Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH:16]1[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][N:16]1[CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)cc(OCCN2CCC2)c1
Temperature: 120 °C

Procedure:
1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.6 mmol), azetidine (0.23 ml, 3.2 mmol) and potassium carbonate (0.58 g, 4.2 mmol) was dissolved in acetonitrile (10 ml). The mixture was heated in a sealed container at 120° C. for 2 h. The reaction mixture was cooled to room temperature, CH2Cl2 (100 ml) was added, solids was filtered off and the volatiles were evaporated. The amine was converted to the fumaric acid salt and re-crystallized from methanol/diethyl ether. MS m/z (relative intensity, 70 eV) 273 (M+, 1), 94 (5), 82 (3), 71 (5), 70 (bp).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:48][CH:49]([C:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[CH:61][CH:60]=1)[CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([NH:48][CH:49]([C:59]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[CH:62]=[CH:61][CH:60]=3)[CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:14])[CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc2ccccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2cccc3ccccc23)cs1
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (104 mg, 0.5 mmol), PyBrOP (384 mg, 0.83 mmol) and diisopropylethyl amine (0.14 mL, 0.83 mmol) in DCM (8 mL) at 25° C. was added 1,1-dimethylethyl [2-amino-2-(1-naphthalenyl)ethyl]carbamate (144 mg, 0.5 mmol) [from Preparation 6]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (76 mg, 32%) as a white solid: LC-MS (ES) m/z=477 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[C:14]([O-])(=[O:16])[CH3:15].[Na+]>C(OC(=O)C)(=O)C>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(OC)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.5 %

Procedure:
Methyl 3-hydroxy-4-(methyloxy)benzoate (27 g, 149 mmol.) was taken into acetic anhydride (150 mL) followed by addition of sodium acetate (24 g, 298 mmol.) and the resulting mixture was stirred at room temperature over 20 hours. The solid was filtered and washed once with ethyl acetate and the combined organic layers concentrated in vacuo to a slurry. The solid was collected by filtration, washed once with water and dried in vacuo to provide methyl 3-(acetyloxy)-4-(methyloxy)benzoate (25.9 g, 77% yield) as a white solid. 1H NMR (400 MHz, CDCl3): 7.92 (dd, 1H), 7.70 (d, 1H), 6.97 (d, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)C(=O)[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:28][O:29][CH:30](OC)[O:31][CH3:32].C([O-])(O)=O.[Na+]>CO>[C:1]([C:4]12[CH2:13][CH:8]([C:30]([O:31][CH3:32])([O:29][CH3:28])[CH2:15][CH:5]1[CH3:6])[C:9]([CH3:12])=[CH:10][CH2:11]2)([CH3:3])=[CH2:2]
Reactant: COC(OC)OC
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C(C)C12CC=C(C)C(C1)C(OC)(OC)CC2C
Yield: 93 %

Procedure:
A soln. of 1.5 g of 5-isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (7.3 mmol), 1.4 g para-toluenesulfonic acid mono hydrate (7.4 mmol 1 eq.), and 0.78 g trimethylorthoformate (7.4 mmol, 1 eq.) in 50 ml methanol was heated at 60° C. for 66 h. The reaction mixture was then cooled and poured into aq. sat. NaHCO3 soln. (20 ml). Extraction with MTBE (2×80 ml) followed by washing of the aq. phases with H2O and aq. sat. NaCl soln., drying of org. phases (MgSO4) led to 1.8 g of crude product. FC (SiO2, Hexane/MTBE 30:1) gave 1.7 g (92%) of compound 5 as colorless liquid. The boiling point of the end product is 130° C. at 0.08 mbar. Rf (hexane/MTBE 8:1) 0.57.
Reaction SMILES: [NH2:1][OH:2].C[O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=O>CO>[OH:2][NH:1][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12
Solvent: CO
Product: O=C(CCCCc1cn(-c2cccnc2)c2ccccc12)NO
Reaction time: 20 h

