Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:9][N:10]=[C:11]([NH2:38])[CH2:12][O:13][C:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:15]=1)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6]>C1(C)C=CC=CC=1>[CH:27]1([NH:26][C:19]2[CH:18]=[C:17]3[C:22]([C:23](=[O:24])[C:14]([O:13][CH2:12][C:11]4[NH:38][C:3](=[O:8])[O:9][N:10]=4)=[CH:15][N:16]3[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:21][C:20]=2[F:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1.[CH:27]1([NH:26][C:19]2[CH:18]=[C:17]3[C:22]([C:23](=[O:24])[C:14]([O:13][CH2:12][C:11]4[N:38]=[C:3]([CH2:4][C:5](=[O:6])[CH3:7])[O:9][N:10]=4)=[CH:15][N:16]3[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:21][C:20]=2[F:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(=O)CC(=O)ON=C(N)COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1nc(COc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)no1
Product: O=c1[nH]c(COc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)no1

Procedure:
5 ml of toluene and 41 mg of 60% sodium hydride were added to 180 mg of N′-(acetoacetyloxy)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}ethanimidamide, followed by heating under reflux for 24 hours. The solvent was evaporated under a reduced pressure, and dilute hydrochloric acid was added to the resulting residue, followed by extraction with ethyl acetate and washing with water and aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 10 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]quinolin-4(1H)-one (Example 64) and 30 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-{[5-(2-oxopropyl)-1,2,4-oxadiazol-3-yl]methoxy}quinolin-4(1H)-one (Example 65).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.N1C=CC=[CH:40][CH:39]=1.C(Cl)(=O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32]6[N:35]=[C:39]([CH3:40])[O:34][N:33]=6)[CH2:30][CH2:31]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)ccc3C)cc12
Solvent: CC(=O)Cl
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5noc(C)n5)CC4)ccc3C)cc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide (46.5 mg, 0.093 mmol, crude) in pyridine (0.5 mL, 6.18 mmol) at r.t. under N2 was added acetyl chloride (0.020 mL, 0.279 mmol). The mixture was stirred at 115° C. for 2 hours. The mixture was cooled to r.t., diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.64-7.95 min. (UV detection at 220 nm). The residue obtained after evaporation of the combined fractions was further purified by preparative TLC, 10% MeOH/CH2Cl2, two 20 cm×20 cm×0.5 mm plates. Rf about 0.67 (10% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.81 (s, 1H), 7.80 ((m overlapped with s, J=2.14, 1H), 7.66 (d, J=8.55, 1H), 7.65 (d, J=1.22, 1H), 7.43 (d, J=8.55, 1H), 7.36 (dd, J=8.55, 1.83, 1H), 7.28 (m, J=8.70, 2H), 2.96 (s, 3H), 2.54 (s, 3H), 2.35 (s, 3H), 1.59 (m, 2H), 1.43 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=525.07, HPLC Rt=1.682 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.67 min; Column: XBridge phenyl 3.5 um, 4.6×150 mm, Rt=5.22 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: XBridge phenyl 3.5 um, 4.6×150 mm, Rt=12.36 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Cl-].ClC=[N+](C)C.[Br:16][CH2:17][CH2:18]O.N1C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:17][CH2:18][O:8][C:7](=[O:9])[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=C(O)Cc1ccco1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccco1)OCCBr
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 15.12 g of furanacetic acid in 120 ml of methylene chloride is cooled to 0°; 15.6 g of chloromethylene-dimethylammonium chloride are added and the mixture is stirred for 10 minutes while cooling with ice. A solution of 30 g of 2-bromoethanol and 19.4 ml of pyridine in 60 ml of methylene chloride is then added dropwise with stirring and the reaction mixture is left to stand for 20 minutes while cooling with ice and for 1 hour at room temperature. The solution is extracted three times with a 5% aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution, dried over sodium sulphate and distilled under reduced pressure. The 2-furanacetic acid 2-bromoethyl ester is obtained at 76°/0.25 mm; infrared absorption spectrum (in methylene chloride): characteristic bands at 3,44μ, 5,72μ, 6,10μ, 7,49μ, 8,20μ, 8,68μ, 9,31μ and 9,86μ.
Reaction SMILES: C(C1[CH:4]=[CH:5][N:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=12)#N.S(=O)(=O)(O)O.[C:17]([OH:20])(=[O:19])[CH3:18]>O>[C:17]([C:18]1[CH:4]=[CH:5][N:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=12)([OH:20])=[O:19]
Reactant: N#Cc1ccn2ccncc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccn2ccncc12
Temperature: 0 °C

