Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CC(N)CN1Cc1ccccc1
Reaction time: 6 h
Yield: 85.4 %

Procedure:
To a solution of 4-azido-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester (6 g, 23 mmol) in THF (100 ml) under N2 was added triphenylphosphine (12.08 g, 46 mmol) and water (1.036 mL, 57.56 mmol). The mixture was refluxed with stirring for 6 h. After removal of THF, the residue was dissolved in Et2O, treated with 0.15N aqueous HCl, stirred for 5 min, and extracted with Et2O (2×150 ml). The aqueous solution was then treated with 10% NaHCO3 until PH>10, and extracted by DCM (2×100 ml). The combined organic phases were dried over anhydrous NaSO4, concentrated to afford product 4-amino-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester 4.6 g (85%) as colorless oil. MS m/e=235.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step A) by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.34 (s,6H), 1.41 (s,9H), 1.90 (m,1H), 2.45 (d,15 Hz, 1H), 2.56 (d,15 Hz, 1H), 2.65 (m,1H), 2.76 (m,1H), 2.92 (m,1H), 4.53 (m,1H), 5.20 (br s,1H), 6.62 (d,15 Hz, 1H), 6.97 (d,8 Hz, 1H), 7.10-7.25 (m,3H), 7.35 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,45%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:28](=[O:41])[CH:29]=[C:30]([CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[O:31][CH:32]=1>CN(C=O)C.O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[C:28](=[O:41])[CH:29]=[C:30]([CH2:33][O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[O:31][CH:32]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Trifluoromethyl-4quinoline-thiol (320 mg, 1.4 mmol) was charged in a 50 mL round-bottomed flask equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (10 mL) and NaH 60% dispersion in oil (55 mg, 1.4 mmol) were successively added at 4° C. After 30 min a solution of 5-(7-bromo-heptyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 4 (520 mg, 1.3 mmol) in DMF (6 mL) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured in 150 mL of H2O, extracted with EtOAc (3×80 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=95:5 to 98:2) to give 5-(7-(7-(trifluoromethyl)quinolin-4-ylthio)heptyloxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one EHT 8883 (310 mg, 43% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(OCC)(=O)C>[NH2:8][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)ccn1
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-aminopyridine (Matrix Scientific, cat. #23809; 1.29 g, 0.01 mol) is dissolved by stirring in 500 ml of ethyl acetate. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.01 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with CH2Cl2. Concentration of the appropriate fractions on a rotovap gives a light tan solid. The solid is dissolved in EtOAc and decolorized with activated carbon. EtoAc is removed using a rotovap and the resulting solid is suspended in ice-cold CH2Cl2 and filtered to give the product as a white solid. (MP 142-143° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.Br[CH:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:6]=1)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: CCCCCCCC(=O)c1ccc(O)cc1
Product: CCCCCCCC(=O)c1ccc(OC(CCCCCC)C(=O)OCC)cc1
Yield: 77.5 %

Procedure:
1-[4-Hydroxyphenyl]-1-octanone (440 mg, 2.0 mmol) and ethyl (RS)-2-bromooctanoate (552 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Octanoylphenoxy]octanoate (605 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 4.66 (dd, J=5.1, 7.4 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 1.88-2.02 (m, 2H), 1.70 (tt, J=7.2, 7.2 Hz, 2H), 1.41-1.56 (m, 2H), 1.25-1.37 (m, 14H), 1.23 (t, J=7.1 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.41, 171.48, 161.81, 131.01, 130.54 (2C), 114.77 (2C), 76.75, 61.62, 38.56, 32.90, 31.94, 31.78, 29.60, 29.38, 29.07, 25.33, 24.80, 22.85, 22.75, 14.39, 14.31, 14.26. The resulting ester (605 mg, 1.6 mmol) was saponified with lithium hydroxide (186 mg, 7.8 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Octanoylphenoxy]octanoic Acid (487 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 9.70 (br s, 1H), 7.89 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.69 (dd, J=5.9, 6.6 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 1.95-2.01 (m, 2H), 1.67 (tt, J=7.2, 7.2 Hz, 2H), 1.43-1.58 (m, 2H), 1.24-1.37 (m, 14H), 0.851 (t, J=6.8 Hz, 3H), 0.849 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 200.38, 176.08, 161.84, 130.85, 130.78 (2C), 114.83 (2C), 76.20, 38.56, 32.79, 31.93, 31.76, 29.57, 29.35, 29.05, 25.34, 24.92, 22.84, 22.74, 14.29, 14.23. The acid (500 mg, 1.4 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Octanoylphenoxy]octanoate (404 mg, 76%) as a white solid. mp 165-170° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.58 (dd, J=6.1, 6.3 Hz, 1H), 2.91 (t, J=7.3 Hz, 2H), 1.91-1.96 (m, 2H), 1.62-1.69 (m, 2H), 1.44-1.58 (m, 2H), 1.25-1.39 (m, 14H), 0.87-0.90 (m, 6H); 13C NMR (101 MHz, CD3OD): S 200.50, 176.40, 162.96, 130.28 (2C), 129.94, 114.71 (2C), 78.38, 38.00, 32.98, 31.79, 31.74, 29.27, 29.20, 29.05, 25.50, 24.79, 22.56, 22.51, 13.36, 13.34; LRMS (ESI): m/z 769 (M2H+), 748 (2M-Na++2H+), 363 (M-Na++2W); HPLC: 3 min.
