Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:39])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:35]4[CH2:38][CH2:37][CH2:36]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.Cl[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.[F-].[Cs+]>COCCOC.CCOC(C)=O.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>[CH:1]1([CH:4]([O:6][C:7](=[O:39])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:35]4[CH2:38][CH2:37][CH2:36]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:2][CH2:3]1
Reactant: Clc1ncccn1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3n2C2CCC2)cc1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(-c4ncccn4)cc3n2C2CCC2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A mixture of {4-[3-cyano-1-cyclobutyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (0.2 g, 0.38 mmol), 2-chloropyrimidine (39 mg, 0.34 mg), Pd(PPh3)4 (22 mg, 0.095 mmol) and cesium fluoride (0.116 g, 0.76 mmol) in DME (2.0 mL) was stirred at 100° C. for 16 h. The mixture was then diluted with EtOAc (20 mL), washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel (CH2Cl2/EtOAc) to provide [4-(3-cyano-1-cyclobutyl-6-pyrimidin-2-yl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (0.15 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:22]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCC4)nc23)CC1
Yield: 50.4 %

Procedure:
Beginning with 0.25 gm (1.08 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.136 gm (1.19 mMol) cyclobutanecarbonyl chloride, 0.17 gm (50.8%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>ClCCl>[OH:27][CH2:26][C:25]([NH:24][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3])([CH3:29])[CH3:28]
Reactant: CC(C)(N)CO
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(=S)NC(C)(C)CO)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A mixture of 10 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 3 parts of 2-amino-2-methyl-1-propanol and 260 parts of dichloromethane was stirred overnight at room temperature. The precipitated product was filtered off, washed with dichloromethane and 2-propanone and dried, yielding 11.7 parts (91.9%) of N-(2-hydroxy-1,1-dimethylethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea; mp. 221.6° C. (int. 7).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.[H][H]>[Pd].C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cccnc1

Procedure:
A mixture of 3 g (20 mmol) of 3-(3-pyridinyl)acrylic acid and 0.3 g of 10% palladium on carbon in 150 ml of ethyl acetate was shaken under 4 atmospheres of hydrogen for 24 h. After filtration, the resulting solution was concentrated in vacuo to provide the desired compound.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[CH:7]=1.[O-:21][Mn](=O)(=O)=O.[K+].C(O)(C)C>CC(C)=O>[C:11]1([N:10]2[C:6]([C:2]([OH:1])=[O:21])=[CH:7][C:8]([C:17]([F:20])([F:19])[F:18])=[N:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Intermediate 6 (2.84 g, 10.2 mmol) was dissolved in acetone (120 ml) and KMnO4 (11.2 gms, 71.45 mmol in 135 ml water) solution was added to it. This mixture was heated at 60° C. for 3 h and then cooled to rt. Then isopropyl alcohol was added to the reaction mixture and stirred at rt overnight. The reaction mixture filtered through celite and filtrate was evaporated on high vacuum. The residue was dissolved in 1N NaOH and washed with petether. Aqueous layer was acidified with 2N HCl solution to obtain the solid. Solid was filtered and dried on high vacuum to obtain the title compound (2.3 g) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.57-7.42 (m, 5H), 7.30 (s, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3].[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[Br:29]>>[Br:29][C:24]1[C:25]([CH3:28])=[N:26][O:27][C:23]=1[NH:22][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccsc1COc1ccc2c(c1Cl)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2COc2ccc3c(c2Cl)OCO3)c1Br
Yield: 47 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, 47% yield, m.p. 152-154° C.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11][C:5]=2[CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A suspension of 1,1-dimethylethyl 7-cyano-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (may be prepared as described in WO2002040471) (5 g, 18.36 mmol), hydroxylamine hydrochloride (2.55 g, 36.7 mmol) and sodium bicarbonate (7.71 g, 92 mmol) in ethanol (250 ml) was heated at 50° C. overnight. Further hydroxylamine hydrochloride (0.638 g, 9.18 mmol) was added to the reaction mixture and heating at 50° C. continued for 5 h. The reaction mixture was allowed to cool and the solid filtered off, the solution was concentrated in vacuo to yield the title compound as a white solid (5.77 g, 17.01 mmol, 93% yield). δH (d6DMSO, 400 MHz): 9.56 (1H, s), 7.52-7.37 (2H, m), 7.14 (1H, d), 5.77 (2H, br s), 3.50-3.32 (4H, m), 2.91-2.80 (4H, m), 1.41 (9H, s). MS (ES): C16H23N3O3 requires 305; found 306 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]([C:7]1[CH:11]=[C:3]([C:1]#[C:2][C:18]2[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:29][CH:30]=3)[N:17]=2)[CH:4]=[CH:5][C:6]=1[CH3:12])(=[O:9])[NH2:10]
