Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[O:17][CH3:18])[CH3:2].[Li][CH2:20]CCC.CI>C1COCC1>[CH2:15]([O:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]([O:17][CH3:18])=[C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])[C:11]=1[CH3:20])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOCOc1ccc(OC)c(OCOCC)c1
Solvent: CI
Solvent: C1CCOC1
Product: CCOCOc1ccc(OC)c(OCOCC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A solution of 4a (632 mg, 2.27 mmol) in anhydrous THF (1.94 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.48 mL, 3.70 mmol) in anhydrous THF (1.62 mL) at room temperature. After one hour, the solution was cooled to −78° C. and methyl iodide (620 μL, 9.87 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 8:1→5:1 Hexane:EtOAc) to afford 5a as a yellow oil (353 mg, 53%): 1H NMR (CDCl3, 500 MHz) 6.74 (d, J=9.0 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H) 5.10 (s, 2H), 5.05 (s, 2H), 3.78 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 3.67 (q, J=7.1 Hz, 2H), 2.14 (s, 3H), 1.18-1.15 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 149.1, 146.5, 121.7, 109.0, 108.4, 96.2, 93.0, 64.3, 63.1, 55.1, 28.7, 14.2, 14.1, 8.8; IR (film) νmax 2918, 2359, 1487, 1260, 1248, 1082, 1055, 945, 798 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for Cl4H22O5, 293.1365; found, 293.1357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15]3=[O:25])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:26][S:27](O)(=[O:29])=[O:28].C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:23][CH:24]=4)[C:15]3=[O:25])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Synthesized according to General Procedure 11. To a solution of (3R,3′S)-3-(3,5-dichlorophenyl)-1′-phenyl-1,3′-bipyrrolidin-2′-one (900 mg, 2.40 mmol) in DCE (10 mL) at 0° C. was added chlorosulfonic acid (1.40 g, 800 μL, 12.0 mmol) slowly. The reaction mixture was then stirred at 0° C. for 30 min, at RT for 1 hour and at 50° C. for 1 hour. At this time more chlorosulfonic acid (279 mg, 160 μL, 2.40 mmol) was added and the reaction mixture was stirred at 50° C. for 1 hour, the reaction mixture was then heated to 70° C. for 10 min, cooled to RT and slowly poured onto ice water. The pH was brought to ˜7 with saturated aqueous NaHCO3 and the reaction mixture was extracted with EtOAc (3×). The combined organic phases were washed with water, brine, dried over MgSO4 and evaporated to dryness to afford 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]benzene-1-sulfonyl chloride as a tan solid (1.00 g, 88%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=473.3; tR=1.58 min.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:32]1[CH2:33][CH2:34][N:29]([CH2:24][C:23]2[CH:22]=[C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccc(CN3CCOCC3)c1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (40 mg, 0.11 mmol), morpholine (28 mg, 0.33 mmol) and acetic acid (33 mg, 0.55 mmol) in methanol (50 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added. After the addition, the mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was resolved with 1N hydrochloric acid and washed with ethyl acetate. The mother liquor was adjusted to pH=8 and extracted with ethyl acetate. The solvent was removed to give 8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (31 mg, yield 66%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.23-2.24 (m, 4H), 3.32-3.43 (q, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.19 (m, 6H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 1H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 439 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22]COC)[CH:19]=[CH:18][C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]COC)=[CH:9][CH:8]=1.Cl.CO.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COCOc1ccc(C=CC(=O)c2ccc(OCOC)cc2O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 50 °C
Yield: 70 %

Procedure:
Then, 1.0 g of 2'-hydroxy-4,4'-bis(methoxymethoxy)-chalcone was dissolved in 7 ml of tetrahydrofuran, and a 5-15% hydrochloric acid/methanol reagent was added to the solution and the mixture was heated at 50° C. for 30 minutes to effect a reaction. After the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 300 ml of ethyl acetate, and the ethyl acetate layer was washed with water (100 ml×3 times), shaken with a saturated aqueous solution of sodium chloride (50 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was subjected to the silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate to obtain 521 mg (yield=70%) of 2',4,4'-trihydroxychalcone in the form of a yellow grain.
Reaction SMILES: C(O)CC.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19]OC)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].COCOC.COCOCOC>ClCCl>[C:5]([C:9]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:11]=2[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COCOCCCc1ccc(C(C)(C)C)cc1
Agent: COCOCOC
Solvent: COCOC
Solvent: CCCO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)COCCC2
Yield: 67 %

