Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([O:20]C(=O)C(C)(C)C)=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:4]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C1(C)C=CC=CC=1>CCOC(C)=O>[N:32]1([CH2:2][C:3]2[C:8]3[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)=[N:10][O:11][C:7]=3[C:6]([OH:20])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:4]=2)[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: CCOC(=O)c1nc(CBr)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Reactant: c1cn[nH]c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(Cn2cccn2)c2c(-c3ccc(OC)cc3)noc2c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
Ethyl 4-(bromomethyl)-3-(4-methoxyphenyl)-7-(pivaloyloxy)isoxazolo[4,5-c]pyridine-6-carboxylate (34 mg, 0.069 mmol) and pyrazole (9.4 mg, 0.138 mmol) were added to 1 mL of toluene, and the mixture was stirred at room temperature for 48 h. An additional equiv. of pyrazole was added, and the mixture was stirred at room temperature for 16 h and then at 45° C. for 16 h. The mixture was diluted with EtOAc (20 mL) and washed with 1M hydrochloric acid. The organic layer was dried over MgSO4 and concentrated, and the residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 19 mg of the title compound. MS: (+) m/z 395.29 (M+1).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[CH:15]=[N:14][N:13]=1>CC#N>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([N:6]1[CH2:5][CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]3[CH2:1]1)=[N:13][N:14]=[CH:15]2
Reactant: Clc1ccc2c(Cl)nncc2c1
Reactant: O=C1CCC2CNCCN12
Solvent: CC#N
Product: O=C1CCC2CN(c3nncc4cc(Cl)ccc34)CCN12
Temperature: 135 °C
Yield: 19.5 %

Procedure:
A mixture of tetrahydropyrrolo[1,2-a]pyrazin-6(1H,2H,7H)-one (Med. Chem. Res., 7:301 (1997); 0.983 g, 7.01 mmol), 1,6-dichlorophthalazine (1.36 g, 6.83 mmol) and TEA (2.00 mL, 14.3 mmol) in 18 mL of CH3CN was heated at 135° C. for 30 min in a microwave oven. The reaction mixture was concentrated onto silica gel and purified using flash chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give 404 mg (20%) an orange foam/amorphous solid. MS m/z: 303.1 [M+1].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][C:6]=2[N:18]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([NH:1][C:2]1[C:3]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][C:6]=2[N:18]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CN(C)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CN(C)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1

Procedure:
Following the procedure of Example 21, 1.62 g of 7-amino-6-(2,6-dichlorophenyl)-2-(3-dimethylamino-propylamino)-pyrido[2,3-d]pyrimidine from Example 27 was reacted with 0.48 g of t-butyl isocyanate to give the title compound; mp gradually dec above 130° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[Na+].[CH3:33][S:34]([O-:36])=[O:35].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1=O
Reactant: CS(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-Cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxaride from Step 1 in N,N-dimethylformamide (20 ml/mmol) was added methanesulfinic acid sodium salt (1.3 eq) and the resulting mixture was stirred at room temperature for 18 hours. To the mixture was added saturated aqueous ammonium chloride solution and ethyl acetate, and the insoluble solid was filtered and washed well with water, hexane, ether and ethyl acetate to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([Cl:25])[N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:21]=[C:20]([Cl:25])[N:19]=[C:18]([Cl:17])[N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.3 equiv) in dry DMF (100 mL) under Ar was added sodium hydride (1.01 g, 23.1 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,4,6-trichloro-pyrimidine (2.82 g, 15.4 mmol, 1.0 equiv; commercially available) was added and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to provide 3.1 g (57%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.24-1.33 (m, 2H), 1.40 (s, 9H), 1.78-1.85 (m, 2H), 2.86-2.96 (m, 2H), 3.49-3.97 (m, 3H), 6.47 (s, 1H). MS (ISP): 347.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(F)cc2F)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(F)c2ccc(F)cc2F)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 78° C. solution of tert-butyl 4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (200 mg, 0.611 mmol) in DCM (3.055 mL) was added DAST (242 μL, 1.833 mmol). The mixture was stirred at −78° C. for 30 min, then quenched with MeOH. Flash silica gel chromatography using a gradient of 0% to 100% EtOAc in hexanes gave tert-butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[CH:16]N(C)C)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[N:23][C:22]([NH2:24])=[N:21][CH:16]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C(=O)c1ccco1)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(Cl)nc2)c(-c2ccco2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 74.2 %

