Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:30]>>[F:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:37][CH:36]=1
Reactant: O=C(CBr)Nc1ccc(F)cc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Product: O=C(COc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1)Nc1ccc(F)cc1

Procedure:
N-(4-Fluoro-phenyl)-2-{4-hydroxyimino-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromen-6-yloxy}-acetamide was prepared in 41% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 2-Bromo-N-(4-fluoro-phenyl)-acetamide (Bioorg. Med. Chem. 11 (2003) 2769-2782).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=O.[CH3:13][NH:14][NH2:15].B(F)(F)F.CCOCC>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[N:14]([CH3:13])[N:15]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: CNN
Reactant: O=c1ccoc2ccc(Br)cc12
Agent: FB(F)F
Solvent: CCO
Solvent: CCOCC
Product: Cn1nccc1-c1cc(Br)ccc1O
Yield: 44.6 %

Procedure:
To a suspension of 6-bromochromone (1.58 g, 0.0070 mol) in ethanol (30 mL) was added methylhydrazine (0.41 mL, 0.0077 mol) and boron trifluoride etherate (1.15 mL, 0.0091 mol). The reaction was heated to reflux for 22 hours. After cooling, the reaction was concentrated in vacuo and the residue purified by automated flash column chromatography using a 0-100% ethyl acetate/hexanes gradient. This provided the title compound (0.79 g, 44%) as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[N:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[C:17](=[O:16])[CH:22]=[CH:21][CH:20]=[N:19]1)#[N:2]
Reactant: Oc1cccnn1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ncccc2=O)[C@@H]1O
Yield: 60.9 %

Procedure:
1 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane and 1 g of 3-hydroxypyridazine are refluxed for 20 hours in 5 ml of dioxane, in the presence of 0.20 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide. The mixture is concentrated under vacuum and the residue is then triturated in 20 ml of water; the precipitate obtained is filtered off, washed with water and isopropyl ether and then recrystallized from 10 ml of isopropyl alcohol to give 0.9 g of the expected product.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:13].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:16][O:15][CH:14]([O:17][CH3:18])[C:12]1([CH3:11])[CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:13]1
Reactant: COC(OC)C(C)=O
Reactant: O=C(CO)c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In 250 ml of toluene were dissolved 30 g (0.22 mmole) of 2-hydroxy acetophenone and 33.8(0.29 mmole) of pyruvic aldehyde dimethyl acetal; and, 6.3 ml (0.09 mmole) of pyridine was added thereto. After stirring at room temperature 30 minutes, the reactants were heated to reflux for 5 hours using Dean-Stark apparatus. The solvent was removed under reduced pressure and 100 ml of 2N HCl aqueous solution was added. The resultant solution was stirred for 1 hour at room temperature, extracted with ethyl acetate (20 ml×2), washed with 100 ml of water and then with 50 ml of saturated sodium chloride aqueous solution and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) to obtain 39 g (0.16 mmole, yield 75%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.[Cu](I)I>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[C:2]([C:27]#[C:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=[N:4][CH:5]=1)[CH3:11]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 50 °C
Yield: 100.3 %

Procedure:
To a solution of ethyl 5-bromonicotinate (1.15 g, 5 mmol) in ethyl acetate (20 mL) under an N2 atmosphere, was added triethylamine (1.1 mL, 7.5 mmol, 1.5 eq.), phenyl acetylene (0.766 g, 7.5 mmol, 1.5 eq.), dichloro-bis(triphenylphosphine)-palladium(II) (176 mg, 0.25 mmol, 0.05 eq.), and copper iodide (10 mg, 0.05 mmol, 0.01 eq). The reaction mixture was heated at 50° C. for 20 h before being cooled to room temperature, filtered through a pad of celite, and solvent evaporated to provide a dark brown oil. Silica gel column chromatography (9/1-4/1 hexanes/EtOAc elution) provided the title compound as a pale yellow oil (1.26 g, yield 100%). 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.8 Hz, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.39 (dd, J=1.8, 2.1 Hz, 1H), 7.56-7.53 (m, 2H), 7.40-7.30 (m, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESI-MS m/z 251.9 (M+H)+.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1.[ClH:19]>C(#N)C>[Cl:19][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1
Reactant: Nc1nc2c(Cl)cccc2s1
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Clc1nc2c(Cl)cccc2s1
Temperature: 65 °C