Reactant: C#Cc1ccc(C)c(C(N)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Temperature: 120 °C
Yield: 68.9 %

Procedure:
To a mixture of 5-ethynyl-2-methylbenzamide (I71) (0.041 g, 0.25 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.105 g, 0.230 mmol), PdCl2(PPh3)2 (0.011 g, 0.016 mmol), triphenylphosphine (0.010 g, 0.038 mmol) and copper(I) iodide (0.010 g, 0.53 mmol) in DMF (2 mL) was added triethylamine (0.091 mL, 0.65 mmol). The mixture was then heated under microwave irradiation at 120° C. for 30 minutes. The resulting mixture was concentrated under reduced pressure then purified using silica gel column chromatography (0-100% EtOAc/petroleum benzine 40-60° C.) to give title compound (I72) (0.092 g, 69%); 1H NMR (400 MHz, d5-DMSO) δ 10.24 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.58 (m, 4H), 7.39 (m, 1H), 6.96 (d, J=9.0 Hz, 2H), 3.46 (dd, J=6.3, 3.3 Hz, 4H), 3.06 (m, 4H), 2.42 (s, 3H), 1.42 (s, 9H). LCMS Method C: rt 6.22 min; m/z 581.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])([OH:17])[CH:11]2[NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:4][CH:3]=1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2cc(Cl)ccc21
Yield: 6 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 350 mg of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 158 mg of 4-aminoindazole. By reaction of 50 mg of imine with 1.8 ml of BBr3 (1N in dichloromethane), 29 mg of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:30])[N:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)=[O:20])[C:3]=1[N+:31]([O-])=O.O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:31][C:3]1[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:30])[N:23]=[C:24]([C:26]([CH3:28])([CH3:27])[CH3:29])[CH:25]=2)=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:17])[F:16])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1N
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide (226 mg, 0.490 mmol, prepared as described in the previous step) in ethanol (10 mL) and water (5 mL) was treated with ammonium chloride (262 mg, 4.90 mmol) and iron powder (137 mg, 2.45 mmol), and the mixture was heated to 50° C. for 4 h. Ethanol was removed in vacuo, and the resulting residue was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 1:4 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [5-amino-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide as an off-white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H23F3N6O: 433.2 (M+H). Measured: 433.2.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1>>[F:29][CH:20]([F:19])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:26][CH:27]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ccc(OC(F)F)cn1
Product: O=C(Nc1ccc(OC(F)F)cn1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 5-(difluoromethoxy)pyridine-2-amine as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]([CH3:25])[CH:23]=O.COC(OC)N(C)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10](=[CH:21][N:22]([CH3:25])[CH3:23])[C:11](=[O:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(=O)CC(=O)Nc1ccccc1Cl
Agent: COC(OC)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)C(=CN(C)C)C(=O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-(2-chlorophenyl)-3-oxobutanamide (2.63 g), potassium carbonate (1.72 g) and N,N-dimethylformamide (31.0 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (3.30 mL) over 30 min at room temperature, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was slowly poured into water, and the mixture was extracted with dichloromethane. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.30 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][C:13]#[N:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([C:13]#[N:14])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2nc(-c3ccccc3)cs2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
A solution of 2-(4-phenylthiazol-2-yl)acetonitrile (0.84 g, 4.19 mmol) in THF (25 mL) was cooled to 0° C. NaH was added (0.5 g, 60% dispersion in oil) portionwise over 10 min. The resulting mixture was allowed to warm up to room temperature and stirred for 20 min. 2-Bromoethyl ether (1.58 mL, 12.5 mmol) was added dropwise. The reaction mixture was further stirred at room temperature for 1 h and then quenched with saturated NH4Cl solution. The reaction mixture was diluted with EtOAc and the organic layer was washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 4-8% EtOAc in petroleum ether) to afford 4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile (0.97 g, yield 85%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.91-7.94 (m, 2H), 7.51 (s, 1H), 7.37-7.48 (m, 3H), 4.07-4.14 (m, 2H), 3.87-3.96 (m, 2H), 2.32-2.43 (m, 4H). MS (ESI) m/z: Calculated for C15H14N2OS: 270.08. found: 271.