Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [186132-96-7] (500 mg, 2.162 mmol; Chem-Impex International, Inc.) in MeOH (9.0 mL), cooled to 0° C., was added with stirring a solution of Cs2CO3 (704 mg, 2.162 mmol) in water (6.0 mL). The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0° C., followed by addition of benzylbromide (0.514 mL, 4.32 mmol) and stirring overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHCO3 (2×) and water (2×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:3) to give the title compound as an oil. MS (LC/MS): 322 [M+H]+, 665 [2M+Na]+; tR (HPLC conditions b): 4.12 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH2:13][CH2:14][O:9][CH2:10][CH:11]=2)=[N:6][CH:7]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Brc1cnc(I)nc1
Solvent: O
Solvent: C1COCCO1
Product: Brc1cnc(C2=CCOCC2)nc1
Temperature: 80 °C

Procedure:
5-bromo-2-iodo-pyrimidine (250 mg; 0.88 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 0.92 mmol) were dissolved in 1,4-dioxane-H2O (10:1; 10 mL) and degassed with a stream of N2 for 10 min. Pd(Ph3)2Cl2 (30 mg, 0.04 mmol) was introduced and the reaction sealed and heated in a microwave reactor for 30 min at 80° C. The reaction was concentrated in vacuo, re-dissolved in DCM, filtered and purified over silica (gradient elution, 0-50% EtOAc-n-heptane) yielding i (105 mg, 50%). MS: 241.1 & 243.0; 1:1 [M+H]+.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[C:2]1([C:1]2[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:19][N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: c1ccc(C2=NNC(c3ccccc3)C2)cc1

Procedure:
There are reacted 12.5 parts of benzalacetophenone and 3.1 parts (by volume) of hydrazine hydrate in methanol to form 3,5-diphenyl-2-pyrazoline. To the latter is added then 5% palladium on carbon catalyst (2 parts) and the reaction mixture is heated at reflux for 1 hour and 20 minutes. The product, 3,5-diphenylpyrazole, is obtained in 97.8% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][C:20](C)(C)C)=[O:18])[N:12]1[C:24](=[O:29])[CH:25]([Br:28])[CH2:26][Br:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]1[C:24](=[O:29])[CH:25]([Br:28])[CH2:26][Br:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)C(Br)CBr
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)C(Br)CBr
Yield: 96.6 %

Procedure:
1.0 g of tert.butyl 1-benzyloxycarbonyl-2-(2,3-dibromopropionyl)-hexahydro-3-pyridazinecarboxylate (2-racemates) was stirred for 1 hour at room temperature with 15 ml of trifluoroacetic acid and the mixture was then evaporated. The resulting oil was dissolved in 10 ml of ethanol and esterified using a solution of diazomethane in diethyl ether to give 0.89 g (95%) of methyl 1-benzyloxycarbonyl-2-(2,3-dibromopropionyl)-hexahydro-3-pyridazinecarboxylate (2 racemates) in the form of a white solid of melting point 132°-134° C. (from ethanol/diethyl ether).
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])=[N:5]1)[CH3:3].[CH3:33][O:34][C:35]1[C:36]([O:58][CH3:59])=[CH:37][C:38]2[C@H:39]3[CH2:57][S:56][CH2:55][CH2:54][C@H:40]3[N:41]=[C:42]([C:45]3[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=3)[C:43]=2[CH:44]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:33][O:34][C:35]1[C:36]([O:58][CH3:59])=[CH:37][C:38]2[C@H:39]3[CH2:57][S:56][CH2:55][CH2:54][C@H:40]3[N:41]=[C:42]([C:45]3[CH:46]=[CH:47][C:48]([C:49]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:50])=[CH:52][CH:53]=3)[C:43]=2[CH:44]=1
Reactant: COc1cc2c(cc1OC)[C@H]1CSCC[C@H]1N=C2c1ccc(C(=O)O)cc1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)c4ccc(C5=N[C@@H]6CCSC[C@@H]6c6cc(OC)c(OC)cc65)cc4)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg, compound B39), 4-[(4aR,10bR)-8,9-dimethoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (220 mg; compound C16) and HBTU (167 mg) in DCM (4.0 ml) is added DIPEA (0.28 ml). The reaction mixture is stirred at RT for 1 h. Saturated aqueous sodium bicarbonate solution (2 ml) is added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc] and subsequently by preparative HPLC and preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluent: EtOAc/MeOH/triethylamine, 91/5/4 (v/v/v)] to yield the title compound as a solid.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([C@@:13]1([C:27]([NH2:29])=[O:28])[CH2:17][C@H:16](OS(C)(=O)=O)[CH2:15][N:14]1[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[N:30]#[N:31].[CH2:3]([O:10][C:11]([C@@:13]1([C:27]([NH2:29])=[O:28])[CH2:17][C@@H:16]([N:30]=[N+:31]=[N-:32])[CH2:15][N:14]1[C:23]([CH3:24])([CH3:26])[CH3:25])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)N1C[C@@H](OS(C)(=O)=O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)N1C[C@H](N=[N+]=[N-])C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Temperature: 75 °C
Yield: 78.8 %

