Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:17]=[C:18](C=C[CH:22]=1)N.NC1C=[CH:42][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])[N:32]=2)=[CH:28][CH:27]=1>ClCCl>[OH:41][CH2:40][CH2:39][CH2:38][NH:37][C:33]1[N:32]=[C:31]([O:30][C:29]2[CH:42]=[CH:11][C:12]([NH:8][C:1]([NH:3][C:7]3[CH:6]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=3)=[O:2])=[CH:27][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)cc1)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 12 h

Procedure:
180 mg (1.11 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 179 mg (1.01 mmol) 3-trifluoromethoxyaniline in 4.0 ml dichloromethane and stirred for 12 h. A solution of 263 mg (1.01 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6.0 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol 95:5). The obtained material was washed with dichloromethane, the precipitate was isolated by filtration and dried. Yield: 160 mg (34%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:27])[C:12]3[CH:19]=[C:18]([CH2:20][NH:21][CH2:22][CH:23]([OH:26])[CH2:24]Cl)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:30][C:31]1[S:35][C:34]([SH:36])=[N:33][N:32]=1.[CH:37](N(C(C)C)CC)(C)C.[Na+].[Cl-]>CCO>[NH2:30][C:31]1[S:35][C:34]([S:36][CH2:24][CH:23]([OH:26])[CH2:22][N:21]([CH2:20][C:18]2[O:17][C:13]3[N:14]([CH3:16])[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])[C:11](=[O:27])[C:12]=3[CH:19]=2)[CH3:37])=[N:33][N:32]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nnc(S)s1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CNCC(O)CCl)oc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)CSc1nnc(N)s1

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(((3-chloro-2-hydroxypropyl)amino)methyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 63, 0.181 g), 5-amino-1,3,4-thiadiazole-2-thiol (0.064 g), and diisopropylethylamine (0.097 mL) in absolute EtOH (16 mL) was heated to reflux overnight. The reaction was poured into 50% saturated aqueous NaCl (40 mL) and extracted with CHCl3. The organic layer was dried and concentrated. The crude product was purified by column chromatography (CHCl3MeOH/NH4OH, 93/7/0.5%) and triturated with Et2O/hexanes. The resulting solid was collected and dried overnight to yield 0.087 g of the title compound as a white solid. Physical characteristics. M.p. 200-204° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.64, 8.54, 7.39, 7.33, 7.23, 6.88, 5.11, 4.54, 3.92, 3.70, 3.29, 3.04, 2.4, 2.28; 3C NMR (DMSO-d6) δ 172.7, 169.2, 164.3, 153.2, 151.2, 141.8, 138.6, 131.3, 129.1, 128.3, 115.2, 113.8, 105.9, 67.2, 60.6, 53.4, 42.6, 41.3, 37.5. Anal. Found: C, 50.41; H, 4.74; N, 15.06.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O>>[C:1]([Cl:15])(=[O:12])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(c1)OCO2