Reaction SMILES: C[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].[CH2:12]([OH:15])[CH2:13]O.B(F)(F)F.[C:20](=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[O:15]1[CH2:12][CH2:13][O:3][CH:2]1[C:4]1([CH3:20])[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][CH2:9]1
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: O=C([O-])O
Reactant: OCCO
Agent: FB(F)F
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C2OCCO2)C=CC(C#N)=CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Cyanoacetophenone (5.0 g, 34.4 mmol) was dissolved in toluene (50 mL), had ethylene glycol (3.4 g, 55.1 mmol) and BF3 etherate (0.5 mL) added to it dropwise, was heated on a water separator for 12 h under reflux, allowed to cool to room temperature (yellow reaction solution), had a 5-percent sodium hydrogencarbonate solution (40 mL) added, was extracted with diethyl ether, washed with saturated sodium chloride solution (30 mL), dried over MgSO4, filtered, evaporated under vacuum, and recrystallized from diethyl ether/n-pentane (1:1), Yield: 2.2 g (34%) colorless solid, m.p. 70° C. 1H-NMR (200 MHz, CDCl3, 25° C.): δ=1.62 (s, 3 H, CH3), 3.72-3.75 (m, 2 H, CH2), 4.02-4.08 (m, 2 H, CH2), 7.57-7.64 ppm (m, 4 H, Haryl). HRMS (C11H12NO2): calc. m/z: 190.086, obs. m/z: 190.087, Δ=1 mmu.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#N)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1.Cl.[OH-:24].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:11]([C:12]([C:17]2[CH:18]=[CH:19][C:14]([CH3:22])=[CH:15][CH:16]=2)=[O:24])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: [OH-]
Reactant: N#Cc1cc2c(nc1N)CCCC2
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cc3c(nc2N)CCCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 2-amino-5,6,7,8-tetrahydroquinoline-3-carbonitrile (1.2 g; 6.93 mmol) in dry tetrahydrofurane (70 mL) under nitrogen atmosphere was slowly added a solution of p-tolylmagnesium bromide (1M in THF) (35 mL; 35 mmol). The resulting solution was stirred at room temperature for 3 h and heated at 50° C. for 3 h. A solution of hydrochloric acid 3N (140 mL) was added to hydrolyse the intermediate imine and the reaction mixture was heated to reflux for 3 h. After cooling at 0° C., the reaction mixture was basified with a solution of sodium hydroxide 6N. The product was extracted with dichloromethane (200 mL) and the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (10-100%) in dichloromethane as eluent furnished 1.51 g (82%) of (2-amino-5,6,7,8-tetrahydroquinolin-3-yl)(p-tolyl)methanone as a bright yellow solid. ESI/APCI(+): 267 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:6])[NH2:5].C([CH:14](Br)[C:15](=O)[C:16]([O-:18])=[O:17])C.[CH2:21](O)[CH3:22]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]1[S:6][CH:14]=[C:15]([C:16]([O:18][CH2:21][CH3:22])=[O:17])[N:5]=1
Reactant: NC(=S)c1c(F)cccc1F
Reactant: CCC(Br)C(=O)C(=O)[O-]
Reactant: CCO
Product: CCOC(=O)c1csc(-c2c(F)cccc2F)n1
Yield: 84 %

Procedure:
A solution of 2,6-difluorobenzothioamide (1.0 eq) and ethylbromopyruvate (1.0 eq.) in ethanol (1.0 M) was heated in the microwave at 130° C. for 30 minutes. Upon removal of volatiles in vacuo, ethyl acetate was added and the solution was washed with Na2CO3(sat.), with NaCl(sat.), was dried over MgSO4, filtered and concentrated yielding ethyl 2-(2,6-difluorophenyl)thiazole-4-carboxylate (84%). LCMS (m/z): 270.1 (MH+); LC Rt=3.79 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1>>[N:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:25]=[N:24][CH:23]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 42.1) and pyrimidin-5-ylboronic acid to afford an off-white solid. UPLC-MS (Condition 1) tR=2.09 min, m/z=361.0 [M+H]+, m/z=359.0 [M−H]−; 1H-NMR: (400 MHz, DMSO-d6) δ ppm: 7.41 (d, J=8.56 Hz, 1H) 7.90 (d, 1H) 8.72 (t, J=2.20 Hz, 1H) 9.16 (dd, 1H) 9.23 (dd, 1H) 9.29 (s, 1H) 9.32 (s, 2H) 10.67 (s, 1H).