Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][NH:14][CH:15]1[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:15]1([N:14]([CH3:13])[CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CNC1CCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C1CCC1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (500 mg, 2.92 mmol) and N-methylcyclobutanamine (0.373 mL, 3.50 mmol) in methylene chloride (15 mL) and added sodium triacetoxyborohydride (929 mg, 4.38 mmol) and the solution stirred at 20° C. for 3 h. The solution was concentrated in vacuo to give a white solid. The solid was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate, and concentrated in vacuo to give a residue which was purified on a 40 g silica gel column eluted with 0 to 70% ethyl acetate in hexanes to give the title compound (342 mg, 1.423 mmol, 48.7%) as a clear, colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.43 (s, 9 H) 1.60-1.75 (m, 2 H) 1.85-2.04 (m, 4 H) 2.07 (s, 3 H) 2.81-2.94 (m, 1 H) 3.27-3.30 (m, 1 H) 3.81-3.88 (m, 2 H) 3.88-3.97 (m, 2 H); MS: 241 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccccc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-bromoaniline to yield 2-[(2-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-])=[CH:14][C:13]3[N:20]=[CH:21][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:31]=C=O)=O.C[O-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:31])[C:13]3[N:20]=[CH:21][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c21
Agent: C[O-]
Agent: [Na+]
Product: CC(C)Cn1cnc2c(N)nc3ccc(OCc4ccccc4)cc3c21
Reaction time: 1 h

Procedure:
A modification of the general method described in Part C of Example 3 was followed using 8-benzyloxy-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinoline (2.0 g, 5.8 mmol) as the starting material. The reaction with trichloroacetyl isocyanate was not complete after one hour as evidenced by a TLC analysis. Additional trichloroacetyl isocyanate (0.1 equivalent) was added, and the reaction was stirred for an additional hour. Following the reaction with sodium methoxide, the solid product was isolated by filtration and recrystallized from ethanol. The crystals were dried overnight in a vacuum oven at 45° C. to provide 1.6 g of 8-benzyloxy-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 214-216° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[NH:17]1[CH:21]=[C:20](B(O)O)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[NH:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)[CH:19]=[N:18]1
Reactant: OB(O)c1cn[nH]c1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2-c2cn[nH]c2)CC1
Yield: 46 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), 1H-pyrazol-4-boronic acid pinnacol ester (21 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative hplc (H2O, MeCN, 95:5) to furnish the title compound as a white solid (11 mg, 46%), m/z (ESI) C14H18N5O requires 272.1506 found [M+H]+272.1509.
Reaction SMILES: [N+:1]([C:4]1[CH:57]=[CH:56][C:7]([O:8][P:9]2([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:14]=[P:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[P:11]([O:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=3)([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].CCCCCC>NC1C=CC=CC=1.[Pt]=O>[NH2:1][C:4]1[CH:57]=[CH:56][C:7]([O:8][P:9]2([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:14]=[P:13]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=3)([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[P:11]([O:39][C:40]3[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=3)([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccccc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: Nc1ccccc1
Solvent: CCCCCC
Product: Nc1ccc(OP2(Oc3ccccc3)=NP(Oc3ccccc3)(Oc3ccc(N)cc3)=NP(Oc3ccccc3)(Oc3ccc(N)cc3)=N2)cc1
Temperature: 50 °C
Yield: 70.1 %