Procedure:
To 1 g of 8-cyanopyrrolo[1,2-a]pyrazine prepared in Preparation Example 8 were added 10 ml of concentrated sulfuric acid, 10 ml of acetic acid and 10 ml of distilled water; and the mixture was refluxed for 1 hour. The reaction mixture was cooled and poured into 100 ml of ice-water. The resulting solid was filtered and dried under reduced pressure to obtain 0.5 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: Clc1ccc(C2CO2)cc1
Product: OC(CNC1CC1)c1ccc(Cl)cc1
Yield: 54.5 %

Procedure:
4-Chloro styrene oxide (1.24 g, 8.0 mmol) and 3 ml of cyclopropylamine in methanolic solution were charged into a flask. The flask was sealed and put in a refrigerator for 5–7 days. The solution was concentrated and the residue crystallized from ether, the title compound was obtained as white needle crystals, mp. 100.2–102° C., yield 54.5%.
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].O>CN(C)C=O>[C:31]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:10])(=[O:33])[CH3:32]
Reactant: O=C(CNc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-anilino-N-[4-(4-pyridinyl)phenyl]acetamide (50 mg) in N,N-dimethylformamide (1.0 mL) were added triethylamine (0.092 mL) and acetyl chloride (0.0352 mL) at ambient temperature and the mixture was stirred at ambient temperature overnight. Water (3 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (5 mL). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (10% methanol in chloroform) to afford 2-[acetyl(phenyl)amino]-N-[4-(4-pyridinyl)phenyl]acetamide (46.9 mg) as a white amorphous.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH3:24].C(OCC)(=O)C>COCCOC.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.CCCCCCC>[F:23][C:21]1[CH:22]=[C:17]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:18]([CH3:24])=[CH:19][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(F)cc1Br
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: [K+]
Solvent: COCCOC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1ccccc1
Yield: 85.5 %

Procedure:
Potassium carbonate (659 mg, 4.27 mmol), phenylboronic acid (388 mg, 3.18 mmol), 2-bromo-4-fluorotoluene (0.20 mL, 1.59 mmol), and tetrakis(triphenylphosphine)palladium(0) (92 mg, 5mol %), in DME (3 mL) were sealed in a microwave vessel and heated at 80° C. for 1200s, then 120° C. for 1200s. Ethyl acetate (5 mL) was added and the reaction was filtered and concentrated in vacuo. The crude material was then purified by flash column chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded 3-fluoro-6-methylbiphenyl (253 mg, 1.36 mmol, 86%).
Reaction SMILES: [K].[SH:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[CH:22][N:21]=1>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:27][O:26][C:25]1[C:20]([CH2:19][S:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[N:21][CH:22]=[CH:23][C:24]=1[O:28][CH3:29]
Reactant: COc1ccnc(CBr)c1OC
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Yield: 70.5 %

Procedure:
To a mixture of potassium salt of 2-mercaptobenzimidazole (1.45 g), potassium carbonate (1.0 g) and dimethylformamide (10 ml) was added dropwise with stirring a solution of 2-bromomethyl-3,4-dimethoxypyridine (1.18 g) in dimethylformamide (2 ml), and the mixture was stirred at room temperature for 30 minutes, to which chloroform (100 ml) was added. The reaction mixture was washed with water, 1N-sodium hydroxide and water in this order, dried (with sodium sulfate) and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (50:1)), to give 2-[(3,4-dimethoxypyrid-2-yl)methylthio]benzimidazole (1.08 g) as a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(F)c(F)cc34)c2)no1

