Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([C:12]2[N:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]3=[N:14][C:13]=2[NH2:22])[CH2:11][CH2:10]1.N1C=CC=CC=1>C(#N)C>[CH:9]1([C:12]2[N:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]3=[N:14][C:13]=2[NH:22][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10]1
Reactant: Nc1nc2ccc(F)cn2c1C1CC1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)CC(=O)Nc1nc2ccc(F)cn2c1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl acetyl chloride (0.040 mL, 0.00029 mol) was added to a solution of 3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-ylamine (compound f, 0.054 g, 0.00027 mol) in acetonitrile (5.00 mL) containing pyridine (0.0637 g, 0.00081 mol) and the mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and crude product purified by column chromatography (50% ethyl acetate/hexanes to neat ethyl acetate) to give N-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-3,3-dimethyl-butyramide as a yellow solid. Rf 0.41, 5% methanol/dichloromethane; MS m/z 289 (M+H). SH-SY5Y_EC50 (μM): 2.5464.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.Cl.[NH2:17][CH:18]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:19]([NH:21][C:22]1([C:31]#[N:32])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]1)=[O:20]>>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6](=[N:17][CH:18]([C:19](=[O:20])[NH:21][C:22]1([C:31]#[N:32])[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:27]1)[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC2CCCCC2)N=C(NC(=O)OCC)N2CCOCC2)CC1

Procedure:
The title compound was prepared starting from (Morpholine-4-carbothioyl)-carbamic acid ethyl ester and 2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt according to the procedure from Example 76, step b, except that the compound was first purified by chromatography over silica gel using 9:1 methylene chloride:methanol as the eluant prior to reverse phase HPLC purification. MS, m/z 505=M+1.
Reaction SMILES: C1(=O)CCCCCCC1.[C:10]1([NH:18][CH:19]=[C:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[OH:28][C:26]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=12
Reactant: CCOC(=O)C(=CNC1=CCCCCCC1)C(=O)OCC
Agent: O=C1CCCCCCC1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c1O)CCCCCC2
Temperature: 25 °C

Procedure:
A solution of 85 g of the mixture of cyclooctanone and diethyl N-(1-cyclooctenyl)-aminomethylenemalonate in 20 ml. of Dowtherm® (a eutectic mixture of diphenyl ether and biphenyl) is added to 380 ml. Dowtherm® at 250°-255° under nitrogen. The distillate is collected in a water separator. After 0.5 hour the mixture is cooled to room temperature and solvent is removed under reduced pressure. The residual solid is triturated with ether to give ethyl 5,6,7,8,9,10-hexahydro-4-hydroxycycloocta[b]pyridine-3-carboxylate, m.p. 219°-222°.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1>CCO>[Cl:15][C:16]1[N:21]=[C:20]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
To a solution of 5-methyl-1H-pyrazol-3-amine (2.78 g, 27.3 mmol) in absolute EtOH (30 ml) was added triethylamine (5 ml) and 2,4,5-trichloropyrimidine (5.0 g, 27.3 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound (4.1 g). m/z: 245.
Reaction SMILES: CS(Cl)(=O)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([OH:15])=O)[N:11]=1.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[C:53](=[O:54])[N:31]2[C:32]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[O:42])=[C:33]([C@H:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[CH2:34][S:35][C@H:30]12.N1C=CC=CC=1>CN(C=O)C>[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([NH:28][C@@H:29]2[C:53](=[O:54])[N:31]3[C:32]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=[O:42])=[C:33]([C@H:36]4[CH2:40][CH2:39][CH2:38][O:37]4)[CH2:34][S:35][C@H:30]23)=[O:15])[N:11]=1
Reactant: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Methanesulphonyl chloride (198μl, 2.56mmol) was added to 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (515mg, 2.56mmol) and N,N-diisopropylethylamine (447μl, 2.57mmol) in DMF (8ml) at -30° C. After stirring at -30±10° C. for 30 min., a solution of 4-methoxybenzyl (6R, 7R) -7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (915mg, 2.35mmol) in DMF (5ml) was added, followed by pyridine (207μl, 2.56mmol). The reaction mixture was transferred to an ice-bath and stirring continued for a further 1.5h. After dilution with ethyl acetate, the solution was washed successively with saturated sodium hydrogen carbonate solution, 5% aqueous citric acid, water (x2) and brine, dried and then concentrated in vacuo. The residue was triturated several times with diethyl ether to yield the title compound as an off-white solid (1.06g, 79%); vmax (CH2Cl2) 3390, 1783, 1730, 1687, 1606, 1516cm-1 ; δH (CDCl3, 250MHz) 1.55-1.70 (1H, m), 1.86-1.98 (2H, m), 2.0-2.14 (1H, m), 3.40 and 3.59 (2H, ABq, J 17.8Hz), 3.78-3.93 (2H, m), 3.91 (3H, s), 4.12 (3H, s), 5.04 (1H, d, J 4.7Hz), 5.15 (1H, dd, J 7.7, 7.7Hz), 5.21 (2H, s), 5.87 (1H, dd, J 8.7, 4.7Hz), 6.55 (2H, br. s, exch.), 6.90 (2H, d, J 8.6Hz), 7.05 (1H, s), 7.36 (2H, d, J 8.6Hz), 7.65 (1H, br. d, J 8.7Hz). [Mass spectrum: +ve ion (thioglycerol) MH+ (574)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][CH:4]=1.[C:13]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:9][CH2:8][CH:7]([C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: COc1ccc(C=CC=O)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccc(OC)cc2)CCN1C(C)=O
Yield: 79.5 %