Procedure:
0.5 g Of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-(methanesulphonyloxy)-L-prolinamide was dissolved in 10 ml of dry dimethylformamide and treated with 0.330 g of sodium azide. The heterogeneous mixture was stirred and heated at 75° C. for 18 hours. The mixture was evaporated under an oil pump vacuum to give a solid which was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was removed by evaporation to give 0.345 g of N2 -(benzyloxycarbonyl)-4(R)-azido-N1 -tert.butyl-L-prolinamide in the form of a gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[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](=[C:22]([NH2:30])[C:23]([NH2:29])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C:39](C)(C)C([O-])([O-])[O-].II>CC#N>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[N:29]=[C:38]([CH3:39])[NH:30][C:22]=5[C:21]=4[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c(N)ccc4c3=O)cc2)CCC1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Agent: II
Solvent: CC#N
Product: Cc1nc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.9 %

Procedure:
To a solution of {1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (80 mg, 0.16 mmol) in CH3CN (8 mL) was added trimethylorthoacetate (25 μL, 0.20 mmol) and iodine (4 mg, 0.016 mmol) and the reaction mixture was stirred at RT for 2.5 hours. Further trimethylorthoacetate (50 μL, 0.40 mmol) and iodine (24 mg, 0.096 mmol) were added and the reaction stirred for 1 hour. The reaction was quenched with aqueous Na2S2O3, diluted with ethyl acetate and the phases separated. The organic extracts were washed with brine, dried (NaSO4), filtered and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, ethyl acetate) to give the title compound as a brown solid (35 mg, 42%). LCMS (Method G): RT=3.18 min, [M+H]+=522.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[CH2:31]([N:37]=[C:38]=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:38]([NH:37][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CCCCCCN=C=O
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCNC(=O)NCc1ccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (12 mL) at 510° C., was added hexyl isocyanate (0.25 g, 1.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-urea as an off-white solid (410 mg, 65% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.05 min (99.0%); mp, 220-222° C.; 1HNMR (DMSO-d6) 0.85 (t, J=6 Hz, 3H, CH3CH2CH2), 1.24-1.38 (m, 8H, CH2CH2CH2CH2), 2.15-2.20 (m, 1H, CHH), 2.56-3.03 (m, 6H, CHCH2, CH3), 4.30 (d, J=6 Hz, 2H, ArCH2NH), 5.26 (dd, J=6, 11 Hz, 1H, Ch), 5.97 (t, J=5 Hz, 1H, CH2NH), 6.40 (t, J=6 Hz, 1H, ArCH2NH), 7.55-7.89 (m, 3H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.88, 20.93, 22.05, 23.38, 26.03, 29.94, 30.63, 31.02, 39.35, 42.44, 56.51, 119.96, 123.46, 126.40, 133.81, 139.87, 145.64, 154.36, 157.99, 160.46, 169.47, 172.60. LCMS MH=428; Anal Calcd For C22H29N5O4: C, 61.81; H, 6.84; N, 16.38. Found: C, 61.50; H, 6.82; N, 16.23.
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C.C(OCC)(=O)C.[OH-].[Na+]>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[O:21][N:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#CCC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Nc1cc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 84 h
Yield: 92.9 %

