Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][CH2:16][O:17][CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: COCCNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting 2-methoxyethylamine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.91 (m, 1H), 7.75 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.55 (s, 4H), 3.35 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 464.1142 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:2]1.[C:23](#N)C.[N+](=C)=[N-]>CCOCC>[CH3:23][O:21][C:20]([C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH:19]=1)=[O:22]
Reactant: O=C(O)c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Reactant: CC#N
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Reaction time: 1 h
Yield: 95 %

Procedure:
To a 10 mL pear-shaped flask was added 2-(3-indolyl)-4-quinolinecarboxylic acid (1 mmol) and 2 mL of acetonitrile followed by a solution of diazomethane (5 mmol) in 2 mL of ether. The reaction mixture was stirred for 1 h and the solvent removed in vacuo to give methyl-2-(3-indolyl)-4-quinolinecarboxylate (95-100% yield).
Reaction SMILES: [CH3:1][C:2]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O:26]1[CH2:17][CH:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:2]([CH3:1])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CCCCCCCCOC(C)(C)C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C(C)(C)OCCCCCCCC1CO1
Yield: 101.3 %

Procedure:
Methyl 2-methyl-2-(8-nonenyloxy)propionate (40 g) was dissolved in 320 ml of methylene chloride, and 40.8 g of 70% 3-chloroperbenzoic acid was added with stirring under ice-cooling, and the mixture was stirred for 15 hours at room temperature. The reaction solution was filtrated to remove insolubles, and the filtrate was concentrated. The residue was dissolved in n-hexane and washed 4 times with aqueous 10% potassium carbonate solution, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 43.2 g of the objective compound as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1[N:21]=[CH:22][N:23]([CH3:25])C)#N.C(O)(=O)C>C(O)C>[F:19][C:18]1[CH:17]=[CH:16][C:15]([F:20])=[C:14]2[C:13]=1[C:25]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[N:23][CH:22]=[N:21]2
Reactant: CN(C)C=Nc1c(F)ccc(F)c1C#N
Reactant: NCCc1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(CCNc2ncnc3c(F)ccc(F)c23)cc1
Temperature: 75 °C
Yield: 78.1 %

Procedure:
A mixture of tyramine (2.62 g, 19 mmol), N′-(2-cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (2.0 g, 9.56 mmol), acetic acid (3.4 mL, 60 mmol) and ethanol (50 mL) was heated at 75° C. for 16 h. Upon cooling, the solvent was removed under reduced pressure and the remaining solid was stirred in water for a few minutes, collected by suction filtration and washed with water. The filter cake was dried under vacuum to give 2.25 g (78%) of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-phenol as an off-white solid, M.P. 221-222° C. 1H NMR (d6-DMSO): δ 9.16 (s, 1H), 8.53 (s, 1H), 7.73 (m, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 3.74 (q, J=7.8, 5.7 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H). LC/MS: 302.04 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:10].[CH3:11][NH2:12]>>[F:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:2]=1[NH:12][CH3:11])[C:8]#[N:9]
Reactant: CN
Reactant: N#Cc1cncc(F)c1Cl
Product: CNc1c(F)cncc1C#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4-Chloro-5-fluoro-nicotinonitrile (3.5 g, 22.4 mmol) was suspended in 41% aqueous methylamine solution (35 mL). The resultant mixture was heated, with stirring, at 80° C. for 30 minutes. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resultant residue triturated in diethyl ether to provide the title compound (2.35 g, 70%) as a white solid. 1H NMR (CDCl3) 8.29 (1H, s), 8.18 (1H, d, J=4.0 Hz), 5.04 (1H, s, br), 3.34 (3H, dd, J=2.2, 5.5 Hz).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16](OC3C=CC([N+]([O-])=O)=CC=3)=[O:17])[CH2:13][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:16]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][C:2]([F:32])([F:33])[F:1])=[CH:9][CH:8]=3)[CH2:11][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]2)=[O:17])[CH2:37][CH2:36]1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 150 °C

