Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>CN(C=O)C>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN(C)S(C)(=O)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 25 °C
Yield: 80 %

Procedure:
6-Methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazolin-4-one (2.24 g, 6.6 mmol) was taken up in thionyl chloride (25 ml) and treated with DMF (5 drops). The resulting solution was then heated at reflux for 1 hour followed by cooling to ambient temperature. The excess thionyl chloride was removed by evaporation followed by azeotroping with toluene (3×). The residue was basified with saturated aqueous sodium hydrogen carbonate solution (to pH8) and extracted twice with ethyl acetate. The organic solution was washed with water, brine, dried (MgSO4) and evaporated to dryness to give 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (1.90 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:26](O)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][N:17]=2)=[O:27])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2nccc3ccccc23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with isoquinoline-1-carboxylic acid. LC-MS (acidic): tR=1.04 min; [M+H]+=368.1.
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([NH:6][C:7](=O)[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])O.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>FC(F)(F)C(O)=O>[F:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([F:15])[C:8]=1[C:7]1[O:17][CH2:3][CH:4]([C:21]2[CH:22]=[CH:23][C:18]([OH:24])=[CH:19][CH:20]=2)[N:6]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)C(O)NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: Oc1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Reaction time: 48 h

Procedure:
The compound of Step A, Example 1 (51 g, 0.2 mol) and phenol (32 g 0.3 mol) were dissolved in trifluoroacetic acid (85 mL), stirred for 2 days and then evaporated under reduced pressure. The residue was taken up in dichloromethane (200 mL), washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was subjected to chromatography on silica gel using hexanes/ethyl acetate (2:1). The residue from the column (30 g) was dissolved in tetrahydrofuran (100 mL) and treated with lithium borohydride (60 mL, 2N in tetrahydrofuran) and heated at reflux for 3 h. The reaction mixture was treated with aqueous hydrochloric acid (1N, 300 mL) and extracted with dichloromethane (200 mL), dried and evaporated. The residue was treated with toluene (150 mL) and thionyl chloride (30 mL, 0.4 mol). After being heated at reflux for 1 h, the mixture was evaporated under reduced pressure. The residue was dissolved in methanol (200 mL) and treated with sodium hydroxide (20 mL, 50%) and heated at reflux for 1 h. The mixture was neutralized with aqueous hydrochloric acid and extracted with dichloromethane (200 mL). The dichloromethane was dried, evaporated, and subjected to chromatography on silica gel with hexanes/ethyl acetate (3:1 to 2:1). The second major fraction to elute was the tide compound (7.7 g) as a white solid: m.p. 145°-147° C. 1H NMR (CDCl3, 200 MHz) δ 9.3 (br s,OH), 7.7-6.8 (m,7H), 5.4 (m,1H), 4.8 (m,1H), 4.3 (m,1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C([O-])=O.[Na+].C(O)=O>CO.[Pd]>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: Cc1nccn1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of 54.0 g of 2-methyl-1-(p-nitrophenyl)imidazole, 2.87 g of palladium black, 36.7 g of sodium formate and 47.4 ml of formic acid in 1100 ml of methyl alcohol is stirred at room temperature for 18 hours under a hydrogen atmosphere. The mixture is filtered and the filtrate evaporated to a residue. The residue is partitioned between saturated potassium bicarbonate and chloroform. The organic layer is dried and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is crystallized from ether:ethanol to give 34.9 g of the desired product as a solid, m.p. 108°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:21](OC(C)(C)C)(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21](=[O:26])[CH2:22][C:23](=[O:24])[CH3:25])=[O:4]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give the title compound as yellow foam. MS (ESI): m/z=406.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[Cl:23][C:24]1[C:29]2[C:30](=[O:44])[N:31]3[CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38](=[N:40]O)[NH2:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[F:45]>CN(C)C=O>[Cl:23][C:24]1[C:29]2[C:30](=[O:44])[N:31]3[CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38]3[N:40]=[C:4]([CH2:3][N:2]([CH3:7])[CH3:1])[O:5][N:39]=3)[C:28]=2[CH:27]=[CH:26][C:25]=1[F:45]
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Reactant: CN(C)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN(C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Reaction time: 3.5 h
Yield: 24.3 %

Procedure:
1.24 g (12 mmol) of N,N-dimethylglycine were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 2.43 g (15 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 70° for 30'. Then, 3.35 g (10 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° for 3.5 hours. By evaporation of the solution, chromatography of the residue on 300 g of silica gel while eluting with ethyl acetate/methanol 9/1 and crystallization from ethyl acetate and hexane there was obtained 0.98 g (24%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-1-[5-(dimethylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 166°-169°, which was converted into the hydrochloride of m.p. 223°-227°.