Procedure:
A suspension of 2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (7.49 g, 27.1 mmol), guanidine hydrochloride (7.7 g, 81.0 mmol) and potassium carbonate (22.4 g, 162 mmol) in N,N-dimethylformamide (105 ml) was stirred at 70° C. for 21 hours. After cooling as it was, the reaction mixture was diluted with water. The resulting crystals were collected by filtration and washed with water, to give the title compound (5.48 g, 74%) as a pale yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1>O1CCOCC1.C(O)(=O)C>[Br:1][C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:14][C:10]=1[CH3:9]
Reactant: CCOC(=O)c1[nH]c(C)cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(Br)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
N-Bromo succinimide (1.40 g, 7.87 mmol) was added to a solution of ethyl 5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.5 g, 6.55 mmol) in a mixture of dioxane (10 mL) and acetic acid (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was warmed to room temperature and stirred for another 15 min. The mixture was quenched with 2N NaOH solution and the organic layer was separated, washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.68 g, 84%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH3:24])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH3:24]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 74.5 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-ethoxybenzaldehyde 1.33 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.55 g.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[CH:10]=1)(=[O:7])[CH3:6]>C(O)(C(F)(F)F)=O>[C:5]([NH:8][C:9]1[C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(O)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
Nitric acid (fuming) (23.8 g, 378 mmol, 1.20 equiv) was added in portions under 50° C. to a mixture of 4-acetamido-2-hydroxybenzoic acid (61.4 g, 315 mmol, 1.00 equiv) and TFA (700 mL) in a 2-L round-bottom flask. The resulting solution was allowed to react, with stirring, for 3 hr at room temperature before being concentrated under vacuum. The residue was dissolved in 800 mL of acetone, stirred for 15 min. at reflux, then cooled. The solids were collected by filtration, giving 21.1 g (28%) of 4-acetamido-2-hydroxy-5-nitrobenzoic acid as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](Br)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=2)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COCCCn1nnnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(F)(F)F)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 71.2 %

Procedure:
The mixture of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-1-(3-methoxy-propyl)-1H-tetrazole (110 mg, 0.22 mmol) and 3-trifluoromethylphenylboronic acid (83 mg, 0.44 mmol) was heated in a mixture of toluene (2 ml), ethanol (2 ml) and saturated sodium bicarbonate (2 ml) under nitrogen in the presence of a catalytic amount of Pd(PPh3)4 (20 mg) at 80° C. for 2-3 h. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 ml×3), and the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to provide 5-(4,6-bis-benzyloxy-3′-trifluoromethyl-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (90 mg, 72%). 400 MHz 1H NMR (CDCl3) δ: 7.84 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.58-7.48 (m, 3H), 7.39-7.22 (m, 10H), 6.77 (s, 1H), 5.11 (s, 2H), 5.10 (s, 2H), 4.33 (t, J=7.6 Hz, 2H), 3.25 (t, J=6.0 Hz, 2H), 3.16 (s, 3H), 2.10-2.09 (m, 2H); LCMS: 575 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2.0 g 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester in 5 ml DMF, 360 mg NaH (60% in mineral oil) and subsequently 2.8 g 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] were added and the mixture was stirred at 80° C. for 1 h. After the addition of 5 ml water the mixture was filtered through a Chem Elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 4 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26])#[N:19]>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([CH:21]=3)[C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: N#Cc1cc(B(O)O)ccc1F
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-cyano-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.40 (s, 1H), 7.38 (t, J=8.9 Hz, 1H), 7.27 (m, 2H), 7.14 (dd, J=8.6, 2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 3.27 (s, 3H), 1.98 (m, 4H), 0.81 (t, J=7.4 Hz, 6H); MS (ESI) m/z 354 ([M+H]+); MS (ESI) m/z 352 ([M−H]−); Anal. calcd for C20H20FN3O2: C, 67.97; H, 5.70; N, 11.89. Found: C, 65.58; H, 5.65; N, 11.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[CH:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[Br:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Br:32][CH2:33][C:34]([N:12]1[CH2:13][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:10]([CH:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH3:15])[CH2:11]1)=[O:35]
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 703.7 %