Procedure:
In 6 ml of thionyl chloride was suspended 5.0 g of piperonylic acid. The suspension was refluxed for 8 hours. Excess volume of thionyl chloride was evaporated off under reduced pressure to give crude crystals of piperonylic acid chloride.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][C:12]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:25]#[N:26])[CH:20]=3)[N:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1.[NH:27]1[CH:31]=[N:30][C:29]([CH2:32][C:33](O)=[O:34])=[N:28]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:25]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:12]([NH:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:33](=[O:34])[CH2:32][C:29]3[N:30]=[CH:31][NH:27][N:28]=3)[CH:5]=1)=[O:13])[NH:23][C:22]2=[O:24])#[N:26]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(CN)c3)[nH]c(=O)c2c1
Reactant: O=C(O)Cc1nc[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(CNC(=O)Cc4nc[nH]n4)c3)[nH]c(=O)c2c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
A solution of N-{[3-(aminomethyl)phenyl]methyl}-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide hydrochloride obtained in Reference Example 47 (170 mg, 0.460 mmol), 1H-1,2,4-triazol-3-ylacetic acid obtained in Reference Example 15 (70.0 mg, 0.551 mmol), diisopropylethylamine (0.079 mL, 0.460 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (106 mg, 0.550 mmol) and 1-hydroxybenzotriazole (74.0 mg, 0.550 mmol) in DMF (10 mL) was stirred at 40° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The resulting solid was collected by filtration, washed with water and IPE, and dried. The obtained crude crystals were recrystallized from ethyl acetate-IPE to give the title compound as a white powder (49.4 mg, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: Oc1ccccc1Br
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1ccccc1Br)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromophenol (8.71 g; 50.3 mmol) and bromoacetophenone (10.1 g; 50.5 mmol) in 50 ml acetone was added K2CO3 (7.02 g; 50.8 mmol). The mixture was heated to reflux for 10 h, cooled to r.t., filtered, diluted with EtOAc (100 ml), washed with HCl (1.0 M, 2×100 ml) and brine, dried over MgSO4 and concentrated. The residual solid was recrystallized from EtOAc:hexane to afford the desired material.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17](/[CH:20]=[CH:21]/[CH2:22][CH2:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[NH2:32][OH:33].O>C1COCC1>[OH:33][NH:32][CH:21]([CH2:20][S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:30])([F:1])[F:31])=[CH:10][N:9]=2)[CH2:16][CH2:15]1)(=[O:19])=[O:18])[CH2:22][CH2:23][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NO
Reactant: O=S(=O)(/C=C/CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(CC(CCc1ncccn1)NO)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of 2-[(3E)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)but-3-en-1-yl]pyrimidine (10.9 g, 23.7 mmol) in THF (200 mL) was added 50% aqueous solution of hydroxylamine (11 mL) and the reaction stirred at room temperature for 2 hours. Water (100 mL) was then added and then this was extracted with EtOAc (3×100 mL) and dried (brine, MgSO4), filtered and concentrated in vacuo to give 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butyl]pyrimidine as a pale yellow solid (11.1 g, 22.6 mmol, 96%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]=1[C:10](Cl)=[O:11])[CH2:2][CH2:3][CH3:4].Br.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]=1[C:10]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)Cl
Reactant: Nc1ccc(-c2ccc(O)cc2)cc1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.9 %

Procedure:
2-Butyl-benzofuran-3-carbonyl chloride (2.22 g, 9.36 mmol), prepared in step 2 of Example 4, in 40 mL of anhydrous THF was added under nitrogen dropwise over 20 minutes to a mixture of the HBr salt of 4′-amino-biphenyl-4-ol (3.26 g, 12.3 mmol), prepared in the previous step, and triethylamine (3.42 mL, 24.5 mmol) in 100 mL of anhydrous THF at ice bath temperature. After the addition the reaction was stirred at room temperature for 20 h. The reaction was filtered and the filtrate concentrated under reduced pressure to give a solid. Purification of the solid on 1 Kg of silica gel (230-400 mesh) using 30% ethyl acetate-hexane as the eluent gave 2-butyl-N-(4′-hydroxy[1,1′-biphenyl]-4-yl)-1-benzofuran-3-carboxamide (2.27 g, 48%) as an off-white solid, mp 181-183° C.; MS (APCI) m/z 386 [M+H]+. Elemental Analysis for C25H23NO3: Calc'd: C, 77.90; H, 6.01; N, 3.63; Found: C, 77.48; H, 5.86; N, 3.56.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:13][C:14](=[O:16])[CH3:15].[Cl-].[NH+]1C=CC=CC=1>Cl.C(OCC)(=O)C>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:13][C:14](=[O:16])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(CC(C)=O)c1F
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 180 °C
Reaction time: 1.25 h
Yield: 96 %