Procedure:
To the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (110 mg, 0.4 mmol) was added 4-chloro-6,7-difluoroquinazoline from the previous step (80 mg, 0.4 mmol) according to the procedure described in Example 1B Step 1, to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+:16]>C(Cl)(Cl)Cl>[CH:3]1[C:4]2[N:16]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:16]5[C:13]6[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=6[C:5]6[C:4]5=[CH:3][CH:2]=[CH:7][CH:6]=6)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:6]=[CH:7][CH:2]=1
Reactant: [NH4+]
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reaction time: 0.25 h

Procedure:
The reaction was conducted for 15 minutes in the same experimental procedures as in Example 16 except for using 4,4′-dibromobiphenyl (9.8 g, 31.6 mol, 1.0 equivalent) as an aryl halide. To the reaction mixture was added an aqueous solution of ammonium chloride, and the mixture was poured into chloroform (500 mL). The aqueous layer was separated off, and the organic layer was passed through a silica gel pad and concentrated to remove the excess chloroform under reduced pressure. To the thus-obtained suspension was added methanol (150 mL), and the crystal was collected from the suspension by suction filtration, washed with methanol and dried under reduced pressure to afford 14.9 g of CBP as a pale yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[S:28][C:27]=1CO>C(Cl)Cl>[Br:24][CH2:20][C:27]1[S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]=1[Cl:25]
Reactant: OCc1sc2ccccc2c1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1c(CBr)sc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of triphenylphosphine (1.74 g, 6.62 mmol) in dry CH2Cl2 (6 mL) was added dropwise to a stirred solution of carbon tetrabromide (2.20 g, 6.62 mmol) and (3-chloro-1-benzothien-2-yl)methanol (0.94 g, 4.73 mmol) in dry CH2Cl2 (35 mL) at 0° C. under N2. The reaction was allowed to warm to room temperature and was stirred for 4 h then concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 nm, 0-25% EtOAc in hexanes gradient) to afford 2-(bromomethyl)-3-chloro-1-benzothiophene. Rf=0.93 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.81 (dd, J=1.3, 7-1 Hz, 1H); 7.78 (dd, J=1.2, 7.2 Hz, 1H); 7.47-7.41 (m, 2H); 4.81 (s, 2H).
Reaction SMILES: C([O-])=O.[NH4+].[CH:5]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH:30]4[CH2:33][N:32](C(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:31]4)[N:21]=3)[N:18]=2)[N:13]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:12]=1)=[O:10])([CH3:7])[CH3:6]>CO.C1COCC1.[Pd]>[CH:5]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH:30]4[CH2:33][NH:32][CH2:31]4)[N:21]=3)[N:18]=2)[N:13]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:53])([CH3:52])[CH3:54])[CH:12]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)nc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CNC4)c4cc(F)ccc34)nc12
Temperature: 50 °C
Yield: 67.8 %

Procedure:
In a round-bottomed flask ammonium formate (135 mg, 2.15 mmol) was dissolved in MeOH (1.5 mL). This solution was added to a solution of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (74 mg, 0.107 mmol) in THF (1.5 mL) which caused a white precipitate to form. This slurry was transferred via pipet to a pressure tube containing 10% palladium on carbon (wet, 23 mg) in MeOH (1 mL). The tube was sealed and heated at 50° C. for 4 h then cooled to room temperature overnight. The mixture was filtered over Celite, rinsing with CH2Cl2. The filtrate was concentrated and the residue was absorbed onto SiO2 and chromatographed with 0% to 10% MeOH/CH2Cl2 (0.5% NH4OH) to afford 38 mg (68%) of 2-(1-azetidin-3-yl-6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a pale yellow foamy solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[Cl:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[Cl:21][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:22]=[C:23]([NH2:25])[S:24][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(Cl)c2)cc1
Solvent: CCO
Product: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(Cl)c2)cc1
Yield: 57.7 %

