Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:18][C:19]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:20]=1[C:21]#[N:22]>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][N:11]([C:24]3[CH:25]=[CH:26][C:19]([F:18])=[C:20]([CH:23]=3)[C:21]#[N:22])[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: N#Cc1cc(I)ccc1F
Solvent: Cc1ccccc1
Product: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.6 g) and 2-fluoro-5-iodobenzonitrile (0.57 g) was dissolved in toluene, which was then degassed 3 times. To the solution in toluene was added sodium tert-butoxide (0.20 g), Tris(dibenzylidene acetone)dipalladium chloroform complex (0.04 g) and Xantphos (0.07 g) under argon atmosphere, and the mixture was stirred at 80° C. for two hours. The mixture was cooled to room temperature and then diluted with ethyl acetate, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-fluorobenzonitrile (0.54 g). m.p. 184-186° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: N#Cc1cccc(N2CCNCC2)c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(N2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-cyano phenylpiperazine (5.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.6 g compound (I-41) with a yield of 70.5%. ESI-MS [M+H]+: m/z 360.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.CC([O-])=O.[Na+].[NH2:16][OH:17].Cl>CCO>[Cl:1][C:2]1[C:7]([CH:8]=[N:16][OH:17])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,6-dichloro-5-pyrimidinecarbaldehyde (8.00 g, 44.8 mmol), NaOAc (3.7 g, 1.0 eq) and NH2OH.HCl (3.1 g, 1.0 eq) in EtOH (320 mL) was stirred at rt for 2 h. The reaction mixture was filtered, concentrated and purified by column chromatography on silica gel (dry loading, first DCM then DCM/EtOAc, 1/9) to give 4,6-dichloro-5-pyrimidinecarbaldehyde oxime as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:34]=[CH:33][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH2:31][OH:32])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:32][CH2:31][C:12]1[N:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([CH3:5])=[CH:34][CH:33]=2)[C:19]2[C:14]([CH:13]=1)=[CH:15][C:16]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=1)=[CH:17][CH:18]=2)(=[O:3])[CH3:2]
Reactant: Cc1ccc(Cn2c(CO)cc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Acetyl chloride (0.222 mL, 3.08 mmol) was added to a stirring solution of {1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-2-yl}methanol (0.507 g, 1.23 mmol) and N,N-diisopropylethylamine (0.547 mL, 3.08 mmol) in methylene chloride (8 mL) at 0° C. under a nitrogen atmosphere over a period of 5 minutes. After the reaction mixture was stirred at room temperature overnight, the reaction was quenched carefully with water. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound as a solid (0.557 g, 99.6%), mp: 125-126° C. Mass spectrum (ESI, [M+H]30 ) m/z 454. 1HNMR (400 MHz, DMSO-d6): δ 7.86 (s, 1H), 8.77 (d, 2H, J=8.96 Hz), 7.48-7.40 (m, 4H), 7.09 (d, 2H, J=7.94 Hz), 6.90 (d, 2H, J=7.94 Hz), 6.70 (s, 1H), 5.44 (s, 2H), 5.23 (s, 2H), 2.23 (s, 3H), and 1.85 ppm (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25]([OH:26])=[C:24]([O:27][CH3:28])[C:23]([O:29][CH3:30])=[CH:22][C:21]=1[CH3:31].N(S([O-])(=O)=O)(S([O-])(=O)=[O:35])[O].[K+].[K+].O.CO>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:35])[C:21]=1[CH3:31]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1080 h
Yield: 60.1 %

