Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][N:8]=2)=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28]([N:13]([C:10]1[CH:9]=[N:8][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:17])=[CH:12][CH:11]=1)[CH3:14])=[O:29]
Reactant: CNc1ccc(Oc2ccc(Cl)cc2C)nc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2c(Cl)cccc2Cl)cn1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine (32 mg, 0.13 mmol) dissolved in methylene chloride (0.25 mL) was treated with triethylamine (0.026 mL, 0.18 mmol) followed by a solution of 2,6-dichlorobenzoyl chloride (31 mg, 0.15 mmol) dissolved in methylene chloride (0.15 mL). The reaction mixture was shaken at 22° C. for 18 hours followed by quenching with saturated aqueous NH4Cl and stirring for an additional 5 hours. The organic layer was separated and dried over Na2SO4 then concentrated in vacuo. The crude product was purified by chromatography on SiO2 using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 422/424 (M+H)+ ; C20H15N2O2Cl3 requires 422.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:11]=1[CH3:23].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:16]([C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[C:11]([CH2:23][Br:1])[CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Oc2ccccc2)ccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Oc2ccccc2)ccc1Br

Procedure:
N-Bromosuccinimide (16.2 g) was added to a solution of 2-bromo-5-phenoxytoluene (15.3 g) in carbon tetrachloride (50 mls) containing benzoyl peroxide (0.05 g) and the mixture refluxed for ten hours. The precipitate of succinimide was filtered off and the filtrate washed with N-sodium hydroxide solution followed by water. Drying over magnesium sulphate and evaporation of the solvent gave, as a light yellow oil, 4-phenoxy-2-bromomethylphenyl bromide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH3:28][NH:29][CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([CH2:30][N:29]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1)[CH3:28])#[N:32]
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: CNCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN(C)CC#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 59 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg). and to the solution were added methylaminoacetonitrile hydrochloride (77 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 14 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[N-(cyanomethyl)-N-methylaminomethyl]phenyl]-3—(4-methylphenyl)cinnamamide (Compound 64) (129 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[Cl-].[NH4+]>[Fe].CO.O>[CH3:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1N)OCO2
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A mixture of 5-methyl-6-nitro-benzo(1,3)dioxole (50 mg, 0.28 mmol), Fe (54 mg, 3.5 eq) and ammonium chloride (51.2 mg, 3.5 eq) in a 1:1 mixture of MeOH/H2O (2.8 mL) was subjected to microwave irradiation (60W, P=100 p.s.i.) at 80° C. for four 10 min periods. The brown solution was allowed to cool to r.t. and more Fe (3.5 eq) and ammonium chloride (3.5 eq) were added. The mixture was subjected to microwave irradiation (60W, P=100 p.s.i.) at 80° C. for an additional 10 min. Fe was filtered off and the solvent evaporated. The crude product was purified on an SCX cartridge (cHex/EtOAc 9:1) to give the title compound as a brown solid (40 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19]C1C(F)=C(B(O)O)C=CC=1>>[Cl:19][C:7]1[C:2]([F:1])=[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2cccc(Cl)c2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (3-chloro-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:25][C:26](=[O:28])[CH3:27])C=CC=CC=1>C1C=CC=CC=1>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][CH:12]1[CH:13]=[CH:25][C:26](=[O:28])[CH3:27])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)C=CC1CCCN1C(=O)OCc1ccccc1
Yield: 59.6 %

Procedure:
