[CH3:34]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)Nc1nc2ccccc2c2c1nc(COCC)n2CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
Triethylamine (2.67 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-{2-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (1.5 g, 1 eq) in dichloromethane (150 mL). A solution of butyl chloroformate (1.73 g, 3.3 eq) in dichloromethane (5 mL) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 24 hours. The reaction mixture was washed sequentially with water (150 mL), 4% sodium carbonate (150 mL), water (150 mL), and brine (150 mL). The organic layer was concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-20% CMA in chloroform, 1500 mL) followed by recrystallization from diethyl ether to provide 1.23 g of propyl 2-ethoxymethyl-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white powder, mp 125-127° C. Anal calcd for C23H33N5O5S: C, 56.19; H, 6.77; N, 14.25. Found: C, 56.35; H, 6.65; N, 14.24.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[C:12]1([CH2:18][N:19]2[CH2:30][CH2:29][C:22]3([NH:27][C:26](=O)[CH2:25][O:24][CH2:23]3)[CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[C:12]1([CH2:18][N:19]2[CH2:30][CH2:29][C:22]3([NH:27][CH2:26][CH2:25][O:24][CH2:23]3)[CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1COCC2(CCN(Cc3ccccc3)CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC3(CC2)COCCN3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
LAH (2.00 g, 52.7 mmol) was added to a THF (100 mL) solution containing 9-(phenylmethyl)-4-oxa-1,9-diazaspiro[5.5]undecan-2-one (3.1893 g, 12.3 mmol). The resulting mixture was stirred 1 h at reflux. The reaction was then cooled to room temperature and the following additions were made slowly: 2 mL of water followed by 2 mL of 1 N NaOH, and finally 4 mL of water. The mixture was then filtered and concentrated to give a thick clear oil (2.66 g, 88% yield). The material was used in the next step without further purification. LCMS-ESI (POS), M/Z, M+1. Found 247, Calculated 247.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)([O-:16])=[O:15].CN(C)C=O>O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:20]1[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 72 h

Procedure:
A mixture of N,N,N′-trimethylethane-1,2-diamine (2.17 g), potassium carbonate (3.0 g), 4-nitrofluorobenzene and dimethylformamide (30 ml) was stirred for 72 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried and concentrated. The product with the molecular weight of 223.28 (C11H17N3O2); MS (ESI): 224 ([M+H]+), was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17](O)=[O:18])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[NH2:29]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:29][C:28]4[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:26]([O:25][CH3:24])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(NC(=O)c2ccc(C)c(NC(=O)c3csc4c(N)ncnc34)c2)cc(OC)c1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3,5-dimethoxyaniline to obtain the title compound (see Table 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].C1COCC1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[S:13]
Reactant: COc1ccccc1C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: COc1ccccc1C(N)=S
Yield: 185.7 %

Procedure:
Combine 2-methoxy benzamide (10.0 g, 66.2-mmol) with phosphorus pentasulfide (10.1 g, 22.7 mmol) and THF (200 mmol) in a sealed vessel and stir for 30 minutes at room temperature. Sonicate the mixture for 1 hour and then allow the mixture to stand at room temperature. Decant the THF solution from the solids and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to give 2-methoxy-thiobenzamide (7.05 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([O:22][CH3:23])[C:9]=2[C:24](OC)=[O:25])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([O:22][CH3:23])[C:9]=2[CH2:24][OH:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(OC)c(C(=O)OC)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(C)C)nc(OC)c(CO)c1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1.48 g (3.95 mmol) of the compound from Example 5 are dissolved in 30 ml of toluene, the solution is cooled to -78° C. under nitrogen and 6.6 ml (10 mmol) of a 1.5 molar solution of diisobutylaluminium hydride in toluene are added dropwise at this temperature. The cooling bath is removed and the mixture is stirred at room temperature for 2 h. After hydrolysis using 20% strength aqueous potassium sodium tartrate solution, the organic phase is separated off, the aqueous phase is washed three times with toluene, and the combined organic phases are washed with saturated sodium chloride solution and dried using sodium sulphate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23]CC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[OH-].[Na+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)CC(C(=O)OC)c1cc(O)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
