Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1C(=O)C2CCCC(=C2)[C:16]1=[O:25].[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([NH2:33])([CH3:32])[CH3:31].CN1[CH2:43][CH2:42][O:41]CC1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:6]1[CH2:7][CH2:2][CH2:3][CH2:4][C:43]=1[C:42]([NH:33][C:30]([C:29]1[CH:34]=[CH:35][CH:36]=[C:27]([Cl:26])[CH:28]=1)([CH3:32])[CH3:31])=[O:41]
Reactant: CC(C)(N)c1cccc(Cl)c1
Reactant: CN1CCOCC1
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.1 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (1.00 g, 2.75 mmol), 3-chlorocumylamine (0.630 g, 3.71 mmol), N-methylmorpholine (0.670 g, 6.62 mmol), and benzene (10 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature, followed by heating at 50° C. for 7 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(3-chlorocumyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.859 g, 58.6% yield).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: NCCC#Cc1cccc(CF)n1
Product: O=C(NCCC#Cc1cccc(CF)n1)c1c(Cl)cccc1Cl
Yield: 27.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39 mg, 0.22 mmol) and 2,6-dichlorobenzoyl chloride (60 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 21 mg (0.06 mmol, 27%) of 2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide as a yellow oil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].C([O:9][C:10](=[O:29])[C:11]([CH3:28])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1C)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)C.[C:30]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]([CH3:54])=[C:39]([CH2:41][CH2:42]OS(C3C=CC(C)=CC=3)(=O)=O)[N:40]=2)=[CH:32][CH:31]=1.[OH-].[Na+]>C(O)C>[C:30]1([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]([CH3:54])=[C:39]([CH2:41][CH2:42][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][C:11]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:4][CH3:1])([CH3:28])[C:10]([OH:9])=[O:29])=[CH:18][CH:17]=3)[N:40]=2)=[CH:32][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1)C(=O)O

Procedure:
Potassium carbonate (0.078 g, 0.56 mmol) was added to a solution of 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester in 4A sieve-dried ethanol (2 mL). The resultant mixture was stirred at 80° C. under an atmosphere of nitrogen for 18 h, then diluted with ethanol (2 mL). 5N NaOH (0.5 mL) was added, then the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated in vacuo, diluted with 1N HCl, and extracted with CH2Cl2. The organic layer was dried through a Varian ChemElut cartridge, concentrated in vacuo, and purified by LCMS. 1H NMR (400 MHz, CDCl3): • 7.96-7.92 (m, 2H), 7.40 (t, 3H, J=3.13 Hz), 7.12 (d, 2H, J=6.65 Hz), 7.06 (t, 1H, J=7.82 Hz), 6.91 (t, 1H, J=7.82 Hz), 6.80 (t, 4H, J=6.65 Hz), 4.17 (t, 2H, J=6.65 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.98 (t, 2H, J=6.65 Hz), 2.17 (s, 3H), 1.48 (s, 3H), 1.24 (s, 3H). MS [ES+] m/z exact mass calcd for C29H30NO5 472.2124, found 472.2129.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].N1[C:31]2[C:22](=[CH:23][CH:24]=[C:25]3[C:30]=2N=CC=C3)C=CC=1.IC1C=CC=CC=1>Cl[Cu].C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:22]2[CH:31]=[CH:30][CH:25]=[CH:24][CH:23]=2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: Cl[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Ic1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
4,4′-dimethyldiphenylamine (0.99 g, 5.0 mmol), KOH (2.52 g, 45.0 mmol), CuCl (99 mg, 1.0 mmol) and 1,10-phenanthroline (180 mg, 1.0 mmol) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and added dried toluene (12 mL) and iodobenzene (0.67 ml, 6.0 mmol). The reaction was heated to 120° C., and stirred for 12 hours. The resulting was filtered to remove metal and then concentrated under reduced pressure and the residue was purified by column chromatography (hexanes/CH2Cl2=1/1) to afford G (916 g, 67%) as white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[C:17]([NH2:23])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[F:33].C(OC(=O)C)=O>C1COCC1>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[C:17]([NH:23][CH:1]=[O:3])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[F:33]
Reactant: COC(=O)c1cc(C(C)=O)c(N)c(F)c1Nc1ccc(Br)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OC=O
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)c1cc(C(C)=O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To acetic anhydride (1.30 equiv.) is added formic acid (1.60 equiv.) at room temperature. The resulting mixture is stirred at 65 OC under N2 atmosphere for 2 hours, cooled to room temperature, and diluted with THF. To a solution of 5-acetyl-4-amino-2-(4-bromo-2-fluorophenylamino)-3-fluorobenzoic acid methyl ester (1.00 equiv.) in THF at 0° C. is added the above solution of acetic formic anhydride in THF. After stirring 30 minutes at 0° C., the reaction is quenched with MeOH. The reaction mixture is concentrated under reduced pressure to give the crude material that is purified by trituration or flash column chromatography to yield the desired product as necessary.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:20])[CH3:19].C(O)C>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccccc1Cl
Temperature: 40 °C
Yield: 33.3 %