Procedure:
To a stirred solution of 6-{(SR)-1-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (XV-B-4) 30 mg (0.083 mmol) in CH2Cl2 (3 mL) at RT, 0.013 ml (0.01 mmol) of Et3N and 0.0083 mL (0.01 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 34 mg (85%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH3:15])[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CCOC(=O)Cc1ccccn1
Reactant: CNC
Solvent: CO
Product: CN(C)C(=O)Cc1ccccn1

Procedure:
To 5.0 g of ethyl 2-pyridylacetate dissolved in 25 ml of MeOH was added 20 ml of dimethyl amine. The mixture was heated at 90° in a steel autoclave for 96 hrs. The solvent/amine mixture was allowed to evaporate until a residual oil was obtained. The residual oil was distilled to afford 4.5 g of the desired N,N-dimethyl-(2-pyridyl)acetamide as a free-flowing yellow oil, bp 105°-110°/0.5 mm.
Reaction SMILES: [N:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[N:3][CH:2]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: c1cnc2ncncc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ncccc12

Procedure:
A mixture of 17.8 g of Pyrido[2,3-d]pyrimidin(4(3H)one and 200 mL of POCl3 was stirred under reflux for one hour. Excess POCl3 was removed under vacuum, and then CH2Cl2, ice, and water were added. A black solid dissolved slowly. The organic layer was then separated, washed with aqueous NaHCO3, and dried over Na2SO4. Solvent was then removed under vacuum to leave a yellow solid, which was recrystallized from toluene/hexane. M.P. 137° dec.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([OH:26])=O)[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:38][S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH3:28])(=[O:36])=[O:37])=[O:26])[O:21][C:22]=3[CH3:23])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1

Procedure:
Compound (173) was prepared from compound (171) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt=10.63 mins, m/z (ES+)=527 (M+H for C27H24F2N2O5S).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1>>[CH3:20][O:19][C:9]1[CH:10]=[C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)=[CH:7][CH:6]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: COc1cc(-n2cccn2)ccc1-c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)nn1
Yield: 100 %

Procedure:
tert-Butyl 4-(6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (151 mg, 0.35 mmol, 100% yield) was prepared from Intermediate 2-1 and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate using General Method 1-4 for Suzuki coupling. LCMS Rt=1.58 min, M+1=434.8 (condition B).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[C:22]1(=[O:26])[CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:22]4([OH:26])[CH2:25][CH2:24][CH2:23]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: O=C1CCC1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C1(O)CCC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with cyclobutanone similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-9-fluoro-3-(1-hydroxycyclobutyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L to provide 10-bromo-9-fluoro-3-(1-hydroxycyclobutyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted as a crude with 2-Methyl-3-butyne-ol via General Procedure F to afford 5.2 mg (5.1%) of 9-fluoro-3-(1-hydroxycyclobutyl)-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=410.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:31])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[C:18]3([CH2:19][O:20][CH2:21]3)[CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[CH3:31]
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CCC34COC4)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]heptan-1-yl)picolinic acid (Example 234 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials. MS (EI): m/e=414.1 [M+H]+.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[C:15]([O:16][CH3:17])=[C:14]([CH3:18])[C:13]([O:19][CH3:20])=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])([O-:5])=[O:4].Cl>CO>[N+:3]([C:6]1[C:15]([O:16][CH3:17])=[C:14]([CH3:18])[C:13]([O:19][CH3:20])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])([O-:5])=[O:4]
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1C
Yield: 80.8 %

Procedure:
Potassium hydroxide (3.71 g, 66.31 mmol) was added to a stirred solution of 188 (4.83 g, 18.95 mmol) in anhydrous methanol (80 mL) and the reaction mixture heated at reflux for 3 h. The reaction mixture was allowed to cool and acidified to pH 2 with 1 N HCl and the solid precipitate was filtered and washed with water (50 mL) and left to air dry to afford the product as a yellow-beige solid (189) (3.69 g, 15.31 mmol, 81%); 1H NMR (270 MHz, CDCl3) δ 13.88 (br s, 1H), 7.23 (s, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 2.14 (s, 3H); 1C NMR (67.8 MHz, CDCl3) δ 164.09, 158.65, 150.09, 139.38, 125.70, 122.50, 107.24, 62.78, 56.34, 9.62.