Procedure:
A mixture of 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one from previous step (454 mg, 21 mmol) and pyridinium chloride (0.9 g, 7.8 mmol) was stirred at 180° C. for 75 min. The reaction was cooled to room temperature, diluted with 1N HCl (3 mL) and ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (2×), dried and concentrated in vacuo to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (410 mg, 96%) as a grey solid, which was used without further purification for the next step. LC/MS; (M+H)+=214. 1HNMR (CDCl3): δ 2.37 (s, 3H), 4.22 (s, 2H), 6.95 (dd, 1H), 7.95 (d, 1H, J=9.35 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.BrC[CH2:28][C:29]#[N:30]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([CH3:17])([CH2:15][CH2:28][C:29]#[N:30])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)c1ccc(Cl)nc1OC
Reactant: N#CCCBr
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CCC#N)c1ccc(Cl)nc1OC
Reaction time: 0.5 h
Yield: 894.4 %

Procedure:
To a solution of methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (100 g, 435 mmol) in THF (1.5 L) was added LiHMDS (609 mL, 609 mmol) dropwise over a period of 60 min at −60° C. while maintaining reaction temperature below −50° C. After the addition, the reaction mixture was stirred below −50° C. for 30 min. Then a solution of 3-bromopropanenitrile (92 g, 697 mmol) in THF (0.4 L) was added dropwise to above solution below −50° C. over a period of 90 min. The resulting mixture was stirred at r.t. for 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (500 mL) below 25° C. The 22 batches were combined for workup together. The mixture was diluted with H2O (15 L), and extracted with EtOAc (15 L). The combined organic layers were washed with water (15 L) and brine (15 L), dried over Na2SO4 and concentrated to dryness. The crude residue was purified by column chromatography (petroleum ether/EtOAc=100:0˜80:20) to give methyl 2-(6-chloro-2-methoxypyridin-3-yl)-4-cyano-2-methylbutanoate (1100 g, 41%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.56 (s, 3H), 2.16-2.33 (m, 3H), 2.35-2.47 (m, 1H), 3.65 (s, 3H), 3.93 (s, 3H), 6.96 (d, 1H), 7.44 (d, 1H).
Reaction SMILES: [NH:1]([C:3](=[O:15])[C:4]([N:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:5])[NH2:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1>CCO>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:2][NH:1][C:3](=[O:15])[C:4]([N:6]([CH3:14])[CH2:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[O:5])=[S:25])=[CH:19][CH:18]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CN(Cc1ccncc1)C(=O)C(=O)NN
Solvent: CCO
Product: CN(Cc1ccncc1)C(=O)C(=O)NNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-hydrazinyl-N-methyl-2-oxo-N-(pyridin-4-ylmethyl)acetamide (78) (0.96 g, 4.61 mmol) and 4-fluorophenyl isothiocyanate (0.71 g, 4.16 mmol) in EtOH was refluxed for 2 h. The reaction was cooled down to room temperature and concentrated in vacuo to afford 2-(2-((4-fluorophenyl)carbamothioyl)hydrazinyl)-N-methyl-2-oxo-N-(pyridin-4-ylmethyl)acetamide (79) as yellow crystals was obtained in a quantitative yield.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=1)C.[ClH:18]>>[ClH:18].[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(NC(C)=O)cc1
Agent: Cl
Product: Nc1ccc(OCC(=O)O)cc1
Temperature: 10 °C
Yield: 77.6 %

Procedure:
(4-Acetylamino-phenoxy)-acetic acid ethyl ester 1 (375 grams, 1.582 mmol), in concentrated Hydrochloric acid (9.36 liters) was refluxed for 12 Hours. Excess concentrated Hydrochloric acid was distilled off in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried to give pure 2(250 g, 77.6%) as a wheat colored powder.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:14])=[C:10]([CH3:12])[N:11]=2)[C:3]1=[O:24].C(=O)([O-])[O-].[K+].[K+].[CH:31]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32]1>O1CCCC1.O>[CH:31]1([CH2:34][CH2:35][NH:36][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[S:8][C:9]([C:13]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[O:14])=[C:10]([CH3:12])[N:11]=3)[C:3]2=[O:24])[CH2:33][CH2:32]1
Reactant: Cc1nc(N2CCC(Br)C2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: NCCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N2CCC(NCCC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60 %