Procedure:
Sodium hydride (1.45 g, 36 mmol) and diethyl carbonate (2.14 g, 18 mmol) were suspended in 10 ml of THF. 1-(2-Chlorophenyl)ethanone (1.4 g, 9 mmol) was gradually added into the reaction flask, maintaining the reaction mixture temperature at 40° C. for 2 h. Then 1 mL of ethanol was added thereto and heated under reflux conditions for 4 h. After cooling, 1 mL of ethanol was added and the mixture was poured onto ice water, and extracted with ether. Ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and evaporated. The resulting oil is purified by flash column chromatography (PE/EA=50/1) to afford the title compound (680 mg, 34%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=6.8 Hz), 4.03 (2H, s), 4.19 (2H, q, J=6.8 Hz), 7.31-7.36 (2H, m), 7.42-7.45 (2H, m). [M+H] Calc'd for C11H11ClO3, 227. Found, 227.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[CH2:30][O:31][CH3:32])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[CH2:30][O:31][CH3:32])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COC[C@H]1CCCN1c1c(C(C)N)cc(Cl)c2cccnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H]1CCCN1c1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c2cccnc12

Procedure:
A mixture of 6-bromo-9H-purine (0.0174 g, 0.0876 mmol), 1-{5-chloro-8-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-7-yl]ethanamine (0.014 g, 0.044 mmol), and N,N-diisopropylethylamine (0.01525 mL, 0.0876 mmol) in ethanol (0.1 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a mixture of diastereoisomers (bis-TFA salts). LCMS calculated for C22H25ClN7O(M+H)+: m/z=438.2; found: 438.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22](Cl)(=[O:24])=[O:23].[Cl-].[Na+]>CN(C)C(=O)C.C(#N)C.N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:6][CH:7]=1)(=[O:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(NNC=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: O=CNNc1ccc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: -5 °C
Yield: 483.4 %

Procedure:
In 90 ml of N,N-dimethylacetamide, 76 ml of acetonitrile, and 19 ml of pyridine were dissolved 35.4 g of 2-(4-aminophenyl)-1-formylhydrazine in a nitrogen gas atmosphere and after cooling the solution to -5° C., 59:9 g of 2-chloro-5-nitrobenzenesulfonyl chloride was gradually added thereto while cooling with stirring so that the liquid temperature was not over -5° C. After further stirring the mixture for 1.5 hours at a temperature below -5° C., the temperature thereof was raised to room temperature and the reaction mixture was poured into 1 liter of a saturated aqueous sodium chloride solution. Crystals formed were collected by filtration and washed with water to provide 63 g of the desired product.
Reaction SMILES: C([C:5]1[N:6](O)[C:7]([C:14]([O:16][CH2:17]C)=[O:15])=[C:8](C(F)(F)F)[N:9]=1)CCC.[N+](=C)=[N-].S([O-])([O-])(=O)=O.[Mg+2]>CO.C(OCC)C>[NH:9]1[CH:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:6]=[CH:5]1
Reactant: CCCCc1nc(C(F)(F)F)c(C(=O)OCC)n1O
Agent: C=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1c[nH]cn1
Yield: 136.4 %

