Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)=[CH:16][CH:15]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(F)cc2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(F)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(4-fluorophenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.57 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.36 g, 55%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[CH3:20]I.O>O1CCCC1>[CH3:20][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[N:8]=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g of sodium hydride (50% dispersion in oil) in 300 ml of anhydrous tetrahydrofuran under argon was added 14.0 g of N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide. The solution was stirred for 0.5 hours, then 3.9 ml of methyl iodide was added. After stirring for 2 hours, the solution was poured onto 400 ml of water and extracted with 100 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and chromatographed on hydrated magnesium silicate with dichloromethane-methanol (98:2) as eluant. The fractions containing the desired product were combined, concentrated in vacuo and recrystalized from acetone-hexane to give 14.1 g of cream crystals, mp 109°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)(=[O:11])=[O:10])=[CH:5][O:6][CH2:7][CH3:8].COC(=O)C(S(C1C=CC(F)=C([Cl:38])C=1)(=O)=O)=COCC.COC(=O)C(S(C1C=C(Cl)C=C(Cl)C=1)(=O)=O)=COCC.COC(=O)C(S(C1C=CC(F)=CC=1)(=O)=O)=COCC.COC(=O)C(S(C1C=C(F)C=C(C#N)C=1)(=O)=O)=COCC>>[CH3:1][O:2][C:3](=[O:19])[C:4]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:38])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[CH:5][O:6][CH2:7][CH3:8]
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1cccc(Cl)c1
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(F)c(Cl)c1
Agent: CCOC=C(C(=O)OC)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: CCOC=C(C(=O)OC)S(=O)(=O)c1cc(F)cc(C#N)c1
Agent: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(F)cc1
Product: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Applying the above procedure the following compounds were prepared: e.g. 2-(3-chloro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=305.1); 2-(3-chloro-4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=323.1); 2-(3,5-dichloro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=340.1); 2-(4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=289.1); 2-(3-cyano-5 fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=314.2).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1
Reactant: O=C1CCCC(C[N+](=O)[O-])C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCCC(O)C1
Yield: 24.5 %

Procedure:
37.2 g of 3-(nitromethyl)cyclohexanone are reduced with lithium aluminum hydride in analog to the procedure for Example 2. In this way 7.5 g (24.5% of theory) of viscous oily 3-(aminomethyl)cyclohexanol are obtained. Rf =0.04 CH2Cl2 :CH3OH=9:1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]4[CH:25]=[CH:24]C([N+]([O-])=O)=C[CH:21]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[O:29]1CC[C@H](O)C1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]4[CH2:25][CH2:24][O:29][CH2:21]4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O[C@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 151.9 %

Procedure:
To 224 mg (0.50 mmol) of 4-nitrophenyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate dissolved in 18 mL of THF, was added (S)-tetrahydrofuran-3-ol (88 mg, 1.0 mmol), followed by 60% NaH (80 mg, 2.0 mmol) and stirred at RT for 2 hr. After 2 hr it was diluted with 30 mL of EtOAc and slowly quench with brine. The organic layer was dried over MgSO4 and concentrated, it was purified using a 40 g silica gel column eluting with 0-10% MeOH/DCM to obtain 301 mg (76% yield) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.01-2.13 (m, 1 H) 2.17-2.29 (m, 1 H) 3.57-3.70 (m, 4 H) 3.74-3.84 (m, 4 H) 3.86-4.01 (m, 4 H) 5.27-5.38 (m, 1 H) 6.37 (d, J=7.83 Hz, 1 H) 7.87 (s, 1 H) 8.28 (d, J=7.83 Hz, 1 H)
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[N:18]=[C:17](O)[CH:16]=[N:15]2)=[CH:10][CH:9]=1.CI.O>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[N:18]=[C:17]([O:4][CH3:1])[CH:16]=[N:15]2)=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cnn(-c2ccc(Br)cc2)n1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COc1cnn(-c2ccc(Br)cc2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Cesium carbonate (4.5 g, 13.7 mmol) was added to a solution of 2-(4-bromophenyl)-2H-1,2,3-triazol-4-ol (1.1 g, 4.6 mmol) and methyl iodide (0.36 mL, 5.7 mmol) in THF (50 mL). The reaction was heated to 60° C. and stirred at this temperature for 16 h. Water (20 mL) was added to the reaction, and the resulting mixture was extracted with EtOAc (2×150 mL). The combined organic phases were dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford the title compound as a tan solid (1.1 g, 95%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.98 (s, 3 H) 7.39 (s, 1 H) 7.55-7.62 (m, 2 H) 7.79-7.86 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH:10]([CH3:16])[C:11]([CH:13]1[CH2:15][CH2:14]1)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:10]([CH3:16])=[C:11]([CH:13]3[CH2:15][CH2:14]3)[N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Br)cn1
Reactant: CC(Br)C(=O)C1CC1
Solvent: CN(C)C=O
Product: Cc1c(C2CC2)nc2ncc(Br)cn12
Temperature: 100 °C
Reaction time: 24 h
Yield: 12.3 %