Procedure:
A solution of hydroxylamine (from 2.06 g of hydroxylamine hydrochloride and 2.02 g of sodium hydroxide) and 7.6 g of 3-(4-methoxycarbonylbutyl)-N-(3-pyridyl)indole in 25 ml of methanol is allowed to stand at room temperature for 20 hours. The methanol is evaporated and the residue is taken up in 5 ml of water and adjusted to pH=7. The mixture is extracted with methylene chloride, the extract is washed with water, dried and evaporated to dryness yielding 3-[4-(hydroxycarbamoyl)butyl]-N-(3-pyridyl)indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>C(=O)(O)[O-].[Na+]>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:16][CH2:15][C:14]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:10][CH:11]=[CH:12][CH:13]=1)=[S:27]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: COc1ccccc1-c1ncccc1CN
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccccc1-c1ncccc1CNC(=S)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To an oven-dried, N2-purged, 25-mL, round-bottomed flask containing a magnetic stir bar was added the crude C-[2-(2-methoxy-phenyl)-pyridin-3-yl]-methylamine (430 mg, 2.0 mmol) from above. The flask was sealed with a septum and purged with N2 atmosphere. Anhydrous tetrahydrofuran (10 mL) was added via syringe. Neat 2,3-dichlorophenylisothiocyanate (510 mg, 356 μL, 2.50 mmol) was added via syringe. The pale green solution was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (10 mL) was added to quench. The mixture was transferred to a separatory funnel and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a tan solid. The product was recrystallized from ethyl acetate/hexanes to give a 712 mg (85%) of the title compound as a white powder. MS (LC-MS, ESI+) m/z 417.0 (M+H)+; 1H NMR (DMSO-d6) δ 3.74 (s, 3H), 4.35 (br s, 1H), 4.66 (br s, 1H), 7.03-7.13 (m, 2H), 7.22 (dd, J=7.5, 1.7 Hz, 1H), 7.31-7.60 (m, 6H), 7.74 (dd, J=7.1, 1.0 Hz, 1H), 8.23 (br s, 1H), 8.51 (dd, J=4.9, 1.5 Hz, 1H), 9.46 (br s, 1H).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cc(Cl)cc(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 78 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 3,5-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 18 h, 1 N aq. HCl (10 mL) was added and the solids were isolated by filtration and washed with water (40 mL). The solids were triturated in EtOAc (10 mL) for 18 h, then isolated by filtration, washed with EtOAc (40 mL) and dried in vacuo to give 1-(3,5-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.36 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 9.14 min (96.29%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 1.86-2.12 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.60 (d, J=16.4 Hz, 1H, CHH), 2.77-3.05 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.38-4.56 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.00 (t, J=5.9 Hz, 1H, NH), 7.08 (t, J=1.7 Hz, 1H, Ar), 7.44 (d, J=7.7 Hz, 1H, Ar), 7.48-7.59 (m, 3H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 9.08 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.83, 47.12, 51.58, 115.78, 120.16, 121.92, 122.94, 126.92, 130.35, 133.93, 142.39, 142.93, 144.43, 154.77, 167.92, 170.98, 172.85; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.61; H, 3.78; N, 11.84; Cl, 15.10.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:19])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C(=O)O
Reaction time: 0.17 h