Procedure:
To a solution of 2-butyl-1-hydroxy-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid, ethyl ester (506 mg, 3.14 mmol) dissolved in a mixture of 5 mL of methanol and 10 mL of diethyl ether was added ethereal diazomethane until disappearance of starting acid was indicated by TLC. Anhydrous magnesium sulfate was then added and the solution filtered and concentrated in vacuo. Flash chromatography on 10 g of Merck silica gel eluted with 2:1, CHCl3 :hexanes, followed by 10:1, CHCl3 :Et2O afforded the title D compound (540 mg).
Reaction SMILES: [CH2:1]([NH:5]/[C:6](/[CH3:12])=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH3:4].Cl.CO.N/C(/C)=C\C(OC)=O.FC(F)(F)CO>>[CH2:1]([NH:5][CH:6]([CH3:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN/C(C)=C\C(=O)OC
Agent: COC(=O)/C=C(/C)N
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: CO
Product: CCCCNC(C)CC(=O)OC
Reaction time: 15 h
Yield: 10.6 %

Procedure:
The reaction was carried out in a manner similar to that in Example 9, except that 26.2 mg (0.0292 mmol) of Ru(OCOCH3)2((S)-tol-binap), 500 mg (2.92 mmol) of methyl 3-(n-butylamino)crotonate and 2.5 ml of 10% hydrogen chloride-methanol solution were used instead of 78.0 mg (0.0869 mmol) of Ru(OCOCH3)2((S)-tol-binap), 1.00 g (8.69 mmol) of methyl 3-aminocrotonate and 5 ml of 2,2,2-trifluoroethanol, respectively, and except that the reaction was carried out for 16 hours instead of 15 hours, and the reaction mixture was treated as in Example 9 to give methyl 3-(n-butylamino)butanoate in a yield of 10.6%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([CH:21]=O)[CH:12]=1.C([O:25][C:26](=O)[C:27](=[O:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:13]4[CH:12]=[N:11][C:20]5[C:15]([CH:14]=4)=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[C:27]([OH:35])[C:26]3=[O:25])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: O=C1C(O)=C(c2ccccc2)C(c2cnc3ccccc3c2)N1c1ccc2[nH]cnc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and Quinoline-3-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-phenyl-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[CH3:10][N:11]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:4]1[N:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:10]#[N:11]
Reactant: CN1CCCC1=O
Reactant: Nc1nccc(Cl)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1c(Cl)ccnc1N
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution 4-chloro-3-iodopyridin-2-amine (200 mg, 0.79 mmol), Zn(CN)2 (46 mg, 0.39 mmol) in NMP (3 mL) was added Pd(PPh3)4 (136 mg, 0.12 mmol). The resulting mixture was allowed to stir at 95° C. under N2 for overnight. The reaction mixture was purified by column chromatography to afford the title compound as a white solid. LC/MS m/z=153.2 [M+H]+
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[CH2:8][CH3:9].[CH2:17]([O:19][C:20](=[O:25])[CH:21]=[C:22](Cl)[CH3:23])[CH3:18]>O1CCCC1>[CH2:17]([O:19][C:20](=[O:25])/[CH:21]=[C:22](/[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:7][CH2:8][CH3:9])\[CH3:23])[CH3:18]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: CCCc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1ccccc1O/C(C)=C/C(=O)OCC
Temperature: 23 °C
Yield: 41.9 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 2-propyl-phenol (6.90 g, 0.051 mol) in tetrahydrofuran (40 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (5.20 g, 41%) as a yellow oil.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[O:20][CH3:21].O>ClCCl>[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][CH3:3])=[O:16])=[CH:13][C:12]=1[O:20][CH3:21]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)Cl)ccc1I
Agent: CN
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(I)c(OC)c1
Yield: 46 %

