Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18](O)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1.[CH3:26][C:27]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1)([CH3:32])[C:28]([O:30][CH3:31])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C.C1COCC1.CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([N:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:51][CH:52]=3)=[CH:43][CH:42]=2)[CH:36]2[CH2:37][CH2:38][N:33]([C:27]([CH3:26])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:34][CH2:35]2)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (20.7 g, 1.3 equiv), methyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B1) (20.0 g, 1.3 equiv), DIPEA (24.0 ml, 3 equiv) and DMF (184 ml) was mechanically stirred, then HATU (27.1 g, 1.5 equiv) was added in one portion and stirring continued for 2 h. The reaction mixture was partioned between diethyl ether/THF (1:1) and sodium carbonate (1M, excess). The organic layer was washed with water and brine, dried and evaporated. Chromatography was run sequentially on three silica columns (firstly 3:1 EtOAc/hexanes; secondly 2% MeOH in DCM; thirdly 1:1 EtOAc/hexanes to 100% EtOAc). Product fractions were evaporated to obtain the desired product as an amorphous pink solid (27.5 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CC)=O.[NH2:20][C:21]1[C:26]([Mg]Br)=[CH:25][CH:24]=[CH:23][N:22]=1>>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:17]
Reactant: CCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1ncccc1[Mg]Br
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O

Procedure:
The process of claim 1, wherein ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide of formula (V) is reacted with 2-amino-pyridyl-magnesium bromide of formula (VI) to give 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][N:6]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>CN(C)C=O>[O:21]1[CH2:20][CH:19]1[CH2:17][O:4][C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:7][N:6]=1
Reactant: BrCC1CO1
Reactant: Cc1c(O)noc1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCC2CO2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
7.32 g of sodium methoxide were added to a solution of 6.00 g of 3-hydroxy-4-methyl-5-phenylisoxazole in 500 ml of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. 10.4 g of epibromohydrin were then added dropwise at room temperature to the mixture, and the mixture was stirred at room temperature for 48 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluted with a 2:1 by volume mixture of cyclohexane and ethyl acetate, to give 5.60 g of the title compound as colorless cotton-like crystals, melting at 87°-88° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([CH2:21][O:22]C(=O)C)=[O:20])[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:26].C([O-])([O-])=O.[Na+].[Na+]>CO>[OH:22][CH2:21][C:19]([NH:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:26])[CH2:4][CH2:5]3)[CH:13]=1)=[O:20]
Reactant: CC(=O)OCC(=O)Nc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(NC(=O)CO)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of acetic acid [5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylcarbamoyl]-methyl ester (example 2, 0.025 g, 0.071 mmol) in MeOH (1 mL) was added a 1M aqueous solution of Na2CO3 (0.354 mL) and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, the residue dissolved in EtOAc (20 mL) and washed with aq. NaHCO3 (5 mL). The organic layer was separated, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.02 g, 91%) as light brown solid. MS: 312.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:5][CH:4]([CH:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CO>[CH3:1][C:2]1([CH3:29])[CH2:5][CH:4]([CH:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(C(Nc2cnc3ccccc3c2)c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a flask containing ethyl 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoate (17.0 mg, 0.0440 mmol) was added tetrahydrofuran (0.110 mL), methanol (0.110 mL), and 1 N sodium hydroxide (0.110 mL, 0.110 mmol). The reaction was stirred for 18 h at room temperature. The reaction was then diluted with ethyl acetate and water. 1 N hydrochloric acid (0.110 mL) was then added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to provide 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoic acid; (14.8 mg, 93% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ: 8.67 (br. s., 1H), 8.06 (d, J=8.2 Hz, 2H), 7.96 (d, J=7.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.46-7.32 (m, 3H), 6.76 (d, J=2.5 Hz, 1H), 4.30 (d, J=9.4 Hz, 1H), 2.62-2.50 (m, 1H), 2.10-1.98 (m, 1H), 1.80-1.69 (m, 2H), 1.69-1.58 (m, 1H), 1.14 (s, 3H), 1.09 (s, 3H). MS (M+1): 361.2.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.C1C[O:32]CC1>>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:32])=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To the solution of 1-ethenyl-4-{[4-(trifluoromethyl)phenyl]oxy}benzene (890 mg, 3.37 mmol) in dry THF (10 mL), was added 9-BBN (10 mL, 5.00 mmol) at 0° C. and stirred at room temperature overnight. Then the reaction mixture was quenched by addition of water (3 mL), followed by aq. NaOH (3M, 4.5 mL), and 30% H2O2 (5 mL). The reaction mixture was heated at 50° C. for 3 h. Then the THF and some water were removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. Purification via flash chromatography afforded the title compound (914 mg, 96% yield). LCMS: rt=3.38 min, [M+H+]=265
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17])=[N+:2]=[N-:3]>C(O)C#C>[OH:16][CH2:15][C:14]1[N:3]=[N:2][N:1]([CH2:4][CH2:5][CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH:13]=1
Reactant: [N-]=[N+]=NCCCN1C(=O)c2ccccc2C1=O
Agent: C#CCO
Product: O=C1c2ccccc2C(=O)N1CCCn1cc(CO)nn1
Reaction time: 18 h