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@:5]([CH3:9])([CH:7]=O)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH3:1][C:2]1([CH3:10])[O:6][C@@:5]([CH3:9])([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@](C)(C=O)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@](C)(C=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(R)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde (6.9 g, 48 mmol) was dissolved in 1:1 methanol water (100 mL), and hydroxylamine hydrochloride (3.3 g, 48 mmol) and Na2CO3 (2.5 g, 24 mmol) were added. The reaction was stirred at ambient temperature overnight. The methanol was removed in vacuo and the remaining material was extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford (S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (5.7 g, 36 mmol, 75% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:38](O)[CH:39]=[CH2:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(Cl)Cl>[CH2:40]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH:39]=[CH2:38]
Reactant: C=CCO
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution containing 7-hydroxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl)phenyl)-2H-chromen-2-one (0.550 g.) in tetrahydrofuran (6 mL) and methylene chloride (6 mL) was added allyl alcohol (0.226 mL) and triphenylphosphine (0.641 g.). Diisopropylazodicarboxylate (0.437 mL) was then added dropwise to the solution. The resultant mixture was allowed to stir for about one hour (or until the starting material was consumed). The solution was concentrated under reduced pressure and extracted with methylene chloride (3×) and water. The organic layers were dried over magnesium sulfate, the magnesium sulfate was filtered and the solvent was concentrated under reduced pressure to provide an orange oil. The oil was purified via silica gel chromatography (6–10% methanol/methylene chloride) to afford 7-prop-2-enyloxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl) Phenyl)-2H-chromen-2-one (0.245 g., 40% yield). MS (m/z) 550 (M+1)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][N:13]=1.[CH2:18]([O:20][C:21](=O)[O:22]CC)[CH3:19]>>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:21]([O:20][CH2:18][CH3:19])=[O:22])=[N:13][CH:14]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)Cc1ccncn1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
To a flask containing LiHMDS (32 mL, 31.89 mmol, 1.0 M in THF) at −70° C., was slowly added 4-methylpyrimidine (1.0 g, 10.63 mmol). After 5 min of stirring at −70° C., diethylcarbonate (1.93 mL, 15.95 mmol) was added, the reaction was slowly warmed to room temperature and stirred for 4 days. The reaction mixture was quenched by addition of 1 N HCl, neutralized with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow oil (1.38 g, 78%). MS 167 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:19][C:20]1C=CC(O)=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]3[C:13]=2[N:19]=[CH:20][CH:21]=[CH:22]3)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: Nc1ccc(O)cc1
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1cc(Oc2ccc(N)c3cccnc23)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 5-amino-8-hydroxyquinoline for 4-aminophenol. 1H-NMR (DMSO-d6) δ 8.72 to 8.66 (m, 2H), 8.60 (dd, J=8.7, 1.8 Hz, 1H), 8.40 (d, J=5.7 Hz, 1H), 7.42 (dd, J=8.7, 4.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.04 (dd, J=5.4, 2.7 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.13 (s, 2H), 2.73 (d, J=5.1 Hz, 3H); MS LC-MS (M+H)+=295.2; TLC (5% MeOH/DCM), Rf=0.31.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[C:4](/[N:6]=[C:7]1\[S:8][C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][N:11]\1[CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1)=[O:5].C(N(CC)CC)C.[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:9]1[S:8]/[C:7](=[N:6]\[C:4](=[O:5])[C:3]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:2]=2/[CH:42]=[CH:41]/[S:38]([CH3:37])(=[O:40])=[O:39])/[N:11]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH:10]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2/C=C/S(C)(=O)=O)s1
Temperature: 140 °C
Yield: 47 %

Procedure:
To a solution of Example 386B (172 mg, 0.350 mmol), triethylamine (53 mg, 0.525 mmol) and methylvinylsulfone (55.7 mg, 0.525 mmol) in acetonitrile (1 mL) was added palladium acetate (4.72 mg, 0.021 mmol) and tri(o-tolyl)phosphine (23.44 mg, 0.077 mmol). This mixture was heated in a microwave at 140° C. for 30 min. The reaction was heated another 30 min at 180° C. The reaction mixture was cooled to room temperature and filtered. The residue was purified by preparative HPLC on a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm), using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to provide the title compound (85 mg, 47%). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H) 1.62-1.71 (m, 1H) 1.76-1.92 (m, 2H) 2.02-2.14 (m, 1H) 3.08 (s, 3H) 3.73-3.87 (m, 2H) 4.22-4.34 (m, 2H) 4.50 (d, J=11.10 Hz, 1H) 6.80 (d, J=15.47 Hz, 1H) 6.97 (s, 1H) 7.59-7.72 (m, 2H) 8.52 (s, 1H) 8.83 (d, J=15.47 Hz, 1H); MS (DCI/NH3) m/z 517 (M+H)+.