10% Pd/C (Aldrich cat no 205699, 0.55 g) was added to a stirred solution of 2-(3,5-bis-benzyloxyphenyl)-4-methyl-pent-4-enoic acid methyl ester (14.1 g, 33.8 mmol) and NaOH (1.50 g, 37.5 mmol) in MeOH (180 mL) at room temperature. Stirring was continued for 1 h under H2 (1 atm.) then the mixture was filtered through Celite, concentrated in vacuo, suspended in water (100 mL) and adjusted to pH 2 with 1M HCl. The mixture was extracted with EtOAc (2×180 mL); the combined organic layer was washed with brine (50 mL), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica, 0-30% EtOAc in petroleum ether) to give the title product as a yellow oil (7.40 g, 67%). 1H-NMR (400 MHz, CDCl3): δ 7.41-7.25 (m, 5H), 6.54 (s, 1H), 6.43 (s, 1H), 6.38 (s, 1H), 5.01 (s, 3H), 4.74 (s, 1H), 4.67 (s, 1H), 3.70 (t, 1H), 3.65 (s, 3H), 2.78 (dd, 1H), 2.38 (dd, 1H), 1.71 (s, 3H); RT==3.14 min. Mass spectrum (ESI, m/z) 325 (M−1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=[O:9])=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Br:18]Br>O.C(Cl)(Cl)Cl>[Br:18][C:5]1[CH:4]=[C:3]([S:7]([OH:10])(=[O:9])=[O:8])[CH:2]=[N:1][CH:6]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: BrBr
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3g. of 3-pyridinesulfonic acid and 8.5g. of phosphorous pentachloride was heated at 120° C for 1.5 hours. Upon cooling to room temperature, the mixture solidified. Chloroform was added thereto and dry hydrogen chloride gas was introduced. The resulting precipitate was collected by filtration and dried. The crystalline substance obtained was heated with bromine (4g.) at 120° C. for 8 hours and water (60 ml.) was added to the mixture. After stirring at 80° C. for 2 hours, the solution was concentrated. On addition of acetone, 2g. of 5-bromo- 3-pyridinesulfonic acid was obtained.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C([Li])(CC)C.[CH:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[OH:48])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 1 g, 2.0 mmol) in anhydrous THF (10 mL), s-butyllithium (4.5 ml, 1.4M in cyclohexane, 6.3 mmol) was added and stirred for 2 h at −78° C. Benzaldehyde (685 mg, 0.0064 mmol) in THF (5 mL) was added dropwise and the solution was stirred for additional 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried (Na2SO4), and solvent was removed. The residue was purified over a silica gel chromatography column using ethyl acetate-pet. ether gradient, providing the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C)C=O.[OH-].[Na+]>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[NH:27][N:26]=[N:25][N:21]=3)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23]
Reactant: CCCc1c(OCc2ccc(CC#N)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccc(Cc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 100 °C

Procedure:
1-[2-Hydroxy-3-propyl-4-(4-cyanomethylphenylmethoxy)phenyl]ethanone (4.25 g; 0.013 m) was dissolved in dry dimethylformamide (70 ml) to which was added sodium azide (3.42 g; 0.052 m) and ammonium chloride (1.4 g; 0.026 m). The resulting suspension was heated at 100° C. for 20 hours with stirring under a capillary air condenser. The cooled suspension was poured onto water with stirring, acidified and filtered to give a pale brown solid. The solid was taken up in aqueous sodium hydroxide (2N), washed with chloroform and acidified with concentrated hydrochloric acid with cooling and stirring, filtered to give a pale brown solid. Recrystallised from methanol to give a fawn crystalline solid m.p. 184°-187° C.
Reaction SMILES: [CH3:1][CH:2]([N:13]=[N+]=[N-])[CH:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:1][CH:2]([NH2:13])[CH:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:4]
Reactant: CC(N=[N+]=[N-])C(C)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(N)C(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 1-methyl-2-benzoxypropylazide (300 mL, 1.46 mmol) in ether (10 mL), lithium aluminum hydride (167 mg, 4.38 mmol) was added. The reaction mixture was stirred at room temperature for 1 hours. Then 0.17 mL of H2O, 0.2 mL of 15% NaOH and 0.42 mL of H2O were added. The solid was filtered. The liquid was concentrated under reduced pressure to give desired product (240 mg, 92%). EI-MS m/z 180 (M+).
