Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:18]=[O:19])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.[CH:22]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])OC(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C.C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:22]([O:27][CH:28]([CH3:29])[CH3:30])[O:31][CH:32]([CH3:33])[CH3:34])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:18]=[O:19])([C:14]([F:16])([F:17])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: CC(F)(F)C1(C=O)c2cc(Cl)ccc2Nc2ncccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(OC(C)C)C1(C(C)(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 18 h
Yield: 49 %

Procedure:
Method PP: To a stirred solution of 7-chloro-5-formyl-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (51) (619 mg, 2.005 mmol) in anhydrous triisopropyl orthoformate (30.0 mL, 134 mmol), anhydrous isopropanol (10 mL) and anhydrous methylene chloride (10 mL) at room temperature was added p-TsOH.H2O (763 mg, 4.010 mmol). After 18 h at room temperature, the reaction was quenched with saturated aqueous NaHCO3 (25 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (30%-40% EtOAc-hexane, gradient elution) afforded 53 (400 mg, 49% yield) as a yellow solid as well as 45% recovery of starting material 51 (280 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[C:17]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[N:18]=[C:19]([O:30][CH2:31][CH2:32][C:33]([OH:42])=[O:34])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCO
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
To a solution of 4-t-butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (3.2 g) in dimethylformamide (50 ml) was added pyridinium dichromate (31.9 g). The mixture was stirred for 12 hours at room temperature, and subsequently supplemented with pyridinium dichromate (10.6 g), followed by stirring for 12 hours. Ethyl acetate was added, and the mixture was washed with 1N-HCl and then with water. The organic layer was extracted with sat. aq. NaHCO3, and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with dilute HCL, and then extracted with ethyl acetate. The organic layer was washed with saturated brine. Drying over anhydrous magnesium sulfate and concentrating under reduced pressure gave 1.85 g of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionic acid as a pale yellow powder.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[OH:17][C:15]1[C:14]([I:18])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(I)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CNCCc2cc(O)c(I)cc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A solution of N-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (25 mg, 0.063 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20° C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 13 mg of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.46 (s, 1H), 6.64 (s, 1H), 3.16 (m, 3H), 2.94 (m, 3H), 2.81 (m, 1H), 1.35 (d, J=7 Hz, 3H). MS calculated for C11H14INO+H: 304, observed: 304.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[NH:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of tert-butyl 2-amino-4-(thiophen-2yl)phenylcarbamate (0.12 g, 0.41 mmol, 1.0 equiv.) in pyridine (2 mL) was added a solution of dimethylcarbamic chloride (0.07 g, 0.62 mmol, 1.5 equiv.) in toluene (0.3 mL). The resulting solution was stirred at room temperature overnight. The crude residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water (10 mL), dried, filtered and concentrated. The crude residue was washed with petroleum ether (5 mL) to afford tert-butyl (2-(3,3-dimethylureido)-4-(thiophen-2-yl)phenyl)carbamate (0.12 g, 80% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CO.C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1c(-c2ccc(N)cc2)csc1N
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3ccccc3)cc2)csc1N
Reaction time: 0.5 h

Procedure:
Crude 2-amino-4-(4-amino-phenyl)-thiophene-3-carboxylic acid amide (0.15 mmoles, 1 eq) is dissolved in 5 mL THF and treated with 400 μL of 0.35 M THF solution of phenyl isocyanate (0.15 mmoles, 1 eq). When the reaction is complete, as judged by TLC analysis, the reaction mixture is diluted with 1 mL methanol and 1 mL triethylamine, stirred for 30 minutes, and concentrated to dryness. The residue is purified by prep HPLC yielding pure 2-amino-4-{4-[3-phenyl-ureido]-phenyl}-thiophene-3-carboxylic acid amide.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]([N:54]1[CH2:59][CH2:58][O:57][CH:56]([C:60]2[CH:65]=[CH:64][C:63](Br)=[CH:62][CH:61]=2)[CH2:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[Cl:67][C:68]1[CH:74]=[CH:73][CH:72]=[C:71]([Cl:75])[C:69]=1[NH2:70].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:47]([N:54]1[CH2:59][CH2:58][O:57][CH:56]([C:60]2[CH:65]=[CH:64][C:63]([NH:70][C:69]3[C:68]([Cl:67])=[CH:74][CH:73]=[CH:72][C:71]=3[Cl:75])=[CH:62][CH:61]=2)[CH2:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Nc1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 100 °C
Yield: 58.7 %