Procedure:
6-(18-Hydroxyoctadecyl)-2,3-dimethoxy-5-methylphenol (0.5 g), prepared by deacetylating the above 18-acetoxy compound in the same manner as in Reference Example 3, is dissolved in dimethylformamide (1 l) followed by addition of potassium nitrosodisulfonate (13 g), water (700 ml), methanol (100 ml) and potassium-dihydrogen phosfate (1 g). The mixture is stirred at room temperature for 45 days. The product is extracted in a conventional manner and recrystallized from hexane to give yellow needles of 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I, n=18, 0.31 g). m.p. 81° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and benzyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[O:14]1.[CH:22](OCC)(OCC)OCC>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH:22]=[C:16]1[C:17](=[O:19])[O:18][C:13]([CH3:21])([CH3:12])[O:14][C:15]1=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(NC=C2C(=O)OC(C)(C)OC2=O)c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a stirred suspension of 5-methyl-2-nitroaniline (10.0 g) in ethanol (20 ml) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (9.95 g) and triethyl orthoformate (10.7 g) at 50° C. The resulting mixture was heated at 120° C. for one hour during which time ethanol (20 ml) was added to the mixture and ethanol liberated was distilled off. After cooling, ethyl acetate (40 ml) was added thereto and the resulting precipitate was collected by filtration. The solid was washed with hot ethanol (40 ml) and allowed to cool to ambient temperature. The precipitate was collected by filtration and air-dried to afford isopropylidene (5-methyl-2-nitroanilino)methylenemalonate (15.2 g) as yellow needles.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][O:7][CH2:8][C:9](=[O:16])[C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>CCOCC>[CH:1]1([C:9]([OH:16])([C:10]#[C:11][Si:12]([CH3:13])([CH3:15])[CH3:14])[CH2:8][O:7][CH3:6])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: COCC(=O)C#C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCC(O)(C#C[Si](C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
52.85 ml of 0.5 M cyclopropylmagnesium bromide (26.43 mmol, Aldrich) are added to a solution of 3 g of 1-methoxy-4-(trimethylsilyl)but-3-yn-2-one (17.62 mmol) in 160 ml of ether. The mixture is stirred at ambient temperature overnight and is then cooled with a water/ice bath and a solution of NH4Claq and ethyl acetate is added. The mixture is extracted 3 times with ethyl acetate and the organic phases are then combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The oily residue is purified by silica column chromatography, elution being carried out with a cyclohexane:ethyl acetate gradient, 100:0 to 80:20, so as to obtain 1.9 g of (±)-2-cyclopropyl-1-methoxy-4-(trimethylsilyl)but-3-yn-2-ol in the form of an oil, with a yield of 51%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]Cl)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH3:25]>O1CCCC1.C(O)C>[NH2:25][CH2:17][C:6]1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Reactant: N
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Temperature: 140 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
A solution of 6-bromo-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (10 g, 24.7 mmol) in tetrahydrofuran (20 mL) and a solution of 2M ammonia in ethanol (200 mL) were sealed in a stainless tube and stirred at 140° C. for 5 h. The reaction mixture was cooled and concentrated. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether and the precipitated crystals were collected by filtration to give 3-aminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (5.6 g, 53%) as crystals.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]Br)([O:3]C(C)(C)C)=[O:2].[CH2:12]([C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH2:32][N:33]([CH2:35][CH3:36])[CH3:34])[CH:26]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:37])[C:15]=1[OH:38])C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:35]([N:33]([CH2:32][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[C:16]([CH3:37])[C:15]([O:38][CH2:10][CH2:9][NH2:8])=[C:14]([CH3:12])[CH:19]=3)[N:24]=2)[CH:30]=[C:29]([CH3:31])[CH:28]=1)[CH3:34])[CH3:36].[CH:1]([O-:3])=[O:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)Cc1cc(C)cc(-c2nc(-c3cc(C)c(OCCN)c(C)c3)no2)c1
Product: O=C[O-]
Temperature: 70 °C
Reaction time: 16 h

Procedure:
2-(Boc-amino)-ethylbromide (66 mg, 285 μmol) was added to a suspension of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (52 mg, 142 μmol) and K2CO3 (60 mg, 427 μmol) in acetonitrile (2 mL). The mixture was stirred at 70° C. for 16 h before it was filtered. The filtrate was concentrated, dissolved in DCM (1 mL) and TFA (1 mL) and stirred at rt for 10 min. The mixture was again concentrated in vacuo and the crude product was purified by prep. HPLC to give the title compound as a formate salt in the form of a white lyophilisate (40 mg). LC-MS: tR=0.47 min; [M+1]+=409.30; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H), 2.16 (s, 3H), 2.38 (s, 3H), 2.43-2.48 (m, 5H), 2.75 (q, J=7.5 Hz, 2H), 3.26 (t, J=5.0 Hz, 2H), 3.56 (s, 2H), 3.99 (t, J=5.0 Hz, 2H), 7.48 (s, 1H), 7.83 (s, 2H), 7.91 (s, 1H), 7.93 (s, 1H), 8.17 (s, 2H, formate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][C@H:6]([NH2:15])[C@@H:7]([OH:14])[C@@H:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12].[CH3:20][C:21]1[CH:22]=[C:23]([C:30]([N:32]([CH2:36][CH2:37][CH3:38])[CH2:33][CH2:34][CH3:35])=[O:31])[CH:24]=[C:25]([CH:29]=1)[C:26](O)=[O:27].[CH3:39]CN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][C@H:6]([NH:15][C:26](=[O:27])[C:25]1[CH:29]=[C:21]([CH3:20])[CH:22]=[C:23]([C:30]([N:32]([CH2:36][CH2:37][CH3:38])[CH2:33][CH2:34][CH3:35])=[O:31])[CH:24]=1)[C@@H:7]([OH:14])[C@@H:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:39]
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: CCCC[C@H](O)[C@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CCN(C(C)C)C(C)C
Product: CCCCC[C@H](O)[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cc(C)cc(C(=O)N(CCC)CCC)c1

