Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC(OC)=CC=2)[O:40][C:39]=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([O:40][CH3:39])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1
Yield: 100 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-methoxy-2-phenyl-chromen-4-one was reacted to give the title compound (80 mg, 100%) as a colourless oil. LCMS (Method A) RT=4.88 min, [M+H]+=498.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[C:3]1=[N:9]O.C(=O)([O-])[O-:12].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[NH:9][C:3]1=[O:12]
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1CCC[C@H](C)C1=NO
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C[C@H]1CCC[C@H](C)C(=O)N1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Into 20 ml of xylene were added 1.3 g of trans-2,6-dimethylcyclohexanone oxime and 6 g of polyphosphoric acid, the mixture was stirred for 10 hours at 100° C. The reaction mixture was cooled to near room temperature, poured into ice-water. Sodium carbonate was added to the mixture, and the mixture was extracted with ethyl acetate three times. The organic layers was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.2 g of trans-3,7-dimethylhexahydro-1H-azepine-2-one.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.Cl.CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)=[CH:38][N:37]=2)=[CH:30][CH:29]=1)(=O)=O>CN(C=O)C>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:35]#[C:34][C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:14]4[CH2:15][CH2:16][CH2:17][CH:13]4[C:12]([O:11][CH3:10])=[O:18])=[CH:33][CH:32]=3)=[N:37][CH:38]=2)=[CH:43][CH:44]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCCN1CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.15 mL ethyldiisopropylamine and 73 mg (0.44 mmol) proline-methyl ester (used as the hydrochloride) are added to a solution of 171 mg (0.4 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl methanesulphonate in 2 mL DMF and the reaction mixture is stirred for 18 h at RT. The mixture is evaporated down i. vac. and the residue is purified by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(/C=C/c2ccc(F)cc2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(/C=C/c3ccc(F)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of (E)-4-[2-(4-fluoro-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid which was directly engaged in the next step without further purification and characterisation.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1C(=O)N([Br:22])C(=O)C1.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:22][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH2:1][N:2]([CH3:3])[CH2:14][CH2:13][C:5]=12
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCc2c(Br)c3ccccc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.7 g) in 40 mL of CHCl3 cooled at 0° C. was added 4 g of NBS in two portions. After stirring for 2 h at r.t., the reaction mixture was treated with 30 mL of water and 20 mL of saturated aqueous solution of NaHCO3, and then extracted with 200 mL of CH2Cl2. The extract was dried over Na2SO4 for 2 days, and then filtered through a pad of silica gel, concentrated to give 4 g of the title compound as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH3:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH3:18])[C:16]([CH3:15])=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)C(C)C(C)=O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(C)c1C
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of 51.6 g (0.250 mol) of 3-amino-5-benzylthio-1,2,4-triazole and 28.5 g (0.250 mol) of 3-methyl-2,4-pentanedione in 350 ml of glacial acetic acid was heated at reflux for 17 hours. Upon cooling to room temperature, the reaction mixture was poured onto ice. The pale yellow solid which separated was collected by filtration, washed with water and dried in vacuo to yield 67.1 g (94%) of the desired product as a pale yellow solid, m.p. 133.5°-135° C. The IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CCNCc1ccccn1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)O)[CH:10]=2)[N:5]=[C:4]([N:27]([CH3:29])[CH3:28])[C:3]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cu]C#N>CN1C(=O)CCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)[CH:10]=2)[N:5]=[C:4]([N:27]([CH3:29])[CH3:28])[C:3]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN(C)c1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Agent: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CN(C)c1nc2ccc(C(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 120 °C

Procedure:
To (4-chloro-2-(dimethylamino)-3-phenylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (83.6 mg, 0.166 mmol, Example 90) in NMP (1.5 mL), was added copper (I) cyanide (16.4 mg, 0.183 mmol). The mixture was heated by microwave irradiation for 10 minutes at 120° C. The mixture was partitioned between MTBE and saturated aqueous NH4OH. The organic phase was washed with water. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA) and fractions were converted to the corresponding free base by extraction from saturated aqueous NaHCO3 with DCM. Further purification by flash column chromatography (silica gel, 10-70% acetone-DCM) afforded the title compound. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=1.96 Hz, 1H), 7.76 (d, J=8.80 Hz, 1H), 7.55 (br. s., 1H), 7.43-7.50 (m, 2H), 7.34-7.42 (m, 4H), 7.30 (d, J=8.56 Hz, 2H), 7.12 (d, J=8.56 Hz, 2H), 6.48 (br. s., 1H), 5.45 (s, 1H), 3.37 (s, 3H), 2.71 (s, 6H); MS m/e 487.0 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22]([O:27][CH2:28][CH3:29])(=[O:26])/[CH:23]=[CH:24]/[CH3:25].CCN(CC)CC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](/[C:24](/[CH3:25])=[CH:23]\[C:22]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C/C=C/C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(/C)c1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 10-3 (500 mg, 1.4 mmoles), ethyl crotonate (1.7 mL, 3.8 mmoles), Pd(OAc)2 (31 mg, 0.14 mmoles), NEt3 (0.78 mL, 8 mmoles), tri-o-tolylphosphine (170 mg, 0.56 mmoles), and CH3CN (7 mL) was heated in a sealed tube at 100° C. for 24 hours. The cooled reaction mixture was diluted with EtOAc and then washed with H2O, 10% KHSO4, saturated NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 12-1 as a waxy yellow solid. Rf 0.33 (silica, 25% EtOAc/hexanes).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ncccn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Product: COc1ccc(N2CCN(C(=O)Cc3ncccn3)[C@@H](Cc3ccccc3)C2)cc1OC(F)F

