Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]2[N:21]=[CH:22][S:23][CH:24]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CO.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>[CH3:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]3[N:21]=[CH:22][S:23][CH:24]=3)[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH:30]=[CH:29][N:28]=1
Reactant: O=C(Nc1cccc(Br)c1)[C@H](Cc1ccccc1)NCc1cscn1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(-c2cccc(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a 5 mL flask was added (S)—N-(3-bromophenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 39.B (50 mg, 0.12 mmol), 2-methylpyridin-4-yl boronic acid (21 mg, 0.16 mmol, available from Combi-Phos), tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol), DMF (0.5 mL) and saturated aqueous K2CO3 (0.5 mL). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was diluted with methanol (3 mL), filtered and purified directly on reverse phase preparative HPLC to afford (2S)—N-(3-(2-methylpyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 39 (27.2 mg, 53% yield) as a white solid. LCMS ESI (pos.) m/e: 429.1. (M+1). 1H NMR (500 MHz, MeOH-D4) δ ppm 9.12 (d, J=1.96 Hz, 1H), 8.74 (d, J=6.36 Hz, 1H), 8.19 (s, 1H), 8.12 (dd, J=6.36, 1.96 Hz, 1H), 8.11 (t, J=1.71 Hz, 1H), 7.82 (d, J=1.96 Hz, 1H), 7.68-7.75 (m, 1H), 7.58 (t, J=7.83 Hz, 1H), 7.52-7.56 (m, 1H), 7.23-7.37 (m, 5H), 4.53 (d, J=4.65 Hz, 2H), 4.35 (dd, J=9.29, 5.87 Hz, 1H), 3.46 (dd, J=13.45, 5.87 Hz, 1H), 3.28 (dd, J=13.45, 9.29 Hz, 1H), 2.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[N:8][OH:9])=[CH:4][CH:3]=1.[CH2:10]([OH:13])[CH:11]=[CH2:12]>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:12][CH:11]([CH2:10][OH:13])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: C=CCO
Reactant: ON=Cc1ccc(Br)s1
Solvent: C1CCOC1
Product: OCC1CC(c2ccc(Br)s2)=NO1
Reaction time: 4 h

Procedure:
5-Bromo-thiophene-2-carbaldehyde oxime (40.2 g, 195.2 mmol) and allyl alcohol (32.4 ml) were added to tetrahydrofuran (200 ml) and then bleach (1318 ml) was added. The reaction was stirred for four hours followed by extraction with tetrahydrofuran (2×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (19 g).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1>C(O)C>[F:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cc(C(F)(F)F)cc(F)n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)cc(F)n1
Yield: 78.3 %

Procedure:
To 9 ml of ethanol were added 0.73 g of sodium bicarbonate and 0.61 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.7 g of 6-fluoro-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 6-fluoro-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC>O1CCOCC1.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3nccs3)c(=O)n12
Temperature: 120 °C
Yield: 71.7 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.32 mmol), and 2-(tributylstannyl)-1,3-thiazole (143 mg, 0.382 mmol) in 1,4-dioxane (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The reaction mixture was heated at 120° C. overnight. After cooling to room temperature, the mixture concentrated under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (73 mg, 72%). LCMS calculated for C12H11N6OS2 (M+H)+: m/z=319.0. Found: 319.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH:14][O:15][CH3:16])=[O:13])=[C:10]([Cl:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[C:11]([C:12](=[N:14][O:15][CH3:16])[O:13][CH3:18])=[C:10]([Cl:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CON=C(OC)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.8 %