Procedure:
1.20 g (2.57 mmol) of the compound from Example 54A, 781 mg (7.72 mmol) of 4-hydroxypiperidine and 533 mg (3.86 mmol) of potassium carbonate were added to 14 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 45 min. For workup, the reaction solutions were combined and filtered, and the residue was purified by means of preparative HPLC. Yield: 733 mg (66% of theory)
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](Cl)=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].[NH2:33][CH2:34][CH:35]([OH:38])[CH2:36][NH2:37]>C(Cl)Cl>[CH2:1]([C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([NH:33][CH2:34][CH:35]([OH:38])[CH2:36][NH2:37])=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)Cl)C1
Reactant: NCC(O)CN
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)NCC(O)CN)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of (R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxy pentyl)piperidine-1-carbonyl chloride (<0.05 mmol) in CH2Cl2, there was added excess 1,3-diaminopropan-2-ol (˜0.1 mL). The resulting solution was stirred at rt for 1 h, the CH2Cl2 was removed, and the residue was purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-amino-2-hydroxypropyl)piperidine-1-carboxamide (10.0 mg, 39%) as its TFA salt. 1H NMR (400 MHz, CD3OD): 7.64 (d, 1H), 7.32 (d, 1H), 7.04-7.20 (m, 4H), 6.74 (d, 1H), 6.56 (d, 1-H), 4.40 (d, 1H), 3.82 (m, 2H), 3.26 (t, 2H), 3.24 (s, 3H), 2.96 (m, 1H), 2.78 (m, 2H), 2.62 (q, 2H), 2.40 (m, 2H), 1.94 (m, 1H), 1.22-1.64 (m, 7H), 1.08 (t, 3H), 0.98 (m, 1H); MS m/z 514 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([N:16]([CH2:28][CH2:29][CH3:30])[C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[CH2:3]1>C(O)(=O)C.[Pd]>[O:1]=[C:2]1[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([N:16]([CH2:28][CH2:29][CH3:30])[C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:3]1
Reactant: CCCN(C(=O)c1cccc([N+](=O)[O-])c1)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCN(C(=O)c1cccc(N)c1)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reaction time: 4 h

Procedure:
N-[4,5-Dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl]-N-propyl-3-nitrobenzamide (33.0 g, 68.3 mmol) was dissolved in glacial acetic acid (300 ml) and 10% palladium on charcoal (3.2 g) was added. The mixture was hydrogenated under pressure (30 atms) for 4 hrs, then the catalyst was removed by filtration through Kieselguhr. The solvent was removed by evaporation and the product was dried under vacuum to give a white glass, 32.5 g, ca 100%. The product was used in the next stage without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33](=[O:51])[N:34]([CH2:38]C2C=C(Cl)C=CC=2CCCOC)[CH:35]2[CH2:37][CH2:36]2)[CH2:9]1)=O)(C)(C)C.Cl.[CH2:53]([Cl:55])Cl>O1CCOCC1>[Cl:55][C:53]1[CH:18]=[CH:19][C:14]([CH2:15][CH2:16][CH2:17][O:20][CH3:21])=[CH:11][C:10]=1[CH2:38][N:34]([CH:35]1[CH2:37][CH2:36]1)[C:33]([C@@H:10]1[C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:25]([Cl:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=3[Cl:30])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9]1)=[O:51]
Reactant: COCCCc1ccc(Cl)cc1CN(C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1)C1CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: COCCCc1ccc(Cl)c(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Compound D4 (0.076 g, 0.10 mmol) was dissolved in CH2Cl2 (1 mL) and the sol. was cooled to 0° C. 4M HCl in dioxane (1 mL) was added and the reaction mixture was stirred for 1 h at rt. The solvents were evaporated under reduced pressure. Purification of the residue by HPLC yielded the title compound (44 mg, 67%). LC-MS: tR=0.99 min, ES+=661.41.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].C1C(=O)N([Cl:29])C(=O)C1.Cl>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:29])=[CH:16][C:15]=1[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.07 g, 5.50 mmol), NCS (789 mg, 5.91 mmol), and catalytic amount of conc. HCl in DMF (41 mL) was stirred for 1 hour at room temperature. The reaction mixture was diluted with EtOAc, and washed with water (5×). The organic layer was dried over MgSO4, filtered, and concentrated to give the crude material which was purified by silica gel flash column chromatography (3 to 5% EtOAc in hexanes) to afford the desired product (2.02 g, 89%).
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=1.C(OCC=[N+]=[N-])(=O)C.C([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#C>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:30]([C:3]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=2)[CH:25]=1
Reactant: C#Cc1ccccn1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Agent: CC(=O)OCC=[N+]=[N-]
Product: CCOC(=O)c1cc(-c2cccnc2)n[nH]1