Procedure:
Prepared by the method outlined for Example 189 using pyrimidin-2-yl-acetic acid and (S)-3-benzyl-1-(3-difluoromethoxy-4-methoxy-phenyl)-piperazine (Example 69, Compound 157) as starting materials. Product as an oil. LC/MS (Method B) 2.46 min, [M+1]+ 468. Potency class ND.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH:7]=[O:8])(=[O:3])[CH3:2].CN1CCCC1=[O:35].CO.[C-]#N.[K+]>[O-2].[Mn+4].[O-2].C(O)(=O)C>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[C:7]([OH:35])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(=O)C=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CN1CCCC1=O
Agent: [Mn+4]
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)O[C@]1(C(=O)C(=O)O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
4.0 g. of 17α-acetoxy-3,20-dioxo-4-pregnen-21-al is agitated at room temperature for 5 minutes in 100 ml. of N-methylpyrrolidone with 32 ml. of methanol, 6.4 ml. of concentrated acetic acid, 12 g. of manganese(IV) oxide, and 1.4 g. of potassium cyanide. The reaction product is then isolated as set forth in Example 39(b). After recrystallization from acetone-petroleum ether, 1.98 g. of the methyl ester of 17α-acetoxy-3,20-dioxo-4-pregnene-21-oic acid is obtained, m.p. 190.3°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[C:15]1[NH:16][CH2:17][C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:2].C(OCC)(=O)C.O>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[C:15]1[NH:16][CH2:17][C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:2]
Reactant: CCCc1nn(C)c2c1N=C(c1cc(/C=C/C(=O)O)ccc1OCC)NC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCCc1nn(C)c2c1N=C(c1cc(CCC(=O)O)ccc1OCC)NC2
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A solution of (E)-4-Ethoxy-3-(-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-5-yl)cinnamic acid (0.426 g, 0.0011 mol) in a mixture of methanol (28.5 ml), ethyl acetate (100 ml) and water (1.5 ml), was stirred with 5% palladium on charcoal catalyst (0.05 g) under a hydrogen atmosphere at room temperature and pressure for 3 hours. The catalyst was removed by filtration and the solvent removed by evaporation under vacuum. Crystallisation of the residue from ethyl acetate-hexane gave the title compound as beige crystals (0.23 g, 54%), m.p. 165°-167° C. Found C,62,24; H,6.17; N,14.09. C20H24N4O4 requires C,62.39; H,6.33; N,14.41%.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=4)[N:9]=[CH:8][C:7]=3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Cl:27]N1C(=O)CCC1=O>CN(C)C=O>[Cl:27][C:6]1[C:7]2[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=3)=[CH:11][C:12]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Cl)cn3C2CC2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
In a 100 mL round bottom flask was added (R)-N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (200 mg, 0.57 mmol) in N,N-dimethylformamide (2.8 mL) to give a light yellow solution. This was followed by addition of N-chlorosuccinimide (76 mg, 0.57 mmol) at room temperature and the mixture was heated to 60° C. After 4 h, another 0.1 eq of N-chlorosuccinimide was added and the mixture was heated for another hour. The mixture was directly loaded onto a silica gel column, eluting with 20-70% EtOAc in hexanes for purification. Product-containing fractions were combined and a pinkish solid was formed upon evaporation of solvents. The solid was collected and washed with 5 ml EtOAc to give the title compound (23, 71 mg, 32%) as a light pink product. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 2 H) 1.10 (dd, J=7.07, 4.55 Hz, 2 H) 1.43 (s, 3 H) 3.42-3.54 (m, 3 H) 4.72 (br. s., 1 H) 5.00 (s, 1 H) 7.56-7.62 (m, 3 H) 8.02 (d, J=8.59 Hz, 2 H) 8.52 (d, J=0.76 Hz, 1 H) 8.56-8.60 (m, 1 H) 10.64 (s, 1 H); ESI-MS: m/z 386 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C(C)C)=[C:17]([I:25])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([I:25])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1
Yield: 87 %

