Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[C:2]([O-:5])(=O)[CH3:3]>>[O:1]=[CH:3][C@@H:2]([C@H:3]([C@@H:2]([C@@H:3]([CH2:2][OH:5])[OH:1])[OH:5])[OH:1])[OH:5]
Reactant: O
Reactant: CC(=O)[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The immobilized enzyme conjugate was assayed at a temperature of 55° C. using as substrate 50 ml of 30% (w/v) corn starch in 0.02M acetate at a pH of 4.2. To carry out the assay, the substrate and enzyme were placed in 250 ml flask and incubated in a 55° C. shaker water bath. At 15 and 75 minutes of reaction time, a 0.2 ml aliquot of reaction mixture was removed and added to 0.5 ml of 0.2N H2SO4 to terminate the reaction. These samples were then diluted by addition of 5.3 ml of distilled water, and then filtered through 0.45μ filter. The products were analyzed by carbohydrate high pressure liquid chromatography (HPLC). One unit of activity represents the amount of enzyme which will produce one micromole of glucose in one minute under the conditions of the assay, and is reported as U/g (units of activity per gram of conjugate).
Reaction SMILES: C1(C(=O)CC(C2C=CC=CC=2)=O)C=CC=CC=1.[H-].[Na+].C(OC(=O)C(Br)C)C.C([O:30][C:31](=[O:51])[CH:32]([CH3:50])[CH:33]([C:42](=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C.[C:52]1([NH:58][NH2:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(O)(=O)C.CN(C)C=O>[CH3:50][CH:32]([C:33]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:59][N:58]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31]([OH:30])=[O:51]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C)C(C(=O)c1ccccc1)C(=O)c1ccccc1
Agent: CCOC(=O)C(C)Br
Agent: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 17 %

Procedure:
20 grams 1,3-diphenyl-1,3-propanedione, 4.3 grams of a 50% suspension of sodium hydride in paraffin oil, 20 grams α-bromopropionic acid-ethyl ester and 300 milliliters dimethylformamide were mixed and the mixture was stirred for 20 hours at room temperature and for another 20 hours at 50° C. The reaction mixture containing the 2-methyl-3,3-dibenzoyl-propionic acid-ethyl ester formed in the reaction was worked up in accordance with a procedure analogous to that set out in Example (2b). The crude product obtained thereby was further reacted with 9.0 grams phenylhydrazine and 8 grams glacial acetic acid in accordance with a procedure analogous to that described in Example (2c). The crude pyrazol ester obtained in this manner was saponified to form the free acid in a procedure analogous to that set above. 5.7 grams Methyl-1,3,5-triphenyl-pyrazol-4-acetic acid, melting at 95°-99° C. were obtained, corresponding to a yield of 17% based on the diketone starting material.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=O.[OH-].[Na+]>C(O)CC>[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:17]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:21]=[CH:20][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: N=C(N)Nc1cccc(-n2ccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: c1cc(Nc2nccc(-c3ccncc3)n2)cc(-n2ccnc2)c1
Yield: 70 %

Procedure:
Two and 73 hundredths grams of [3-(1H-imidazol-1-yl)phenyl]guanidine, dihydrochloride (2) from Example 1, 1.76 grams of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one, 25 ml of n-propanol and 2 equivalents (2 ml) of 10N NaOH at pH=11 is refluxed for twenty-four (24) hours. The products are isolated by quenching the reaction mixture including any precipitated solids into water followed by filtration. These filtered solids are re-suspended in water to remove inorganic salts, filtered and air dried to give 2.2 g (70% yield) of the desired product, mp 244°-245° C.
Reaction SMILES: [F:1][C:2]1([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.NN>C(O)C>[F:1][C:2]1([CH2:8][NH2:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CC1(F)CCOCC1
Agent: NN
Solvent: CCO
Product: NCC1(F)CCOCC1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 409B (1.4 g) and hydrazine (1.548 mL) in ethanol (40 mL) was heated at 70° C. overnight, cooled to room temperature, slurried with CH2C12 (200 mL) and the solid removed by filtration. The filtrate was concentrated and chromatographed on silica gel with 100:5:1 ethyl acetate/methanol/NH4OH as eluent to give the product.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](O)=[O:4].C(Cl)(=O)C>>[CH3:1][CH:2]1[CH:6]([CH3:10])[C:7](=[O:9])[O:8][C:3]1=[O:4]
Reactant: CC(C(=O)O)C(C)C(=O)O
Solvent: CC(=O)Cl
Product: CC1C(=O)OC(=O)C1C
Temperature: 65 °C

Procedure:
To the 2,3-dimethyl succinic acid (5.13 g, 35.1 mmol), was added acetyl chloride (8.27 g, 7.49 mL, 105 mmol) at room temperature. The reaction mixture was refluxed at about 65° C. for 2 hrs. Workup consisted of concentration in vacuo, and drying in high vacuo. The desired product (4.95 g, with a little impurity of acetic acid) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1.S(=O)(=O)(O)O.[C:18]1(C)C=CC=CC=1>Cl.C(O)C>[CH2:1]([O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)[CH3:18]
Reactant: COC(=O)Cc1ccnc(C)c1
Reactant: Cc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1ccnc(C)c1
Temperature: 25 °C