Procedure:
To a solution of methyl 5-chlorosalicylate (20 g.) in acetone 110 ml.) was added 2 N sodium hydroxide (66 ml.) and dimethyl sulphate (13.86 g.). The mixture was stirred for 10 minutes, sodium hydroxide 33 ml., 2N) and dimethyl sulphate (6.93 g.) added, and the mixture was heated under reflux for 45 minutes. The product was then cooled, the acetone evaporated off, and the residue was taken up in ether. The ether was extracted with dilute sodium hydroxide, evaporated off, and the residue heated under reflux for 1 hour with 10 aqueous sodium hydroxide (100 ml.). The product was cooled and acidified. The precipitate acid was filtered off and recrystallized from ethanol-water to give 8 g., m.p. 80°-81° (45%) with a second crop of 0.8 g., m.p. 77°-79° (4.5%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH2:40]([O:39][CH:38]([O:42][CH2:43][CH3:44])[C@@H:37]([N:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)[C:23](=[O:24])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH3:45])[CH3:41]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 57 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-4-oxobutanoate (Compound IV-17) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1)[N:6]=[CH:5]2.[OH-].[Na+].Cl>CO.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1)[N:6]=[CH:5]2
Reactant: COC(=O)C1CCN(c2ncc3cc(O)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)C1CCN(c2ncc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a solution of methyl 1-(6-hydroxyquinazolin-2-yl)piperidine-4-carboxylate (330 mg, crude from above) in MeOH (10 mL) was added aqueous NaOH (10 mL, 2M). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was acidified with 1N HCl to pH=1-2, then concentrated to give a residue, which was diluted with EtOAc (100 mL), filtered and concentrated to give the crude product which was purified by prep-HPLC (0.1% TFA as additive). Most of the solvent was removed in vacuo followed by lyophilization to give the product (70 mg, 2-step yield: 19%) as a solid. 1H NMR (DMSO-d6 400 MHz): δ 9.15 (s, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.2, 2.8 Hz, 1H), 7.13 (d, J=2.8 Hz, 1H), 4.59 (d, J=13.2 Hz, 2H), 3.16 (t, J=11.4 Hz, 2H), 2.68-2.52 (m, 1H), 1.93 (dd, J=13.2, 3.2 Hz, 2H), 1.62-1.48 (m, 2H). MS (ESI): m/z 274.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]=[O:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:20][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]([OH:19])[CH3:20])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2cccc(Cl)c2)c2ncccc2c1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2cccc(Cl)c2)c2ncccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
8-(3-Chlorophenyl)-6-quinolincarbaldehyde (0.8 g) was dissolved in 20 mL of tetrahydrofuran and cooled to -78° C. Methyllithium (4.5 mL, 1.4M) in diethyl ether was added dropwise to the solution over 5 minutes, stirred for 20 minutes, poured into 50 mL of saturated ammonium chloride, and stirred for 5 minutes. The solution was extracted with ethyl acetate (2×75 mL). The extracts were combined and dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (30:70 ethyl acetate:hexanes) to obtain 0.72 g of 8-(3-chlorophenyl)-6-(1-hydroxyethyl)quinoline as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[CH:11]=2)[C:6]2[N:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[CH3:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][C:32]1[N:33]([CH2:2][C:3]2[C:8](=[O:9])[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)[CH:11]=3)[C:6]3[N:27]=[CH:28][CH:29]=[CH:30][C:5]=3[N:4]=2)[CH:34]=[CH:35][N:36]=1
Reactant: O=C(Nc1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Yield: 47.5 %

Procedure:
The solution of 2-bromomethyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (105 mg) and 2-methylimidazole (171 mg) in N,N-dimethylformamide (10 ml) was stirred for 3 hours at 70° C. and 1 hour at 80° C. The mixture was poured into aqueous sodium hydrogencarbonate and extracted by ethyl acetate (100 ml). The organic layer was evaporated and chromatographed to obtain 2-[(2-methylimidazol-1-yl)-methyl]-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (50 mg) in brown powder form.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:28][CH2:27]2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cccc(CNC2CC2)c1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COc1cccc(CN(C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)=[O:8])[CH3:2].[NH:18]([C:25]1[C:30]([Br:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH:18]([C:25]1[C:30]([Br:31])=[CH:29][N:28]=[C:27]([NH:13][C:12]2[CH:11]=[CH:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:16][CH3:17])=[CH:15][CH:14]=2)[N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1
Product: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 103, but starting from 4-{N-[2-(diethylamino)ethyl]carbamoyl}aniline and 4-anilino-5-bromo-2-chloropyrimidine (Method 15), the product was obtained. NMR: 1.0 (t, 6H), 2.4 (m, 4H), 3.3 (m, 4H) 7.2 (t, 1H), 7.4 (t, 2H), 7.6 (t, 6H), 8.1 (bs, 1H), 8.2 (s, 1H), 8.7 (s, 1H), 9.6 (s, 1H); MS (MH+): 483, 485.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CO.C(N(CC)CC)C>[Pd]>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][CH:2]=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnccc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (35.0 mg, 0.106 mmol) in Methanol (1.91 mL, 47.1 mmol) was added Triethylamine (0.0147 mL, 0.106 mmol) and Palladium (0.0113 g, 0.0106 mmol). The reaction was stirred overnight at room temperature under H2 atm. The reaction was filtered thru celite. The solute was concentrated then diluted with EtOAc, wash with H2O. The organic layer was dried Na2SO4, concentrated. The crude product was purified by isco column to give 364. MS: (ESI+)=297.1. 1H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.05 (d, J=5.7 Hz, 1H), 5.90 (dt, J=13.2, 6.5 Hz, 1H), 4.59 (dt, J=26.2, 13.1 Hz, 4H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14](NC(C)(C)C)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:22]>O1CCOCC1.O>[C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14]([OH:15])=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1occc1C(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1)c1ccoc1C(=O)O
Temperature: 120 °C