Procedure:
To a solution of 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (0.050 g, 0.12 mmol) in a mixture of tetrahydrofuran and water (1/0.1, v/v) was added potassium carbonate (0.034 g, 0.24 mmol) and 2-cyclopropylethanamine (0.012 g, 0.15 mmol). The reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes (3/1)) to afford the title compound as a white solid (0.030 g, 60%): mp 151-152° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.05-6.96 (m, 2H), 6.01 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.27-4.17 (m, 1H), 3.93-3.81 (m, 1H), 3.76-3.66 (m, 1H), 2.88-2.67 (m, 2H), 2.61 (s, 3H), 2.58-2.44 (m, 1H), 2.10-1.91 (m, 1H), 1.52-1.29 (m, 2H), 0.75-0.59 (m, 1H), 0.49-0.37 (m, 2H), 0.08-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.6, 162.3, 162.2, 155.2, 152.9, 133.7, 129.6, 118.6, 115.6, 59.5, 47.9, 44.9, 43.4, 35.0, 26.9, 17.3, 8.8, 4.4, 4.2; MS (ES+) m/z 417.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([Br:12])[CH:6]=2.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH2:31]([O:30][C:28]([NH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([Br:12])[CH:6]=2)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1nc2cc(Br)ncc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1nc2cc(Br)ncc2cc1NC(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 59.6 %

Procedure:
To a solution of ethyl 3-amino-7-bromo-1,6-naphthyridine-2-carboxylate (47 mg, 0.16 mmol) and DIPEA (83 μL, 0.48 mmol) in DCM (1.5 mL), a solution of benzyl chloroformate (68 μL, 0.48 mmol) was added and the resulting mixture was heated at 60° C. in a sealed vial for 14 h. The crude reaction mixture was then concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-60% EtOAc/hexanes) to afford the sub-title compound (41 mg, 60%). LCMS (ESI) calc. for C19H17BrN3O4[M+H]+: m/z=430.0. found: 429.9.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)=[CH:13][CH:12]=1
Reactant: OCCN1CCNCC1
Reactant: Fc1ccc(CCl)cc1
Product: OCCN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
The title compound was synthesized by using 2-(1-piperazinyl)ethanol and p-fluorobenzyl chloride according to the same process as in Preparation Example 4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[CH3:14][O:13][C:3]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:12])[CH:9]=2)[N:4]=1
Reactant: COc1nc2ccc(C)cc2nc1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
3-Amino-2-methoxy-6-methylquinoxaline (568 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with n-hexane:ethyl acetate (3:1) mixture and concentration gave 768 mg of the titled compound (yield, 98%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([NH:34][CH2:33][CH2:31][OH:32])[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: NCCO
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)NCCO

Procedure:
N-Cyclopropyl-N-{1-[3-(2-hydroxyethylamino)hexanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (40) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.56 mmol) and ethanolamine (2 mL) as described in Example 26 above. The reaction mixture was cooled and partitioned between ether (100 mL) and 1M sodium hydroxide solution (100 mL). The organic phase was separated, dried (MgSO4) and the solvent evaporated to dryness in vacuo to leave a colourless gum. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the free base 40 (100 mg). This was converted to the fumarate salt (95 mg, 27%) which was a white solid. LC: 100%. MS: m/z=506.2, 507.3, 508.2 (M+H). 1H NMR (400 MHz, DMSO-d6): (1:1 mixture of rotamers) δ 8.22 (1H, d, J=7.5 Hz), 8.13 (2H, m), 7.92 (1H, t, J=7.5 Hz), 6.47 (1H, s), 4.43 (1H, d, J=13.3 Hz), 4.10 (1H, t, J=13.3 Hz), 3.88 (1H, d, J=13.3 Hz), 3.55 (2H, m), 3.25 (1H, m), 3.05 (1H, t, J=13.3 Hz), 2.85 (2H, m), 2.70-2.50 (3H, m), 1.96 (1H, m), 1.80-1.20 (8H, m), 0.88-0.65 (7H, m).
Reaction SMILES: CN(C1CCCCC1)[CH:3]1CCCC[CH2:4]1.Br[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]([CH2:28][C:29]([C:31]([F:34])([F:33])[F:32])=[O:30])=[O:27])=[CH:18][CH:17]=1.C=C.Cl>O.CCOCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH:3]([C:19]1([C:26]([CH2:28][C:29]([C:31]([F:34])([F:33])[F:32])=[O:30])=[O:27])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH2:18]1)=[CH2:4]
Reactant: CN(C1CCCCC1)C1CCCCC1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)c2ccccc12
Agent: C=C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: C=CC1(C(=O)CC(=O)C(F)(F)F)CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.9 %