Procedure:
The above-mentioned propanol was then converted into 1-tert-butyl-4-(3-methoxymethoxypropyl)benzene by means of dimethoxymethane, in an analogous manner to that described by J. L. Gras et al. in Synthesis 74, (1985), but using 12 equivalents of dimethoxymethane for 1 equivalent of alcohol. The above-mentioned methoxymethylether was then transformed as described by A. Rieche et al., Chem. Ber. 95, 91 (1962) but using dichloromethane as solvent. The concentration of methoxymethylether in this solvent varied between 0.1 and 0.3 M. The reaction product was purified by chromatography to provide 8-tert-butyl-1,3,4,5-tetrahydro-2-benzoxepine (yield 67%, purety>99%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[CH3:10][C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([O:16][C:17](=O)[C:12]=12)=[O:15]>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:17](=[O:16])[C:12]3=[C:11]([CH3:10])[CH:21]=[CH:20][CH:19]=[C:13]3[C:14]2=[O:15])[CH2:3]1)[CH3:9]
Reactant: Cc1cccc2c1C(=O)OC2=O
Reactant: CCN1CCCC(N)C1
Product: CCN1CCCC(N2C(=O)c3cccc(C)c3C2=O)C1

Procedure:
3-Amino-1-ethylpiperidine and 3-methylphthalic anhydride are reacted in a similar manner so that described in Example 3 to give the title compound.
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][CH2:7][C@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[O:5]=[CH:6][CH2:7][C@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(N[C@@H](CCO)c1ccccc1)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Sulphur trioxide pyridine complex (965 g, 6.1 mol) was slurried in dichloromethane (2 l) under an atmosphere of nitrogen. Dimethylsulfoxide (2 l) was added and the resultant solution was cooled to 0° C. A solution of benzyl (1S)-3-hydroxy-1-phenylpropylcarbamate (577 g, 2.0 mol), triethylamine (845 ml, 6.1 mol) and dimethylsulfoxide (1 l) in dichloromethane (1 ml) was added slowly to the reaction mixture keeping temperature below 10° C. The resultant yellow solution was stirred at 0° C. for 2.5 hours. A sample was analysed by TLC indicating that all starting material was consumed. Water (8.6 l) was added and a biphasic mixture was obtained. The mixture was diluted with toluene (8.6 l) and the layers were separated. The organic layer was concentrated under reduced pressure to yield a brown foam, which was taken on to Preparation 19 without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10](C(=O)C(F)(F)F)[CH2:11][CH2:12][C:6]=2[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:27][C:28]1[CH:42]=[CH:41][C:31]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=2)=[CH:30][CH:29]=1.[OH-].[Na+]>CN(C=O)C>[F:27][C:28]1[CH:42]=[CH:41][C:31]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][N:37]([CH2:2][CH2:3][C:4]3[CH:20]=[CH:19][C:7]4[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=4[CH:5]=3)[C:36](=[O:40])[CH:35]=2)=[CH:30][CH:29]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: O=C(N1CCc2ccc(CCCl)cc2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.05 g (3.42 mmol) 1-[7-(2-chloro-ethyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-2,2,2-trifluoro-ethanone in 5 mL DMF is added at 0° C. cesium carbonate and after 15 min 600 mg (2.74 mmol) 4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (preparation 22.1). The reaction mixture is stirred overnight at RT and is then added to 50 mL 1 M aqueous NaOH-solution. The mixture is stirred 2 h at RT. The aqueous phase is extracted with tert-butylmethylether. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile (0.15% formic acid) 95:5 to 5:95).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([C:29]5[NH:30][N:31]=[CH:32][CH:33]=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:41]([O:45]C(=O)NC1(C2C=CC(C3C(=O)C4C(=CC(Br)=C(OC)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([C:29]5[NH:30][N:31]=[CH:32][CH:33]=5)=[C:24]([O:45][CH3:41])[CH:25]=4)[O:20][C:19]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1-c1ccn[nH]1
Yield: 65 %

Procedure:
Following the procedure used to prepare (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(7-bromo-6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a colourless oil (55 mg, 65%). LCMS (Method B): RT=4.90 min, [M+H]+=564.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:34])[C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C)[C@H](C(N)=O)C1
Yield: 56.2 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (5) (3.1 g, 6.97 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.93 g, 13.9 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (1.8 g, 56%): 1H NMR Spectrum: (DMSO d6) 1.86-1.91 (m, 3H), 2.07-2.09 (m, 1H), 2.20 (s, 3H), 2.47-2.49 (m, 1H), 2.71-2.81 (m, 2H), 3.96 (s, 3H), 4.82 (m, 1H), 7.02 (s, 1H), 7.23 (s, 1H), 7.26-7.29 (m, 2H), 7.47-7.53 (m, 2H), 7.82 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C@@H:13]1[CH2:15][O:14]1)=O.[OH-].[K+]>O1CCOCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH2:12][C@@H:13]([CH2:15][OH:14])[O:3][C:4]=2[CH:9]=1
Reactant: O=COc1cc(Br)ccc1OC[C@@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OC[C@@H]1COc2ccc(Br)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
5-bromo-2-[(2S)-oxiran-2-ylmethoxy]phenyl formate (8.5 g, 31 mmol) was dissolved in dioxane. At 0° C., KOH (10%) was added. The mixture was stirred in rt for 1 h and 30 min and was then concentrated. Water was added. Aqueous HCl (1 N) was added to neutralize and the solution was then extracted with EtOAc (3×75 ml). The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) gave the crude title compound (4.4 g). MS m/z (rel. intensity, 70 eV) 245 (M+, 97) 244 (M+, bp), 189 (48), 188 (50) 70 (39).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](OS(C(F)(F)F)(=O)=O)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:20][C:21]1[N:22]=[C:23]([CH3:26])[S:24][CH:25]=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Oc1nccc2ccc(Cl)nc12)C(F)(F)F
Reactant: Cc1nc(N)cs1
Product: Cc1nc(Nc2nccc3ccc(Cl)nc23)cs1

