Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.O1CCCC1.S([O-])([O-])(=O)=O.[OH:21][NH3+:22].O[NH3+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:22][OH:21]
Reactant: [NH3+]O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ON=Cc1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
50.0 g (0.286 mol) of 2,6-dichlorobenzaldehyde were added to 250 ml of tetrahydrofuran and 250 ml of water, and 26.0 g (0.159 mol) of hydroxylammonium sulfate were added. The mixture was then stirred at 40° C. for 3 h, keeping the pH at 4-5 by adding sodium bicarbonate solution. The tetrahydrofuran was then distilled off under reduced pressure, and the residue was extracted with methyl tert-butyl ether, and the solution was dried over sodium sulfate and concentrated under reduced pressure. Yield 54.3 g (99.9%) of solid of melting point 150° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH2:20])[C:10]1=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:20][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:32])=[CH:31][CH:30]=2)[C:10]1=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)Cc2ccccc21
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CN(C)c1ccc(C(=O)NC2Cc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)cc1
Yield: 43.5 %

Procedure:
The title compound (0.2 gm) was prepared from 0.3 gm of 1-t-butoxycarbonylmethyl-3-aminohomodihydrocarbostyril (Example 2, Compound B), 0.19 gm of 4-dimethylaminobenzoic acid, 0.15 gm of 1-hydroxybenzotriazole and 0.23 gm of dicyclohexylcarbodiimide by a procedure analogous to the one employed in Example 10.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C)C.Cl.O.[OH-].[Na+].C[C:28](C)=[O:29]>>[CH:8]1([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:4][CH:28]=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)=O
Reactant: CCOC(OCC)C(c1ccccn1)C(C)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=CCC(CC1CCCCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Pyridyl-3-cyclohexyl-butyraldehyde diethyl acetal (650 mg) was dissolved in acetone (10 mL), treated with HCl (a solution of 2.5 mL concentrated HCl and 7.5 mL water) and the reaction was stirred at room temperature overnight. 1N sodium hydroxide (30 mL) was then added and the neutralized reaction mixture was extracted with ethyl acetate (2 times). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 4-cyclohexyl-3-(2-pyridyl)-butyraldehyde (480 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][OH:12]
Reactant: Oc1cccc(Br)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-phenol (10 g, 56.64 mmol), 2-bromoethanol (4.65 mL) and cesium carbonate (18.64 g, 1 eq.) in DMF (25 mL) was stirred at rt for overnight. The mixture was then heated in a 70° C. oil bath for about 3 hours. More 2-bromoethanol (3 mL) was added and heating was increased to 80° C. and stirred for overnight. The reaction was allowed to cool to rt and the insolubles were filtered off. The filtrate was poured into water and extracted with ethyl acetate (2×200 mL), washed with 10% Na2CO3 (3×), brine (2×), dried and concentrated. The residue was purified on a silica gel column to give 2-(3-bromo-phenoxy)-ethanol.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:11]([F:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1>N1C=CC=CC=1>[Si:1]([O:8][CH:9]([CH2:27][OH:28])[CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:11]([F:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)[C@H](F)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(C(CO)O[Si](C)(C)C(C)(C)C)[C@H](F)c1ccccc1
Reaction time: 6 h

Procedure:
To a plastic bottle containing (R)-tert-butyl 3,4-bis(tert-butyldimethylsilyloxy)-1-fluoro-1-phenylbutan-2-ylcarbamate was added 10 ml THF, 3 ml pyridine, 1 ml HF-pyr at 0° C. The mixture was stirred for 6 h and then carefully quench with sodium bicarbonate. The aq. layer was extracted with DCM (4×25 ml). The combined organics were washed with brine, dried with sodium sulfate, filtered, concentrated and the crude purified on a 40 g ISCO column to give 225 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:17]3[CH2:19][CH2:18]3)[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]=2[O:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].CS(C)=O>C(#N)C>[Si:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][N:12]([C:10]1[C:9]([CH:17]2[CH2:18][CH2:19]2)=[CH:8][C:7]2[C:3]([C:1]#[N:2])=[C:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[O:5][C:6]=2[CH:11]=1)[S:13]([CH3:16])(=[O:15])=[O:14])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Yield: 68.9 %