Procedure:
Anhydrous CuCl2 (Aldrich, 4.37 g, 32.5 mmol), t-butyl nitrite (Aldrich, 4.83 mL, 40.6 mmol) and anhydrous acetonitrile (EM, 50 mL) were added to a 3-necked round-bottomed flask equipped with a reflux condenser, an additional funnel and a gas outlet tube. The mixture was warmed to 65° C. and a suspension of 2-amino-4-chlorobenzothiazole in 50 mL of acetonitrile. During the addition, the reaction mixture tuned to black and gas evolved. After gas evolution is complete, the reaction was allowed to reach room temperature. The reaction mixture was poured to 300 mL of 20% aqueous HCl, extracted 3× with EtOAc (400 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography with 60% CH2Cl2/hexanes to give 4.8 g of product.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:7])[NH:5][N:6]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:5]1[C:4](=[O:7])[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:2]([Br:1])=[N:6]1
Reactant: O=c1[nH]nc(Br)n1Cc1cccc(F)c1
Reactant: COC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nc(Br)n(Cc2cccc(F)c2)c1=O

Procedure:
1.50 g (4.69 mmol) of the compound from Example 137A are stirred under reflux for 4 hrs together with 508 mg (4.69 mmol) of methyl chloroacetate and 1.30 g (9.4 mmol) of potassium carbonate in 33 ml acetonitrile. After cooling, the mixture is neutralized with 1 N hydrochloric acid and diluted with ethyl acetate. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and freed of the volatile components on the rotary evaporator. The residue is dissolved in 20 ml dichloromethane and absorbed onto 3 g of diatomaceous earth. After removal of the solvent on the rotary evaporator the solid is transferred to a silica gel chromatography column and the product purified by elution with cyclohexane/ethyl acetate (gradient 5:1→1:1). 1.36 g (84% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15]>C(#N)C>[CH3:18][C:12]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:3]([C:2]([F:10])([F:9])[F:1])[CH:4]=[C:5]([CH3:6])[N:11]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1c(C(F)(F)F)cc(C)nc1C

Procedure:
1,1,1-Trifluoro-2,4-pentanedione (25.01 g, 135.3 mmol) was dissolved in acetonitrile (230 mL). Methyl 3-aminocrotonate (15.57 g, 135.2 mmol) was added to the solution, followed by refluxing for 20 hours. The reaction mixture was allowed to stand for cooling, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (eluent: n-hexane/acetone=10/1), to thereby yield methyl 2,6-dimethyl-4-trifluoromethylpyridine-3-carboxylate as a yellow oil (22.30 g, 71%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20.0 g amount of 7-(3-(trifluoromethyl)-phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxylic acid, ethyl ester (U.S. Pat. No. 4,178,449, Example 16) stirred in 100 ml of glacial acetic acid and cooled in a water bath is added portionwise 10.0 g of sodium cyanoborohydride under nitrogen. The mixture is stirred at room temperature for 3 hours. Evaporation of the mixture in vacuo gives an oil which solidifies on treatment with water. This solid is collected by filtration and is then stirred with a saturated solution of sodium bicarbonate, then is filtered, washed with water and dried in vacuo to give a white solid. Recrystallization from isopropyl alcohol gives 18.2 g of the desired product, mp 108-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:3]=1.[CH3:17][PH:18](=[O:20])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][P:18](=[O:20])([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:3]=1
Reactant: C[PH](C)=O
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a stirring solution of 4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene (0.44 g, 1.6 mmol) and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1 mL of DMF, was added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), Xanphos (55 mg, 0.10 mmol). The reaction mixture was stirred at 110 degrees C. overnight. The reaction mixture was cooled to room temperature and filtered through celite. The desired product was isolated through prep-HPLC to yield a brownish yellow solid (0.24 g, 55% yield)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]12[C:12](=[O:13])[O:11][C:9](=[O:10])[CH:6]1[CH2:7][CH2:8]2.Cl[CH2:15][CH2:16]Cl>>[O:10]=[C:9]([C@H:6]1[CH2:7][CH2:8][C@H:5]1[C:12]([OH:11])=[O:13])[CH:15]=[CH2:16]
Reactant: ClCCCl
Reactant: O=C1OC(=O)C2CCC12
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)[C@H]1CC[C@H]1C(=O)O

