Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([C:16]([O:18]C)=[O:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[CH3:15][O:14][C:12]([C:10]1[C:9]([C:16]([OH:18])=[O:17])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=1)=[O:13]
Reactant: COC(=O)c1nn(-c2ccccc2)nc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1nn(-c2ccccc2)nc1C(=O)O
Temperature: 23 °C
Reaction time: 17 h
Yield: 84.9 %

Procedure:
A solution of dimethyl 2-phenyl-2H-1,2,3-triazole-4,5-dicarboxylate (0.522 g, 2.00 mmol) in methanol (40 mL) at 23° C. was treated with a solution of KOH (0.236 g, 4.20 mmol) in methanol (5 mL). The resulting solution was stirred at 23° C. for 17 h and partitioned between NaHCO3 (sat. aq. sol.) and ether. The aqueous layer was washed with ether and acidified carefully to pH 1 with HCl (conc.). The resulting mixture, was extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by radial chromatography (2 mm plate, CH2Cl2-methanol-acetic acid 90:10:1) to afford 0.42 g (85%) of 5-methoxycarbonyl-2-phenyl-2H-1,2,3-triazole-4carboxylic acid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=1>ClCCl>[CH3:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=1.[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: Cc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(OC3CCNCC3)n2)cc(-c2cccnc2)c1
Reaction time: 2 h

Procedure:
TFA deprotection: 1:1 Dichloromethane:TFA (1.00 mL) solution was added to the isolated tert-butyl 4-[(2-{[3-methyl-5-(pyridin-3-yl)phenyl]amino}pyrimidin-4-yl)oxy]piperidine-1-carboxylate at room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (5-50% acetonitrile in water+0.05% TFA) to yield N-[3-methyl-5-(pyridin-3-yl)phenyl]-4-(piperidin-4-yloxy)pyrimidin-2-amine as a TFA salt. MS APCI calc'd for C21H24N5O [M+H]+ 362. found 362. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.91 (s, 1H), 8.65 (d, J=3.7 Hz, 1H), 8.47 (s, 2H), 8.25 (d, J=5.7 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.71-7.61 (m, 1H), 7.59 (s, 1H), 7.17 (s, 1H), 6.31 (d, J=5.7 Hz, 1H), 5.24 (s, 1H), 3.19 (s, 2H), 2.97 (s, 2H), 2.36 (s, 2H), 2.09 (s, 3H), 1.90 (s, 2H).
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:8])[CH2:6][F:7])=[N+:2]=[N-:3].[C:9]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N+:17]([O-:19])=[O:18])#[C:10][CH3:11]>>[F:7][CH2:6][CH:5]([OH:8])[CH2:4][N:1]1[CH:11]=[C:10]([CH2:9][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[N+:17]([O-:19])=[O:18])[N:3]=[N:2]1
Reactant: CC#Cn1ccnc1[N+](=O)[O-]
Reactant: [N-]=[N+]=NCC(O)CF
Product: O=[N+]([O-])c1nccn1Cc1cn(CC(O)CF)nn1
Temperature: 60 °C

Procedure:
To a vial is added fluoroazide 17 (5.79 mmol) and 1-propynyl-2-nitroimidazole (5.79 mmol). The solution is heated at 60° C. overnight. The material is then purified on a silica gel column using EtOAc:Hex as the eluent. The material is then further purified via recrystallization using EtOAc:Hex to afford pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH:11]([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[O:16])(=[O:25])=[O:24])=[O:28])[N:7]=1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(C)nc(N)n1
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)n1
Yield: 51.1 %