Procedure:
4-Iodo-3-methoxy-N-methylbenzamide. N,N-Dimethylformamide (0.1 mL) was added to a solution of 4-iodo-3-methoxybenzoic acid (2.0 g, 7.2 mmol) in sulfuryl dichloride (20 mL), and the mixture was heated to reflux for 2 h. The excess sulfuryl dichloride was removed under reduced pressure to give the crude product 4-iodo-3-methoxy-benzoyl chloride. To a solution of methyl amine (0.72 g, 10.8 mmol) and triethylamine (2.18 g, 21.6 mmol) in dichloromethane (20 mL) was added dropwise a solution of the above 4-iodo-3-methoxy-benzoyl chloride in dichloromethane (15 mL) at 0° C. After the reaction was completed, water was added, the organic layer was separated, dried over sodium sulfate evaporated to give the crude product, which was purified on silica gel column (eluting with 10-17% ethyl acetate in petroleum ether) to give 4-iodo-3-methoxy-N-methylbenzamide (0.92 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.92 (d, J=8.0 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.31 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[C:16]([Cl:28])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([Cl:28])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(O)cc1Cl

Procedure:
This compound was prepared in a manner analogous to that of Step A of Example 3, using 4.1 grams (0.0096 mole) of N-{3-[2,6-dichloro-4-(phenylmethoxy)phenoxy]propyl}(tert.-butoxy)carboxamide, a catalytic amount of 10% palladium on carbon and a theoretical amount of hydrogen gas in 60 mL of 1:1 ethanol and ethyl acetate in a Parr Hydrogenator. The yield of the subject compound was 3.5 grams.
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1>>[CH3:11][CH:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[N:12]1[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC1CCCCC1=O
Product: CC1CC2CCCCC2N1c1ccc(C(=O)O)cc1
Yield: 65 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 2-(2-oxopropyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 65% yield (98% purity by HPLC). MS(ESI+): 256.4; MS(ESI−): 254.4.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:37]([N:44]1[C:48]2=[N:49][CH:50]=[N:51][C:52](Cl)=[C:47]2[CH:46]=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[CH2:37]([N:44]1[C:48]2=[N:49][CH:50]=[N:51][C:52]([O:36][C@@H:25]([CH2:24][O:23][CH2:22][CH2:21][O:20][Si:3]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=3)=[O:27])=[C:47]2[CH:46]=[N:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Reactant: Clc1ncnc2c1cnn2Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3Cc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
Sodium hydride (90 mg, 2.25 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (538 mg, 1.12 mmol) (Intermediate AU2) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-benzyl-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AL2) (250 mg, 1.02 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was neutralised with 1M citric acid, diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in isohexane to afford the product (540 mg, 77%). m/z (ES+) (M+H)+=687; HPLC tR=3.89 min.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH-].[K+].Cl[C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>CS(C)=O>[CH2:1]([O:3][C:7]1[C:8]([C:20]([F:21])([F:22])[F:23])=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][C:12]=1[C:13]([F:14])([F:15])[F:16])[CH3:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethanol (20 mL, 343 mmol) was treated with potassium hydroxide (956 mg, 17.0 mmol) and the mixture was stirred at RT for 1 h. A solution of 2-chloro-5-nitro-1,3-bis(trifluoromethyl)benzene (1) (1.00 g, 3.41 mmol) in DMSO (10 mL) was added dropwise. The resultant mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and water and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to afford 2-ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene (2) (1.00 g, 93%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.72 (2H, s), 4.21 (2H, q), 1.41 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8](I)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([Zn]C#N)#[N:15].O.CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:14]#[N:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(I)cc(Cl)nc1Cl
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium (34.8 mg, 0.03 mmol), methyl 2,6-dichloro-4-iodonicotinate (100 mg, 0.301 mmol) and dicyanozinc (38.9 mg, 0.331 mmol) in DMF (2 mL) was stirred at 100° C. overnight under N2 atmosphere. To the resulting mixture were added H2O and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with H2O and brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a white solid (28 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.99 (s, 3H), 8.44 (s, 1H).