Procedure:
A mixture of 2-bromo-1-(2-chloro-4-(4-methoxyphenylsulfanyl)-6-methylphenyl)ethanone (3-3, 0.127 g) and thiourea (30 mg, 0.33 mmol) in 95% EtOH (3.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-chloro-4-(4-methoxyphenylsulfanyl)-6-methylphenyl)thiazol-2-ylamine (3-4, 70 mg, 0.19 mmol) as yellow solids in 58% yield: 1H NMR (500 MHz, CDCl3) δ 7.44 (m, 2 H), 6.97 (d, J=1.45 Hz, 1 H), 6.93 (m, 3 H), 6.34 (s, 1 H), 3.84 (s, 3 H), 2.13 (s, 3 H); ESI-MS m/z 363.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC1(C)[O:25][C:24](=O)[C:21]2([CH2:23][CH2:22]2)[C:20](=[O:27])[O:19]1>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][CH:21]([C:20]([OH:27])=[O:19])[C:24]3=[O:25])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Product: O=C(O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 3c) from 4-(4-fluoro-benzyloxy)-phenylamine and 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione. Yield: 56% of a colorless solid. MS: m/e=284.1 (M−CO2).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].[K+].F[C:15]1[CH:16]=[C:17]2[C:22](=[O:23])[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1.S1(CCCC1)(=O)=O>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][C:15]1[CH:16]=[C:17]2[C:22](=[O:23])[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: Oc1ccccc1C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=C1OC(=O)c2cc(Oc3ccccc3C(F)(F)F)ccc21
Temperature: 190 °C

Procedure:
Following the general procedure of Example 12, 0.47 parts of α,α,α-trifluoro-o-cresol, 0.23 parts of KF and 0.44 parts of 4-fluorophthalic anhydride in 1.56 parts of sulfolane were heated for 4 hours at 190° C., with stirring. The mixture contained 67 percent (by area) of the above product as identified by GC/MS.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](Cl)=[O:36]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:35]([C:31]3[S:30][CH:34]=[CH:33][N:32]=3)=[O:36])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1nccs1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4nccs4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.57 g, 1.75 mmol) in CH3CN (10 ml), were added triethyl amine (0.61 mL, 4.4 mmol) and 1,3-thiazole-2-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford thiazole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.52 g, 74%): mp, 189-191° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.9 min (97%); 1H NMR (DMSO-d6): δ 2.05-2.12 (m, 1H), 2.53-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.94 (d, J=6.2 Hz, 2H), 5.18 (dd, J=5, 11 Hz, 1H), 7.68-8.10 (m, 5H), 9.50 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.32, 48.88, 121.98, 125.99, 127.17, 131.56, 132.92, 134.85, 138.43, 143.98, 159.59, 163.18, 166.93, 167.51, 169.81, 172.73. Anal Calcd for C18H14N4O5S: C, 54.27; H, 3.54; N, 14.06; S, 8.05. Found: C, 53.98; H, 3.49; N, 13.75; S, 8.22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]([C:30]1[C@H:31]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[Cl:50])[N:32]=[C:33]([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[NH:34][C:35]=1[CH2:36]Br)=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[N:16]([CH2:36][C:35]3[NH:34][C:33]([C:38]4[S:39][CH:40]=[CH:41][N:42]=4)=[N:32][C@@H:31]([C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[Cl:50])[C:30]=3[C:28]([O:27][CH3:26])=[O:29])[CH:14]([CH2:13][O:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (171 mg, 0.75 mmol) and DIPEA (0.45 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (222 mg, 0.5 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester as yellow oil (0.28 g, 94%). MS: calc'd (MH+) 592, measured (MH+) 592.