Procedure:
A mixture of 16.0 g (0.058 mol) of methyl 2,4-dichloro-3-methoxyaminocarbonylbenzoate and 10.1 g (0.073 mol) of potassium carbonate in 300 ml of dimethylformamide was stirred at room temperature for 30 minutes. 11.0 g (0.087 mol) of dimethyl sulfate were then added, the mixture was stirred for 12 hours at room temperature, and a further 11.0 g of dimethyl sulfate were added. The reaction mixture was heated to 60° C. for 6 hours, cooled and stirred into 2 l of ice-water. The aqueous phase was then extracted with ethyl acetate, the combined organic phases were dried and the solvent was distilled off under reduced pressure. Silica gel chromatography of the residue (eluent:toluene/ethyl acetate=9/1) afforded 2.0 g of methyl 2,4-dichloro-3-(1′-methoxyimino-1-(methoxy)methyl)benzoate.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C1C(=O)N([Br:23])C(=O)C1>ClCCl>[Br:23][CH2:1][C:2]1[C:15]2[C:10]([N:9]=[C:8]3[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c2ccccc2nc2ccccc12
Solvent: ClCCl
Product: BrCc1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 9-methylacridine (1.93 g, 10 mmol) in dichloromethane (100 mL) was added NBS (1.78 g, 10 mmol) portion-wise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:5) as eluent to afford 10 (2.08 g) in 77% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.8 Hz, 4H), 7.81 (t, J=8.0 Hz, 2H), 7.68 (t, J=8.0 Hz, 2H), 5.42 (s, 2H). 13C NMR (400 MHz, CDCl3) δ 148.9, 138.7, 130.5, 130.1, 126.8, 123.8, 123.4, 23.1. MS (FAB) m/z Calcd for C14H10BrN 272.1. Found 2722. [M]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[N:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2cn[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 5 %

Procedure:
The title compound is prepared from 1H-indazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 5% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc([N+](=O)[O-])cc2Cl)CC1
Temperature: 80 °C
Yield: 92.6 %

Procedure:
Place 2,3-dichloro-5-nitro-pyridine (2.0 g, 10.36 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.12 g, 11.40 mmol), and potassium carbonate (1.72 g, 12.43 mmol) in DMF (20 mL). Heat to 80° C. for 2.5 days. Cool to room temperature and add ethyl acetate and water. Separate organic layer and wash with water and saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 20% EtOAc:hexane to yield 3.29 g (93%) of 4-(3-chloro-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester. MS(ES): m/z=341 [M+H].
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:7][CH2:8][CH2:9][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11]/[CH:12]=[CH:13]/[CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:4][CH3:5].[CH2:48](Br)[CH3:49]>CN(C=O)C>[CH2:48]([N:19]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:17][CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]/[CH:13]=[CH:12]/[CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9][CH2:8][CH2:7][N:6]([CH2:3][CH2:4][CH3:5])[C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH3:49]
Reactant: CCCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.05 g (1.25 mmol) of sodium hydride dispersion (approx. 60%) is added, with stirring, to a solution of 0.40 g (0.622 mmol) of (E)-1-propyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 1a) in 6 ml of DMF. The mixture is stirred for 5 min. at room temperature; 0.093 ml (1.25 mmol) of ethyl bromide is added, and the reaction mixture is stirred for a further 36 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a) yields the title compound, Rf value=0.55 (silica gel/ethyl acetate:hexane (1:1)).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C>O>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[C:18]3[S:12][C:13](=[S:14])[NH:15][C:16]3=[O:17])=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C1CSC(=S)N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Twenty grams (133.2 mmol) of piperonal were reacted with 17.74 g (133.2 mmol)of rhodanine in 38.24 g (466.2 mmol) of glacial acetic acid at reflux for about 3 hours. The mixture was then poured into water and stirred overnight. A precipitate formed which was recovered by filtration and then air dried overnight to provide 27.8 g of title product. m.p. 194°-195° C. Analysis for C11H7N1O3S2 : Calculated: C, 49.80; H, 2.66; N 5.28; S, 24.17; Found: C, 50.04; H, 2.38; N 5.27; S, 23.98.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27](O)[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:23][CH:22]=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl>[Br:46][CH:27]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCCC(O)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(Br)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 46.2 %