Reaction SMILES: C1(C2[O:12][CH2:11][C:10]([CH2:19][O:20][C:21](=[O:24])[CH:22]=[CH2:23])([CH2:13][O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:9][O:8]2)C=CC=CC=1.COC1C=CC(O)=CC=1.C(O)(=O)C(O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)C1C=CC=CC=1>O>[C:15]([O:14][CH2:13][C:10]([CH2:19][O:20][C:21](=[O:24])[CH:22]=[CH2:23])([CH2:9][OH:8])[CH2:11][OH:12])(=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)OCC1(COC(=O)C=C)COC(c2ccccc2)OC1
Agent: COc1ccc(O)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O=Cc1ccccc1
Solvent: O
Product: C=CC(=O)OCC(CO)(CO)COC(=O)C=C

Procedure:
Into a two-liter flask equipped with an agitator, means for steam distillation, and a Claisen head with an efficient condenser was placed 664 g (2 moles) of 2-phenyl-5,5- bis(acryloyloxymethyl)-1,3-dioxane, two grams of 4-methoxyphenol and a hot solution of 8 grams of oxalic acid and 1.6 grams of potassium carbonate in 200 ml water. A slow stream of air was introduced into the steam inlet and the mixture stirred and warmed very slightly until the mixture appeared to be a homogeneous emulsion. Steam was then added to the air stream whereon benzaldehyde began to steam distill. It is desirable during the steam distillation that rapid stirring be maintained to provide intimate contact between the organic and aqueous layers in order to decrease the time required for hydrolysis as much as possible. After benzyaldehyde was no longer distilling, the still residue was cooled, saturated with sodium sulfate, filtered and extracted with ethyl acetate. The combined extracts were dried, preferably, by azeotropic distillation of water and ethyl acetate under reduced pressure. The 2,2-bis(acryloyloxymethyl)-1,3-propanediol obtained was a viscous, hydroscopic liquid. NMR spectroscopy confirmed the fact that no monol or triol was present in the product.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[C:3]1([CH3:26])[CH3:25].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:4]1[C:3]([CH3:25])([CH3:26])[CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5]1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccccc1[N+](=O)[O-])N2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Temperature: 0 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
To a mixture of (E)-methyl 4-(2-nitrobenzylideneamino) benzoate (3.26 g, 11.5 mmol) and yttrium(III) trifluoromethanesulfonate (140 mg, 0.27 mmol) in tetrahydrofuran (28 mL) was added isobutylaldehyde (1.9 mL, 20.6 mmol) at room temperature under nitrogen, then the resultant mixture was stirred at room temperature overnight. Thin layer chromatography and LC-MS showed the starting material was completely consumed. The reaction was quenched with water and separated. The aqueous layer was extracted with ethyl acetate twice and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 1.34 g of methyl 4-hydroxy-3,3-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield: 32.7%. To an ice-cooled mixture of methyl 4-hydroxy-3,3-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.5 g, 4.2 mmol) and triethylsilane (1.48 g, 12.6 mmol) in dichloro methane (150 mL) was added dropwise a solution of trifluoroacetic acid (1.92 g, 16.8 mmol) in dichloromethane (50 mL) over 45 min under nitrogen. The mixture was kept at 0° C. at room temperature for 12 h. Thin layer chromatography and LC-MS showed the starting material was completely consumed. Solid sodium carbonate (2.0 g) was added to the reaction mixture and stirred for 10 min., filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 1.26 g of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield: 86%.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15](Cl)=[O:16]>C1COCC1>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][N:20]=[C:12]([Cl:11])[CH:13]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of anthranilamide (2.36 g, 17.33 mmol) in 100 mL of THF at RT was added 2-chloroisonicotinoyl chloride (3.35 g, 19.04 mmol). A precipitate appeared and the reaction was heated to reflux overnight. The reaction was cooled to RT and concentrated. The precipitate was filtered and washed with H2O, CH2Cl2, and Et2O to give N-(2-carbamoyl-phenyl)-2-chloro-isonicotinamide as a light brown solid.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:13])[CH2:4][N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11].C[O-].[Na+]>>[CH2:4]([N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11])[CH:3]1[O:13][CH2:2]1