Procedure:
To a solution of 5-bromopyrimidin-2-amine (500 mg) in DMF (10 ml) was added 2-bromo-1-cyclopropylpropan-1-one (1.02 g) at room temperature, and the mixture was stirred at 100° C. for 24 h. The mixture was partitioned between EtOAc and 1 M NaOH, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (89 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[Cl:6][CH2:7][C:8]([CH2:10][Cl:11])=[O:9].O>CN(C)C=O.[Zn]>[Cl:6][CH2:7][C:8]([C:2]([F:4])([F:3])[F:1])([OH:9])[CH2:10][Cl:11]
Reactant: O=C(CCl)CCl
Reactant: FC(F)(F)I
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCl)(CCl)C(F)(F)F

Procedure:
A mixture of commercial zinc powder (1.30 g, 0.02 mole), trifluoromethyl iodide (2.15 g, 11 mmole) and 1,3-dichloroacetone (5.6 g, 44 mmole) in 30 ml dimethylformamide (DMF) is irradiated in the water bath of an ultrasound laboratory cleaner (35 Watts, 32 KHz) for 30 minutes. The mixture is partitioned between 2% w/v aqueous hydrochloric acid and diethyl ether. The ether extract is dried (MgSO4) and the solvent evaporated to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:43]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=5[O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:42][CH:40]([F:41])[CH2:39][O:38][C:29]1[CH:30]=[C:31]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:32]=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:43]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c(OCC(F)F)c1

Procedure:
{8-[2-(2,2-Difluoro-ethoxy)-4-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine was prepared from 7-{8-[2-(2,2-difluoro-ethoxy)-4-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.285 g, 0.465 mmol) and trifluoroacetic acid (2 mL) in a manner analogous to Example 312 to give product (0.203 g, 85%). MP=128-131° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.82 (d, 1H), 7.95 (d, 1H), 7.72 (s, 1H), 7.65 (m, 2H), 7.40 (d, 1H), 7.32 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.22 (br m, 1H), 4.53 (m, 2H), 2.84 (br m, 8H), 2.67 (br m 1H), 2.50 (s, 3H). MS=514 (MH)+.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:43])[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[F:29][C:23]1[CH:24]=[C:25]([NH:26][C:40](=[O:41])[CH2:39][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[O:43])[CH:27]=[CH:28][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][N:10]=3)[S:20][C:19]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To intermediate 38 (0.40 g, 0.98 mmol) in dry DMF (20 mL) was added 3-(4-fluorophenylamino)-3-oxopropanoic acid (47) (0.39 g, 2.0 mmol) [U.S. 2007/0004675 A 1], and EDC.HCl (0.38 g, 2.0 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water resulting in precipitate. The precipitate was isolated by suction filtration and combined with the organic phase from the filtrate, concentrated, and dried in vacuum. The residue was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), heated to reflux for 3 h, then cooled and concentrated. The precipitated product was isolated by suction filtration, and dried in vacuum to afford intermediate 48 (0.35 g, 66%, presumably as the trifluoroacetate salt). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 10.29 (s, 1H), 10.14 (s, 1H), 9.15 (s, 1H). 8.59 (s, 1H), 8.58 (m, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.39 (dd, J=8.2, 2.0 Hz, 1H), 7.90 (dd, J=13.1, 2.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.54-7.44 (m, 2H), 7.17 (t, J=8.8 Hz, 2H), 6.75 (d, J=5.5 Hz, 1H), ˜3.50 (s, 2H, obscured by water peak). MS (m/z): 545.2 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:9]1([CH3:8])[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH3:21]
Reactant: CC1CCCC1=O
Reactant: CCOC(=O)CBr
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)CCCC1=O
Reaction time: 3 h