Procedure:
A mixture of aluminum chloride (66.7 g., 0.5 M), 1,2-cyclobutanedicarboxylic anhydride (31.5 g., 0.24 M) and 1,2-dichloroethane (1 liter) in a 2 liter 3-neck flask equipped with a gas inlet tube, a mechanical stirrer and a drying tube is stirred rapidly and ethylene is bubbled in for 4.5 hours. This mixture is poured into 900 ml. 5% hydrochloric acid and ice. The layers are separated and the organic layer is washed with water and taken to dryness in vacuo. The aqueous layer is extracted with ether (300 ml.). The extract is washed with water and combined with material from the original organic layer and taken to dryness. The residue is heated with 150 ml. of 10% potassium carbonate on a steam bath for fifteen minutes. After cooling the mixture is extracted three times with ether. The aqueous portion is acidified and the product (1.5 g.) is extracted into ether. The original ether extracts are combined and extracted with 150 ml. of 10% potassium carbonate solution. This aqueous layer is then acidified with hydrochloric acid and the product cis-2-[1-oxo-2-propenyl]cyclobutanecarboxylic acid (24.3 g.) is extracted into ether. Both samples (25.8 g., 67%) crystallize on standing.
Reaction SMILES: C(OC([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.Cl.C[OH:32]>>[OH:32][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CO
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Agent: Cl
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
Intermediate 24a (168 mg) obtained in Step A mentioned above was added with 10% hydrogen chloride/methanol (4 ml), and the mixture was stirred at 60° C. for 30 hours. The solvent was evaporated under reduced pressure to obtain the title compound as hydrochloride (123 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)[CH:5]=[O:6]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-chloro-4-fluorobenzaldehyde and 3-(trifluoromethyl)phenol.
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20](Cl)[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20]([C:34]4[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=4)[C:37]([O:39][CH3:40])=[O:38])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1nc(Nc2cccc(N3C[C@H]4CC[C@@H](C3)O4)c2)c2ncsc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
The mixture of N-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (0.095 g, 0.254 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.073 g, 0.28 mmol), Pd (PPh3)4 (0.015 g, 0.013 mmol) and Na2CO3 (0.081 g, 0.762 mmol) in dioxane (20 mL) and H2O (5 mL) was heated to 100° C. for 16 h under N2 atmosphere. Then it was concentrated to dryness. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with ethyl acetate:petroleum ether=1:2) to afford methyl 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (0.094 g, 78%) as a yellow solid. LC-MS: 474 [M+H]+, tR=1.84 min.
Reaction SMILES: [Cl-].[C:2]([CH:4]=[C:5]1[CH2:10][CH2:9][NH2+:8][CH2:7][CH2:6]1)#[N:3].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[C:48]([O:54][CH3:55])[CH:47]=1.C([O-])([O-])=O.[Cs+].[Cs+].[N-]=C=O>CC(O)(C)C.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]>[CH3:53][O:52][C:49]1[CH:50]=[C:51]([N:8]2[CH2:9][CH2:10][C:5](=[CH:4][C:2]#[N:3])[CH2:6][CH2:7]2)[CH:46]=[CH:47][C:48]=1[O:54][CH3:55]
Reactant: COc1ccc(Br)cc1OC
Reactant: N#CC=C1CC[NH2+]CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc(N2CCC(=CC#N)CC2)cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
In a sealed tube, 4-(cyanomethylidene)piperidinium chloride (16 mg, 0.10 mmol), Pd2(dba)3 (14 mg, 0.015 mmol), X-Phos (20 mg, 0.020 mmol), 4-bromo-1,2-dimethoxybenzene (33 mg, 0.15 mmol), and Cs2CO3 (98 mg, 0.30 mmol) were suspended in t-BuOH (0.5 mL). The reaction mixture was purged with argon for 5 minutes, the reaction flask was capped, and heated to 90° C. for 12 hours. The reaction was then cooled to ambient temperature and diluted with DMF/MeCN (1.0 mL, 50:50). To this mixture, Silica Supported-DMT (0.50 mmol, 0.57 mmol/g) followed by Silica Supported-Isocyanate (0.15 mmol, 1.33 mmol/g) was added. The resulting mixture was then shaken at 50° C. for 4 hours. The mixture was then passed through a nylon syringe filter (0.45 μm), and the filtrate was concentrated in vacuo to afford the title compound. The crude residue was used without further purification. LRMS (ESI) calc'd for C15H15N2O2 [M+H]+: 259. Found: 259.
Reaction SMILES: CI.[I:3][C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:14][C:7]1[CH:6]=[CH:5][C:4]([I:3])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.29 ml, 4.68 mmol) was added to a mixture of 1.0 g (3.60 mmol) of methyl 5-iodosalicylate, 0.50 g (3.60 mmol) of potassium carbonate and 4 ml of dimethylformamide, and they were stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite and then after-treated in by an ordinary method to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O:11]CC)=[O:10].[OH-].[Na+:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O-:11])=[O:10].[Na+:18]
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C(=O)Nc1cc(Cl)ccc1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g of ethyl 5-chloro-2-hydroxyoxanilate, 50 ml of ethanol, and 8.2 ml of a 1 normal sodium hydroxide solution was stirred for one hour at 60° C. The reaction mixture was concentrated under reduced pressure and the crystals formed were recovered and dissolved in 100 ml of water. Activated carbon was added to the solution and after filtering the mixture, the filtrate was concentrated under reduced pressure to 10 ml. After adding 10 ml of water to the concentrate, the mixture was allowed to stand overnight and the crystals formed were recovered by filtration to provide 1.1 g of sodium 5-chloro-2-hydroxyoxanilate.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[C:9]1[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.C1COCC1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>CC#N.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:9]1([C@@H:4]2[C@H:3]([CH3:2])[CH2:8][CH2:7][N:6]([C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:5]2)[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1CCN(C(=O)Oc2ccccc2)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 25 °C
Yield: 12.9 %

