Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)=[CH:10][C:9]=1[CH3:28])([CH3:6])[C:3]([OH:5])=[O:4].[I-].[Na+].Cl[Si](Cl)(Cl)Cl>>[CH3:28][C:9]1[CH:10]=[C:11]([CH2:14][CH2:15][C:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)=[O:27])[CH:12]=[CH:13][C:8]=1[O:7][C:2]([CH3:6])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCCSc1ccc(C(=O)C=Cc2ccc(OC(C)(C)C(=O)O)c(C)c2)cc1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [I-]
Agent: [Na+]
Product: CCCSc1ccc(C(=O)CCc2ccc(OC(C)(C)C(=O)O)c(C)c2)cc1

Procedure:
This compound was prepared following the general procedure B, using 2-methyl-2-(2-methyl-4-(3-oxo-3-(4-(propylthio)phenyl)prop-1-enyl)phenoxy)propanoic acid tertiobutyl ester, and 3 equivalents amounts of sodium iodide and 3 equivalent amounts of tetrachlorosilane;
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pt]=O.C(O)C>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([NH2:12])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1ccc(N)c(N)c1

Procedure:
4-n-Butyl-2-nitroaniline (12.5 g, 0.065 mole), platinum oxide (0.75 g) and ethanol (125 ml) were mixed together and shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature. After six hours 5.2 liters of hydrogen had been absorbed. The mixture was filtered and ethanol removed from the filtrate by distillation. Benzene (40 ml) was added to the residual oil and this was then also removed by distillation. The crude 4-n-butyl-1,2-phenylenediamine thus obtained was used directly in the preparation of 1,2-bis-(3-methoxycarbonyl-2-thioureiddo)-4-n-butylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([SH:14])[CH2:11][CH2:12][SH:13]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[S:14][CH2:10][CH2:11][CH2:12][S:13]2)[CH:7]=[CH:8][CH:9]=1
Reactant: SCCCS
Reactant: O=Cc1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Clc1cccc(C2SCCCS2)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorobenzaldehyde (100 mmol) in chloroform (250 mL) is added 1,3-propanedithiol (110 mmol). The mixture is chilled to −10° C. and HCl gas is gently bubbled through the mixture for 20 minutes. The mixture is stirred at −10° C. for one hour, then allowed to warm to room temperature overnight. The solution is washed with 1 M KOH, water, brine, and dried (K2CO3). After filtering, the organic extract is concentrated in vacuo to afford 2-(3-chlorophenyl)-1,3-dithiane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of 7.25 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride, prepared using substantially the procedure of Step A of Example 1 from the corresponding acid, in 20 ml of acetonitrile was added to solution of 1.43 g (7.25 mmol) of 4-aminobenzotrifluoride, hydrochloride and 1.83 g (18.1 mmol) of triethylamine in 10 ml of acetonitrile. The reaction mixture was warmed at reflux for a period of 4 hours and then poured over crushed ice. The resulting precipitate was collected by filtration and then recrystallized from acetonitrile to give 2.40 g (68 percent of theoretical) of the above-named product as a tan solid which melted at 176°-178° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 5)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O>[N+:1]([C:7]1[CH:6]=[C:5]([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[C:16]([F:17])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1nncn1-c1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(-n2cnnc2C(F)(F)F)c1
Yield: 63.9 %

Procedure:
Fuming nitric acid (0.5 g) was added to 4-phenyl-3-trifluoromethyl-1,2,4-triazole (1.06 g) (see Example 1) in concentrated sulphuric acid (15 ml) at 5°-10° and then slowly heated to 85° for 1 hr. The cooled acid solution was poured onto ice to give 4-(3-nitrophenyl)-3-trifluoromethyl-1,2,4-triazole (0.82 g, 63.4%) m.p. 142° (from benzene). Found: C, 41.70%; H, 2.13%; F, 22.1%; N, 21.43%. C9H5F3N4O2 requires: C, 41.87%; H, 1.95%; F, 22.1%; N, 21.70%). High resolution nmr spectroscopy indicated substitution in the m-position of the phenyl ring. m/e, 259.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Br.[CH3:12][C:13]([C:16]([NH2:18])=[NH:17])([CH3:15])[CH3:14].Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(#N)C>[C:13]([C:16]1[NH:17][CH:5]=[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:18]=1)([CH3:15])([CH3:14])[CH3:12]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)c1nc(-c2ccccc2Cl)c[nH]1
Temperature: 90 °C
Yield: 42.1 %