Procedure:
A solution of sodium tert.-amylate in toluene (70 ml, 0.1 mole) is added dropwise with stirring under an atmosphere of nitrogen to a solution of 2-methylcyclopentanone (9.8 g, 0.1 mole) and ethyl bromoacetate (16.7 g, 0.1 mole) in dry benzene (100 ml). The reaction is exothermic, a precipitate is formed, and the mixture turns yellow-orange. Stirring is continued for 3 hrs. at room temperature, the solution is washed with 1% HCl, cold water, and brine, dried over anhydrous magnesium sulfate and the solvent evaporated to yield 1-methyl-2-oxocyclopentane acetic acid ethyl ester as a pale yellow oil which is used without further purification in the subsequent step and which is identical with the same compound described in Example 5.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:19][CH3:20])[C:13](N(OC)C)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30]2[N:31]=[CH:32][O:33][CH:34]=2)=[CH:24][C:23]=1[O:35][CH3:36]>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:19][CH3:20])[C:13]([C:32]3[O:33][CH:34]=[C:30]([C:25]4[CH:24]=[C:23]([O:35][CH3:36])[C:22]([Br:21])=[C:27]([O:28][CH3:29])[CH:26]=4)[N:31]=3)=[O:14])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1cc(-c2cocn2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cccn2)cc1
Product: COc1cc(-c2coc(C(=O)C(OC)c3ccc(-n4cccn4)cc3)n2)cc(OC)c1Br

Procedure:
2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl) oxazol-2-yl)-2-methoxyethanone was synthesized from 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole by a method similar to that used for Example 2 except that the amide was added to the reaction mixture at −50° C. MS: m/z 498.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[C:9]([O:15][CH3:16])=[CH:10]C(C#N)=[CH:12][C:7]=2[N:6]=[C:5]1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[C:26]([OH:29])(=O)[CH3:27].[PH2]([O-])=O.[Na+].N1C=CC=C[CH:35]=1>O.[Ni]>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([C:5]2[N:4]([CH2:3][CH2:2][O:1][CH3:35])[C:8]3[C:9]([O:15][CH3:16])=[CH:10][C:27]([CH:26]=[O:29])=[CH:12][C:7]=3[N:6]=2)=[CH:18][CH:19]=1)([CH3:25])[CH3:24]
Reactant: COc1cc(C#N)cc2nc(-c3ccc(C(C)C)cc3)n(CCO)c12
Reactant: c1ccncc1
Reactant: CC(=O)O
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Temperature: 50 °C

Procedure:
To a solution of 7.02 g (20.1 mmol) of 1-(2-Hydroxy-ethyl)-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole-5-carbonitrile in 280 ml pyridine is added 140 ml acetic acid. After addition of a solution of 14.1 g (161 mmol) sodium hypophosphite in 140 ml water and heating to 50° C. Raney-Nickel is added in 50 mg portions (3× over 12 h) until the reaction is complete. The reaction mixtures is cooled to RT, ice/water is added and the reaction mixture is extracted with ethyl acetate (3×). The organic layer is washed with water, in vacuo and azeotroped with toluene. The residue is suspended in 100 ml CH2Cl2, filtered and washed with CH2Cl2 and ethyl acetate. The mother liquor is evaporated and purified by flash-chromatography on silica gel (hexanes/EtOAc) to give 3.78 g of colorless crystals.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[CH2:9]([NH:16][C:17](=[O:39])[N:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][C:27]=2[OH:38])[CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:9]([NH:16][C:17](=[O:39])[N:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][C:27]=2[O:38][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])[CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC(F)(F)F)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (3.78 mmol, 5.8 eq) of 1-iodo-4,4,4-trifluorobutane and 280 mg (0.65 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.5 eq) of potassium carbonate at 80° C. for 12 hours, methyl 3-[3′-(3-heptyl-1-methylureido)-2-(4,4,4-trifluorobutoxy)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[OH:21])([CH3:10])([CH3:9])[CH3:8]>>[C:17]([C:13]1[CH:14]=[C:15]([CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]=1[OH:21])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=CC(=O)OC
Product: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 140 °C