To a stirred solution of N-Cbz-L-prolinal (6.3 g, 27 mmol, from step 24d above) in 30 mL of benzene was added 9.42 g (29.6 mmol) of 1-triphenylphosphoranylidene-2-propanone (Aldrich) at room temperature. The reaction mixture was heated to reflux for 4 hr. The benzene was removed under vacuum, and the residue was dissolved in ether and cooled for 16 hr. The phosphine oxide by product was removed by filtration, and the solution was further purified by column chromatography on silica gel, eluting with 20% ethyl acetate in hexanes, to afford 4.4 g of the title product (69% yield).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[CH3:48])[CH2:43]Br>C(#N)C.O.Cl>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:43][C:42]3[CH:45]=[CH:46][C:47]([CH3:48])=[C:40]([F:39])[CH:41]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CBr)cc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(C)c(F)c3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.046 mmol) in Acetonitrile (0.45 mL) was treated with Cs2CO3 (59.4 mg, 0.182 mmol), 3-fluoro-4-methylbenzyl bromide (13.89 mg, 0.068 mmol), and then stirred at 70° C. for 90 min. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-60% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1-(3-fluoro-4-methylbenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (21.5 mg, 0.038 mmol, 84% yield) as clear oil: LCMS (m/z) ES+=561 (M+1). The intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with LiOH (0.100 mL, 0.200 mmol), and stirred overnight at 60° C. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (13.5 mg, 0.024 mmol, 64.7% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.36-7.29 (m, 0.4H), 7.12 (t, J=7.8 Hz, 1H), 7.04-6.87 (m, 3.6H), 6.80-6.66 (m, 1H), 5.97-5.59 (m, 3H), 5.46-5.40 (m, 0.4H), 5.21-5.11 (m, 0.6H), 4.27-4.10 (m, 2H), 3.71-3.61 (m, 3H), 2.77-2.58 (m, 2H), 2.27-2.19 (m, 3H), 2.16-2.05 (m, 2H), 2.02 (s, 2H), 1.94 (s, 1H), 1.19-1.11 (m, 6H), 1.05-0.99 (m, 3; LCMS (m/z) ES+=547 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:29][N:30]([CH3:32])[CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc(CCNC(=O)Cc2ccc(C)cc2)cc1OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(C)cc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
One gram (1.0 g) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-methylphenyl) acetamide (3.2 mmol), 1.68 g (9.64 mmol) of t-butoxybis(dimethylamino)methane and 15 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 1.20 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[NH:17][C:16]2=[O:29])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[N+:41]([C:44]1[CH:54]=[CH:53][C:47]([CH2:48][O:49][CH2:50][CH2:51]Cl)=[CH:46][CH:45]=1)([O-:43])=[O:42].P([O-])([O-])([O-])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[N:17]([CH2:51][CH2:50][O:49][CH2:48][C:47]3[CH:53]=[CH:54][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)[C:16]2=[O:29])[CH3:14])=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
1.00 g (2.25 mmole) of (3S, 4R)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-[(phenylthio)carbonyl-methyl]-2-azetidinone was dissolved in 20 ml of methylene chloride. To the solutiion were added 350 mg (2.71 mmole) of diisopropylethylamine and then 660 mg (2.71 mmole) of p-nitrobenzyloxyethyl chloride, with stirring at 0° C. After 15 minutes, a further 230 mg (1.78 mmole) of diisopropylethylamine and 433 mg (1.78 mmole) of p-nitrobenzyloxyethyl chloride were added, and the mixture was stirred at that temperature for 15 minutes. After completion of the reaction, 30 ml of a 0.1M phosphate buffer solution (pH 7.1) was added to the reaction mixture and the organic layer was separated. The aqueous lager was extracted with chloroform. The organic layer was combined with the chloroform extract and then the solvent was distilled from the mixture. The residue was dissolved in 50 ml of a 1:1 by volume mixture of benzene and ethyl acetate, washed successively with 0.02N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off, to afford 1.47 g (yield 100%) of the title product as crystals which were recrystallized from a mixture of benzene and ethyl acetate, to afford the pure product melting at 129°-130° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23](C(O)=O)=[CH:24][C:19]3=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.N1C2C(=CC=CC=2)C=CC=1.Cl.O1CCOCC1>[Cu]>[F:41][C:37]1[C:36]([CH3:42])=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][C:17]1[C:18]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][N:20]2[C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cccnn2c1C(=O)N1CCNCC1