Procedure:
A solution of 2-(3-azidopropyl)isoindoline-1,3-dione, 20, (0.62 g, 2.69 mmol) in propargyl alcohol (4 mL) was warmed to 90° C. and stirred for 18 h. The reaction mixture was concentrated under reduced pressure. The crude product containing both regioisomers (˜1:1 ratio) was used in the next step without further purification. ESI+ MS: m/z (rel intensity) 301.1 (100, [M+H]+).
Reaction SMILES: [Li+].[F:2][C:3]([F:22])([F:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O-:20])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:57]([C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[CH:62][C:61]=1[C:73]([F:76])([F:75])[F:74])([O-:59])=[O:58]>CN(C)C=O.ClCCl.O1CCCC1>[N+:57]([C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH:67]2[CH2:68][CH2:69][N:70]([C:18](=[O:20])[CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:2])([F:22])[F:21])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:71][CH2:72]2)=[CH:62][C:61]=1[C:73]([F:76])([F:74])[F:75])([O-:59])=[O:58]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-propionic acid lithium salt (33 mg; 0.11 mmol, prepared in accordance with Example 13), diisopropylethyl amine (37 μL; 0.22 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (36 mg; 0.10 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (33 mg; 0.10 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 4 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (34 mg; 0.06 mmol). The structure was confirmed using Protocol II-F. Calculated mass=574; observed mass=575; HPLC retention time=11.47 min.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=O)[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1CCCO1>[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=[CH2:1])[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC1CCCO1
Product: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (2.2 eq.) in 2-methyl tetrahydrofuran (3 vol) was added rapidly solid potassium tert-butoxide (2.3 eq.) maintaining the temperature around 0° C. The temperature was kept at +20° C. for 2 hours (a suspension remained) and re-cooled to 0° C. Keeping the temperature below 6° C., (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (1 eq.) was added over 40 minutes. The reaction was warmed to room temperature and stirred for 16 h and then cooled to 0° C. The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) and the aqueous layer was separated. The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite®. The aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol). The organic phase was dried (MgSO4) and the solvent removed. The crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol). The combined aqueous layers were acidified at ambient temperature with 6 N HCl to pH=3, and extracted twice with ethyl acetate (10 vol, then 8 vol). The combined extracts were dried (Na2SO4), the solvent removed and the crude product was recrystallized from cyclohexane (5 vol) to afford the title compound. 1H-NMR (400 MHz, DMSO): δ 12.9, (broad, 1H); 5.00 (m, 2H); 4.24 (dt, J=1.9H, J=7.3 Hz, 1H), 3.91 (m, 2H); 2.98 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.41 and 1.36 (2 s rotamers, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[O:10][CH2:9][CH2:8][CH2:7]1>>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[CH2:6][CH2:7][CH2:8][C:9]1=[O:10]
Reactant: NCCCO
Reactant: O=C1CCCO1
Product: O=C1CCCN1CCCO
Yield: 78.6 %

Procedure:
3-aminopropanol reacted in similar manner to Example 2 with butyrolactone furnished a 78.6% yield of N-(3-hydroxypropyl)-2-pyrrolidinone, b.p. 160° C./3 torr.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.I[CH3:14]>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:12][CH3:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: COc1ncc(C(F)(F)F)cc1Br
Yield: 42.3 %

Procedure:
To a suspension of 3-bromo-5-trifluoromethyl-2(1H)-pyridone (2.0 g, 8.26 mmol) and silver carbonate (2.32 g, 8.4 mmol) in hexane (50 mL) was added iodomethane (1.05 mL, 16.8 mmol) and the resulting mixture heated at reflux for 16 hrs. The suspension was cooled, and filtered, and the filtrate concentrated in vacuo. The residue was purified by silica chromatography to give the product as an oil (893 mg, 3.49 mmol, 42% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]=[CH:5][C@H:6]([NH:22]C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:30])[CH:4]=[CH:5][CH:6]([NH2:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)C=C[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C=CC(N)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
(R)-5-(4-Benzyloxy-phenyl)-4-tert-butoxycarbonylamino-pent-2-enoic acid methyl ester (3.0 g, 0.0073 mol) was added to TFA (10 ml) at 0° C. with stirring. After 10 min, ice was added, and the mixture extracted into EtOAc. The extracts were washed with K2CO3 solution (20% w/v) and brine, dried with MgSO4, and evaporated to afford 2.23 g (98%) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][C:18]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:17][C:18]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: NCC1(O)CCCC1
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(NCC2(O)CCCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (Acros Organics) and 1-(aminomethyl)cyclopentanol hydrochloride (J. Med. Chem. 1981, 24, 7-12).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].FC(F)(F)C1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31]NCC2)=C([N+]([O-])=O)C=1>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]2[CH2:24][CH2:25][CH2:26][CH2:31][CH2:32]2)[CH:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCNCC1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (100 mg) was dissolved in acetonitrile (5 ml) and (4-trifluromethyl-2-nitrophenyl)piperazine (253 mg) added. The solution was stirred overnight at room temperature. After this time the solvent was removed in vacuo. Purification by flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (98:2, then 93:7 v/v) afforded the title compound. m/z (ES+) 521 (MH)+
Reaction SMILES: [Cl:1][C:2]([F:18])([F:17])[C:3]([C:6]1[NH:11][C:10](=[O:12])[C:9]([C:13]([O:15]C)=O)=[CH:8][CH:7]=1)([F:5])[F:4].Cl.[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]([F:18])([F:17])[C:3]([C:6]1[NH:11][C:10](=[O:12])[C:9]([C:13]([NH:22][CH2:20][CH3:21])=[O:15])=[CH:8][CH:7]=1)([F:4])[F:5]
Reactant: CCN
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)Cl)[nH]c1=O
Agent: Cl
Product: CCNC(=O)c1ccc(C(F)(F)C(F)(F)Cl)[nH]c1=O