Procedure:
A mixture of 2-chlorophenacyl bromide (310 mg, 1.33 mmol), tert-butylcarbamidine hydrochloride (210 mg, 1.53 mmol), potassium carbonate (0.420 mg, 3.04 mmol), and acetonitrile (6 mL) was refluxed at 90° C. for 3 hours. After the mixture was left to cool to room temperature, an aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to give 2-tert-butyl-4-(2-chlorophenyl)-1H-imidazole (132 mg, 0.56 mmol, yield: 42%).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=O)[CH2:9]Br)[N:7]=1.[C:12]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])(=[S:14])[NH2:13]>C(O)C>[C:17]([NH:16][CH2:15][C:12]1[S:14][CH:9]=[C:8]([C:6]2[N:7]=[C:3]([NH2:2])[S:4][CH:5]=2)[N:13]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)NCC(N)=S
Reactant: Nc1nc(C(=O)CBr)cs1
Agent: Br
Solvent: CCO
Product: CC(=O)NCc1nc(-c2csc(N)n2)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.7 %

Procedure:
A suspension of 2-amino-4-bromoacetylthiazole hydrobromide (14.0 g) and N-[(thiocarbamoyl)methyl]-acetamide (6.1 g) in ethanol (300 ml) was stirred at room temperature for 24 hours. The insoluble material was removed by filtration. The solvent was removed under reduced pressure. The residue was suspended in water (300 ml). The mixture was alkalized to pH 10 with a saturated aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (500 ml) and tetrahydrofuran (100 ml). The extract was dried over magnesium sulfate and then was evaporated to afford 4-(2-acetylaminomethylthiazol-4-yl)-2-aminothiazole (5.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Reactant: C1COCCN1
Product: COC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 8 h
Yield: 83 %

Procedure:
30 ml of morpholine was added to 4 g (13 mmol) of 1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was refluxed under heating for 1 hour. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration to obtain 3.8 g (83%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1ccc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (2.21 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2.12 g) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[CH2:11]([O:14][CH2:15]Cl)[C:12]#[CH:13]>C(C(C)=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][O:14][CH2:11][C:12]#[CH:13])=[CH:6][CH:5]=1)#[N:3]
Reactant: C#CCOCCl
Reactant: N#Cc1ccc(O)cc1
Agent: [Na]
Solvent: CCC(C)=O
Product: C#CCOCOc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A sodium salt of p-cyanophenol(14.1 g) was dissolved in methyl ethyl ketone (20 ml), and chloromethyl 2-propynyl ether (Intermediate I-a) (10.6g, 0.1 mol) prepared in example 1 was added dropwise to the solution with stirring at room temperature. The reaction mixture was stirred for further 2 hours and the solvent was then evaporated off. The residue was extracted with toluene (30 ml) and the organic layer was washed with distilled water (20 g). The solvent was then evaporated off to obtain a crude reaction product (18.7 g). This was recrystallized from hexane (60 ml) to obtain 1-cyano-4-[(2-propynyloxy)methoxy]benzene (Intermediate II-i) (15.0 g, 79.7% yield). Its chemical purity by HPLC was 99.0%.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1.[CH3:30][O:31][C:32](=[O:44])[CH:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][SH:35].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.N1C=CN=C1.CP(C)C>ClCCl.CCCCCCC>[CH3:30][O:31][C:32](=[O:44])[CH:33]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:34][S:35][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][N:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:29])([F:1])[F:28])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)[CH:15]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(CS)NC(=O)OC(C)(C)C
Reactant: OCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1
Agent: CP(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCCC
Product: COC(=O)C(CSCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of [3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-yl]-methanol (0.257 g, 0.65 mmol), 2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester (0.304 g, 1.29 mmol), 1,1′-(azodicarbonyl)dipiperidine (0.343 g, 1.36 mmol), and imidazole (0.92 g, 1.36 mmol) in dichloromethane (10 mL, 0.07 M) was treated with trimethylphosphine (1 M in toluene; 1.4 mL, 1.36 mmol) in a dropwise manner at room temperature. After stirring for 1 hour, an equal volume of heptane was added and the resulting precipitate was removed by filtration. The filtrate was concentrated and purified by flash chromatography (20% ethyl acetate in heptane) to give 2-tert-butoxycarbonylamino-3-[3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-ylmethylsulfanyl]-propionic acid methyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15]>O.C(O)(C)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(-c2ccc(=O)[nH]n2)cc1Cl