Procedure:
Was prepared in a similar way to ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate using diazoethyl acetate (Purchased from Aldrich) and 2-ethynyl-pyridine (Purchased from Aldrich)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)([O-])=O.CO>[Pd].C(OCC)(=O)C>[N:35]1[CH:36]=[CH:37][C:32]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[N:9]([C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To 5-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazoie (0.8954 g, 0.00185 mol), 10% activated palladium on carbon (0.8954 g, 1 eq by weight) was added. The reaction flask was put under vacuum, and methanol (18.5 mL) and ethyl acetate (2 mL) was added. Hydrogen gas was bubbled through the reaction for 15 minutes. The reaction was stirred at room temperature for and additional 16 h. The reaction was filtered through celite and concentrated under vacuo. The crude product (0.819 g, 95% yield) was progressed to the next step without further purification.
Reaction SMILES: [CH3:1][C@@:2]1([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[N:12]=[C:11]2[CH3:24])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]>C(OCC)(=O)C.CO.[Pd]>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:10]([C@:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[C:11]([CH3:24])=[N:12]2
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1[C@]1(C)CCC(=O)NC1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2cccc(N)c2c(=O)n1[C@]1(C)CCC(=O)NC1=O
Yield: 44 %

Procedure:
A mixture of (R)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (0.40 g, 1.2 mmol) and 10% Pd—C (0.2 g, 50% wet), in 200 mL of 3:1 ethyl acetate-methanol was shaken under 50 psi H2 for 3 hours. The mixture was filtered through Celite, and the solvent was evaporated. The residue was chromatographed on silica gel using a dichloromethane-acetonitrile gradient, providing (R)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-3-methylpiperidine-2,6-dione as an off-white solid (0.16 g 44% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 1.62 (98.71%); mp 295-297° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H, CH3), 2.31-2.36 (m, 1H, CHH), 2.53-2.59 (m, 2H, 2CHH), 2.62 (s, 3H, CH3), 2.71-2.84 (m, 1H, CHH), 6.53-6.56 (m, 2H, Ar), 6.95 (br, 2H, NH2), 7.35 (t, J=8 Hz, 1H, Ar), 10.72 (s, 1H, NH); 13C NMR (DMSO-d6) δ 24.5, 26.3, 28.3, 29.0, 62.2, 104.2, 110.5, 110.8, 135.0, 147.4, 150.4, 152.9, 164.9, 171.5, 173.0; Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66. Found: C, 59.73; H, 5.26; N, 18.69.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CS([C:19]1[N:20]=[CH:21][C:22]2[C:28](=[O:29])[C:27]([C:30]#[N:31])=[CH:26][N:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:23]=2[N:24]=1)(=O)=O>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:19]3[N:20]=[CH:21][C:22]4[C:28](=[O:29])[C:27]([C:30]#[N:31])=[CH:26][N:25]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:23]=4[N:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C#N)cn(-c3ccccc3)c2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C#N)cn(-c5ccccc5)c4n3)cc2)CC1

Procedure:
Using the procedure outlined in Example 1(G) the title compound was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (32 mg, 0.16 mmol) and 2-methanesulfonyl-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (Example 13 (D) above, 50 mg, 0.15 mmol). The product was obtained as a yellow solid (17.1 mg). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.34 (s, 1H), 8.55 (br, 1H), 7.61 (m, 3H), 7.41 (d, 2H), 7.24 (m, 2H), 6.55 (d, 2H), 3.00 (m, 4H), 2.55 (m, 4H), 2.35 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H23N7O: 438.20 (M+H), Found: 438.5.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[F:22][C:23]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:22][C:23]1([F:29])[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2Br)cc1
Reactant: FC1(F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC1(F)CCN(CCOc2ccccc2Br)CC1
Temperature: 60 °C