Temperature: 170 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of the compound of example 8, step 11 (0.057 g, 0.10 mmol), copper powder (0.007 g, 0.10 mmol) and quinoline (0.40 ml) was plunged into an oil bath pre-heated at 170° C. for 1.25 h. After cooling to room temperature and evaporation of the volatiles under reduced pressure, the residue was dissolved in EA (10 ml) and the solution washed with water and brine, dried over magnesium sulfate, filtered and concentrated to dryness. The obtained orange oil was purified by chromatography on silica gel (DCM/MOH, 100:0, then 90:10). The product was dissolved in 2 ml of DCM and a 4 N solution of hydrogen chloride in dioxane (0.25 ml, 0.98 mmol) was added. After stirring at room temperature overnight, the solution was evaporated to dryness. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 50° C. to give 0.016 g of the title compound in the form of [6-(3-fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1,2-b]pyridazin-7-yl]-piperazin-1-yl-methanone hydrochloride as an orange solid with the following characteristics:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C([NH:29][CH:30]([C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:62][CH:61]=1)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:33][CH:32]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl>ClCCl>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]([NH2:29])[C:60]2[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:62][CH:61]=2)=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To dichloromethane (10 ml) was added DBU (1,8-diazabicyclo[5,4,0]-7-undecene, 200 μl), and N-Fmoc-di(4-docosoxyphenyl)methylamine (500 mg, 474 μmol) obtained in Example 4 was added and the mixture was stirred at room temperature for 5 hr. 1N Hydrochloric acid (1.3 ml) was added dropwise and, after stirring, the solvent was evaporated and the residue was washed with acetonitrile (10 ml) to give di(4-docosoxyphenyl)methylamine (340 mg, 408 μmol, yield 86%).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)[CH3:4].[OH:19][NH:20]Cl>CO>[C:3](=[N:20][OH:19])([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:4]
Reactant: ONCl
Reactant: CC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of 1.0 g of potassium hydroxide in 25 ml of methanol, there is added a mixture of 0.85 g of 3-acetyl-β-carboline, 75 ml of methanol and 1.0 g of hydroxyamino hydrochloride. The reaction mixture is allowed to stand for 4 hours at room temperature. After evaporation, water is added and then the mixture is brought to pH 7 with glacial acetic acid. The solid reaction product is filtered and washed with water and ether. 0.6 g of 3-acetyl-β-carboline-oxime with an m.p. of 250° C. (decomposition) is obtained. In analogous manner there is obtained: 3-pentanoyl-β-carboline-oxime, m.p. 95°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH2:10][OH:11])=[CH2:9])=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CCO.[Pd]>[Cl:1][C:2]1[C:7]([CH:8]([CH3:9])[CH2:10][OH:11])=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: C=C(CO)c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Agent: [Pd]
Solvent: CCO
Product: CC(CO)c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(3-hydroxyprop-1-en-2-yl)phenyl)carbamate (161 mg, 0.521 mmol) was taken up in EtOH (3 mL) and the solution was purged with N2. Next, Pd/C (55.5 mg, 0.052 mmol) was added and the solution was again evacuated and purged with N2 3×. Next, a balloon with H2 was added, and the reaction was stirred for 1 h. The reaction mixture was filtered through celite, rinsing with MeOH. The solvent was removed in vacuo and the material was purified by flash column chromatography (0-50% EtOAc/Hex; 40 g column). Tert-butyl (2-chloro-5-cyano-3-(1-hydroxypropan-2-yl)phenyl)carbamate (36 mg) was obtained as a colorless glass.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[CH2:31][CH2:32][O:28][C:29]3=[O:33])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 58.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 9 and oxazolidin-2-one (87 mg), the title compound (269 mg) was obtained.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=1[CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>>[C:5]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=1[CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCCCc1ccc(CCCCN(C)C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cc(CCCCN(C)C)ccc1CCCCN(C)C
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To 1 ml of acetic anhydride was added 0.58 g of 2-amino-1,4-bis(4-dimethylaminobutyl)benzene, and the solution was stirred at 50° C. for 2.5 hours. After adding 8 ml of 5% sodium carbonate, the mixture was stirred at a room temperature for 5 hours, alkalized with 10% sodium hydroxide, subjected to salting out and extracted with total 70 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution, dried over potassium carbonate, and evaporated under a reduced pressure to obtain 0.56 g of the title compound as a pale brown crystal.