Reaction SMILES: [C-]#N.[Na+].[N:4]12CCN(CC1)C[CH2:5]2.[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][NH:19][C:20]([C:22]2[C:23]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25](Cl)=[N:26][CH:27]=2)=[O:21])=[CH:16][CH:15]=1>O.CS(C)=O>[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][NH:19][C:20]([C:22]2[C:23]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25]([C:5]#[N:4])=[N:26][CH:27]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(CNC(=O)c2cnc(Cl)nc2NCC(C)(C)C)cc1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNC(=O)c2cnc(C#N)nc2NCC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of NaCN (95 mg, 1.9 mmol) in water (1 ml) and DMSO (10 ml) are added 1,4-diazabicyclo[2,2,2]octane (48 mg, 0.43 mmol) and 2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid 4-methoxy-benzylamide (470 mg, 1.3 mmol) in DMSO (2 ml) successively at ambient temperature. After being stirred for 2 hours at 50° C., the reaction mixture is poured into cold water and extracted with AcOEt. The combined extracts are washed with water, brine and dried over MgSO4. The concentrated residue is purified by silica gel column chromatography (eluent:n-hexane:AcOEt=2:1) give 2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid 4-methoxy-benzylamide. Rf=0.45 (n-hexane:AcOEt=2:1). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (s, 9H), 3.37 (d, 2H), 3.81 (s, 3H), 4.53 (d, 2H), 6.36 (brs, 1H), 6.89 (d, 2H), 7.25 (d, 2H), 8.28 (s, 1H), 9.08 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][P:18]([C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1)([O:20][CH2:21][CH3:22])=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CC#N>[OH:14][C:3]1[C:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]2[CH:24]=[C:23]([P:18](=[O:19])([O:17][CH2:15][CH3:16])[O:20][CH2:21][CH3:22])[CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[C:5]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:4]=1
Reactant: CCOP(=O)(OCC)c1cccc(CC(=O)O)c1
Reactant: Nc1cnc(-c2cccnn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1cccc(CC(=O)Nc2cnc(-c3cccnn3)nc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 5-amino-2-(pyridazin-3-yl)pyrimidin-4-ol, 35i-h, (0.5 g, 2.6 mmol), 2-(3-(diethoxyphosphoryl)phenyl)acetic acid, 35i-d, (0.7 g, 2.6 mmol), HATU (1.5 g, 3.9 mmol) and Et3N (1.2 g, 11.8 mmol) in MeCN (25 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum. The residue was extracted with EA (100 mL), and then washed with sat. NH4Cl (50 mL), water (50 mL), and brine (50 mL). The organic layer was concentrated and the residue was purified by column chromatography to afford the product, 35i, (280 mg, 25%). LC-MS (M+H)+ 444.1.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([N+:26]([O-:28])=[O:27])([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[CH:10]=[CH:9][CH:8]=1)[CH3:5].[OH-].[Na+].O>C(#N)C>[Cl:20][C:19]1[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=1)[O:6][C:4]([N+:26]([O-:28])=[O:27])([CH3:5])[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(C)(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)O)[N+](=O)[O-]
Yield: 70.4 %

Procedure:
135 g (0.3 mol) of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-α-phenoxy-propionic acid methyl ester and 30 ml of concentrated aqueous sodium hydroxide solution were stirred in 400 ml of acetonitrile and 150 ml of water at 20° C. for 24 hours. The solution was concentrated, the residue was taken up in 500 ml of water and the aqueous mixture was acidified with 50 ml of concentrated hydrochloric acid. 93 g (71% of theory) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-α-phenoxy-propionic acid were obtained in the form of pale yellow crystals of melting point 146° C. (after recrystallization from toluene/cyclohexane).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:16]=[C:15]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Li+].[OH-].[Na+]>CO>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[CH:14]=1)[C:3]([OH:23])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2nccn2C)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2nccn2C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dissolve N-methyl-5-(1-methyl-1H-imidazol-2-yl)-N-propyl-isophthalamic acid methyl ester (100 mg, 0.32 mmol) in methanol (10 mL). Dropwise add 1 N lithium hydroxide (0.38 mL) and stir overnight at room temperature. Add 2 N NaOH (0.1 mL) and stir for 48 h at room temperature. Acidify the mixture to about pH=6 by DOWEX® 50WX2-100 ion exchange resin and filter. Concentrate filtrate and lyophilize (1:1 acetonitrile:water) to give the title compound.