Procedure:
2-(2-Bromophenoxy)ethyl tosylate (1.86 g), 4,4-difluoropiperidine (0.73 g) and potassium carbonate (0.97 g) were mixed with dimethylformamide (30 ml) and heated to 60° C. for 18 h. The mixture was cooled and added to water (300 ml). The mixture was extracted with diethyl ether (×3), dried and evaporated. Purification was achieved using cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures yielding, 4-difluoro-(2-(2-bromophenoxy)ethyl)piperidine (0.77 g).
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Cl:40][CH2:41][CH2:42][N:43]=[C:44]=[O:45]>C1COCC1>[Cl:40][CH2:41][CH2:42][NH:43][C:44](=[O:45])[NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C=NCCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(=O)NCCCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg, 0.19 mmol) in THF, 1-chloro-2-isocyanatoethane (60 mg, 0.57 mmol) was added at 80° C. Then the reaction mixture was stirred at room temperature overnight. The mixture was extracted with EtOAc, washed with brine, dried and concentrated to provide 6-(3-(2-chloroethyl)ureido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (80 mg, yield: 66.5%) without further purification. MS (M+H)+: 628.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([N:10]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:22])=[O:21])[CH3:11])=[O:9])[CH3:2].FC1C=CC(S(NC2C(C(OC)=O)=C3C(C4CC4CO3)=CC=2)(=O)=O)=C(CNC)C=1.C(N1CCC[C@H]1C(O)=O)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([N:10]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:22])=[O:21])[CH3:11])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@@H]1C(=O)N(C)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: CCN1CCC[C@H]1C(=O)O
Agent: CNCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Product: CCN1CCC[C@H]1C(=O)N(C)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 155, starting from methyl (1aRS,7bSR)-5-(4-fluoro-2-methylaminomethylbenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (intermediate 156) and (S)-1-ethylpyrrolidine-2-carboxylic acid (Intermediate 106) as a solid.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[S:14][C:15]([Cl:20])=[CH:16][C:17]=1[O:18][CH3:19].[CH:21]1([C:24]2[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1.[Cl-].[NH4+]>C1COCC1>[Cl:20][C:15]1[S:14][C:13]([C:28]([C:27]2[CH:34]=[CH:35][C:24]([CH:21]3[CH2:22][CH2:23]3)=[CH:25][CH:26]=2)=[O:29])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: COc1cc(Cl)sc1Br
Reactant: CON(C)C(=O)c1ccc(C2CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(Cl)sc1C(=O)c1ccc(C2CC2)cc1
Temperature: -78 °C
Yield: 62.9 %

Procedure:
In a nitrogen stream, an n-butyllithium n-hexane solution (1.6 M, 2.43 mL, 3.88 mmol) was added dropwise to a solution of 2-bromo-5-chloro-3-methoxythiophene (882 mg, 3.88 mmol) as synthesized by the method described in a document [L. Org. Chem., 58, 4629-4633 (1993)] in anhydrous THF (15 mL) at −78° C. This mixture was stirred at −78° C. for ten minutes, and a solution of 4-cyclopropyl-N-methoxy-N-methylbenzamide (875 mg, 4.26 mmol) in THF (3 mL) was added dropwise thereto. The reaction mixture was stirred at −78° C. for 30 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=n-hexane:ethyl acetate (4:1)] to obtain the title compound (714 mg, 63%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](C(O)=O)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C(=O)(O)[O-].[Na+].[Br:23]NC(=O)CCC(N)=O>CN(C=O)C.O.C(OCC)(=O)C>[Br:23][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][N:10]2[CH2:12][CH2:13][CH2:14][C:9]=12
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c(-c2ccccn2)nn2c1CCC2
Yield: 70.5 %

Procedure:
Stir a mixture of 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (2 g, 8.7 mmol), sodium bicarbonate (3.3 g, 38.4 mmol), and N-bromosuccinamide (1.7 g, 9.6 mmol) in DMF (50 mL) at room temperature for 2 h. Dilute the crude mixture with water (50 mL) and ethyl acetate (100 mL). Separate the ethyl acetate layer, extract with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and evaporate to a solid mass. Purify by MPLC (SiO2, 1:1 ethyl acetate/hexane) to obtain 1.62 g (70%) of the title compound as a cream solid. MS ES+ m/e 264 (M+1), MS ES+ m/e 266 (M+2).
Reaction SMILES: [C:1]1([OH:15])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:16]Br.O>C(O)(=O)C>[Br:16][C:4]1[C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[C:1]([OH:15])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: Oc1cccc2c1Sc1ccccc1S2
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Br)c2c1Sc1ccccc1S2

Procedure:
Thianthren-1-ol (6.5 g, 27.98 mmol) was dissolved in glacial acetic acid (100 ml) and to this solution was added bromine (17.1 μl, 13.99 mmol) in a dropwise fashion over 30 minutes. Water (200 ml) was added to the amber solution and the mixture extracted with EtOAc (3×100 ml). The combined organic extracts were then washed with saturated potassium bicarbonate solution (3×100 ml), dried using MgSO4, filtered and concentrated in vacuo to give the title compound. (7.56 g, 87%). m/z (LC-MS, ESP):, RT=4.92 min, (M++1)=309.