Procedure:
A 250-ml heater-equipped autoclave pressure bottle was charged with a solution of 20 (16.0 g) in aniline (40 ml), containing catalyst platinum oxide (0.075 g). The mixture was agitated vigorously at 50° C. and 60 psi of hydrogen until no further pressure drop was observed (3-4 h). The reaction mixture was filtered and concentrated under reduced pressure to 10 ml and poured slowly into hexane. The hexane was decanted off. The light brown paste was then extracted with hot hexane until the maceration was difficult. The thick paste was cooled in ice to give a light-yellow solid, which recrystallized from o-dichlorobenzene to give a white solid. The solid was further boiled with n-hexane, filtered, and dried to yield 21 (10.0 g). DTA examination of this solid showed a melting point range from 115°-145° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#C[Si](C)(C)C)CC1
Temperature: -40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a cooled (-40° C.) solution of trimethylsilylacetylene (34 ml 241 mmol) in anhydrous tetrahydrofuran (400 ml) under an atmosphere of nitrogen was added slowly n-butyl lithium (96 ml of a 2.5. M solution in hexanes, 241 mmol). After addition the mixture was stirred at -40° C. for 1 hour then cooled to -78° C. To this mixture was added via a cannula a solution of 1-tert-butyloxycarbonyl-4-piperidone (40 g, 201 mmol) in anhydrous tetrahydrofuran (250 ml). After addition the mixture was stirred at -78° C. for 1 hour, the cooling bath removed and the mixture stirred at room temperature for 72 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (300 ml), stirred for a further 10 minutes and poured into water (500 ml) and extracted with ethyl acetate (3×300 ml). The combined organic solutions were washed with water (500 ml), brine (300 ml), dried (MgSO4) and evaporated to afford the title compound (55 g, 92%); mp 75° C.; δH (250 MHz, CDCl3) 0.19 (9H, s), 1.48 (9H, s), 1.63-1.74 (2H, m), 1.80-1.92 (2H, m), 3.18-3.28 (2H, m), 3.71-3.84 (2H, m); mlz (ES) 298 (M+ +1).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenyl(piperidin-4-yl)methanol (J. Med. Chem. 1989, 32(1), 105-118) (0.42 g, 1.57 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (3 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to yield the trifluoroacetic acid salt of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.35 (tt, J=7.33, 1.65 Hz, 4H), 7.26 (m, 4H), 7.15 (dt, J=6.36, 1.57 Hz, 2H), 3.15 (m, 4H), 2.43 (t, 4H); MS (DCI) m/z 250 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH2:21]([B-](F)(F)F)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[K+]>>[CH2:21]([C:12]1[N:8]2[CH2:9][CH2:10][O:11][C:5]3[CH:4]=[C:3]([F:20])[C:2]([Br:1])=[CH:19][C:6]=3[C:7]2=[N:14][C:13]=1[C:15]([NH2:17])=[O:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: F[B-](F)(F)Cc1ccccc1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Agent: [K+]
Product: NC(=O)c1nc2n(c1Cc1ccccc1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (70 mg) was reacted with potassium benzyltrifluoroborate similar to as described in Example 5 and purified by reverse phase hplc to give 3-benzyl-10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 4.9 mg of 3-benzyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 420 (M)+. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=8.2 Hz, 1H), 7.28 (d, J=7.1 Hz, 1H), 7.22-7.15 (m, 3H), 6.69 (d, J=9.9 Hz, 1H), 5.46 (s, 1H), 4.59 (s, 2H), 4.31 (dd, J=5.2, 3.1 Hz, 2H), 4.04 (dd, J=5.1, 3.1 Hz, 2H), 1.65 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4C(OC(C)(C)C)=O)=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][NH:18]4)=[N:12][N:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-n2nnnc2CN2C[C@@H]3C[C@H]2CN3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of 1,1-dimethylethyl (1S,4S)-5-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (470 mg, 1.107 mmol, Intermediate 17) in methanol was added 4M hydrogen chloride in 1,4-dioxane (5 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and poured onto a 5 g SCX cartridge. The cartridge was washed with methanol (2 column volumes) and eluted with ammonia in methanol (2 column volumes). The ammonia in methanol fractions were concentrated and the residue dried in vacuo to yield the title compound as white crystals (363 mg)
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Product: CCCCCCCCCCCCc1ccc(NC(C)=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 1-liter flask fitted with a stirrer and reflux condenser is added 137.5 grams (0.525 mole) of p-n-dodecylaniline, dissolved in 138 ml of tolune. To this is added over a 15-minute period 57.5 ml of acetic anhydride. The temperature rises from 40° to 80° C. After all the acetic anhydride is added, the reaction mixture is stirred at 40° C. for 3 hours. The reaction mixture is then cooled to yield the crude product which is recrystallized from 800 ml of methanol to give 151.1 grams of the above-named material as a solid melting at 100°-102° C.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH3:16].C(O)(=O)C(O)=O>CO>[CH2:8]([OH:7])[C:9]#[C:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH3:16]
Reactant: CCC/C=C/CC#CCOC1CCCCO1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCC/C=C/CC#CCO
Yield: 96.8 %

Procedure:
To a solution of 1-(2-tetrahydropyranyloxy)-trans-5-nonen-2-yne (61.5 g) in methanol (250 ml) was added 4% oxalic acid (250 ml). The reaction mixture was refluxed for 2 hours and concentrated under reduced pressure to give a residue, which was extracted with ether, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a yellowish oily residue. The oily residue was distilled under reduced pressure to give colorless oily trans-5-nonen-2-yne-1-ol (37 g).
Reaction SMILES: Cl[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1COCC1>[CH:13]1[C:14]2[CH:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: ClC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc2c(c1)-c1ccccc1C2N1CCNCC1
Yield: 81.1 %

