Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16](OC)=[S:17])=[CH:5][CH:4]=1.[H-].[Na+].[C:22]([OH:25])(=[O:24])[CH3:23]>O1CCCC1.CN(C)C=O>[C:22]([O:25][C:10]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:16]=2[S:17][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: COC(=S)c1ccncc1Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cnccc3c2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 0.200 g (0.69 mmol) of methyl 3-(4-methoxyphenyl)methylthiopyridine-4-carboxylate in 2 mL of dry tetrahydrofuran was added to a suspension of 83 mg (2.1 mmol) of 60% dispersion of sodium hydride in 2 mL of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 3 hours, then poured onto ice water and acidified with glacial acetic acid. The solid material (product) was collected by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate extract was dried, concentrated and combined with the solid precipitate that had been collected. This material was heated at reflux with 100 mg sodium acetate in 2 mL of acetic anhydride for 2 hours, then was partitioned between ethyl acetate and water. The aqueous layer was washed with two portions of ethyl acetate and the combined extracts were dried and concentrated. The residue was crystallized from methanol to afford 100 mg (48%) of white crystalline material, m.p. 141°-142° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([O:28]C)=O)=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]#N.N>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:30])=[O:28])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Reactant: N#N
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester, (0.229 g, 0.60 mM) in 8 mL THF was placed in an Ace Glass pressure tube (203 mm×38 mm) with a small stirring bar. A N2(g) stream was installed over the solution surface. The pressure tube and reaction solution were cooled to −78° C., and ˜8 mL NH3(l) was condensed into the reaction vessel by introduction of an NH3(g) stream. The pressure tube was sealed with a teflon O-ring screw cap, the resultant orange solution stirred at −78° C. for 10 minutes, then the cooling bath was removed and the reaction solution allowed to warm to ambient temperature behind a blast shield. After 48 h, the pressure tube was re-cooled to −78° C. and the internal NH3(g) pressure was released by careful removal of the Teflon™ cap. The reaction solution was allowed to slowly warm to room temperature while NH3(g) bubbled off, then the solution was concentrated in vacuo to afford 0.22 g (99%) of the title compound 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid amide as a yellowish-green solid (MW 366.42).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>>[OH:13][C@@H:12]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:11]1[CH:14]=[CH:15][C:8]([CH3:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-methylbenzaldehyde (0.40 mmol) was added thereto. After reacting for 92 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-methylphenyl)methylphosphonate as a final product in a yield of 82%. The chemical reaction in this Example is shown in chemical formula 29.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:36])([F:35])[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:34]=[CH:33][C:24]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:30]1[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:14]3[C:13]4[C:18](=[CH:19][C:10]([C:9]([F:8])([F:35])[F:36])=[CH:11][CH:12]=4)[N:17]=[CH:16][CH:15]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:29]1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: Clc1ncccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(c2ncccn2)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A mixture of 1.30 g (0.0114 mol) of 2-chloropyrimidine, 3.50 g (0.00875 mol) of 1-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, and 1.2 g of triethylamine in 50 ml of ethanol is stirred at 50° C. for 15 hours and at reflux for 8 hours. The mixture is partitioned between methylene chloride and aqueous 1 N sodium hydroxide. The organic phase is dried and concentrated. The residue is re-crystallized from methylene chloride and ethanol to yield 4.00 g of 4-(2-pyrimidinyl)-1-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, of melting point 246°-247.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH3:20][C:21]1([CH3:29])[O:25][C@@H:24]([CH2:26][O:27][NH2:28])[CH2:23][O:22]1>>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:28][O:27][CH2:26][C@H:24]1[CH2:23][O:22][C:21]([CH3:29])([CH3:20])[O:25]1)=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Product: CC1(C)OC[C@H](CONC(=O)c2ccnc(Cl)c2Nc2ccc(I)cc2F)O1

Procedure:
2-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 2-chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid and 0.3 mmol of O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-hydroxylamine LC/MS [9.19 min; 522 (M+1)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([NH:26][CH2:27][C:28]#[CH:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(N(CC)CC)C>ClCCl>[Cl:12][C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([NH:26][CH2:27][C:28]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:29]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: C#CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: ON=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Temperature: 40 °C
Yield: 78.8 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (54 g, 230 mmol), prepared as described in Parts A through C of Example 11, was added to a solution of 2-chloro-3-nitro-N-prop-2-ynylquinolin-4-amine (30.2 g, 115 mmol), prepared as described in Part A of Example 3, in dichloromethane (1 L) at room temperature. Triethylamine (26 g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40° C. under nitrogen for 16.5 hours and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate, and the work-up and isolation procedures described in Part B of Example 18 were followed to provide 36.12 g of 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH:34]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>ClCCl>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:34]([C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2=[O:1])=[O:13])[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)c1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Example 5 (500 mg, 2.84 mmol) in dichloromethane (10 mL) was added 1,3-diisopropylcarbodiimide (0.44 mL, 2.84 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), and di-t-butyl iminodiacetate (1.04 g, 4.26 mmol). The mixture was stirred at room temperature for about 24 hours, quenched with water, and extracted with diethyl ether. The combined organic extracts were washed with brine and saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the mobile phase to provide the desired product. MS (ESI): m/z 402 (M−H)−.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.[Cl:27][C:28]1[CH:33]=[C:32](O)[CH:31]=[CH:30][N:29]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[Cl:27][C:28]1[CH:33]=[C:32]([O:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:31]=[CH:30][N:29]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cc(OC2CCOCC2)ccn1
Temperature: 55 °C
Yield: 82.9 %