Procedure:
To a solution of 3-oxo-4-phenylbutanenitrile (690 mg, 4.34 mmol) in ethanol (25 mL) is added pyridine (4.91 mL, 60.7 mmol) and hydroxylamine hydrochloride (301 mg, 4.34 mmol). The reaction mixture is allowed to stir at room temperature 84 h. The mixture is diluted with ethyl acetate and 1M aqueous NaOH solution. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine, dried (Na2SO4), and the solvent is removed in vacuo to afford the title compound as a yellow solid (702 mg, 93%). LCMS: 175.20 (M+H+).
Reaction SMILES: [C:1]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[C:1]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[C:22]([F:21])([F:31])[F:32])=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CCCCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCCCC#Cc1ccc(CNCc2ccccc2C(F)(F)F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dodec-1-ynylbenzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 430.4. HPLC (Condition A), Rt: 5.05 min (HPLC purity: 96.9%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].P(=O)(O)(O)O.[CH3:10][C:11]([S:16][CH3:17])([CH3:15])[CH:12]=[N:13][OH:14]>O>[CH3:1][NH:2][C:3]([O:14][N:13]=[CH:12][C:11]([CH3:15])([S:16][CH3:17])[CH3:10])=[O:4]
Reactant: CSC(C)(C)C=NO
Reactant: CN=C=O
Agent: O=P(O)(O)O
Solvent: O
Product: CNC(=O)ON=CC(C)(C)SC
Temperature: 20 °C
Reaction time: 0.01 h
Yield: 87.9 %

Procedure:
Into a one liter glass resin kettle equipped with an air-driven stirrer, a pressure-equalizing dropping funnel with Teflon® tube for subsurface addition, a thermometer and a dry ice/acetone cooled condenser was added 66.5 grams (0.50mole) of 2-methyl-2-(methylthio) propionaldehyde oxime and 266 milliliters of water. After the mixture was cooled to a temperature of 5° C. with a salt/water/ice bath, 0.52 grams (0.005mole) of triethylamine was added to the kettle under a nitrogen atmosphere. A stoichiometric amount of methyl isocyanate (29.5 milliliters, 0.50 mole) was then added in a slow stream subsurface over a period of 30 minutes at a temperature of 5° C.-12° C. with vigorous stirring. The mixture was stirred for an additional 45 minutes at a temperature of 10° C.-20° C. after which the reaction mixture was transferred to a Waring Blendor® using water to flush out the resin kettle. The mixture was then blended at high speed for a period of 30 seconds to give uniformly small particles after which an additional 3.0 milliliters (0.05 mole) of methyl isocyanate was added as the mixture was blended at high speed for another 30 second period. The reaction temperature rose to 21° C. The reaction mixture was then transferred back into the glass resin kettle and 1.0 milliliter (0.02 mole) of methyl isocyanate was added with vigorous stirring at a temperature of 20° C. The mixture was then stirred for a period of 30 minutes after which 2.9 grams of phosphoric acid in 10 milliliters of water was added in a slow stream subsurface. The resulting solid product was filtered off on a sintered glass funnel to give 97.88 grams (wet weight) of a fine white powder. High pressure liquid chromatographic analysis (internal standard) indicated the following: 91.88 percent 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (87.9 percent yield based on aldicarb oxime) and 0.34 percent 2-methyl-2-(methylthio) propionaldehyde oxime; 12.66 percent water content was determined by Karl Fischer titration.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].F[C:28](F)(F)C1C=C(N2CCN(CCO)CC2)C=CC=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH2:19][CH3:28])=[O:17]
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: CCOC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
Using the procedure of Example 13, methyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate and 2-[-4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethanol were reacted to obtain 2-[4-3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluorobenzoate. The said product was dissolved in absolute ethanol and an ethanolic solution of hydrogen chloride was added thereto followed by anhydrous ether. The mixture crystallized was vacuum filtered and the product was washed with anhydrous ether and was dried to form the desired hydrochloride salt melting at 230°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH2:15][CH:16]1[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][CH2:17]1>O1CCOCC1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([CH2:15][N:11]3[CH2:12][CH2:13][CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:10]3)[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: COc1ccccc1C1CCNC1
Reactant: BrCC1CCC2(CC1)OCCO2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: C1COCCO1
Product: COc1ccccc1C1CCN(CC2CCC3(CC2)OCCO3)C1
Reaction time: 8 h

