Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:19][C:20]1[N:21]=[CH:22][C:23]([C:26](Cl)=[O:27])=[N:24][CH:25]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:26]([C:23]2[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][N:24]=2)=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cnc(Cl)cn1
Reactant: COc1ccc(N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cnc(Cl)cn2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a mixture of 3,4-dimethoxy phenylamine (0.306 g, 2 mmol) and triethylamine (0.557 ml, 4 mmol) in dichloromethane (20 ml) was added 5-chloro-pyrazine-2-carbonyl chloride (0.354 g, 2 mmol) at 0-5° C. The mixture was allowed to stir at room temperature for 3 hours. The mixture was diluted with methylene chloride (20 ml), washed with saturated NaHCO3 (20 ml), brine (20 ml), dried (anhyd. Na2SO4) and concentrated to get 0.42 g of crude 5-chloro-pyrazine-2 carboxylic acid (3,4-dimethoxy-phenyl)-amide, which was directly used in the next reaction.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](O)=O)=O)(C)(C)C.[F:18][C:19]1[CH:20]=[C:21]([NH2:27])[C:22]([NH2:26])=[CH:23][C:24]=1[F:25].C(=O)([O-])[O-].[K+].[K+]>>[F:18][C:19]1[C:24]([F:25])=[CH:23][C:22]2[NH:26][C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[N:27][C:21]=2[CH:20]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Temperature: 140 °C
Yield: 69.3 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (10.0 g, 41 mmol) and 4,5-difluoro-benzene-1,2-diamine (5.95 g, 41 mmol) in polyphosphoric acid (140 g) was heated at 140° C. for 7 h. The cooled reaction mixture was poured onto excess solid potassium carbonate and crushed ice. The resulting basic, aqueous solution was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether, ethyl acetate and pentane to afford the title compound as a light brown solid (7.14 g, 69%).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[CH:18][N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Br)[N:23]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[C:24]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[CH:18][N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])[N:23]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.086 mmol), 2-amino-6-bromopurine (0.033 g, 0.16 mmol), and N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H16FN8OS (M+H)+: m/z=423.1. Found: 423.0. 1H NMR (DMSO-d6, 400 MHz) δ 7.98 (1H, d, J=4.8 Hz), 7.63 (1H, s), 7.52 (1H, d, J=4.8 Hz), 7.46 (1H, m), 7.20 (2H, m), 6.84 (1H, br s), 5.41 (1H, br s), 5.07 (1H, m), 1.26 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −114 ppm.
Reaction SMILES: [CH3:1]COCC.[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([CH3:19])([CH3:18])C)N=1)([CH3:9])(C)C>C1(C)C=CC=CC=1.C([Pd]Cl)C=C>[CH2:15]([C:14]12[CH2:18][CH:16]([CH2:12][CH2:13]1)[CH:19]=[CH:1]2)[CH2:10][CH2:6][CH3:9]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: CCOCC
Agent: C=CC[Pd]Cl
Solvent: Cc1ccccc1
Product: CCCCC12C=CC(CC1)C2

Procedure:
A 50 weight percent solution of butylnorbornene (5.0 g, 0.033 mol) was prepared in toluene. Lithium tetrakis(pentafluorophenyl)borate·2.5 Et2O (0.0012 g, 0.0014 mmol) was combined with (allyl)palladiumchloride dimer (100 μl of a 1.4 mmol solution in toluene) and 2,6-di-t-butylpyridine (100 μl of a 2.9 mmol solution in toluene) in toluene and added to the monomer mixture. A polymeric puck formed within 5-10 min at room temperature.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[C:27]([F:44])=[C:28]([NH:32][S:33]([C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (94 mg, 0.145 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 52 mg of the title compound. MS (ESI): 547.1 [M+1]+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[C:12]=12>C(O)C>[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([N:26]=[CH:1][C:2]4[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=4[OH:4])=[CH:22][CH:21]=3)[C:12]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)CC1
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N=Cc4ccccc4O)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (0.063 g, 0.000513 mol) and tert-butyl 4-[4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (0.200 g, 0.000489 mol) were combined in absolute ethanol (5 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate which was used without further purification. Trimethylsulfoxonium iodide (0.269 g, 0.00122 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.049 g, 0.00122 mol) was added at once. After 10 min., the solution of tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (70 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. The crude compound was dissolved in ethyl acetate (5 mL )and treated with a 4N aqueous solution of hydrochloric acid (1.5 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield 3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.038 g, 0.000078 mol) as a white solid