Procedure:
Triphenylphosphine (1.61 g, 6.12 mmol) was added to a solution of tert-butyl 3-(4-chlorophenyl)-3-hydroxypropylcarbamate (1.40 g, 4.90 mmol) in DCM (30 mL) at about 0° C. NBS (1.05 g, 5.88 mmol) was added portionwise. After 2 h, the reaction mixture was loaded to a short silica gel pad and eluted with EtOAc:hexanes (1:5) to give tert-butyl 3-bromo-3-(4-chlorophenyl)propylcarbamate (0.79 g, 46%) as an oil, which solidified on standing. 1H NMR (CDCl3, 400 MHz) δ 7.35 (m, 4H), 4.96 (m, 1H), 4.63 (br s, 1H), 3.28 (m, 2H), 3.21 (m, 1H), 2.37 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2O.P(Cl)(Cl)([Cl:25])=O.[OH-].[Na+].[NH4+].[OH-]>>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1nc2ccc(I)cc2c(Cl)c1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6-iodo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol (1.54 g, 3.71 mmol, Intermediate 5, step a) in phosphoryl trichloride (5 mL, 53.8 mmol) was heated at 110° C. for 1 hour 45 min, and then cooled to room temperature. Ice-water was added, and the mixture was basified at 4° C. with 50% NaOH and conc. NH4OH until pH 9. The precipitated solid was filtered, washed with water and Et2O, and dried to provide the title compound. The filtrate was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (80 g silica gel column, 0-5% EtOAc in heptane), affording a mixture of the title compound and des-iodo by-product in about 8:1 ratio as a thick oil, which solidified overnight.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1I)[CH2:2][CH2:3][CH3:4].[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)Cc1ccccc1I
Reactant: Nc1c(Cl)cccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCN(CCCC)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 81.1 %

Procedure:
A mixture of 3.5 g (0.0095 mole) of N,N-di-n-butyl-o-iodophenylacetamide, 1.70 g (0.0105 mole) of 2,6-dichloroaniline, 1.46 g (0.0104 mole) of anhydrous potassium carbonate, 1.0 g of copper powder and 1.0 g of cuprous iodide was reacted in 53 ml of xylene for 45 hours. After completion of the reaction, the post treatment was carried out in the same manner as in Example 12 to obtain 3.14 g of N,N-di-n-butyl-o-(2,6-dichloroanilino)phenylacetamide in the form of a colorless needle having a melting point of 66° to 68° C. (after recrystallization from methanol).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH2:48][OH:49])=[CH:31][CH:30]=1.[OH-].[Na+]>C(Cl)Cl.CC#N.CCOCC.CCCCCC.CCOC(C)=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH:48]=[O:49])=[CH:31][CH:30]=1
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of Dess-Martin periodinane (1.04 gm, 2.45 mmol) in dry CH2Cl2 (12 ml) was treated with t-butanol (182 mg, 2.46 mmol) and stirred at room temperature for 15 minutes. A slurry of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol (555 mg, 1.89 mmol) in CH2Cl2 (10 ml) and CH3CN (2 ml) was then added and stirring was continued for 25 minutes. The mixture was diluted with Et2O (50 ml) and poured into 1N NaOH (25 ml) and stirred for 5 minutes. The phases were separated and the organic layer was washed successfully with 1N NaOH, H2O, and brine, then dried (Na2SO4). Filtration and removal of the solvent afforded a solid. The solid was dissolved in hot hexane/EtOAc and the resulting solution was cooled to 0° C., filtered and stripped to give a residue which was chromatographed (Flash, Merck SiO2, 20% EtOAc in hexane). 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde was obtained as a white solid (458 mg, 83%). Analytically pure material was obtained by recrystallization from hot hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[S:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=1>C(O)CCC>[CH3:21][C:16]([CH3:20])([CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24]3[S:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:22])[C:17]([OH:19])=[O:18]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: CC(C)(CC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)O
Solvent: CCCCO
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3ncc([N+](=O)[O-])s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Yield: 10.5 %