Procedure:
The title compound, MS: m/e=277.0/279.1 (M+H+), was prepared in accordance with the general method of example 1 from trifluoro-methanesulfonic acid 2-chloro-[1,7]naphthyridin-8-yl ester (Example G) and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][CH:26]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 10 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazine (64 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (10% yield). LCMS: m/z=550.11 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53 (2H, m), 1.80 (7H, m), 2.25 (1H, m), 2.57 (4H, m), 2.98 (2H, m), 3.48 (2H, t, J=4.7 Hz), 3.65 (2H, m), 3.82 (1H, bs), 4.49 (2H, s), 4.59 (1H, m), 5.00 (1H, bs), 6.63 (1H, d, J=1.3 Hz), 7.21 (1H, dd, J=8.6, 2.5 Hz), 7.29 (1H, d, J=2.5 Hz), 37.38 (5H, m), 7.73 (1H, d, J=1.8 Hz).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Li+].C1COCC1.O>CO>[CH:25]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)[CH2:16][CH2:15]2)=[O:18])[CH2:24][CH2:23]1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C(C)C)CC3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)O)cc3)CC2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture 3.5 g (13.8 mmol) of cis-(4-Isopropyl-piperazin-1-yl)-(4-hydroxycyclohexyl)-methanone, 2.35 g (15.4 mmol) of methyl 4-hydroxybenzoate, 4.47 g (17.0 mmol) of triphenylphosphine in 12 ml of THF, a mixture of 3.88 g (16.9 mmol) of di-tert-butyl azodicarboxylate in 13 ml of THF was added dropwise at 0° C., and stirred for 24 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and methanol=from 98:2 to 9:1. After evaporation of the combined products, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and MeOH=from 100:0 to 19:1. The combined product fractions were evaporated to dryness to yield 1.34 g (25%) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester. A mixture of 0.6 g (1.5 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester, 42 mg (1.8 mmol) of lithium hydroxide, 6 ml of THF, 3 ml of water, and 1 ml of methanol was stirred at 80° C. for 16 h. After evaporation, the residue was acidified with 2N hydrochloric acid solution and evaporated. The precipitate was washed with water and dried to yield 0.56 g (97%) of the titled compound. MS (m/e): 375 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([CH3:9])[CH3:8])[NH:4][N:3]=1.[C:10]1([CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[CH:7]([C:5]1[N:6]=[C:2]2[N:1]=[C:17]([OH:18])[C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:22]([OH:23])[N:3]2[N:4]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)c1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 0.5 h

Procedure:
A solution of 5.00 g 3-amino-5-isopropyl-1,2,4-triazol and 11.24 g diethyl phenylmalonate in 18 mL N,N-dibutylbutan-1-amine was stirred at 185° C. over night. The solution was diluted with 20% w/w NaOH solution, the resulting mixture was stirred for 30 min. The aqueous layer was washed with diethylether, acidified at 0° C. with concentrated HCl until precipitation of the product was complete. The precipitate was collected by filtration to yield the product, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([C@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=[O:9])[C:4](=[O:15])[O:3]1.[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28]>C(Cl)Cl>[F:17][C:18]1[C:23]([O:9][C:8](=[O:10])[C@H:7]([C@@H:5]2[C:4](=[O:15])[O:3][C:2]([CH3:1])([CH3:16])[O:6]2)[CH2:11][CH:12]([CH3:13])[CH3:14])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28]
Reactant: CC(C)C[C@H](C(=O)O)[C@H]1OC(C)(C)OC1=O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Product: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@H]1OC(C)(C)OC1=O
Yield: 73.4 %

Procedure:
A solution of 2-(S)-(2,2-dimethyl-5-oxo-1.3-dioxolan-4-(R)-yl)-4-methylpentanoic acid (1.1 g, 4.78 mmole), pentafluorophenol (970 mg, 5.27 mmole), and 1-dimethylaminopropyl-3-ethyl carbodiimide methiodide (1.42 g, 4.78 mmole) in CH2Cl2 (25 ml) was stirred at 23° for 24 h. The reaction was washed with H2O, 5% aqueous K2CO3, H2O, dried (K2CO3), and the solvent evaporated, to yield the title compound (1.39 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][OH:25]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:25][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of 2-chloro-1-fluoro-4-nitro-benzene (8.75 g, 50 mmol) in dry Acetone (100 ml) was added 10.0 g of K2CO3 and 5.45 g of 2-pyridylmethanol (50 mmol). The reaction mixture was then stirred at 65° C. overnight. Filtration and concentration gave a solid which was recrystallized to give the desired product as a white solid (10.2 g).