Procedure:
Triphenylphosphine (6.88 g, 26.2 mmol) was added to a mixture of tetrahydro-2H-pyran-4-ol (2.68 g, 26.2 mmol) and 2-chloropyridin-4-ol (2.72 g, 21.00 mmol) in THF (70 mL) under argon. Diisopropyl azodicarboxylate (DIAD) (5.28 mL, 26.9 mmol) was added dropwise over 5 mins and then the mixture was heated to 55° C. overnight. The mixture was cooled to RT and the solvent was removed in vacuo to give an oil. The oil was purified by silica gel chromatography to give crude 2-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyridine as an oil. This material was dissolved in ethyl acetate and then washed with 1N aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyridine (3.71 g, 17.4 mmol, 83% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:5][C:6]=1[C:7](=[O:9])[CH3:8].[CH3:20][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:5][C:6]=1[C:7]([OH:9])([CH3:20])[CH3:8]
Reactant: CC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanone (0.58 g, 2.15 mmol) is stirred in tetrahydrofuran (25 mL) at zero deg. C. Methyl magnesium bromide (1.1 mL, 3.23 mmol, 3 M in ether) is added and the reaction stirred at room temperature 2 hr. The mixture is cooled on ice/water and quenched with saturated ammonium chloride (5 mL). The product is extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to afford the product as a tan solid, 0.40 g, 65%). MS M++1 286. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)[O:7][CH:12]=1)[CH3:19]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=O)c1ccc(O)cc1
Solvent: CO
Product: CCOC(=O)Cc1coc(-c2ccc(O)cc2)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 4-hydroxybenzamide (25.2 g, 0.18 mol) and ethyl chloroacetoacetate (90 mL) is heated to 110° C. After 1 h, more ethyl chloroacetoacetate (30 mL) is added, and continue to heat for 3 h more. The mixture is cooled to approximately 60° C., and MeOH is added. The mixture is filtered and dried to yield the title compound (36.6 g, 80%) as an off-white solid. MS (m/e): 248.3 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1ccc2ccccc2n1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccc2ccccc2n1

Procedure:
The title compound (0.1 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.5 ml) and 2-chloroquinoline (0.5 g) according to the procedure of D8.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:14]([O:21][CH2:22][CH2:23][CH2:24][OH:25])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CN1CCOCC1>C(Cl)Cl>[Si:14]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=1)=[O:10])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 0.604 g (3.00 mmol) sample of p-nitrophenoxycarbonylchloride in 3 mL of methylene chloride was added to a solution of 0.570 g (3.00 mmol) of 3-(t-butyldimethylsilyloxy)-1-propanol and 0.329 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 2 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.831 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][NH:27][S:28](=[O:31])(=[O:30])[NH2:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[NH:27][CH3:26])=[O:8]
Reactant: CNS(N)(=O)=O
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), methyl(sulfamoyl)amine (23 mg, 0.21 mmol), 1-ethyl-(3-dimethylamino-propyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in DCM (20 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase Combiflash (18%-25% MeCN in 0.5% NH4HCO3) to give target product (35.4 mg, 56%) as a pale yellow solid. LCMS (ESI) Method A: RT=5.78 min, m/z: 456.7 [M+H]+; 1H-NMR (500 MHz, MeOH-d4,): δ 7.77 (d, J=6.0 Hz, 1H), 7.42 (d, J=10.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.52 (dd, J=9.0, 2.5 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.71 (s, 3H), 1.80 (t, J=6.5 Hz, 2H), 1.32 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:41]5[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1