Procedure:
At room temperature, 300 mg (1.04 mmol) of methyl 6-(2-chloro-1,1,2,2-tetrafluoroethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were stirred in 5 ml of aqueous ethylamine solution (70%) for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 310 mg (98% of theory) of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])O.[Na+]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:27]1[CH:32]=[N:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: O=C(Nc1ccc(O)c(F)c1)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a solution of benzyl (3-fluoro-4-hydroxyphenyl)carbamate (80 g, 252 mmol) in dimethyl sulfoxide (600 mL) were added cesium carbonate (123 g, 378 mmol) and 5-chloro-2-nitropyridine (40 g, 252 mmol), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate (1000 mL) and water (1000 mL) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=3/1) and collected by filtration to give the title compound (79.8 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8]([O:10]CC)=[O:9]>[OH-].[Na+]>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)Cc1sccc1Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1sccc1Br
Reaction time: 14 h

Procedure:
10% aqueous sodium hydroxide solution (100 ml) was added to this ester and stirring carried out for 14 hours at 50° C., after which ether extraction was carried out and unnecessary organic material eliminated. Next, acidification was performed with dilute hydrochloric acid and extraction carried out with dichloromethane. After drying, the solvent was distilled off and there was obtained 3-bromo-2-thiopheneacetic acid (4.7 g).
Reaction SMILES: [C:1](=[O:18])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]3[CH:42]=[C:41]4[C:36]([CH2:37][CH2:38][NH:39][CH2:40]4)=[CH:35][CH:34]=3)[N:30]=[C:29]([NH2:43])[N:28]=2)[CH2:23][CH2:22]1>>[NH2:43][C:29]1[N:30]=[C:31]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][N:39]([C:1]([O:2][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:18])[CH2:40]3)=[CH:35][CH:34]=2)[CH:32]=[C:27]([N:24]2[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]2)[N:28]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from cyclopentyl 4-nitrophenyl carbonate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=437.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: NCc1ccccn1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Product: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see Intermediate 18, 2.5 g, 7.5 mmol) and 2-aminomethylpyridine (2 eq, 1.41 g) in CH3CN (30 ml) was heated at 60° C. for 2 h. The mixture was extracted with DCM. The organic phase washed with saturated aqueous sodium hydrogen carbonate and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue taken up in diethyl ether. The precipitate was filtered off and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitro-N-(2-pyridinylmethyl)-4-quinolinamine (2.5 g) which was used without purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C1COCC1.[Li]CCCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([Cl:39])[CH:19]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:39][C:20]1[CH:19]=[C:18]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:22][C:21]=1[C:23]1[N:27]2[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:26]2=[N:25][C:24]=1[CH3:38]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Reactant: Cn1cccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccnn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a −78° C. solution of 1-methyl-1H-pyrazole (0.12 g, 1.45 mmol) and THF (4 mL) is added 1.6 M n-BuLi (0.91 mL, 1.45 mmol). After 45 minutes 0.5 M ZnCl2 (2.9 mL, 1.45 mmol) is added and the solution is warmed to ambient temperature. After 30 minutes 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (example Rupp-88) (0.30 g, 0.73 mmol) and PdCl2(dppf) (0.027 g, 0.036 mmol) are added and the solution heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient) furnish the title compound (0.15 g, 0.36 mmol, 50%). 1H NMR (CDCl3) δ 0.88 (d, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.52 (s, 6H), 3.26-3.36 (m, 1H), 4.05 (s, 3H), 6.45 (d, J=1.9 Hz, 1H), 6.71 (s, 1H), 7.14 (s, 1H), 7.49 (d, J=1.9 Hz, 1H). LC/MS (m/z): calcd. for C21H24ClN5S (M+H)+: 414.2; found: 414.2.