Procedure:
To slurry of 3-benzoyl-N-tert-butylfuran-2-carboxamide (0.863 g, 3.18 mmol) in 4 mL dioxane and 3 mL water was added sulfuric acid (1.02 ml, 19.1 mmol). The mixture was sealed and heated to 120° C. for a total of 48 h. Additional 3.0 equiv H2SO4 was added, and the reaction was heated for 8 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (4×), and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-benzoylfuran-2-carboxylic acid as a brown semi-solid. This material was carried on without further purification. MS m/z=217 [M+H]+. Calc'd for C12H8O4: 216.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[C:5]2[S:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.[CH:40]1([NH:43][C:44](=[O:62])[C:45]2[CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[C:48]([CH3:60])=[C:47]([F:61])[CH:46]=2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C:14]([CH3:25])([CH3:24])[CH2:13][N:7]1[CH:6]=[C:5]([S:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28]2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:49]3[CH:50]=[C:45]([C:44](=[O:62])[NH:43][CH:40]4[CH2:41][CH2:42]4)[CH:46]=[C:47]([F:61])[C:48]=3[CH3:60])[CH:3]=2)[C:8]1=[O:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(SC2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 42.2 %

Procedure:
A solution of tert-butyl 4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}piperidine-1-carboxylate (Example 58c, 0.248 g) in DMF (4 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.124 g), Pd-118 (0.007 g) and potassium carbonate (0.107 g). The reaction was stirred at 80° C. for 6 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate (2×100 mL), and the combined organics were washed with water (3×100 mL) and brine (3×100 mL). The organics were dried (MgSO4), filtered, and evaporated under reduced pressure. The crude product was purified (SiO2 chromatography, eluting with 10-50% ethyl acetate/isohexane) to afford the subtitle compound (0.123 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH:13]([CH2:17][CH2:18][C:19](=[O:21])[NH2:20])[C:14](O)=[O:15])[C:7]2=[O:12])#[N:2]>C(#N)C>[O:15]=[C:14]1[CH:13]([N:6]2[CH2:5][C:4]3[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:12])[CH2:17][CH2:18][C:19](=[O:21])[NH:20]1
Reactant: N#Cc1cccc2c1CN(C(CCC(N)=O)C(=O)O)C2=O
Solvent: CC#N
Product: N#Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of 2-(4-cyano-1-oxoisoindolin-2-yl)-4carbamoylbutanoic acid (0.6 g, 2.09 mmol) and 1,1-carbonyldiimidazole (0.44 g, 2.72 mmol) in acetonitrile (20 mL) was heated to reflux for 2 hours. The mixture was cooled to room temperature and filtered to give 2-(2,6-dioxo(3-piperidyl))-1-oxoisoindoline-4-carbonitrile (0.44 g, 83%) as a white solid: mp 312–314° C.; 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 8.16 (d, J=7.0 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 5.20–5.13 (dd, J=5.2 and 13.2 Hz, 1H), 4.69 (d, J=181.1 Hz, 1H), 4.57 (d, J=18.1 Hz, 1H), 2.97–2.85 (m, 1H), 2.64–2.45 (m, 2H), 2.05–1.97 (m, 1H); 13C NMR (DMSO-d6) δ 172.81, 170.69, 166.49, 145.36, 135.37, 132.85, 129.36, 127.91, 116.01, 107.09. 51.77, 46.72, 31.14, 22.22; Anal. Calced. For C14H11N3O3: C, 62.45; H, 4.12; N, 15.61. Found: C, 62.26; H, 4.10; N, 15.51.