Procedure:
The hydrochloride salt of (1S,2R,3S)-1-(3,5-difluorobenzyl)-2,3-dihydroxyheptylamine (0.1 mmol) was reacted with 5-methyl-N,N-dipropyl-isophthalamic acid as described in method A (addition of an extra equivalent of DIEA to neutralize the amine salt) to give N1-[(1S,2R,3S)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-octyl]-5-methyl-N3,N3-dipropyl-isophthalamide. MS (ESI+) for C29H40F2N2O4 m/z 540.9 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cn2)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2ccc(NCc3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-dichlorobenzaldehyde (1.28 g, 7.3 mmol) was added to a solution of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]propionate (2.1 g, 7.3 mmol) in ethanol (20 mL), and the resulting solution was stirred for 2 hours at 40° C. To the resulting reaction solution was added sodium borohydride (0.55 g, 15.7 mmol) under ice cooling, and stirred at the same temperature for 1 hour. To the solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 2.71 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:9])[S:8][C:4]=2[CH:3]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[Cl:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][CH2:12][CH2:13][CH2:14][CH3:15])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: CCCC=O
Reactant: Nc1ccc2nc(Cl)sc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCNc1ccc2nc(Cl)sc2c1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of (29) (0.2 mmol, 36.8 mg) in 2 ml dichloroethane was added 0.2 mmol butyraldehyde (18 μl), followed by 63.6 mg sodium triacetoxyborohydride, and 12 μl acetic acid. After 2 h, the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and the solvent removed by rotary evaporation, yielding 44.2 mg of a yellow solid. 1H-NMR (CDCl3): δ 7.67 (d, 1H, J=9.2 Hz), 6.84 (d, 1H, 3=2.4 Hz), 6.72 (dd, 1H, 3=2.4, 9.2 Hz), 3.35 (bt, 1H), 3.15 (t, 2H), 1.65 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H, J=7.6 Hz).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].[NH3:13]>[Ni]>[C:1]1([CH:7]([CH3:10])[CH:8]=[N:13][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C=O)c1ccccc1
Reactant: N
Reactant: [H][H]
Agent: [Ni]
Product: CC(C=NCC(C)c1ccccc1)c1ccccc1

Procedure:
In a flask as described in Example 1, 1000 g 2-phenylpropanal are reacted in the presence of 90 g of a commercially available nickel containing carrier catalyst (containing about 52 to 53% by weight nickel, and employing chromium (3)-oxide as activator) at a temperature of 130°, with a total of 300 l ammonia and hydrogen (volume ratio 1 : 1) during a reaction time of 2 hours. After termination of the reaction, the catalyst is separated by filtration. 921 g 2-phenylpropylidene-2-phenylpropylamine are obtained.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.O>CN(C)C=O>[N:3]1([C:8]2[N:9]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]c(N3CCCC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (402 mg, 11 mmol) was added to a suspension of 2-pyrrolidino-1H-benzimidazole (1.9 g, 10.1 mmol) in dry N,N-dimethylformamide (30 mL). All solids dissolved. The solution was allowed to stir at ambient temperature for 15 minutes following the cessation of foaming. The solution was cooled to 5° C. and a solid formed. Methyl 4-(bromomethyl)benzoate (2.1 g, 01 mol) was added to the suspension and all the solids dissolved. The solution was allowed to stir at ambient temperature and a solid formed. The mixture was stirred at ambient temperature overnight and then it was poured into cold water. A solid was isolated by filtration, washed with water and dried to provide 3.0 g of crude product as an off-white solid. This material was recrystallized from methanol to provide methyl 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2]O.[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]=[O:14])=[C:9]([CH3:17])[CH:8]=1.B(F)(F)F.CCOCC>CCOCC.O1CCCC1>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]2[O:5][C:1](=[O:4])[CH2:2][O:14]2)=[C:9]([CH3:17])[CH:8]=1
Reactant: Cc1cc(Cl)ccc1OCC=O
Reactant: O=C(O)CO
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1OCC1OCC(=O)O1
Reaction time: 24 h
Yield: 62.6 %