Procedure:
To a solution of 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.06 g, 0.21 mmol) in MeCN (1 mL) at about 0° C. was added TEA (0.06 mL, 0.41 mmol), THF (0.6 mL) and DMAP (0.006 g, 0.050 mmol) then phenyl chloroformate (0.026 mL, 0.206 mmol) and stirred for about 1 h. The reaction mixture was warmed to ambient temperature and concd under reduced pressure. The crude residue was dissolved in DCM (3 mL) and washed with water (2 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude residue was dissolved in DCM (5 mL) and washed with water (2 mL) and brine (2 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by RP-HPLC (Table 1, Method g) to give (3R,4R)-phenyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (0.010 g, 11%): LC/MS (Table 1, Method b) Rt=1.95 min; MS m/z 376 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH2:11][CH2:10][C:9]2=[O:21])=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>Br>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][CH2:10][C:9]2=[O:21])=[CH:3][CH:2]=1
Reactant: COc1cccc(C2CCC(=O)N2Cc2ccncc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCC(c2cccc(O)c2)N1Cc1ccncc1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a suspension of petroleum ether washed sodium hydride (80% oil dispersion, 0.94 g) in dry dimethylformamide (30 ml) was added 5-(3-methoxyphenyl)-2-pyrrolidinone (2.5 g) followed by 4-picolyl chloride hydrochloride (2.3 g) at ambient temperature, under nitrogen. The solution was warmed at 60° C. for 0.5 hr and allowed to cool to ambient temperature. The reaction mixture was quenched with ammonium chloride solution, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (5 times). The combined organic extracts were concentrated, the residue was diluted with a small volume of ethyl acetate, and the solution was washed with water (2 times). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2.9 g (78%) of 1-(4-pyridinylmethyl)-5-(3-methoxyphenyl)-2-pyrrolidinone. 1-(4-pyridinylmethyl)-5-(3-methoxyphenyl)-2-pyrrolidinone (2.9 g) in 48% hydrobromic acid (40 ml) was heated at 100° C. for 5.5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution, and extracted with dichloromethane (3 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtration was concentrated. The residue was purified by flash column chromatography (silica gel, ether/0-20% methanol). The appropriate fractions were collected and concentrated to give 2.3 g (81%) of 1-(4-pyridinylmethyl)-5-(3-hydroxyphenyl)-2-pyrrolidinone.