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][C@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C1CCOC1
Reactant: C[C@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
THF (100 mL) and 1,1′-carbonyldiimidazole (10.6 g, 65.6 mmol) were sequentially added to a solution of 2-chloro-N4-[(1S)-1-phenylethyl]quinoline-3,4-diamine (13.0 g, 43.7 mmol) in pyridine (100 mL), and the reaction was heated at 90° C. for one hour. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added as heating at 90° C. was continued overnight. The reaction was still incomplete, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added in portions as heating at 90° C. was continued for a second night. The reaction was cooled to approximately 0° C., and water (300 mL) was added. The mixture was stirred for two hours. A precipitate was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 9.98 g of 4-chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=O)[NH:8][C:4]=2[CH:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:7]1[N:6]([CH3:10])[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2cc(F)ccc21
Solvent: CCN(CC)c1ccccc1
Product: Cn1c(Cl)nc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.9 g 5-fluoro-1-methyl-1,3-dihydro-benzimidazole-2-one are suspended in 80 ml phosphorus oxychloride and the reaction mixture is stirred for 2 hours at reflux temperature. 50 ml diethylaniline are added. The reaction mixture is stirred for a further 10 minutes at reflux temperature and slowly mixed with ice water. The product is extracted with dichloromethane and purified by chromatography (silica gel, cyclohexane, methylene chloride/acetone 20/1). 1.4 g product are obtained as a solid. M.p=138-141° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.[CH2:21](Br)[CH:22]=[CH2:23].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:23][CH:22]=[CH2:21])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1
Reactant: COC(=O)CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)OC)O2
Yield: 83.1 %

Procedure:
Using the procedure of Example 12, 1.42 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-acetic acid methyl ester was alkylated with allyl bromide (2.79 g) and sodium hydride (5.58 mmole) in anhydrous N,N-dimethylformamide. There was obtained 1.35 g (83.1%) of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(2-propenyloxy)-2H-1-benzopyran-2-acetic acid methyl ester as a yellow oil, after column chromatographic purification (silica gel, 9:1 hexane-ethyl acetate).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: N#CCCN1C[C@@H](O)C[C@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](O)C[C@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using (3S,5S)-5-hydroxymethylpyrrolidin-3-ol described in Collect. Czech. Chem. Commun., vol. 61, pp, S234-S237 (1996), 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the sample manner as in Example 1b (e) and using 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [OH-].[Na+].[I:3][CH2:4][CH2:5][O:6][N:7]=[C:8]([C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)[C:9]([O:11]CC)=[O:10]>O1CCOCC1.C(O)C>[I:3][CH2:4][CH2:5][O:6][N:7]=[C:8]([C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 72 h

Procedure:
5.5 ml of a 2 N sodium hydroxide solution was added dropwise under an inert atmosphere to a mixture of 6.7 g of the product of Step A in 5.5 ml of dioxane and 44 ml of absolute ethanol and after the addition of 7 ml of absolute ethanol the mixture was stirred overnight to room temperature and was vacuum filtered. The recovered product was rinsed twice with 3 ml of a 4-1 ethanol-dioxane mixture and was then empasted with ether. The product was placed in a mixture of 100 ml of water and 100 ml of chloroform and the pH was adjusted to 2 by addition of N hydrochloric acid. The decanted organic phase was washed with an aqueous saturated sodium chloride solution, was dried and evaporated to dryness under reduced pressure. The residue was dissolved in 35 ml of dichloroethane at 40° C. and crystallization was induced. The mixture stood at room temperature for 72 hours and was vacuum filtered. The recovered product was rinsed and dried to obtain 5.4 g of the syn isomer of 2-(2-iodoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetic acid solvated with dichloroethane melting at 161° C. (= to 4.61 g of pure product).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1>CN(C)C=O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1nn2ccnc2c2c1CCCC2)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