Procedure:
A solution containing 2.5 g (0.033 mole) of glycolic acid, 4.1 g (0.025 mole) of 4-chloro-2-methylphenoxyacetaldehyde and 10 g (0.07 mole) or boron trifluoride etherate in 50 ml of ether and 30 ml of tetrahydrofuran was allowed to stand at room temperature for 24 hours. The dark solution was washed with aqueous sodium bicarbonate, dried and concentrated to dryness. Recrystallization from ether - hexane gave 3.8 g of 2-(4-chloro-2-methylphenoxymethyl)-1,3-dioxolan-4-one having a melting point of 42°-44°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18](=[O:24])[CH:19](Br)[CH2:20][CH2:21][Br:22]>CN(C=O)C>[CH3:16][O:17][C:18](=[O:24])[CH:19]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH2:20][CH2:21][Br:22]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)C(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCBr)Oc1ccc(F)cc1F
Temperature: 60 °C
Yield: 61.6 %

Procedure:
To a solution of 2,4-difluoro phenol (0.35 g, 2.73 mmol) in DMF (5 ml), added potassium carbonate (0.38 g, 2.73 mmol) and 2,4-Dibromo-butyric acid methyl ester (0.71 g, 2.74 mmol) and heated at 60° C. for 3 h. Reaction mixture was cooled to r.t. It was then extracted in EtOAc (30 ml) and washed with brine (2×10 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product, purification on silica gel to yield 4-Bromo-2-(2,4-difluoro-phenoxy)-butyric acid methyl ester (0.52 g, 61%). 1H NMR (400 MHz, CDCl3): δ 12.42-2.56 (m, 2H), 3.53-3.71 (m, 2H), 3.77 (s, 3H), 4.81 (dd, J=3.6 and 8.8 Hz, 1H), 6.72-6.80 (m, 1H), 6.85-6.90 (m, 1H), 6.95-7.02 (m, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH2:23])[CH:20]=[N:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:20]=[N:19][CH:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cncc(C=C2c3ccccc3CCc3ccccc32)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cncc(C=C2c3ccccc3CCc3ccccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Mix 6-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyrazin-2-ylamine (35 mg, 0.117 mmol), triethylamine (34 μL, 0.234 mmol), N,N-dimethylaminopyridine (2 mg, 0.018 mmol), and methanesulfonyl chloride (10 μL, 0.123 mmol) in CH2Cl2 (2 mL). Stir at room temperature overnight and add 150 μL triethylamine and 40 μL methanesulfonyl chloride. Stir at room temperature for 6 h and add 1.00N aqueous HCl (1 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge, then elute, collect, and concentrate 45 mL CH2Cl2. Dissolve crude product in THF (5 mL), add 1.0M tetrabutylammonium fluoride (0.30 mL), and heat to reflux for 1 h. Cool to room temperature and dilute with H2O and brine. Extract into ethyl acetate, dry (MgSO4) and concentrate organics. Chromatograph on silica gel (4 g), eluting with 20%→35% ethyl acetate/hexanes to afford 19 mg (43%) of the title compound as a white solid. MS (ES) 378 (M+H), 376 (M−H); HPLC shows 100% purity.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:25][CH2:24][CH2:23][NH:26][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C(O)c1cn(Cc2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: NCCNc1ccc2c(=O)c(C(=O)O)cn(Cc3ccccc3)c2c1
Temperature: 130 °C
Yield: 52.1 %

Procedure:
To a solution of 7-chloro-1-benzyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g) in 1-methyl-2-pyrrolidinone (10 mL) was added ethylenediamine (0.95 g). The mixture was heated at 130° C. for 10 h. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered to give the title compound (560 mg).