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[F:33].C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(F)c(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and 3-chloro-4-fluorophenylisocyanate (0.31 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(3-chloro-4-fluoro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.47 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.40 min (98.65%); mp: 224-226° C.; 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H), 2.29-2.47 (m, 1H), 2.55-2.66 (m, 1H), 2.81-3.01 (m, 1H), 4.31 (m, J=17.2 Hz, 1H), 4.37-4.53 (m, 3H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 6.86 (t, J=5.9 Hz, 1H), 7.18-7.33 (m, 2H), 7.44 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.78 (dd, J=6.8, J=1.7 Hz, 1H), 8.88 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.1, 42.7, 47.0, 51.5, 116.6 (d, J=22.0 Hz), 117.8 (d, J=6.6 Hz), 119.0 (d, J=11.0 Hz), 121.9, 122.9, 126.9, 130.3, 137.7 (d, J=3.3 Hz), 142.3, 144.6, 150.2, 153.4, 155.0, 167.9, 170.9, 172.8; LCMS: MH=445/447; Anal Calcd for C21H18ClFN4O4: C, 56.70; H, 4.08; N, 12.59. Found: C, 56.54; H, 3.93; N, 12.23.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:18][N:17]=2)=[CH:10][CH:9]=1)(=O)=O.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:34][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:9][CH:10]=3)=[N:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(CCNC4CCCC4)cc3)nc2)cc1

Procedure:
The product was prepared analogously to Example 1.1g from 60 mg (0.15 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}ethyl methanesulfonate and 0.03 mL (0.30 mmol) of cyclopentylamine (6 hours at 50° C., potassium carbonate as base). Yield: 20 mg (34% of theoretical); C26H25ClN2 (M=400.943); calc.: molpeak (M+H)+:401/403 (Cl); found: molpeak (M+H)+:401/403 (Cl); HPLC-MS: 5.0 minutes (method H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])CCC=[CH:3][CH2:2]1.C[N+]1([O-])CC[O:18]CC1.OS([O-])=O.[Na+].[CH3:27][C:28]([CH3:30])=[O:29]>C(O)(C)C.O=[Os](=O)(=O)=O>[OH:29][CH:28]1[CH:30]([OH:18])[CH2:3][CH2:2][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(O)C(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a mixture of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate (2.40 g, 13.10 mmol, 1 eq) and NMO (2.65 g, 19.60 mmol, 1.5 eq) in acetone (60 mL) was added a solution of OsO4 (20 mg) in isopropanol (5 mL). The mixture was stirred overnight at room temperature. To this, 10 mL of saturated NaHSO3 aqueous solution was added dropwise, the reaction mixture was stirred for 0.5 h at room temperature and concentrated in vacuo. The pH was adjusted to 5-6 by adding dilute hydrochloric acid. The organic phase was extracted with CH2Cl2 (50 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as colorless oil (2.60 g, 92.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 218.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[C:15](=[O:17])=[O:16]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1cc(Cl)cc(Cl)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dichloro-5-methylbenzene (2.0 g, 12.4 mmol) in THF (20 mL) was added n-BuLi (2.0 M in hexane, 9.3 mL, 18.6 mmol) at −78° C. dropwise over a period of 10 min and mixture was stirred at −78° C. for 30 min. A dry-ice was added to the reaction mixture slowly and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was slowly warmed to room temperature, quenched with 6 M HCl (10 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get compound A111-1 (1.1 g, 44%) as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)C)=[CH:7][CH:6]=1)[C:2]#[CH:3].Br[CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[NH:20][C:19]2=[O:33].CC(C)(C)C(OC[N:40]1C(=O)C2C(=CC=C(CBr)C=2)N=C1)=O>>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([NH:26][C:21]1[NH:20][C:19](=[O:33])[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([CH2:15][N:4]([CH2:1][C:2]#[CH:3])[C:5]3[CH:6]=[CH:7][C:8]([C:11]#[N:40])=[CH:9][CH:10]=3)[CH:17]=2)[N:22]=1)=[O:32]