Procedure:
3 In a mixture of water and isopropanol (20 : 5) was suspended 0.34 g. of 6-(4-amino-3-chlorophenyl)-4,5-dihydro-3(2H)pyridazinone. The resulting suspension was then treated in the manner as in Example 7 - 3 to give 0.18 g. of the desired product of m.p. 280° - 282° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[CH3:18][C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:15](=[O:17])[CH2:14][C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:13][CH:12]=3)=[N:28][CH:29]=2)[CH:23]=1
Reactant: Cc1cn(-c2ccc(N)nc2)cn1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-n4cnc(C)c4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (22 mg, 0.1 mmol), 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine 143-3 (18 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (40 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (52 μL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give N-(5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 143. MS m/z 384.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.91 (s, 1H), 8.58 (dd, 1H), 8.43 (d, 1H), 8.10 (m, 2H), 7.99 (m, 1H), 7.77 (d, 2H), 7.51 (s, 1H), 7.43-7.40 (m, 4H), 3.75 (s, 2H), 2.46 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C:34]5[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][NH:50][CH3:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C:34]5[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43][N:50]([CH3:51])[CH3:49])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5c(Cl)cccc5Cl)n4c3)c3ccccc32)n(CCOS(C)(=O)=O)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A mixture of Intermediate 28a (110 mg, 0.15 mmol) and dimethylamine (2.0M in THF, 1.54 mL, 3.09 mmol) in anhydrous THF (2 mL) was stirred at 60° C. for 18 h in a sealed vial. The volatiles were concentrated in vacuo and the resultant residue was purified by MDAP (Method 7) to afford the title compound (44 mg, 43%). LCMS (Method 5): Rt 3.50 min, m/z 661 [MH+]. 1H NMR (400 MHz, DMSO): 1.19 (9H, s), 1.83-2.14 (4H, m), 2.18 (6H, s), 2.59 (2H, t, J=6.9 Hz), 3.96 (2H, t, J=6.9 Hz), 4.79-4.87 (1H, m), 5.53 (1H, t, J=4.0 Hz), 6.01 (1H, s), 6.92 (1H, d, J=8.7 Hz), 7.22-7.28 (1H, m), 7.30-7.38 (4H, m), 7.68-7.78 (3H, m), 7.90 (1H, dd, J=9.9, 0.8 Hz), 7.96 (1H, d, J=2.0 Hz), 8.15 (1H, s), 8.44 (1H, s).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3[O:18][CH3:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=5[O:18][CH3:19])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: COc1cccc(-c2cccn3nc(Cl)nc23)c1OC
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1OC

Procedure:
4-{4-[8-(2,3-Dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2,3-dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.200 g, 0.690 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.229 g, 0.828 mmol) in a manner analogous to Example 311a and 311b to give product (0.264 g, 72%). MP=93-95° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.77 (d, 1H), 7.52 (m, 3H), 7.15 (m, 6H), 4.05 (m, 2H), 3.87 (s, 3H), 3.68 (s, 3H), 2.88 (br m, 2H), 2.60 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H). MS=530 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:30]1(B(OC(C)C)OC(C)C)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P(=O)(O)(O)O>CN(C)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.O>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CC(C)OB(OC(C)C)c1ccccc1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2c(cccc2-c2ccccc2)O1
Temperature: 100 °C
Yield: 56.8 %