Procedure:
Following general procedure II, tert-butyl(1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]pyridin-2-yl}piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.24 mmol) to afford crude product which was carried forward without any purification: ESI MS m/z 607 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:21][N:22]=2)[N:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added the isocyanatobenzene (2.5 mg, 0.021 mmol) in DCM (0.1 mL) dropwise. The reaction was slowly warmed to ambient temperature and stirred for 1 hour. The reaction was diluted with DCM (2 mL), washed with water, and concentrated. The crude product was purified by silica gel chromatography (eluent=50% EtOAc/hexanes first, then 5% MeOH in DCM) to yield the pure final product as a solid (5 mg, 60%). MS (apci) m/z=435.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([C:6]1[C:7]([OH:20])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)[CH3:5].[F-].[Cs+].I[CH2:24][CH2:25][CH3:26]>CN(C=O)C.CCOC(C)=O>[OH:1][CH2:2]/[CH:3]=[C:4](\[C:6]1[C:7]([O:20][CH2:24][CH2:25][CH3:26])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)/[CH3:5]
Reactant: CCCI
Reactant: CC(=CCO)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cc2c(cc1/C(C)=C\CO)C(C)(C)CCC2(C)C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
(2Z)-3-(4-Hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy)naphthalene (Structure 8 of Schemes 1 and 2, where R1, R4, R6=H, R2 and R3 together form a tetramethyl saturated six-membered carbocyclic ring, R5=methyl, R7=n-propyl). To a flame-dried 25-mL r.b. flask containing 3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (133 mg, 0.48 mmol) in 2 mL anhydrous DMF at room temperature was added cesium fluoride (365 mg, 2.40 mmol, 5.00 equiv) and 1-iodopropane (52.0 μL, 0.53 mmol, 1.10 equiv), and the mixture was stirred for 12 h. The reaction mixture was then diluted with EtOAc (20 mL) and the resultant organic layer was washed with water (2×10 mL), brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure to afford 150 mg (99%) of (2Z)-3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy) naphthalene as a colorless viscous oil. 1H NMR (400 MHz, CDCl3) 6.91 (s, 1H), 6.77 (s, 1H), 5.78 (dt, 1H, J=6.6, 1.4 Hz), 3.88 (m, 4H), 2.04 (s, 3H), 1.75 (m, 2H), 1.28 and 1.23 (2s, 2×3H), 1.01 (t, 3H, J=7.5 Hz). 13C NMR (100 MHz, CDCl3) 153.3, 144.9, 138.4, 137.0, 127.7, 126.5, 110.1, 70.3, 60.7 35.2, 35.1, 34.4, 33.6, 31.9, 31.8, 25.1, 22.8, 10.7. IR (thin film) 3336 (br, s), 2919 (s), 1498 (m), 1455 (m). Anal. Calcd for C21 H32O2: C, 79.70; H, 10.19. Found: C, 79.60; H, 10.44.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:22][CH:21]=[N:20][CH:19]=2)=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O>[O:22]1[C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH2:7])=[CH:9][CH:10]=2)=[CH:19][N:20]=[CH:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnco2)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnco2)c2ccccc12
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Compound 503C (1.34 g, 4.3 mmol) was dissolved in trifluoroacetic acid (10 mL) and the resulting mixture was allowed to stand for 1 h at room temperature. After removing the volatiles in vacuo, the residue was co-evaporated from ethyl acetate/heptane (2×50 mL) to remove traces of trifluoroacetic acid. After partitioning the residue between ethyl acetate (100 mL) and 1N NaOH (75 mL), the organic layer was washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 900 mg (99%) of compound 503D as a yellow crystalline solid. HPLC conditions: 95% at 0.92 min (retention time) (Phenomenex 5 micron ODScolumn, 4.6×30 mm, 10%-90% aqueous methanol over 2 min gradient with 0.1% TFA, monitoring at 254 nm.). MS (ES): m/z 211.22 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]=[N:11]O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C([O-])(O)=O.[Na+]>O>[Br:8][C:5]1[N:4]2[N:11]=[CH:10][N:9]=[C:3]2[C:2]([Br:1])=[N:7][CH:6]=1
Reactant: ON=CNc1nc(Br)cnc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1ncc(Br)n2ncnc12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 62.1 %

Procedure:
N-(3,6-dibromo-pyrazin-2-yl)-N′-hydroxyformamidine (17.4 mg, 58.80 mmol) is treated with polyphosphoric acid (150 g) for one hour at 50° C. and then for 1.75 hours at 70° C. After cooling to room temperature, water is added to the reaction mixture. The resultant suspension is brought to pH 8 by careful addition of solid NaHCO3 in small portions. The precipitate formed is collected by filtration, washed once with 1N NaOH, three times with water and dried in vacuo. The residue is partitioned between ethyl acetate and 1N NaOH and the organic phase is washed one more time with 1N NaOH and once with brine. The organic phase is dried over MgSO4, filtered and evaporated to give the title compound (10.15 g) as a white solid. 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 8.43 (s, 1H), 8.92 (s, 1H). LCMS: Rt 2.73 min (94.2%), m/z (APCI) 277 (M+H)+.