Procedure:
A mixture of Example 11A (0.1302 g, 0.352 mmol) and potassium carbonate (0.058 g, 0.422 mmol) in acetonitrile (2 mL) was heated at reflux for 30 minutes, then (4-iodobutoxy)-tert-butyldimethylsilane (0.122 g, 0.387 mmol) was added and the resultant mixture was stirred at reflux for 0.5 hour. The reaction mixture became thick so additional acetonitrile (2 mL) and dimethyl sulfoxide (2 mL) were added, and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil that was taken up in ethyl acetate (100 mL) and washed with 1 N aqueous H3PO4, 10% aqueous NaHCO3, and 10% aqueous NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo leaving a yellow oil. Purification on a silica gel column (12 g) eluting with a gradient of 10/90 ethyl acetate/hexane to 50/50 ethyl acetate/hexane over 20 minutes afforded the title compound (0.135 g, 69%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[OH:27])([CH3:20])[CH3:19]>O>[CH:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][C:8](=[O:9])[NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)C1CCCCC1O
Reactant: Cc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(NC(=O)OC2CCCCC2C(C)C)cc1
Yield: 56.8 %

Procedure:
75.6 g (0.56 mol) of para-tolylisocyanate were placed with 500 ml toluene in a one litre vessel and subsequently 73.4 g (0.51 mol) of 2-isopropylcyclohexanol were added. The reaction mixture was heated to reflux for 6 hours. After cooling to room temperature 50 g of water were added and the mixture was refluxed for one more hour. After phase separation the solvent was stripped off and the crude product recrystallized from 235 g of n-heptane. The product (79.8 g) was obtained in form of off-white crystals in 99.2% purity. This corresponds to a theoretical yield of 56%.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[C:25]=3[CH3:33])=[CH:18][CH:17]=2)=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:30][C:26]1[C:25]([CH3:33])=[C:24]([N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:12]3[CH:13]=[CH:14][C:2]([Cl:1])=[C:3]([CH:11]=3)[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:18]=2)[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc(N)c3C)cc2)ccc1Cl

Procedure:
The product from Example 306B in ethanol (1.2 mL) and H2O (0.6 mL) was treated with iron powder (100 mg, 1.8 mmoles) and NH4Cl (10 mg, 0.18 mmoles) at 80° C. overnight. The reaction mixture filtered, residue washed with methanol and dichloromethane, the filtrate concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:20]#[N:21])=[C:15]([CH:17]=[CH:18][CH:19]=2)[NH2:16])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:35])[C:32](Cl)=[O:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:35])[C:32]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:22]=[CH:23][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:27])[C:6]=2[CH2:24][CH2:25][CH3:26])[C:14]=1[C:20]#[N:21])=[O:33])[CH3:29]
Reactant: CCCc1c(OCCCOc2cccc(N)c2C#N)ccc(C(C)=O)c1O
Reactant: CCOC(=O)C(=O)Cl
Product: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)OCC)c2C#N)ccc(C(C)=O)c1O

Procedure:
In a manner analogous to that described in Examples 8 and 9, starting from 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanoaniline, by reaction with chloro-oxalic acid ethyl ester there is obtained N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-oxamic acid ethyl ester having a melting point of 158°-159°, and, by hydrolysis of that compound, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-oxamic acid is obtained in the form of the triethanolammonium salt having a melting point of 79°-81°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:39](=[O:56])[C:40]2[C:41]([O:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[C:42]([O:46][CH3:47])[N:43]=[CH:44][CH:45]=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:39](=[O:56])[C:40]4[C:41]([O:48][C:49]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:42]([O:46][CH3:47])[N:43]=[CH:44][CH:45]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1nccc2c(=O)c(I)c(-c3ccccc3)oc12
Product: COc1nccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 71 %