Procedure:
The mixture of (2-methyl-pyridin-4-yl)-acetic acid methyl ester and the bis adduct (20 g) was dissolved in concentrated hydrochloric acid and heated to reflux for 1 hour. The solution was cooled, diluted with toluene, and concentrated in vacuo to give the crude acid. The acid was dissolved in ethanol, treated with a catalytic amount of sulfuric acid, and heated to reflux for 3 h. The solution was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution. The mixture was filtered and the filtrate concentrated to give 14 g of the title compound as a crude oil. MS(ES): m/e (EI*) 180.1 [M+H]
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:73]=[CH:72][C:71]([N:74]5[CH2:79][CH2:78][N:77]([CH2:80][C@@H:81]([OH:83])[CH3:82])[CH2:76][CH2:75]5)=[CH:70][CH:69]=4)[CH:66]=3)[N:61](S(C3C=CC(C)=CC=3)(=O)=O)[CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[CH:70][C:71]([N:74]5[CH2:79][CH2:78][N:77]([CH2:80][C@@H:81]([OH:83])[CH3:82])[CH2:76][CH2:75]5)=[CH:72][CH:73]=4)[CH:66]=3)[NH:61][CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2)CC1
Yield: 39.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (100 mg, 0.151 mmol) was hydrolyzed with lithium hydroxide (13 mg, 0.302 mmol) in THF/methanol/water (5./1/1 mL) to yield 30 mg (31.9% yield) desired product. 1H NMR (CD3OD, 400 MHz): δ 8.56-8.55 (d, 1H), 8.49-8.48 (d, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.68-7.66 (d, 2H), 7.26-7.19 (m, 4H), 7.14-7.10 (m, 3H), 4.47-4.44 (t, 2H), 4.30-4.25 (m, 1H), 3.99-3.94 (m, 2H), 3.78-3.74 (m, 2H), 3.31-3.21 (m, 2H), 3.19-3.12 (m, 4H), 1.29-1.28 (d, 3H). MS: m/z=507.60 (M+1), HPLC: 91.80% in method A.
Reaction SMILES: BrCCC[CH2:5][C:6]([CH3:21])([C:15]1C=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22]CCCCCC(C)(C)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:6]([CH3:21])([CH3:5])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Reactant: CC(C)(CO)CCCCCBr
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCCCBr)COC1CCCCO1
Yield: 46 %

Procedure:
According to the method described for the synthesis of 207d, 206g (36.0 g, 161 mmol) was treated with 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and p-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in CH2Cl2 (60 mL). After filtration through neutral aluminum oxide (200 g) and concentration, the crude product was purified by column chromatography (silica gel; hexanes/ethyl acetate=50/1), affording 207g (23.0 g, 46%) as an oil. 1H NMR (CDCl3): δ 4.54 (t, 1H, J=3.0), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (CDCl3): δ 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, gly): Calcd for C14H28BrO2 (MH+): 307.1272. found: 307.1245.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[OH:19])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: NCC(O)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC(O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 21, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-amino-1-phenyl-ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCCO
Solvent: CCN(CC)CC
Product: OCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(3-hydroxypropyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-amino-1-propanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[Li]CCCC.[C:26](=[O:28])=[O:27]>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:6]2[O:5][C:4]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:3][C:2]=2[C:26]([OH:28])=[O:27])=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: Clc1ccc(Sc2oc(C3CCOCC3)nc2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a dry flask was added 4-bromo-5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (50 mg, 0.133 mmol) and THF (2669 μl), and the reaction mixture was cooled to −78° C. nBuLi (92 μl, 0.147 mmol) was added slowly and the reaction mixture was stirred at −78° C. for 30 min. Crushed dry ice was added, the reaction mixture was stirred at −78° C. for 20 min, quenched with 10% KHSO4, and allowed to warm to RT. The reaction mixture was extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo to give 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylic acid (47 mg crude) to be used as is in the next step. MS: M+H=340.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([CH:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C1C(=CC=CC=1)C(N)=O.C(C(O)C1C=CC=C(OC2C=CC=CC=2)C=1)#C>>[C:12]1([CH:18]([NH:20][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]([OH:6])=[O:11])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: C#CC(O)c1cccc(Oc2ccccc2)c1
Agent: NC(=O)c1ccccc1C(=O)O
Product: CC(NC(=O)c1ccccc1C(=O)O)c1ccccc1

Procedure:
(-)-N-α-phenylethylphthalamic acid was prepared from phthalic anhydride and (-)α-phenylethylamine by the method of Mann and Watson (J. Chem. Soc., 1947, 510). The ester of this phthalamic acid with racemic α-ethynyl-3-phenoxybenzyl alcohol was prepared by the method of Human and Mills (J. Chem. Soc., 1949, S77). The individual (-)(+) and (-)(-) ester diastereoisomers were separated by chromatography (HPLC) and then hydrolysed with a slight excess of alkali to recover the resolved α-ethylnyl-30'-phenoxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[NH:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:5]=2[O:9]1
Reactant: COC(=O)Cl
Reactant: NCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Yield: 97.6 %