Procedure:
0.23 g (0.2 mmol) of tetrakistriphenylphosphinepalladium is added under nitrogen to a solution of 2.93 g (9 mmol) of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)benzodioxin-4-one in 50 ml of dimethylformamide, the mixture is stirred for a few minutes and 2.97 g (14 mmol) of potassium phosphate and 2.04 g (9.9 mmol) of diisopropyl phenylboronate are then added. The mixture is heated to 100° C. until conversion is complete (about 16 h). After cooling, the reaction solution is poured into a mixture of 250 ml of water and 6 g of orthophosphoric acid and extracted three times with methyl tert-butyl ether, and the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. 2.6 g of a dark oil remain, which is chromatographed on silica gel using toluene/acetone. 1.3 g (57%) of a colorless solid are obtained, m.p. 158°-163° C. (recrystallized from hexane).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]3)[CH:21]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:9]=1.Cl>CO.O.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:3][C:4]1[CH:5]=[C:6]([C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:23][CH:24]([C:26]([OH:28])=[O:27])[CH2:25]3)[CH:21]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: COC(=O)C1CC(n2cc(-c3cc(C)cc(Nc4ncccn4)c3)cn2)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncccn2)cc(-c2cnn(C3CC(C(=O)O)C3)c2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (1.0 M in water, 1.68 mL, 1.68 mmol) was added to a solution of methyl 3-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) (203 mg, 0.559 mmol) in methanol (4.0 mL) and water (1.0 mL). The reaction mixture was heated to 50° C. and stirred for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with hydrochloric acid (1.0 M in water, 1.68 mL, 1.68 mmol) while stirring. The resulting suspension was diluted with ethyl acetate (100 mL) and brine (10 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 3-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid (Isomer 1). The material was used without purification in the subsequent step. MS ESI calc'd. for C19H20N5O2 [M+H]+ 350. found 350.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14](N)=[O:15]>O>[Br:12][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([O:10][CH3:11])[CH:8]=1)[N:1]=[C:14]([OH:15])[N:13]=[CH:4]2
Reactant: NC(N)=O
Reactant: COc1cc(Br)cc(C=O)c1N
Solvent: O
Product: COc1cc(Br)cc2cnc(O)nc12
Temperature: 180 °C
Yield: 111 %

Procedure:
The mixture of 2-amino-5-bromo-3-methoxybenzaldehyde (43.96 mmol, crude material from step 3) and urea (35 g, 583 mmol) from the previous step was heated to 180° C. under argon for 1 hour. Water (300 mL) was added after cooling to room temperature. The solid was collected by filtration and air dried to give 12.45 g of powder. ES/MS m/z 254/256 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][CH2:13][CH:14]([CH3:18])[C:15](Cl)=[O:16]>>[Cl:12][CH2:13][CH:14]([CH3:18])[C:15]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: CC(CCl)C(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CCl)C(=O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a slurry of 22.7 g. (0.17 mole) of anhydrous aluminum chloride and 9.6 g. (0.10 mole) of fluorobenzene is added 14.1 g. (0.10 mole) of β-chloroisobutyrylchloride over 30 minutes at 20° to 25°C. The mixture is aged for 30 minutes at 20° to 25°C and then quenched in ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-chloro-4'-fluoro-2-methylpropiophenone.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.[CH2:11]([CH:13]([C:19](=O)[CH3:20])[C:14](OCC)=[O:15])[CH3:12].C[O-].[Na+]>C(O)C>[Cl:2][C:3]1[S:7][C:6]([C:8]2[NH:10][C:14](=[O:15])[C:13]([CH2:19][CH3:20])=[C:11]([CH3:12])[N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: N=C(N)c1ccc(Cl)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)[nH]c1=O
Temperature: 25 °C
Yield: 51 %

Procedure:
A 250-mL round bottomed flask was charged with 5-chlorothiophene-2-carboxamidine HCl salt (6.81 g, 34.6 mmol, 1 eq.), ethyl 2-ethyl-3-oxo-butanoate (12 g, 72 mmol, 2 eq.), and ethanol (100 ml). To the mixture was added sodium methoxide (25 w % in methanol, 23 g, 107 mmol, 3 eq.). The resulting mixture was stirred under reflux for 7 hr. After cooling to room temperature, the mixture was evaporated under reduced pressure to dryness and the residue was treated with 2N HCl (60 ml). Solid was collected by filtration and washed with water followed by ether. The product thus obtained was forwarded to the next step without any further purification (4.53 g, 51% yield).