Reactant: CC(C)C1OCCN1CC(O)CCl
Agent: C[O-]
Agent: [Na+]
Product: CC(C)C1OCCN1CC1CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
3-(3-Chloro-2-hydroxypropyl)-2-isopropyl-1,3-oxazolidine (621 g., 3.0 mole) is charged into a 2-liter, three-necked flask equipped with a mechanical stirrer, thermometer and a dropping funnel. The flask is cooled to 0°-5° C. and 628 g. (2.91 moles) of sodium methoxide (25% solution in methanol) is added dropwise over a period of 31/2 hours, the clear solution becoming cloudy upon addition of the first several drops. Stirring is continued for an additional two hours after addition is completed. The solution is allowed to warm to room temperature and the sodium chloride is filtered off. The filtrate is concentrated on an evaporating rotary at 40° C/20 mm. Hg and the residue is refiltered to remove the remaining sodium chloride. The solution is then stripped at 40° C/20 mm. Hg until solvent is no longer removed. The resulting pale yellow liquid weighing 520 g. (98% yield) is wiping-film distilled at 100° C/0.5 mm. Hg to produce 368 g. (71% yield) of 3-(glycidyl)-2-isopropyl-1,3-oxazolidine in the form of a colorless mobile liquid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (1.00 g) and phenethyl alcohol (0.64 mL) were added to triphenylphosphine (1.54 g) and diisopropylazodicarboxylate (1.04 mL) in tetrahydrofuran (20 mL) at 0° C., and the reaction was stirred at room temperature for 24 hours. The mixture was chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]2[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][C:23]1=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:37])([CH3:21])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]=4[CH:27]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 6′-chloro-2,3,5,6-tetrahydro-1,2′-bipyrazinyl-4-carboxylic acid tert-butyl ester (preparation analogous to US 2005/176722) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]=C)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC(C)=[O:16].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: C=Cc1ccc(C(=O)NC)c(F)c1
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-N-methyl-4-vinylbenzamide (0.62 g) in a mixed solvent of acetone (23 mL)-acetonitrile (23 mL)-water (23 mL) were added osmium oxide (fixed catalyst I) (0.44 g) and sodium periodate (3.69 g), and the mixture was stirred overnight at room temperature. The insoluble substance was removed by filtration, and the filtrate was diluted with ethyl acetate and water. The insoluble substance was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to short silica gel column chromatography, and the solvent was evaporated under reduced pressure to give the title compound (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCN1CCC(=O)CC1
Product: COCCN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-(2-methoxy-ethyl)piperidin-4-one using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1-(2-methoxy-ethyl)-piperidin-4-yl]-methyl-amine as an off white solid (32% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 343 as a solid (43% yield). NMR (CDCl3, 400 MHz), 0.95-0.99 (2H, m), 1.68-1.77 (2H, m), 1.81-1.84 (2H, m), 2.02 (2H, t, J=10.3), 2.37 (3H, s), 2.50-2.59 (3H, m), 3.06 (2H, d, J=11.5), 3.37 (3H, s), 3.88-3.91 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.23 (2H, br s), 7.26 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=499