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-8-methoxy-2-phenyl-pyrano[2,3-c]pyridin-4-one was reacted to give the title compound (53.4 mg, 71%) as a white solid. LCMS (Method A): RT=4.91 min, [M+H]+=499.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:13][C:12]#[CH:11])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: C#CCBr
Reactant: Oc1cc(Br)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cc(Br)cc(F)c1F

Procedure:
50.0 g (0.24 mol) of 5-bromo-2,3-difluorophenol are refluxed for 3 h together with 32.0 ml (0.29 mol) of propargyl bromide (80% soln. in toluene) and 39.7 g (0.29 mol) of potassium carbonate in 860 ml of ethyl methyl ketone. The batch is filtered, and the filter residue is washed with MTBE. The filtrate is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccccc1
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1onc(-c2nonc2COc2ccccc2)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (15 mg, 0.0480 mmol), phenol (14 mg, 0.14 mmol) and triphenylphosphine (16 mg, 0.062 mmol) were dissolved in anhydrous THF (500 μL) then cooled to 0° C., followed by a dropwise addition of diethyl azodicarboxylate (9.8 μL, 0.062 mmol) in a solution of THF. Reaction was allowed to warm to rt then stirred 4 hrs. After concentration in vacuo, the sample was purified by reverse phase HPLC to yield a white powder (9 mg, 48%). MF═C17H10ClFN4O4; LCMS calculated for C17H10ClFN4O4 (M+H)+: m/z=389.045
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33].[N:34]1[CH:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][N:28]([CH2:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)[CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33]
Reactant: O=Cc1ccncc1
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCNCC1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCN(Cc2ccncc2)CC1

Procedure:
Intermediate 85 was coupled with pyridine 4-carboxaldehyde following procedure E. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 557. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.4 (d, 2H), 8.2 (d, 1H), 8.1 (s, 1H), 7.8 (d, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 3H), 7.0 (d, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.6 (s, 4H), 3.4 (d, 2H), 3.1 (d, 2H), 2.7 (m, 3H), 1.9-1.8 (m, 4H), 1.6-1.4 (m, 4H), 0.94 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:13]=[C:12]([CH3:29])[N:11]=2)[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:29][C:12]1[N:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=2)[C:1]#[N:2])[CH:15]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=1
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)cc(Nc2cc(C#N)ccn2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CCNCC2)cc(Nc2cc(C#N)ccn2)n1
Yield: 138.8 %

Procedure:
To a solution of tert-butyl 4-(2-((4-cyanopyridin-2-yl)amino)-6-methylpyridin-4-yl)piperidine-1-carboxylate (216 mg, 0.550 mmol) in CH2Cl2 (2.2 mL) was added trifluoroacetic acid (1.1 mL) and stirring was maintained for 2 hr. Concentrated to dryness afforded 2-((6-methyl-4-(piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile (1×TFA salt by 1H NMR) as a yellow solid (224 mg, >99%); 1H NMR (400 MHz, DMSO) δ 10.47 (br s, 1H), 8.65 (br s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.38 (br s, 1H), 8.07 (s, 1H), 7.36 (s, 1H), 7.32 (d, J=5.1 Hz, 1H), 6.80 (s, 1H), 3.40 (m, 2H), 3.02 (m, 2H), 2.93 (m, 1H), 2.47 (s, 3H), 1.96 (m, 2H), 1.76 (m, 2H); ESI-LRMS m/z [M+1]+=294.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:29][C:11]2[N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:29][C:11]2[N:12]=[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:32]([O:34][C:35]4[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=4)=[O:33])[CH:17]=3)[C:10]=2[C:9]=1[NH2:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 5-amino-2-phenyl-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(g), 2.0 g) was dissolved in dry CH2Cl2 (20 ml). Subsequently, a solution of p-nitro-phenyl chloroformate (520 mg) in dry CH2Cl2 (10 ml) was added dropwise and the reaction mixture was stirred at room temperature. After 3 h, the reaction mixture was washed with H2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc2ncnc(O)c2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Product: COCCOc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1
Yield: 18.8 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (138 mg, 0.5 mmol) and 4-chloro-6-(2-methoxyethoxy)quinazoline from Example 40A Step 5 (119 mg, 0.5 mmol) using the procedure of Example 16C. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (45 mg, 0.094 mmol, 20%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.62 (s, 1H), 7.94 (d, 1H), 7.74-7.64 (m, 3H), 7.60 (s, 1H), 7.42 (t, 1H), 7.27 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 4.37-4.31 (m, 2H), 3.78-3.71 (m, 2H), 3.34 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](O)=[O:14])([O-:3])=[O:2].B.CO>O1CCCC1>[N+:1]([C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][OH:14])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1c(CO)cccc1CO
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 2-nitro-1,3-benzenedicarboxylic acid (12.7 g, 0.06 mole) in tetrahydrofuran (60 ml) is cooled to 0° C. and 1N borane:tetrahydrofuran (300 ml, 0.3 mole) is added dropwise over one hour. The mixture is allowed to warm slowly to 25° C. and is stirred for 36 hours. Methanol (50 ml) is added slowly, the mixture is filtered and evaporated. The residue is dissolved in ethyl acetate (100 ml) and washed with water (25 ml), dried (MgSO4), filtered, and evaporated to yield a yellow solid. This is further purified by flash chromatography over silica (elution with 1:1 hexane:ethyl acetate) to afford after concentration pure 2-nitro-1,3-benzenedimethanol, mp 100°-101° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CC(C)=O>[NH:1]1[CH:5]=[C:4]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2c[nH]nn2)cc1
Reaction time: 7.5 h