0.59 g of 60% oily sodium hydride was suspended in 20 ml of dimethylformamide. To this suspension, 1.18 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for 30 minutes. To this mixture was added 1.35 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine, followed by stirring at 60° C. for 1.5 hours. After dimethylformamide was distilled off under reduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 6 by the addition of 5 N hydrochloric acid and then extracted with ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (20:20:1). The fraction containing the desired product was concentrated, and ethyl ether was added to separate a crystal, which was collected by filtration, to yield 0.66 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].CS([C:17]1[O:18][C:19]2[CH:25]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][NH:13][C:17]2[O:18][C:19]3[CH:25]=[C:24]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33](=[O:34])[NH:35][CH3:36])[CH:28]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CN)CCCCC1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Solvent: C1CCOC1
Product: CCOC(=O)C1(CNc2nc3ccc(Oc4ccnc(C(=O)NC)c4)cc3o2)CCCCC1
Reaction time: 2 h

Procedure:
To a solution of 1-aminomethyl-cyclohexanecarboxylic acid ethyl ester in THF was added 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide from Step 3 of Example 2. After reacting at room temperature for 2 hours the solvent was removed and the crude product was diluted with ethyl acetate and some dichloromethane, then washed three times with brine, dried with anhydrous sodium sulfate, filtered and concentrated. The final product was purified by reverse phase preparatory HPLC. MH+=453.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([S:35][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=5)[N:8]=[C:7]4[C:6]=3[CH:24]=2)[CH2:31][CH2:30]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)N1CCC(S)CC1
Reactant: FC(F)(F)c1n[nH]cc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4c[nH]nc4C(F)(F)F)cn2CCO3)CC1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
A mixture of 9-bromo-2-(3-trifluoromethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (73 mg, 0.18 mmol), 1-tert-butylpiperidine-4-thiol (63 mg, 0.37 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (35 mg, 0.06 mmol) and DIPEA (125 μL, 0.73 mmol) in dioxane (3 mL) was purged with argon and heated at 100° C. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 5-95%, 0.1% HCO2H in acetonitrile/water) affording 159 (56 mg, 31%). LCMS: RT 3.11 min [M+H]+ 492.1. 1H NMR (DMSO, 400 MHz): δ 8.51 (1H, d, J=2.40 Hz), 8.26-8.25 (1H, m), 8.21 (1H, s), 7.42 (1H, s), 7.31 (1H, dd, J=8.46, 2.42 Hz), 7.01 (1H, d, J=8.46 Hz), 4.47 (4H, s), 3.12-3.01 (1H, m), 3.05-2.93 (2H, m), 2.24 (2H, t, J=11.08 Hz), 1.92 (2H, d, J=12.67 Hz), 1.48-1.47 (2H, m), 1.02 (9H, s)
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[B:13](OCC)([O:17]CC)[O:14]CC>O1CCCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[B:13]([OH:17])[OH:14]
Reactant: CCOB(OCC)OCC
Reactant: Brc1ccc2ccccc2c1
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
Magnesium (60.27 mmol) and tetrahydrofuran (30 mL) were put in a three-necked round bottom flask and stirred. To the solution, 2-bromonaphthalene (13.07 mmol) was added, and the reaction mixture was heated. After that, 2-bromonaphthalene (32.02 mmol) dissolved in tetrahydrofuran (30 mL) was added dropwise to the solution. The reaction mixture was heated and refluxed for 4.5 hours. After that, the mixture was cooled to −78° C. (EtO)3B (111.66 mmol) was added dropwise over 15 minutes. Then, the mixture was warmed to room temperature and stirred for additional 5 hours. Then, the mixture was cooled to 0° C. The reaction was quenched by the addition of 1 M hydrochloric acid stirring for 2 hours. The reaction mixture was extracted with diethyl ether three times. The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After the drying, the extract was filtered. Then the filtrate was concentrated. The obtained solid was recrystallized in benzene to give GA40 (9 mmol, yield: 77%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.[F-].[Cs+].C(O[Si](OCC)(OCC)OCC)C.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>O1CCCC1>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:37][CH2:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: CCO[Si](OCC)(OCC)OCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCn1ccc(OCc2ccccc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.50 g, 1.78 mmol) and cesium fluoride (0.0027 g, 0.178 mmol) were suspended in tetrahydrofuran (10 mL) followed by dropwise addition of tetraethylortho silicate (0.37 g, 1.78 mmol) at room temperature. After stirring for 10 minutes at room temperature, ethyl acrylate (0.23 g, 2.32 mmol) was added dropwise and the reaction stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated and the resulting residue subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford a white solid (0.62 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.79 Hz, 1H), 7.41-7.29 (m, 5H), 6.03 (d, J=7.65 Hz, 1H), 5.20 (s, 2H), 4.17 (t, J=5.98 Hz, 2H), 4.07 (q, J=7.16 Hz, 2H), 2.83 (t, J=5.98 Hz, 2H), 1.19 (t, J=7.18 Hz, 3H). ES-HRMS m/z 380.0523 (M+H C17H18BrNO4 requires 380.0492).