Procedure:
1,4-Dioxane (40 mL), tri-t-butylphosphine (0.182 g, 0.9 mmol), and methyldicyclohexylamine (19.5 g, 100 mmol) were placed into a Schlenk flask and transferred by syringe to a PPI LC series 300 mL reactor containing dipalladium tris(dibenzylidenelacetone) (0.420 g, 0.45 mmol) and 4-bromonapthoyltrifluoroacetone (10.4 g, 30 mmol) under an argon atmosphere. The reactor was charged to 300 psi with ethylene and the reaction was allowed to stir for 48 hours at room temperature. Upon completion of the reaction the contents taken up in water (50 mL) and ether (50 mL), the aqueous phase acidified by addition of concentrated hydrochloric acid, and extracted with ether (2×50 mL). The combined organic phase was rinsed with saturated sodium chloride solution, and the organic phase was dried over magnesium sulfate overnight. The solution was filtered, the solvent was removed by vacuum, and the residue dissolved in chloroform (3 mL). The product was isolated by column chromatography from silica gel (Selecto, mesh size 63-200) with 10% ether in chloroform as eluent. The solvent was removed to give a light brown oil (9.08 g, 99% yield). 1H-NMR (90 MHz, 25° C., CDCl3): δ 14.49 (s, 1H), 8.48 (m, 1H), 8.06 (m, 1H), 7.58 (m, 4H), 7.45 (dd, 1H), 6.45 (s, 1H), 5.91 (dd, 1H), 5.62 (dd, 1H). Anal.: (found/calc for C17H14O2) 65.75 (81.58), H 3.79 (5.59).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)([O:7][CH3:8])[CH2:5][CH3:6].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>>[CH3:1][O:2][CH2:3][C:4]([O:7][CH3:8])([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:14]=1)[CH2:5][CH3:6]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCC(COC)(OC)c1cncc(O)c1
Product: CCC(COC)(OC)c1cncc(OCc2ccc3ccccc3c2)c1
Yield: 37.2 %

Procedure:
Using the procedure described in Example 12, 2-(5-hydroxypyrid-3-yl)-2-methoxybut-1-yl methyl ether (0.21 g) was reacted with 2-bromomethylnaphthalene (0.25 g) to give 2-methoxy-2-[5-(naphth-2-ylmethoxy)pyrid-3-yl]but-1-yl methyl ether (0.13 g, 37%), as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:11][C:4]1[CH:5]=[N:6][C:7]([CH:8]2[CH2:9][CH2:10]2)=[C:2]([Cl:1])[CH:3]=1)[C:16]#[N:17]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2cnc(C3CC3)c(Cl)c2)c(Br)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
5-chloro-6-cyclopropylpyridin-3-ol (250 mg, 1.47 mmol), 3-bromo-4-fluorobenzonitrile (Preparation 37, 295 mg, 1.47 mmol) and potassium carbonate (611 mg, 4.42 mmol) were suspended in dimethylsulfoxide (6 mL). The reaction mixture was stirred at 5 hours at 50° C. then water (60 mL) was added and the suspension was extracted by ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a clear oil which solidified on standing (485 mg, 94%).