Procedure:
To 26.8 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 300 ml anhydrous methylene chloride was added 67.0 g of 2-isopropoxycarbonylbenzenesulfonyl isocyanate in 100 ml anhydrous methylene chloride. The resultant suspension was stirred at ambient temperature for 72 hours, and filtered to yield 40.0 g of the desired product as a white solid, m.p. 193°-196° C. The solid showed infrared absorption peaks at 1700 and 1710 cm-1 consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-(isopropoxycarbonyl)benzenesulfonamide.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)cc5)n4)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
Ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.094 mmol), 4-chlorophenylboronic acid (59 mg, 0.38 mmol), Na2CO3 (30 mg, 0.28 mmol) and Pd(PPh3)4 (11 mg, 0.0094 mmol) were place in a 1 mL vial and diluted with toluene (800 μL) and water (80 μL). The vial was purged with argon, sealed and heated to 100° C. After stirring for 12 hours, the reaction was cooled and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.089 mmol, 94% yield).
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CO.[Cl-].[NH4+]>[CH3:17][CH:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C[O-]
Reactant: CCCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 8-bromo-2-[(1-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (493 mg) in dry MeOH (4.37 mL) was added sodium methoxide solution (0.722 mL, 30% wt. in MeOH) and the mixture was stirred at reflux for 6 h. A further portion of sodium methoxide solution (0.120 mL, 30% wt. in MeOH) was added and the reaction was continued for 90 mins. The reaction was cooled and concentrated in vacuo to give an orange residue. The residue was taken up in saturated ammonium chloride (25 mL) and washed with EtOAc (25 mL). The organics were separated and washed with water (15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange foam (313 mg).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]#[N:23])=[CH:19][CH:20]=2)[C:15]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([Cl:34])[CH:27]=2)=[N:14][N:13]=1>>[ClH:11].[Cl:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH2:25][NH:24][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:12]([N:7]2[CH2:8][CH2:9][C:4]([OH:10])([CH2:3][OH:2])[CH2:5][CH2:6]2)=[N:13][N:14]=1
Reactant: OCC1(O)CCNCC1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Agent: Cl
Product: COc1ccc(CNc2nnc(N3CCC(O)(CO)CC3)c3ccc(C#N)cc23)cc1Cl

Procedure:
The resulting 4-(hydroxymethyl)-4-piperidinol hydrochloride was reacted with 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine in the same manner as in Example 4 to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]=[O:12].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[O:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=1)[CH3:10]
Reactant: C=O
Reactant: CN(C)CCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CCc1ccc(CO)o1

Procedure:
N,N-Dimethyl-2-furanethanamine (9.8 g), 30% aqueous formaldehyde (17.5 g) and glacial acetic acid (18 ml) were heated at 70° for 5 hr. The reaction was cooled, basified with sodium hydroxide and extracted with ether. The organic extracts were distilled to give an oil b.p. 90°-100° (0.5 mm).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:19]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:33]>CO>[CH2:31]([O:30][CH2:29][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:19]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:33])[C:11]=2[N:12]=1)[CH3:32]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(-c2cccnc2)no1
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCc1cc(-c2cccnc2)no1

Procedure:
A slurry of 4-chloro-2-(ethoxymethyl)-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.78 g, 3.97 mmol) in a solution of 7 M ammonia in methanol (20 mL) was heated at 150° C. for 20 hours in a Parr pressure vessel. The volatiles were removed under reduced pressure and the resulting oil was partitioned between dichloromethane and 1 M KOH. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 9:1 to 4:1 chloroform/CMA). After concentration of the appropriate fractions, a white solid was obtained. The white solid was triturated with diethyl ether and dried at 80° C. under vacuum to provide 2-(ethoxymethyl)-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 199.0-200.0° C.
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[F:24])[CH:13]=2)=[CH:6][CH:5]=1.[C:28]([O-:31])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([N:10]3[CH2:7][CH2:6][C@@H:28]([OH:31])[CH2:11]3)=[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[F:24])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(-c2[nH]ncc2F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-3-(4-fluoro-1H-pyrazol-5-yl)benzamide (Stage 24.1, 62 mg, 0.147 mmol), R-3-hydroxypyrrolidine (0.031 mL, 0.206 mmol) and TEA (0.062 mL, 0.442 mmol) in DMSO (0.5 mL) was stirred at 100° C. for 16 h. The RM was diluted with EtOAc (30 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed under reduced pressure. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in DCM and treated with n-hexane to give the title product as a white solid. HPLC (Condition 5) tR=6.61 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=467.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.95 (m, 2H) 2.79 (d, J=10.56 Hz, 1H) 3.06-3.20 (m, 2H) 3.22-3.35 (m, 1H) 4.13-4.30 (m, 1H) 4.79-4.96 (m, 1H) 6.75-6.92 (m, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.86 (m, J=9.38 Hz, 5H) 10.11 (s, 1H) 12.67-13.12 (m, 1H).
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>O1CCOCC1>[C:25]([O:28][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18])(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)OC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Temperature: 85 °C
Reaction time: 6 h
Yield: 36.8 %

Procedure:
To a solution of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one (50 mg, 0.15 mmol) in dioxane (2 mL) was added sodium acetate (90 mg, 1.1 mmol), the reaction mixture was stirred at 85° C. for 6 h and quenched by the addition of saturated ammonium chloride solution (10 mL). The organic layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford crude product, ant it was purified by Pre-TLC (eluent: Hexane/EtOAc=1/1) to give product (20 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 7.33-7.38 (m, 6H), 7.25 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 2.35 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H). MS (ESI) m/e [M+1]+ 363.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-(6-methoxypyridin-3-yl)-6-(3-(piperazin-1-yl)propoxy)-1H-inden-1-one (90 mg, 1.2 eq, 0.2 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (20%).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Yield: 31.6 %