Reaction SMILES: C1CO[C:3]([CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH3:4])[O:2]1.Cl>CC(C)=O>[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][C:3](=[O:2])[CH3:4]
Reactant: CC(C)=CCCOCCCC1(C)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)CCCOCCC=C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.7 %

Procedure:
A suspension of 19.7 g of the product of Step A in 100 ml of acetone containing 200 ml of 0.1N hydrochloric acid was stirred at room temperature for 17 hours and the acetone was then evaporated under reduced pressure. The mixture was then extracted with methylene chloride and the organic solution was washed with aqueous sodium bicarbonate solution, then with water, dried over sodium sulfate and evaporated to dryness to obtain 15.7 g of 10-methyl-6-oxa-9-undecene-2-one in the form of a colorless liquid used as is for the next step.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([C:7](OCC)=[O:8])[CH2:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1.[NH3:19]>CO>[OH:1][CH:2]1[CH:6]([C:7]([NH2:19])=[O:8])[CH2:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1
Reactant: N
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1O
Solvent: CO
Product: NC(=O)C1CN(Cc2ccccc2)CC1O
Yield: 22.1 %

Procedure:
A solution of 11.0 g (44.0 mmol) of 3-hydroxy-4-ethyloxycarbonyl-1-phenylmethyl pyrrolidine (prepared according to E. JAEGER and J. H. BIEL in J. Org. Chem. 1965, 30, (740) in 40 g of 25% ammonia in methanol was heated at 100° C. under pressure overnight. The solution was cooled and evaporated to dryness. The oily residue was purified by chromatography using dichloromethane-methanol (85:15) to yield 2.14 g (22%) of the title compound. M.P. 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([N:17]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH2:17])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cc(N=C(c3ccccc3)c3ccccc3)c3c(n2)CCC3)c1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(-c2cccc(Cl)c2)nc2c1CCC2
Reaction time: 18 h
Yield: 88.8 %

Procedure:
A 250-mL round bottom flask was charged with 2-(3-chlorophenyl)-N-(diphenylmethylene)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (0.47 g, 1.15 mmol) and 2N aqueous HCl (12 mL, 24 mmol) in THF (50 mL). After 18 h at rt, the resultant solution was concentrated under reduced pressure. The solid residue was washed with 2N aqueous HCl (10 mL) then diethyl ether. The solid and aqueous layers were combined diluted with ethyl acetate then treated with 2N aqueous NaOH. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extract was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (0.25 g, 89%) as a white solid. MW=244.72. 1H NMR (DMSO-d6, 500 MHz) δ 7.92 (t, J=7.0 Hz, 1H), 7.81 (dt, J=7.5, 1.5 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.41-7.38 (m, 1H), 6.86 (s, 1H), 5.86 (s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.02 (quin, J=7.5 Hz, 2H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][N:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])=[CH:11][N:10]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1ccsc1Br
Product: Cc1ccsc1-c1ccc(F)nc1
Yield: 75.9 %

Procedure:
This compound was prepared in analogy to Example 52, starting from 2-bromo-3-methylthiophene (2.6 g, 15 mmol) and 2-fluoro-5-pyridine-boronic acid (2.3 g, 16.5 mmol, 1.1 equiv.) to obtain 2.2 g of the desired compound as a light yellow oil. MS (ES): m/e 194.2 (M+H)