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([NH2:46])[CH:37]=[CH:38][C:39]=1[N:40]1[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]1.[C:47]([C:51]1[CH:52]=[C:53]([NH:57][C:58]2[C:63]([F:64])=[CH:62][N:61]=[C:60](Cl)[N:59]=2)[N:54]([CH3:56])[N:55]=1)([CH3:50])([CH3:49])[CH3:48].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:47]([C:51]1[CH:52]=[C:53]([NH:57][C:58]2[C:63]([F:64])=[CH:62][N:61]=[C:60]([NH:46][C:36]3[CH:37]=[CH:38][C:39]([N:40]4[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]4)=[C:34]([O:33][CH3:32])[CH:35]=3)[N:59]=2)[N:54]([CH3:56])[N:55]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: Cn1nc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2ncc(F)c(Nc3cc(C(C)(C)C)nn3C)n2)ccc1-n1cnc(C)c1
Yield: 30.3 %

Procedure:
Palladium(II) acetate (5.4 mg, 0.024 mmol) and 2-(dicyclohexylphosphino)biphenyl (17 mg, 0.048 mmol) were stirred in dioxane (2.7 mL) for 10 minutes at 20° C. under an atmosphere of nitrogen. Sodium tert.-butoxide (44 mg, 0.45 mmol), 3-methoxy-4-(4-methyl-imidazole-1-yl)-phenylamine (61 mg, 0.30 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine (94 mg, 0.33 mmol, WO2008099210) were added. The reaction was heated for 30 minutes to 200° C. in a microwave oven. Palladium(II) acetate (5.4 mg, 0.024 mmol), 2-(dicyclohexylphosphino)-biphenyl (17 mg, 0.048 mmol), sodium carbonate (48 mg, 0.45 mmol), (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine (85 mg, 0.3 mmol) and dioxane (1 mL) were added. The reaction was heated again for 30 minutes to 200° C. in a microwave oven. Water was added to the cooled reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane and then dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound as a yellow solid (41 mg, 30%). MS ISP (m/e): 451.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.02 (s, 1H), 7.60 (s, 1H), 7.30 (s, 1H), 7.09 (d, 1H), 7.03 (m, 2H), 6.82 (s, 1H), 6.45 (br s, 1H, NH), 6.11 (s, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.29 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[CH:10]2[CH3:13])=[CH:5][CH:4]=1.I[CH3:16].OS([O-])(=O)=O.[K+]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[C:10]2([CH3:16])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methoxy-1-methyl-3,4-dihydro-1H-naphthalen-2-one (1.95 g, 10.3 mmol) in THF (30 ml) was added NHMDS (11.3 mmol, 11.3 ml, 1M in THF) at 0° C. under nitrogen. The resulted solution was stirred at 0° C. for 1 hr. Iodomethane (7.29 g, 3.19 ml, 51.3 mmol) was added and stirred for an additional 3 hrs. 10% KHSO4 aqueous solution was added to acidify the reaction mixture, diluted with brine, extracted with ethylacetate, washed with brine, dried over MgSO4, filtered. The filtrate was evaporated under vacuo. The residue was purified by chromatography using ethylacetate:hexane (0.9:9.5) as eluant to give the desired product as white solid. (1.77 g, 85%). 1H NMR (CDCl3) δ: 7.08(d, 1H, J=8.3 Hz), 6.88(d, 1H, J=2.7 Hz), 6.74(dd, 1H, J=2.7 and 8.3 Hz), 3.80(s, 3H), 3.03(t, 2H, J=6.6 Hz), 2.65(t, 2H, J=6.6 Hz), 1.42(s, 6H). 13C NMR (CDCl3) δ: 213.7, 157.8, 143.9, 128.1, 126.5, 111.3, 110.4, 54.4, 46.9, 36.5, 26.8, 25.8.
Reaction SMILES: OO.C(O)(=O)C.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>O>[Cl:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]2[C:9]([CH:10]=1)=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:17][N:7]=2
Reactant: Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reaction time: 8 h
Yield: 49.8 %

Procedure:
A solution of 175 ml of 30% hydrogen peroxide and 600 ml of glacial acetic acid was heated on a steam bath for 1 hr and cooled. The solution was treated with 36.8 g (0.15 mole) of (2-amino-5-chloro-3-methylphenyl)phenylmethanone and the mixture was heated at 55°-70° C. for 7 hr and let stand overnight at ambient temperature. The mixture was diluted with 2 liters of water and the solid was collected by filtration, washed with water and dried. The solid was recrystallized from 2-propanol to yield 18.2 g (50%) of pale-yellow needles, m.p. 108°-109° C.