Procedure:
To a solution of BINAP (112.45 mg; 0.18 mmol) in degassed toluene (20 mL) was added 4-benzyl-2-(4-bromo-phenyl)-morpholine (1.00 g; 3.01 mmol), 2,6-dichloroaniline (0.49 g; 3.01 mmol), Pd2(dba)3 (55.12 mg; 0.06 mmol) and NaOtBu (0.29 g; 3.01 mmol). The resulting mixture was heated at 100° C. for 18 h. After cooling to RT the resulting mixture was filtered over kieselguhr, rinsed with CH2Cl2, and concentrated in vacuo. The residue was purified by column chromatography (Et2O:hexanes 1:3) to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dichloro-phenyl)-amine (0.73 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])=[N:6][CH:7]=1.[C:25](=[NH:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([N:38]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:3][CH:4]=2)=[C:9]([O:23][CH3:24])[CH:10]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(Cl)cn1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(N=C(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C

Procedure:
2-[4-(5-chloropyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole (100 mg, 0.30 mmol), benzophenone imine (60 μL, 0.36 mmol), Pd2(dba)3 (15 mg, 0.015 mmol), 1,1′-biphenyl-2-yl(dicyclohexyl)phosphine (10 mg, 0.015 mmol), NaOtBu (40 mg, 0.42 mmol) were combined in a sealable tube evacuated and backfilled with argon. Toluene (600 μL) was added and the mixture was degassed with a stream of argon for 5 min. The tube was sealed and the mixture was heated to 80° C. for 24 h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford 6-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]-N-(diphenylmethylene)pyridin-3-amine as a yellow solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A suspension of 3.40 g (13.5 mmol) of Cbz-valine and 1.56 g (13.5 mmol) of N-hydroxysuccinimide in 200 ml of dichloromethane was treated with 2.86 g (14.9 mmol) of N-ethyl-N'-(dimethylaminopropyl) carbodiimide hydrochloride and stirred at ambient temperature for 4 h. The resulting solution was washed sequentially with 10% citric acid, aqueous NaHCO3, and water; dried over Na2SO4, and concentrated in vacuo to provide 4.00 g (85%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O.CC#N.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
3,4-dichloroaniline (100 g, 0.617 mol), ethyl bromoacetate (68.4 mL, 0.617 mol), and di-isopropylethylamine (129.0 mL, 0.740 mol) were combined in 300 mL of dry N-methyl pyrrolidinone and stirred at room temperature for 18 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) after 18 hours at room temperature showed that most of the starting material (Rt=5.2 min) was gone and that a new peak had formed (Rt=7.9 min). The reaction was heated to 90° C. to push it to completion, which was achieved after one hour at 90° C., as shown by HPLC. The reaction was allowed to cool to room temperature and then poured onto 2.5 L of ice, 1.5 L of water, and 240 g of NaHCO3. A tan precipitate formed immediately and this suspension was stirred vigorously for 10 minutes and then filtered through a fritted glass funnel. The tan solid was air-dried for 20 hours in a crystallizing dish and then transferred to a 1 L flask and dried by rotary evaporation to remove the bulk of the remaining water. The tan solid was then dried under high vacuum to give 147.8 g (0.596 mol, 97%) of ethyl N-(3,4-dichlorophenyl)glycinate. LC/MS (APCI) m/e 248 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[C@@H:7]([N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:23]1=[O:24])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](Nc1ccccc1N)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of (S)-2-(2-Amino-phenylamino)-propionic acid tert-butyl ester (1.5 g, 6.3 mmol) in THF (10 mL) was added CDI (1.03 g, 6.3 mmol). The reaction mixture was stirred at room temperature for 1 h. When the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 1.6 g of the desired product as an oily residue. The LCMS indicated only 40% purity; however, this product was used for the next reaction without further purification. LCMS (ESMS): m/z 263.38 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][N:14](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.OS(O)(=O)=O.C(O)C>C(OCC)C>[CH3:1][N:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: CN1CCNCCNCCNCCNCC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
A mixture of 1-methyl-4,7,10,13-tetra(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 15C (3.6 g, 4.3 mmol) and concentrated H2SO4 (15 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (30 mL) was added dropwise with stirring at 5° C. followed by ethyl ether (80 ml). The tan solid was filtered and dissolved in H2O (10 ml). The pH of the solution was adjusted to 10 with 1ON NaOH and the solution was extracted with 6 x CHCl3. The extracts were combined, dried (Na2SO4) and the solvent removed in vacuo. The crude solid was purified by crystallization from cold (-20° C.) CH3CN to give 0.50 g (51% yield) of the product as colorless needles: mp 71.0°-2.5° C.; 1H NMR (CDCl3) δ1.90 (br s, 4 H), 2.22 (s, 3 H), 2.52 (m, 4 H), 2.68 (m, 12 H), 2.78 (m, 4 H); Anal. calcd. for C11H27N5 : C, 57.60; H, 11.86; N, 30.53. Found: C, 57.17; H, 12 . 13; N, 30.12.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-:20]#[N:21].[K+].O>CN(C=O)C>[F:19][C:16]([F:17])([F:18])[C:13]1([CH2:12][C:20]#[N:21])[CH2:14][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1(C(F)(F)F)CC1
Temperature: 60 °C
Yield: 39.4 %