Procedure:
N-Acetyl-2-ethoxycarbonyl-3-(4-methoxyphenyl)proline, ethyl ester (13 g, 72%) was prepared from 4-methoxycinnamaldehyde (Lancaster, 8.1 g, 50 mmol) and diethyl acetamidomalonate (Aldrich, 9.9 g, 45 mmol) by the procedure described by Chung et al (J. Org. Chem. 1990, 55, 270).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.N([O-])=[O:15].[Na+].OS(O)(=O)=O>Cl.O>[OH:15][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(O)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A solution of 9.73 g of 3-amino-5-methoxy-1-trifluoromethylbenzene in 400 ml of 2N HCl is cooled to 10° C., and a solution of 3.80 g of sodium nitrite in 20 ml of water is added in the course of 10 minutes. The mixture is left stirring for 30 minutes at 10° C., and a solution of 800 ml of concentrated H2SO4 in 800 ml of water is added while the temperature is maintained below 20° C. The mixture is then heated to 95° C. for 2 hours and left overnight at r.t. 1000 g of ice are added to the reaction medium, the mixture is extracted with ether, the organic phase is washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is evaporated off under vacuum. 9.8 g of 3-hydroxy-5-methoxy-1-trifluoromethylbenzene, m.p.≈75° C. (according to J. Chem. Soc., 1951, 2013) are obtained.
Reaction SMILES: [OH:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:21][CH2:22][O-].[Na+].[Na].C(OS(C1C=CC=CC=1)(=O)=O)C>C(O)C.CCOCC>[ClH:19].[CH2:21]([O:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:22]
Reactant: CC[O-]
Reactant: Cc1cc(Cl)c(O)c(CN(C)C2CCCCCCC2)c1
Agent: CCOS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOc1c(Cl)cc(C)cc1CN(C)C1CCCCCCC1
Product: Cl
Reaction time: 5 h