Procedure:
8 g of 1,2,3-triazole, 10.67 g of potassium carbonate and 750 mg of potassium iodide are added in succession to a solution of 15.13 g of 4-bromomethylbenzonitrile in 375 ml of acetone. The reaction mixture is then stirred at 55° for 7.5 hours, and is then cooled and concentrated. The residue is dissolved in CH2Cl2 and washed in succession with water and brine. After drying over sodium sulfate, the solution is concentrated and the resulting crude product is purified by column chromatography (SiO2, toluene/ethyl acetate 3:19) to yield the precursor (1), IR (CH2Cl2): 2230, 1615, 1225, 1075 cm-1.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>>[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[N+:10]([O-:13])=[O:11])[NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(=O)Nc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(C)C(=O)Nc1ccc([N+](=O)[O-])c(Br)c1

Procedure:
Prepare a solution of 260 ml. of 30-33% oleum and 20 g. of 90% nitric acid. Cool the solution to 0° and add in small portion 60.5 g. of metabromo isobutyranilide. Maintain the reaction at 0°-5° C. for an additional 30 minutes with agitation. Isolate the product by the procedure described in Example 1 to obtain 3'-bromo-4'-nitro-isobutyranilide.
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:22]([F:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](F)[N:14]=1)([CH3:11])([CH3:10])[CH3:9].[CH3:25][C:26]([NH2:33])([CH3:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:8]([NH:12][C:13]1[C:22]([F:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([NH:33][C:26]([CH3:32])([CH3:25])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:14]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: COC(=O)c1cc(F)c(NC(C)(C)C)nc1F
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(F)c(NC(C)(C)C)nc1NC(C)(C)CC(C)(C)C
Temperature: 140 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To 7 ml N-methylpyrrolidone were added 2.44 g of methyl 6-t-butylamino-2,5-difluoronicotinate and 4.0 g of 1,1,3,3-tetramethylbutylamine, and the mixture was stirred at 140° C. for 16 hours and allowed to cool. After adding 50 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue was subjected to column chromatography (silica gel, 40 g; eluent:chloroform:n-hexane, 1:1) to obtain 2.90 g of the title compound as a colorless oily residue.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1b using 5-cyclohexyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (Example 4b) and C-(3-trifluoromethyl-1,2,4-oxadiazol-5-yl)-methylamine (CAN 944905-93-5) as starting materials; MS (ESI) 453.1 (M+H)+.