Procedure:
Treat a solution of (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (12 g, 40.8 mmol) in DMF (150 mL) with potassium cyanide (3.5 g, 53 mmol) and heat at 50-70° C. for 3 days. Treat the mixture with water, extract with EtOAc (3×), wash the combined organics with water, then brine, dry and concentrate under reduced pressure to give the title compound (2.4 g, 39% yield). 1H NMR (400 MHz, CDCl3): δ 2.81 (s, 2H), 1.24-1.18 (m, 2H), 0.95-0.92 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:11])[CH:9]=[O:10].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)\[CH2:34][CH2:35]C(O)=O)=[CH:28][CH:27]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:7][N:8]([CH3:11])[C:9](=[O:10])[CH2:35][CH2:34]/[C:33](=[N:32]\[O:31][CH2:30][C:29]1[CH:45]=[CH:46][C:26]([O:25][CH2:24][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:17][C:13]=2[CH3:12])=[CH:27][CH:28]=1)/[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)N(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixture of a 40% aqueous dimethylamine (20 ml) and ethyl acetate (20 ml) at 0° C. After stirred at room temperature for 2 hours, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain E-N,N-dimethyl-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanamide (511 mg, yield 69%) as a colorless oil from an ethyl acetate-hexane (2:1, v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1([C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:11])[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1
Reactant: BrCc1ccccc1
Reactant: COC1(C(=O)O)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(C(=O)OCc2ccccc2)CCC(=O)CC1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
To a flask containing 1-methoxy-4-oxocyclohexanecarboxylic acid (0.253 g, 1.469 mmol) was added potassium carbonate (0.406 g, 2.94 mmol). The mixture was diluted with DMF (5 mL) and benzyl bromide (0.192 mL, 1.616 mmol) was added. The mixture was heated to 60° C. for 15.5 h, then cooled to rt, diluted with water (20 mL), and extracted with ethyl acetate (20 mL). The organic layer was washed with water three times, then with sat. aq. NaCl, and was finally dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-50% EtOAc in hexanes gradient and a 12 g silica gel column to give the title product (0.294 g, 1.12 mmol, 76% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ=7.41-7.31 (m, 5H), 5.23 (s, 2H), 3.35 (s, 3H), 2.62-2.53 (m, 2H), 2.37-2.28 (m, 4H), 2.19-2.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]([CH3:24])[C:21](N)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH:20]([CH3:24])[CH3:19])[CH:7]=1)=[O:18]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: CC(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)C(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
To a 10 ml microwave tube was added N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (60 mg, 0.21 mmol), followed by 2-methylpropanamide (43 mg, 0.5 mmol), cesium carbonate (162 mg, 0.5 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 11 mg, 0.02 mmol). The tube was degassed and filled with N2 three times. The resulting mixture was then heated 100° C. overnight. The next day, the mixture was cooled to room temperature, filtered through celite. The filtrate was concentrated to dryness and the resulting thick oil was dissolved in EtOAc (10 mL), and washed with H2O (10 mL). The aqueous layer was further extracted with EtOAc (10 mL). Combined organics were dried over Na2SO4, concentrated and purified by reverse-phase HPLC (Gemini, 3×10 cm, gradient: 5-85% CH3CN/H2O with 0.1% NH4OH over 10 min) to afford the desired product (30 mg, 49% yield). 1HNMR: (DMSO-d6, 400 MHz): δ 11.2 (s, 1H), 10.4 (s, 1H), 8.4 (s, 1H), 8.2 (d, J=5.2 Hz, 1H), 7.60-7.46 (m, 4H), 2.74 (m, 1H), 1.1 (d, J=6.8 Hz, 6H). LCMS (ESI) (m/z): 352.0 [M+H+].
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[C:17](=[O:19])=[O:18].Cl>CCCCCC.O1CCCC1>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]([O:7][CH3:6])[C:13]=1[C:17]([OH:19])=[O:18]
Reactant: COc1cc(C)cc(OC)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C)cc(OC)c1C(=O)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
104 ml of 1.6M n-butyllithium solution in hexane are added to 200 ml of tetrahydrofuran, followed by dropwise addition of 25 ml of 3,5-dimethoxytoluene, at a temperature between 0° and 5° C. The reaction medium is stirred at 5° C. for 1 h 30, followed by introduction of excess gaseous CO2 over 30 minutes. The mixture is introduced into 200 ml of aqueous 0.5N HCl solution and the aqueous phase is extracted with ethyl acetate. The residue is concentrated and chromatographied on a silica column (eluent: dichloromethane/methanol - 93/7).