Procedure:
When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 87% yield, as white solid. 1H-NMR (CDCl3) 8.47 (d, 1H, J=1.95 Hz); 8.11 (d, 2H, J=8.94 Hz); 8.03 (dd, 1H, J=8.46, 2.01 Hz); 7.07 (d, 2H, J=8.49 Hz); 4.11 (q, 2H, J=6.96, 13.98 Hz); 1.45 (t, 3H, J=6.96 Hz).
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[C:15]([NH:25][S:26]([CH:29]2[CH2:32][CH:31]([O:33]CC3C=CC=CC=3)[CH2:30]2)(=[O:28])=[O:27])=[C:16]2[S:24][CH2:23][CH2:22][N:17]2[C:18](=[O:21])[C:19]=1[CH3:20].CO>C(Cl)Cl.C(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[C:15]([NH:25][S:26]([CH:29]2[CH2:32][CH:31]([OH:33])[CH2:30]2)(=[O:27])=[O:28])=[C:16]2[S:24][CH2:23][CH2:22][N:17]2[C:18](=[O:21])[C:19]=1[CH3:20]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCS2
Agent: ClB(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(O)C2)c2n(c1=O)CCS2
Temperature: -78 °C
Reaction time: 3 h
Yield: 17.4 %

Procedure:
1M BCl3 (0.46 mL, 0.468 mmol) was added to a solution of 3-benzyloxy-cyclobutanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-8-yl]-amide (0.1 g, 0.156 mmol) in dry DCM (3 mL) at −78° C. The resulting mixture was stirred at −78° C. for 3 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was quenched with methanol, basified with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% MeOH in CHCl3), followed by preparative HPLC afforded 0.015 g of the product (18% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([CH3:16])[C:13]([CH3:15])=[CH:14][C:9]=2[N:8]=[N:7]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:15][C:13]1[C:12]([CH3:16])=[CH:11][C:10]2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=4)[CH2:30][CH2:29]3)[N:7]=[N:8][C:9]=2[CH:14]=1
Reactant: Cc1cc2nnn(CCCCCl)c2cc1C
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2cc1C
Temperature: 25 °C
Yield: 70.3 %

Procedure:
1-(4-chlorobutyl)-5,6-dimethyl-1H-benzotriazole (8.56 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 9.1 g compound (I-33) with a yield of 70.3%. ESI-MS [M+H]+: m/z 432.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[Cl:17][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:18][C:19]3[N:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cc1ccc(N)nc1
Reactant: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Temperature: 110 °C
Yield: 86.2 %

Procedure:
A 20-mL vial was charged with 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.380 g, 1.43 mmol), ethyl 2-(6-aminopyridin-3-yl)acetate (0.410 g, 2.27 mmol), palladium acetate (0.016 g, 0.071 mmol), rac-BINAP (0.069 g, 0.11 mmol) and cesium carbonate (1.17 g, 3.58 mmol) in dioxane (10 mL) under argon. The reaction mixture was heated to 110° C. under microwave irradiation for 1.25 h. The reaction mixture was cooled, and diluted with ethyl acetate and filtered through celite. The filtrate was washed with saturated sodium chloride (2×10 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.504 g, 86%) as an off-white solid. MW=408.88. M.p. 133-135° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.13 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.0, 1.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.62 (br s, 1H), 7.59-7.52 (m, 2H), 4.10 (q, J=7.5 Hz, 2H), 3.68 (s, 2H), 2.07 (septet, J=4.5 Hz, 1H), 1.21 (t, J=7.0 Hz, 3H), 1.14-1.10 (m, 2H), 1.06-1.00 (m, 2H); APCI MS m/z 409 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]=1[CH:41]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:39]=[CH:40][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2ccccc2c1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc2ccccc2c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-methoxy-naphthalene-1-carbaldehyde. MS (ESI) m/z 379.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[N+:5]([O-])=[CH:6][CH:7]=1.C[CH2:16][N:17](CC)CC.C[Si](C#N)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:16]#[N:17])[N:5]=[C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)OC(=O)c1cc(Cl)cc[n+]1[O-]
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(Cl)cc(C#N)n1
Yield: 67.3 %

Procedure:
A solution of 200 mg (0.86 mmol) of isopropyl 4-chloropyridine-2-carboxylate 1-oxide (Intermediate 223), 0.14 ml (1 mmol) Et3N and 0.36 ml (2.7 mmol) of trimethylsilylcyanide in 3 ml CH3CN was heated at 90° C. overnight. The solution was diluted with EtOAc and washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil that was purified by chromatography on silica gel (100% CH2Cl2 followed by gradient elution to 10% EtOAc in CH2Cl2) to afford 130 mg of product as a white solid. MS (ES) (MH+): 224 for C19H9ClN2O2; NMR (d6-DMSO): 1.35 (d, 6H), 5.2 (septet, 1H), 8.4 (s, 1H), 8.6 (s, 1H).