Procedure:
The reaction was heated to 140° C. to remove the water/toluene azeotrope. A white slurry was obtained and 7.2 g hazy toluene was collected in the trap. The Dean-Stark trap was removed and a cooling condenser was connected to the reactor. The heating was reset to 120° C. Vigorous condensation was observed and 99.1 g (1.15 mol) of methyl acrylate was added over a 45-minute period. After three hours of heating at 120° C., the 2,6-di-tert-butylphenol conversion was about 98.5% complete.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.Cl.[CH3:16][NH:17][O:18][CH3:19]>C(N(CC)CC)C>[CH3:19][O:18][N:17]([CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNOC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93459.2 %

Procedure:
A mixture of 6-chloronicotinic acid (80 g, 0.48 mmol) and thionyl chloride (400 ml) was heated under reflux for 3 hours. The cooled mixture was evaporated under reduced pressure and the residue was dissolved in dichloromethane (600 ml). N,O-dimethylhydroxylamine hydrochloride (54.6 g, 0.56 mmol) was added to the mixture which was then cooled in ice and treated with triethylamine (200 ml). The suspension was stirred for 1 hour at room temperature and was then filtered. The filtrate was washed with dilute sodium hydroxide solution (2N, 300 ml), brine (200 ml) and dried (MgSO4). The solution was evaporated under reduced pressure then distilled to give the title compound, (90 g), b.p. 106°-110° C. at 0.5 mm.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]1O)[CH3:2].[H][H]>[Ni]>[CH2:17]([CH:12]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6]1)[CH3:18]
Reactant: CCCCC(CC)CC1CCCC(CC(CC)CCCC)C1O
Reactant: [H][H]
Agent: [Ni]
Product: CCCCC(CC)CC1CCCC(CC(CC)CCCC)C1

Procedure:
300 Grams of 2,6-di(2-ethylhexyl)-cyclohexanol were hydrogenated with 30 gm of Girdler nickel 49A for six hours at 250° C. and 250 bar of hydrogen pressure. After filtration of the catalyst, 260 gm of 1,3-di-(2-ethylhexyl)-cyclohexane remained with the following characteristics:
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[Se:9][C:5]=2[C:4](=[O:14])[NH:3][N:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:15][N:3]1[C:4](=[O:14])[C:5]2[Se:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[N:1]=[N:2]1
Reactant: O=c1[nH]nnc2c1[se]c1ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nnc2c([se]c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 3H-benzo[b]1,2,3-triazino[4,5-d]selenophen-4-one (200 mg, 0.8 mmol) in acetone (50 mL) was added sequentially potassium carbonate (400 mg, 1.6 mmol), iodomethane (0.1 mL, 0.9 mmol) and a catalytic amount of PEG-400 was added at rt and the mixture was stirred at rt for 16 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure and the residue was chromatographed over silica gel column using hexane-chloroform (70:30) as eluents to give the product as a off-white solid (120 mg, 47%), mp 190-192° C. IR (neat) νmax 3431, 1673, 1220, 1021 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.56-8.58 (1H, m, H-9), 7.98-8.01 (1H, m, H-6), 7.58-7.66 (2H, m, H-7,8), 4.13 (3H, s, —NCH3); 13C NMR (100 MHz, CDCl3): δ 155.5, 152.8, 142.3, 135.3, 130.4, 129.8, 126.4, 126.2, 126.0, 37.8; LC-MS (positive ion mode): m/z 286, 288 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.I[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CCOC(=O)CI
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (952 mg, 3.96 mmol), ethyl 2-iodoacetate (1.27 g, 5.93 mmol) in DMF (14 ml) was added K2CO3 (1.64 g, 11.9 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to remove DMF. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed successively with water and saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. The residual solid was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 1:1) to afford a pale yellow solid. The solid was triturated with hexane/ethyl acetate (4:1), collected by filtration, rinsed with hexane/ethyl acetate (5:1) and dried to afford ethyl 2-(2-chloro-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate (953 mg, 2.92 mmol, 74% yield) as a white solid. MS [M+H] found 327.