Procedure:
7-Fluoro-1-methylamino-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 2.25 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.4 g of piperazine in 30 cm3 of pyridine. After recrystallizing 3 times from, in total, 400 cm3 of dimethylformamide, 0.82 g of 7-fluoro-1-methylamino-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a deep yellow solid melting at 322-324° C., solvated by 13.6% of dimethylformamide.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:7]([C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=3)[C:4]3[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=3)=[CH:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(Br)cc3)cc2)cc1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
Di-p-tolylamine (6.0 g, 30.4 mmol), 4,4′-dibromobiphenyl (23.7 g, 76.0 mmol), sodium tert-butoxide (7.26 g, 91.2 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (Pd(dppf)Cl2) (666 mg, 0.912 mmol, 3 mol %) were added to anhydrous toluene (about 250 ml) and degassed in argon for about 30 minutes. The resulting mixture was heated at about 80° C. for about 6 hours, after which a TLC analysis indicated that most of the di-p-tolylamine was consumed. After being cooled to RT, the mixture was poured into saturated aqueous sodium bicarbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled, washed with water and brine, then dried over MgSO4. After filtration the extract was concentrated to dryness on a rotary evaporator, then loaded onto silica gel. A flash column (gradient of 100% hexane to 1% methylene chloride in hexane) resulted in 9.4 g (72%) of a white solid confirmed by 1H NMR in CDCl3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2ccc(Br)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 11 h

Procedure:
5-bromoisatin (0.113 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 11 hours. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2]1.S(=O)(=O)(O)O.[CH3:15]O>CCOCC>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9][CH3:15])=[O:8])[CH2:2]1
Reactant: O=C(O)CC1CCOC1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)CC1CCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A mixture of 2-(tetrahydrofuran-3-yl)acetic acid (2.00 g, 15.4 mmol, 1.00 equiv) and sulfuric acid (2 mL) in methanol (20 mL) was stiffed for 3 h at 80° C. in an oil bath. After cooling to ambient temperature, the mixture was diluted with 50 mL of ether and washed with 2×20 mL of water, 2×20 mL of sodium bicarbonate (aq., sat. Note: gas evolution), and 2×20 mL of brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1.50 g (68%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.[NH2:14][NH2:15].O>CCO>[NH2:1][C:2]1[C:3]([C:9]([NH:14][NH2:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NN
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 70 °C
Yield: 96.3 %

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (10.18 g, 43.87 mmol) was suspended in EtOH (50.90 mL) and hydrazine hydrate (4.392 g, 4.268 mL, 87.74 mmol) was added and the reaction mixture heated at 70° C. for 2 h. Water (50 mL) was added and the precipitate isolated by filtration. The solid was washed with methanol and dried under vacuum to leave the product as a pale yellow powder (9.8 g, 96% yield); 1H NMR (400 MHz, DMSO) d 4.53 (bs s, 2H), 7.62 (br s, 2H) and 9.78 (br s, 1H) ppm; MS (ES+) 232.06
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13].CC(C)([O-])C.[K+]>O>[F:10][C:11]([F:15])([F:14])[CH2:12][O:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-chloronicotinonitrile (0.30 g, 2.2 mmol) was a mixture of 2,2,2-trifluoroethanol (0.19 mL, 2.6 mmol) and potassium tert-butoxide (1M solution in THF, 2.5 mL, 2.5 mmol) added at 0-5° C. The resulting mixture was stirred at ambient temperature for 1 hour. Water was added (20 mL) followed by extraction with ethyl acetate (2×20 mL). The organic layer was dried over sodium sulphate and concentrated in vacuum affording 6-(2,2,2-trifluoroethoxy)nicotinonitrile, 0.42 g (96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J=2.26 Hz, 1 H) 8.28 (dd, J=8.53, 2.26 Hz, 1 H) 7.21 (d, J=8.78 Hz, 1 H) 5.0 (q, J=8.95 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:15][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])[CH:14]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 2.1 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (640 mg, 3.2 mmol) and triphenylphosphine (840 mg, 3.2 mmol) in anhydrous tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.5 ml, 3.2 mmol) dropwise. After being stirred under an argon atmosphere at room temperature for 4 hours, the mixture was diluted with water (15 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 20% ethyl acetate in hexanes) to give 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (740 mg, 84%) as a pale yellow solid.