Reactant: CC(C)(C)C(=O)OCn1cnc2ccc(CBr)cc2c1=O
Reactant: C#CCNc1ccc(C(C)=O)cc1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc(CBr)cc2c(=O)[nH]1
Product: C#CCN(Cc1ccc2nc(NC(=O)C(C)(C)C)[nH]c(=O)c2c1)c1ccc(C#N)cc1

Procedure:
In a process analogous to Example 1 by substituting 4-(2-propynylamino)benzonitrile (see Example F) for 1-[4-(2-propynylamino)phenyl]ethanone and N-[6-(bromomethyl)-3,4-dihydro-4-oxo-2-quinazolinyl]-2,2-dimethylpropanamide (Journal of Heterocyclic Chemistry, Vol. 12, pp. 1283-1286 (1975)) for 2,2-dimethylpropanoic acid, [6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl]methyl ester (European patent application No. 204,529) one obtains 4-[[[2-[(2,2-dimethyl-1-oxopropyl)amino]-3,4-dihydro-4-oxo-6-quinazolinyl]methyl]-2-propynylamino]benzonitrile; mp 183°-186° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22]>C(Cl)(Cl)Cl>[CH2:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CCCN1CCNCC1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Solvent: ClC(Cl)Cl
Product: CCCN1CCN(c2ncc3c(=O)c(C(=O)OCC)cn(CC)c3n2)CC1
Yield: 84.6 %

Procedure:
As described in Example XII, the condensation of 2.8 g of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydropyrido(2,3-d)pyrimidine with 2.2 g of 1-propyl-piperazine, in chloroform (40 cm3) gives, after the treatments described in Example XII, 3.14 g of 2-(4'-propylpiperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine (yield 84%); melting point 149° C., after recrystallisation from ethyl acetate.
Reaction SMILES: [N+](C1C=CC(C([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=O)=CC=1)([O-])=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:24](Cl)=[O:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:24]([N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])=[O:25]
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Product: O=C1CCCCCN1C(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 3,5-dichlorobenzoylchloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[S:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][N:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:15]1[CH2:16][CH2:17][CH:12]([N:2]([CH3:1])[C:3]2[S:4][C:5]([C:8]([F:11])([F:9])[F:10])=[N:6][N:7]=2)[CH2:13][CH2:14]1
Reactant: CN(c1nnc(C(F)(F)F)s1)C1CCNCC1
Reactant: Fc1cccc(CBr)c1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nnc(C(F)(F)F)s1)C1CCN(Cc2cccc(F)c2)CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
A mixture of methyl-piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D2) (0.050 g, 0.19 mmol), 3-fluorobenzyl bromide (0.030 ml, 0.24 mmol) and diisopropylethylamine (0.050 ml, 0.28 mmol) in acetonitrile (3 ml) was stirred at 100° C. for 5 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-1.5% ammonia in methanol (7M)/dichloromethane) to yield E2 (0.062 g, 88%) as a solid. C16H18F4N4S requires 374. Found 375 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](=[O:15])[CH3:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl.CC(O)=O>[Br:17][CH2:14][C:13]([C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[N:9][O:10][C:11]=1[CH3:16])=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccc(Br)cc2)noc1C
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1onc(-c2ccc(Br)cc2)c1C(=O)CBr
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To a solution of 1-[3-(4-bromo-phenyl)-5-methyl-isoxazol-4-yl]-ethanone (2.49 g, 8.89 mmol) in carbontetrachloride (5.8 mL) and AcOH (0.3 mL) at 48° C. was added a solution of bromine (0.48 mL, 8.89 mmol) in carbontetrachloride (4.7 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (20 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=8:2) afforded the title compound (1.49 g, 47%) as a light yellow oil. MS m/e: 355.9/358.1/360.0 [M+H]+.