Procedure:
In a 8-mL screw-cap vial, a mixture of 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid (60 mg, 0.20 mmol) and 2-bromo-5-nitro-1,3-thiazole (63.3 mg, 0.30 mmol) in 4 mL n-butanol was heated at 90° C. overnight. The solvent was removed under reduced pressure. The mixture was dissolved in 5 mL 1:4 MeOH/DMF and purified by reverse-phase HPLC to provide 8.9 mg (10%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (br s, 1H), 8.50 (s, 11H), 7.70-8.05 (m, 8H), 3.15 (d, 1H), 1.25 (s, 6H); LC-MS m/z 426.2 (MH+), ret. time 3.12 min.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])=[CH:12][C:11]=1[N+:22]([O-])=O.C([O-])(O)=O.[Na+]>O.CCO>[NH2:22][C:11]1[CH:12]=[C:13]([CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])[CH:14]=[CH:15][C:10]=1[Cl:9]
Reactant: CC(=O)NC(C)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)NC(C)c1ccc(Cl)c(N)c1
Reaction time: 1.5 h

Procedure:
A solution of sodium dithionite (1.08 g, 6.1 mmol) in H2O (4 mL) was added to a vigorously stirred mixture of N-[1-(4-chloro-3-nitrophenyl)ethyl]acetamide (0.30 g, 1.2 mmol) in EtOH (20 mL) at 55° C. After 4 h at 55° C. additional sodium dithionite (0.20 g, 1.1 mmol) was added and stirring was continued at 55° C. for 1.5 h. The mixture was allowed to cool and NaHCO3 (aq, sat) was added. The mixture was extracted with EtOAc and the combined extracts were dried over Na2SO4 and concentrated to give the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:5][C:6]1[C:7](=[O:23])[N:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[CH3:12].[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:27][C:25]1[CH:26]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:7](=[O:23])[N:8]([CH2:13][C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][N:15]=3)[CH:9]=[CH:10][C:11]=2[CH3:12])[CH:24]=1)[C:28]#[N:29]
Reactant: Cc1ccn(Cc2n[nH]c3ncccc23)c(=O)c1Oc1cc(Cl)cc(Br)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccn(Cc2n[nH]c3ncccc23)c(=O)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 90 °C

Procedure:
To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-methyl-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)pyridin-2(1H)-one (11-6; 100 mg, 0.224 mmol) and zinc cyanide (29 mg, 0.247 mmol) in DMF (1 mL) was added palladium tetrakis triphenylphosphine (51.9 mg, 0.045 mmol) and the mixture was degassed and heated to 90° C. for 20 minutes. After this time, additional zinc cyanide (29 mg, 0.247 mmol) and palladium tetrakis triphenylphosphine (51.9 mg, 0.045 mmol) were added and the mixture heated to 90° C. for 20 hours. The reaction mixture was then filtered through Gelman Acrodisc and purified on Gilson LC using a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA). Fractions containing desired compound were combine and the solvent concentrated in vacuo on a rotary evaporator. The residue was further purified using RediSep (4 g) and eluting with a 0-65% EtOAc/CH2Cl2 gradient. The desired fractions were combined and the solvent removed on the rotary evaporator to provide the title compound. 1H NMR (CDCl3): δ 11.48 (br s, 1H), 8.55 (d, 1H), 8.26 (d, 1H), 7.40 (d, 1H), 7.27 (dd, 1H), 7.14 (dd, 1H), 7.09 (dd, 1H), 6.96 (dd, 1H), 6.09 (dd, 1H), 5.48 (s, 2H) and 2.08 (s, 3H) ppm. LRMS (M+1)=392.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)C.[CH2:34]([NH:36][CH3:37])[CH3:35]>>[CH2:34]([N:36]([CH3:37])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)[CH3:35]
Reactant: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OCC
Reactant: CCNC
Product: CCN(C)CCOc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1

Procedure:
Using 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine obtained in Example 5-1) and ethyl(methyl)amine, and in the same manner as in Example 5-2) and 5-3) or according to a method similar to it or according to a combination thereof with an ordinary method, 6-[(5-{2-[ethyl(methyl)amino]ethoxy}pyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (76 mg) was obtained.