Procedure:
1 g of 3-(2-Methoxyphenyl)pyrrolidine is dissolved in 60 ml of dioxane and 0.85 g Nal, followed by 1.2 ml of N,N-ethyldiisopropylamine and 1.5 g of 8-bromomethyl-1.4-dioxaspiro[4.5]decane, dissolved in 5 ml of dioxane, are added. The reaction mixture is stirred overnight at 80°, evaporated and the residue extracted with ethylacetate/2N Na2CO3, followed by aqueous NaCl. The combined, dried and evaporated organic phases yields an oily residue which is purified by flash chromatography on silica gel using t-butylmethylether as a solvent system providing the product as an oil. MS (EI): M+=331; NMR (DMSO): 1.1 (2H, m), 1.45 (3H, m), 1.6-1.8 (5H, m), 2.15 (1H, m), 2.25 (2H, m), 2.4 (1H, t), 2.6 (2H, m), 2.8 (1H, t), 3.6 (1H, t), 3.75 (3H, s), 3.85 (4H, s), 6.9 (2H, dd), 7.15 (1H, t), 7.3 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[C:6]=1[CH3:11]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (3.90 g, 23 mmol) and 4-nitrobenzyl bromide (4.60 g, 20.7 mmol) in acetonitrile is added K2CO3 (2.76 g, 19.9 mmol) and the mixture is stirred for one hour at room temperature. The reaction mixture is poured into water and extracted twice with ethyl acetate. The organic phase is dried over MgSO4 and evaporated under reduced pressure. To yield 7.50 g of [3,5-Dimethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid methyl ester (ESI mass spectrum: [M+H]+=304). b) To a solution of [3,5-dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid methyl ester (3.90 g, 10.3 mmol) in methanol (10 mL) is added 10% palladium on charcoal (500 mg) and the mixture is hydrogenated. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The mixture is purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3) to yield 1.18 g of the title compound (ESI mass spectrum: [M+H]+=274; Retention time HPLC: 2.13 min (method A))
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[C:6]2[O:22][CH:21]=[CH:20][C:7]=2[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:9]=1)(=[O:3])[CH3:2]>[Pd].CO>[OH:3][CH:1]([C:4]1[C:5](=[O:23])[C:6]2[O:22][CH2:21][CH2:20][C:7]=2[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[N:9]=1)[CH3:2]
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)c2ccoc2c1=O
Agent: [Pd]
Solvent: CO
Product: CC(O)c1nn(-c2cccc(C(F)(F)F)c2)c2c(c1=O)OCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.1 %

Procedure:
A suspension of 3-acetyl-1-[3-(trifluoromethyl)phenyl]furo[3,2-c]pyridazin-4(1H)-one (806 mg) and 10% palladium on carbon (containing water (50%), 400% mg) in methanol (25 mL) was stirred at room temperature for 24 hr under a hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from hexane/ethyl acetate to give the title compound (686 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](=[O:32])[CH3:31]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH3:22])[C:30](=[O:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Cc1ccccc1C
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C(C)=O)c1ccccc1C)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (1.58 g, 4.80 mmol) in DMF (24 mL) was added cesium carbonate (1.56 g, 4.80 mmol) and the mixture was stirred at 23° C. for 45 min. 1-(2-Methylphenyl)-propan-2-one (0.783 g, 5.28 mmol) and cesium carbonate (2.35 g, 7.20 mmol) were added and the resulting mixture was stirred for 18 h. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate→40% ethyl acetate/hexane) gave the title compound. MS: m/z=350.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:9][C:10]#[N:11].CI.[CH3:14]CC([O-])(C)C.[Na+].C1(C)C=CC=CC=1>C1C=CC=CC=1>[CH3:14][C:3]1([CH2:9][C:10]#[N:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]1=[O:1]
Reactant: CCC(C)(C)[O-]
Reactant: N#CCC1CCCCCC1=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: c1ccccc1
Product: CC1(CC#N)CCCCCC1=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-oxocycloheptaneacetonitrile (44.6 g, 0.297 mole), and methyl iodide (42.6 g, 0.3 mole) in dry benzene (200 ml) under nitrogen, is added dropwise a solution of sodium tert-amylate in toluene (340 ml, 0.297 mole). The reaction is exothermic and a bright yellow colour appears. The mixture is stirred at 65° C. for 4 hr., then allowed to stand overnight at room temperature. The mixture is washed with 1% aqueous HCl, cold water, then brine, dried (MgSO4) and concentrated to give an oily residue. Distillation under reduced pressure gives 1-methyl-2-oxocycloheptaneacetonitrile (13, R1 = CH3, R2 = H and m = 4), bp 152°-158° C./14 mm.