Procedure:
A solution of 9-chlorofluorene (8.4 g), triethylamine (0.85 mL) and piperazine (27 g) in THF (200 mL) was refluxed under argon for 6 hours. It was then filtered and the solvent was removed under vacuum. The crude product was washed with water, chromatographed on silica gel and eluted with 5% MeOH saturated with NH3 in CH2Cl2 to afford the title compound (8.5 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CN1CCOCC1.[Cl:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>C(#N)C>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:33])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:18]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
N-Boc-cis-4-Amino-L-proline methylester hydrochlorid (5 g) was dissolved in acetonitrile (25 ml) and suspended with NMM (1.2 g) for 15 min at 25° C. (Suspension A). 5-Chlorothiophene-2-carboxylic acid (5.184 g) was dissolved in acetonitrile (25 ml), NMM (2.4 g) and IBCF (4.865 g) were added to the solution. This solution was stirred for 30 min at 25° C. and then added to the above mentioned suspension A. The whole mixture was stirred for 24 h at 25° C. The mixture was then evaporated to dryness and purified by chromatography (silica gel; gradient: CH2Cl2->methanol 2N NH3) to yield (2S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) as a light yellow gum. MH+=289.1 (Cl-isotopes, loss of Boc-group).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>CN1CCCC1=O>[CH3:8][C:6]1[CH:7]=[C:2]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc(N(C)CCO)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 5-fluoro-2-nitrotoluene (1.5 g, 9.6 mmol), N-methylethanolamine (0.90 mL, 0.012 mol) and triethylamine (1.6 mL, 0.012 mol) in N-methyl-2-pyrrolidone (15 mL) was stirred at 60° C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford 2-[(3-methyl-4-nitrophenyl)-N-methylamino]ethanol as solid (2.0 g, y. 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.C(O)(=O)C.[Br:25]Br>O>[Br:25][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)naphthalene (9.68 g, 36.6 mmol) and glacial acetic acid (150 mL) was slowly added a solution of bromine (5.85 g, 36.6 mmol) in glacial acefic acid (20 mL). The mixture was stirred for 1 hour and the resulting suspension was poured into water (200 mL) and the solid product was collected by filtration. The solid was triturated first with water and then with ethyl acetate to yield 11.25 g (90%) of the title compound as a white solid: mp 172–174° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.05 (3H, s), 7.04 (2H, d, J=8.56 Hz), 7.30 (1H, d, J=9.01 Hz), 7.67 (2H, d, J=8.65 Hz), 7.81 (1H, dd, J=1.61 Hz, J=8.84 Hz), 7.87(1H, J=9.04 Hz), 7.94 (1H, d, J=1.47 Hz), 8.27 (1H, d, J=8.92 Hz); MS (El) m/z 343 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([OH:10])=[N:6][O:7][C:8]=1[CH3:9].[H-].[Na+].[C:13](Cl)(=[O:15])[CH3:14]>O1CCCC1>[C:13]([O:10][C:5]1[C:4]([CH2:3][CH2:2][OH:1])=[C:8]([CH3:9])[O:7][N:6]=1)(=[O:15])[CH3:14]
Reactant: Cc1onc(O)c1CCO
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1noc(C)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
7.8 g of 4-(2-hydroxyethyl)-5-methylisoxazol-3-ol was dissolved in 1 l of tetrahydrofuran. 1.70 g of sodium hydride was added to the solution under cooling with ice. The mixture was stirred at room temperature for 30 min and then cooled again with ice. 4.7 g of acetyl chloride was added thereto and the mixture was stirred at room temperature. The solvent was distilled off and water was added to the residue. After extraction with chloroform, the extract was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified according to silica gel column chromatography (chloroform) to obtain 2.96 g of the intended compound in the form of colorless prismatic crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[C:13]([NH:18][NH2:19])(=[O:17])[CH2:14][CH2:15][CH3:16].C(O)C>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:19][NH:18][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:3][CH:2]=1
Reactant: CCCC(=O)NN
Reactant: O=Cc1ccnc2ccccc12
Solvent: CCO
Solvent: O
Product: CCCC(=O)NN=Cc1ccnc2ccccc12
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 7.85 gm (0.05 mole) of 4-quinolinecarboxaldehyde, 5.11 gm (0.05 mole) of butyric acid hydrazide and 100 ml of ethanol is refluxed 4 hr. The reaction mixture is diluted with water and cooled to room temperature. The mixture is chilled. The solid that separates is collected, washed with water and dried to give 10.3 gm of the title compound, having a melting point of 130.4° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]1[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.CN(C)C=O>C(Cl)Cl>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:26][CH2:25][CH2:24][NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH3:12])[CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1cc(NCCN)c2ccccc2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(NCCNCC(O)COc2ccccc2)c2ccccc2n1
Reaction time: 48 h

Procedure:
A solution of 4.4 g. phenyl glycidyl ether and 12 g. 2-methyl-4-(2-aminoethylamino)-quinoline in 60 ml. dimethylformamide is left to stand for 48 hours at ambient temperature. The reaction mixture is then taken up in methylene chloride, washed with water, dried and purified chromatographically on a silica gel column using, as elution agent, methylene chloride-methanoltriethylamine (26:3:0.6 v/v/v), and then recrystallized from isopropyl alcohol. There are obtained 3.5 g. (34% of theory) of the desired product in the form of colorless crystals; m.p. 151°-152° C.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.5 mg, 53.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 7.40-7.10 (m, 5H), 7.05 (m, 2H), 6.97 (apparent d, 1H, J=8.7 Hz), 6.86 (m, 2H), 6.79 (apparent dt, 1H, J=2.4, 7.9 Hz), 5.31 (apparent dd, 1H, J=4.5, 8.0 Hz), 3.39 (m, 2H), 2.97 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.5 Hz), 2.3-2.1 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 475.7 (M+H)+.