Procedure:
Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.20 g, 7.28 mmol) with diisopropylethylamine (2.94 g, 22.7 mmol) and methyl chloroformate (1.08 g, 11.4 mmol) generally according to the procedure described for Intermediate 12 provided 2.30 g (93%) of (±)-methyl(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 100-103° C.; Anal. calcd. for C17H22ClNO3: C, 63.06; H, 6.85; N, 4.33. Found: C, 63.16; H, 6.3; N, 4.25.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=1[Cl:39])[C:12]([C:14]1[S:28][C:17]2[C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1.O.O.[OH-].[Li+]>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=1[Cl:39])[C:12]([C:14]1[S:28][C:17]2[C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2cc3c(s2)-c2c(C)cccc2OCC3)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1-c1sc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)c3ccc(C(=O)O)cc3Cl)cc1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of methyl 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-10-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.250 g, 0.436 mmol) in tetrahydrofuran (10.2 mL, 126 mmol;) and water (10.2 mL, 566 mmol) was added lithium hydroxide, monohydrate (0.0732 g, 1.74 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, acidified with 1M HCl, and extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-10-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (yield 60%). MS: (ESI+) 559.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:7](=[O:20])[NH:6]1.[H-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:7](=[O:20])[N:6]1[CH2:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc(C)c(C)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1C(=O)N(Cc2ccc(C)c(C)c2)C(=O)N1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 102.1 %

Procedure:
A 0° C. solution of compound [1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester (2.24 g, 7.71 mmol) in DMF (30 mL) was treated with sodium hydride (60% dispersion, 0.37 g, 9.25 mmol) and warmed to room temperature and stirred under N2 for 20 minutes. The resultant mixture was cooled to 0° C. and then treated with 4-methoxybenzyl chloride (2.41 g, 15.4 mmol) and then warmed to room temperature and stirred for 16 h. The reaction was quenched with 25 mL of aqueous 1 N HCl and then worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give crude product that was purified by flash chromatography using a gradient of 5:1 hexanes:actetone to afford 3.23 g (100%) [1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. MS (ES+) Calc'd for C23H26N2O5 (M+1) 411. Found m/z. 411 (100%). 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N+]=[N-])=[CH:4][CH:3]=1.[O:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:21][C:20]2([CH3:22])[CH:19]=[O:18])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C=C(C)C=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC1(C=O)CC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 40 °C

Procedure:
A solution of bis(4-fluorophenyl)diazomethane, prepared as above from the action of activated manganese dioxide (32.3 g) on 4,4'-difluorobenzophenone hydrazone (23.2 g) in dichloromethane (105 mL), was added to a solution of methacrolein (12.5 mL) in heptane (100 mL). The mixture was heated at 40° C. for 6 hours then the amber colored solution was evaporated in vacuo. The resulting solid was triturated with hexane (100 mL) to give 22.0 g of 2,2-bis(4-fluorophenyl)-1-methylcyclopropanecarboxaldehyde, mp 110°-113° C. Recrystallization of a sample from hexane provide the analytical specimen, mp 111°-113° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:64][C:57]1[CH:56]=[C:55]([C:50]2[CH:51]=[CH:52][CH:53]=[C:54]3[C:49]=2[CH:48]=[CH:47][NH:46]3)[CH:63]=[C:62]2[C:58]=1[CH:59]=[N:60][NH:61]2)=[O:8])[CH3:2]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CCOc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 8 h

Procedure:
To a solution of 2-(ethyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml), HATU (248 mg, 0.40 mmol) and DIPEA (0.211 mL, 1.21 mmol) were added. The reaction was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol). The reaction was stirred overnight then it was loaded onto a PS-aminopropyl cartridge (5 g) and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH:DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. Appropriate fractions were dried under a stream of nitrogen to give title compound, 27 mg.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:31]5[CH:30]=[CH:29][CH:28]=[C:27]([NH2:26])[CH:32]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccc(N)c4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3-aminophenyl boronic acid. Mass spectrum (ESI) 407.2 (M+1)
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=1>C(Cl)(Cl)Cl>[CH2:20]([N:19]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)Cc1ccc(C#N)cc1
Yield: 97.3 %

Procedure:
Dioctadecylamine (26.0 g., 0.05 M), α-bromo-p-tolunitrile (4.9 g., 0.025 M) and chloroform (500 ml.) are stirred at room temperature for 24 hours. The precipitate of dioctadecylamine hydrobromide is filtered off and the filtrate concentrated under reduced pressure. The residue is slurried in methanol, filtered, and evaporated to give 1-(dioctadecylamino)methyl-4-cyanobenzene (15.5 g., 97.5% yield).