Procedure:
7.4 g of 2-hydroxy-3-chloro-5-methyl-N-methyl-N-cyclooctylbenzylamine were dissolved in 40 ml of hot absolute ethanol and added to a sodium ethylate solution that had been prepared from 0.6 g of sodium in 25 ml of absolute ethanol. After addition of 4.5 g of benzenesulfonic acid ethyl ester, the whole was stirred for 5 hours under reflux, concentrated, the residue was dissolved in 50 ml of 5% sodium hydroxide solution, extracted with ether and the organic phase was dried over sodium sulfate. The solvent was removed and after addition of 70 ml of water and hydrochloric acid until acid reaction the residue was covered with 50 ml of ether and allowed to stand for several days at 0° C. In this manner, 6 g of 2-ethoxy-3-chloro-5-methyl-N-methyl-N-cyclooctyl-benzylamine-hydrochloride were obtained. Melting point 197° C (ethanol/ether).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:49])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[S:35][C:36]([CH2:39][CH2:40][O:41]C3CCCCO3)=[N:37][N:38]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[S:35][C:36]([CH2:39][CH2:40][OH:41])=[N:37][N:38]=4)[CH:29]=3)[CH2:26][C:25](=[O:49])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nnc(CCO)s3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (0.15) and crude 3-oxo-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-phenyl)-propionic acid tert-butyl ester (0.24 g) (Example K30) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:12]2[NH:16][C:15](=[O:17])[O:14][N:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CC#N.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:12]2[N:16]([CH3:24])[C:15](=[O:17])[O:14][N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CC#N
Product: Cn1c(/C(=N\OCc2cccc(N)n2)c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (1 g, 3.21 mmol, 1 eq.) in MeCN (50 ml) and DMF (10 ml) was added potassium carbonate (532 mg, 3.85 mmol, 1.2 eq.) followed by iodomethane (547 mg, 3.85 mmol, 1.2 eq.). The reaction was stirred at room temperature overnight. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (906 mg, 85% yield) has a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl-:6].[Cl-].[Cl-].[Cl-].[Zr+4:10]>C(OCC)C>[Cl-:6].[Cl-:6].[CH3:4][C:3]1[CH:4]=[CH:3][C:2]([CH:1]2[CH2:4][CH:3]3[C:2](=[CH:3][CH:4]=[CH:1][CH2:2]3)[CH:1]2[Zr+2:10])=[CH:1][CH:2]=1
Reactant: [Li]CCCC
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccc(C2CC3CC=CC=C3C2[Zr+2])cc1

Procedure:
In this case the procedure of Example I was used except 0.476 mmol of 2-(para-methylphenyl) tetrahydroindenyl, 0.52 mmol of butyllithium, and 0.242 of zirconium tetrachloride, and 4 ml of diethylether were employed. The solid was identified as bis(2-para-methylphenyl) tetrahydroindenyl zirconium dichloride.
Reaction SMILES: C(OC([NH:8][C@@:9]1([CH3:16])[C:13]2([CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.F[C:18]1([N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28](F)[C:29]=3[CH3:31])[C:24](=[O:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22]2)[CH2:20][CH2:19]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl.CS(C)=O>[NH2:8][C@@:9]1([CH3:16])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:28]2[C:29]([CH3:31])=[C:30]3[C:25]([C:24](=[O:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][N:21]3[CH:18]3[CH2:19][CH2:20]3)=[CH:26][CH:27]=2)[CH2:10]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn(C3(F)CC3)c12
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CNCC12CC2
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(N2CC3(CC3)[C@](C)(N)C2)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 75 °C
Reaction time: 120 h

Procedure:
A mixture of (75)-7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (524 mg, 2.31 mmol), 1-fluorocyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (503 mg, 1.925 mmol), triethylamine (0.537 mL, 3.85 mmol), and dimethyl sulfoxide (6 mL) was stirred in nitrogen atmosphere in an oil bath at 75° C. for 5 days, and in an oil bath at 85° C. for 2 days. To the reaction mixture was added 10% aqueous solution of citric acid (10 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2) to obtain a pale yellow foam solid. The purified pale yellow foam solid was dissolved in concentrated hydrochloric acid (8 mL) at room temperature, and after transferring the resulting acidic aqueous solution to a separatory funnel while washing with 6N hydrochloric acid, the solution was washed with chloroform (50 mL×8). To the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath, and hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3), and the organic layer was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by recrystallization from ethanol, and dried under reduced pressure to obtain 268 mg (0.641 mmol, 2 steps, 33%) of the title compound as a pale yellow powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[F:29])[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH:13]=1.CN1C(=O)CCC1.[CH3:37][N:38]([CH2:40]/[CH:41]=[CH:42]/[C:43](Cl)=[O:44])[CH3:39]>C1COCC1.CN(C=O)C.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[F:29])[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([NH:25][C:43](=[O:44])/[CH:42]=[CH:41]/[CH2:40][N:38]([CH3:39])[CH3:37])[CH:22]=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CN(C)C/C=C/C(=O)Cl
Reactant: Nc1cccc(Nc2cc(Oc3ccc(F)c(Cl)c3)ncn2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Oc3ccc(F)c(Cl)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (155 mg, 1.2 mmol) was added dropwise to a mixture of 4-N,N-dimethyl aminocrotonic acid HCl salt (200 mg, 1.2 mmol) in 5 mL of THF at 0° C. To this mixture was added 3 drops of DMF/THF solution (made from 5 drops of DMF in 1 mL of THF). The reaction mixture was stirred at RT for 2 h, then was cooled to 0° C. ice bath. A solution of N1-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-yl)benzene-1,3-diamine (200 mg, 0.6 mmol) 2 mL of NMP) was added to the dimethylaminocrotonyl chloride solution and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 3 mL of 1N NaOH, and was extracted with EtOAc (2×25 mL). The crude product mixture was purified by flash chromatography on silica gel with MeOH/NH4OH/DCM solvent system to afford (E)-N-(3-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-ylamino)phenyl)-4-(dimethylamino)but-2-enamide (I-92) as a light colored solid. MS (m/z): MH+=442, 444 (3:1), 1H-NMR (DMSO) δ 10.08 (s, 1H), 9.67 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.59 (d, 1H), 7.57 (t, 1H), 7.53-7.24 (m, 4H), 6.29 (b, 1H), 6.23 (s, 1H), 3.51 (d, 2H), 2.21 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[S:7][C:6]=2[C:13]=1[Cl:14].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: CCOC(=O)COc1cc2cc(C(C)O)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Yield: 77.5 %

Procedure:
To 16 g of ethyl [(6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetate in 300 ml 95% ethanol is added 300 ml of a 6N sodium hydroxide and the mixture is refluxed at 100° for 30 mins. The cooled mixture is concentrated to a white slurry which is diluted with 200 ml of ice-water and 200 ml of ethyl ether. With stirring and efficient cooling, the mixture is acidified with 6N hydrochloric acid. The acidic mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the crude product from acetone and hexane gives 11.4 g of [(6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetic acid, mp 173°-175°.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][NH2:21].CCOC(C)=O>N1C=CC=CC=1>[CH3:19][O:20][N:21]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1
Reactant: CON
Reactant: O=C(c1ccccc1)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CON=C(c1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a 100-mL round-bottomed flask, phenyl(4-(trifluoromethyl)phenyl)-methanone (1.0105 g, 4.039 mmol) and methoxyamine (0.4208 g, 5.038 mmol) were dissolved in pyridine (10 mL). The mixture was stirred at rt overnight. Additional methoxyamine (0.1625 g) was added, and the solution was stirred at rt for 7 h. EtOAc was added and the organic phase was washed with water, 1 N HCl (2×), water, and then with brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a clear oil. The oil thus obtained was purified by Biotage (EtOAc/hexanes 0-20%) to afford the title compound (1.12 g, 99.4%) as a clear oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH2:15]O>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[NH:13][CH2:14][CH2:15][S:12]1)([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CC(C)c1ccccc1N=C=S
Solvent: CCOCC
Product: CC(C)c1ccccc1N=C1NCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of (2-isopropylphenyl)isothiocyanate (2.00 g) in diethylether (20 ml) was added 2-aminoethanol (0.69 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. To the obtained oil was added concentrated hydrochloric acid (5 ml). The mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into an aqueous solution of 20% sodium hydroxide (25 ml). The mixture was extracted with dichloromethane (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-1,3-thiazolidine (1.80 g, yield: 73%) as a white crystal. M.p. 76–77° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:20])=[CH:7][CH:6]=1)[CH3:3].[CH:23]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[O-:34][CH2:35][CH3:36].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]2[CH:30]([C:29]3[CH:32]=[CH:33][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=3)[C:35](=[O:34])[C:36]3[C:16]([C:15]([O:14][CH2:13][CH3:12])=[O:20])=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10]2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC[O-]
Reactant: CN(C)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (588 mg, 2 mmol) and 4-isopropylbenzaldehyde (296 mg, 2 mmol) in ethyl propionate (15 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was then purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the title compound (210 mg, yield 22%). LC-MS (ESI) m/z: 471 (M+1)+.