Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9]1([CH:12]=[N:13][OH:14])[CH2:11][CH2:10]1.[CH3:15][C:16]1[CH:17]=[C:18]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)[CH:19]=[C:20]([CH3:28])[C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26]#[CH:27].C(N(CC)CC)C>CN(C)C=O.N1C=CC=CC=1>[CH:9]1([C:12]2[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][O:22][C:21]3[C:16]([CH3:15])=[CH:17][C:18]([C:29]4[N:33]=[C:32]([CH3:34])[O:31][N:30]=4)=[CH:19][C:20]=3[CH3:28])[O:14][N:13]=2)[CH2:11][CH2:10]1
Reactant: ON=CC1CC1
Reactant: C#CCCCOc1c(C)cc(-c2noc(C)n2)cc1C
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(C)c(OCCCc3cc(C4CC4)no3)c(C)c2)no1

Procedure:
Following a procedure similar to that described in Example 2(b) and using 0.52 g N-chlorosuccinimide in 5 mls dimethylformamide, two drops of pyridine, 0.33 g cyclopropanecarboxaldehyde oxime from part (a) above in 10 mls dimethylformamide, 0.53 g 3-[3,5-dimethyl-4-(3-ethinylpropoxy)phenyl]-5-methyl-1,2,4-oxadiazole prepared by a procedure similar to that described in Example 1(b), and 0.40 g triethylamine in 20 mls dimethylformamide, there was obtained after chroamtography (MPLC, silica gel; 20:80 ethyl acetate/hexane) and recrystallization (methyl alcohol) 0.312 g of the title compound, m.p. 50.5°-51° C.
Reaction SMILES: C([C:4]1[CH:12]=[N:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)N.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C[N:31](C)[CH:32]=[O:33]>>[C:5]12[C:4](=[CH:12][N:11]=[CH:10][CH:9]=1)[NH:31][C:32](=[O:33])[O:8][C:6]2=[O:7]
Reactant: NC(=O)c1cnccc1C(=O)O
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=c1[nH]c2cnccc2c(=O)o1
Reaction time: 0.17 h

Procedure:
A 50 ml. flask was charged with 0.94 g. 3-carbamylisonicotinic acid suspended in 8 ml. dimethylformamide. A 2.5 g. portion of lead tetra-acetate was added to the suspension, and the reaction mixture was stirred at 20° for 10 minutes. The reaction mixture was then warmed to 45° and stirred for 10 minutes. The cooled mixture was poured onto 30 grams crushed ice and the pale yellow solids were collected by filtration and dried in vacuo. Extensive decomposition of the product occurred upon attempted recrystallization from organic solvents. The final yield of 4-azaisatoic anhydride amounted to 0.65 g., melting point 218°, with decomposition, and represented 70 percent of theory. The structure was identified by elemental analysis, infrared spectroscopy and mass spectrometry.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].Cl.N1C=CC=CC=1.C(OCCO)C>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)c(C(F)(F)F)c3)c2cc1OC
Temperature: 139 °C
Yield: 65.2 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.215 g of 4-chloro-3-trifluoromethylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 1.5 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of IM NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.266 g (65.5%) of the desired product as cream crystals. MP 265-267° C.;: mass spectrum (electrospray, m/e,): 408.2(M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]1[CH2:18]CC[CH2:15]1.[H-].[Na+].COCCl>O>[CH3:15][O:14][CH2:18][O:13][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]=1
Reactant: OCc1coc(-c2ccccc2)n1
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOCc1coc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a mixture of (2-phenyl-4-oxazolyl)methanol (15.60 g) and tetrahydrofuran (300 mL) was added sodium hydride (60%, oil, 4.28 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Chloromethyl methyl ether (9.34 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 4-methoxymethoxymethyl-2-phenyloxazole as a colorless oil (10.86 g, 56%) from a fraction eluted with ethyl acetate-hexane (1:8, v/v).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]([C:15]([CH2:17][Cl:4])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOC)C(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC)C(=O)CCl

Procedure:
Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 l.) After extracting with methylene chloride (500 ml.) and twice with methylene chloride (200 ml.), the extracts were combined. The combined extract were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).
Reaction SMILES: [Na+:1].[C:2](/[C:6](=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH2:7][S:8]([O-:11])(=[O:10])=[O:9])([O:4][CH3:5])=[O:3].[H][H]>[Ni].CO.O>[Na+:1].[C:2]([CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][S:8]([O-:11])(=[O:10])=[O:9])([O:4][CH3:5])=[O:3]
Reactant: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)[O-]
Reaction time: 24 h
Yield: 88 %

Procedure:
To the 8 L of 1:1 methanol/water mixture containing the resultant compound from Example 1C was added 60 g of W-24 raney nickel. The resulting suspension was pressurized under 50 psi of hydrogen and was allowed to shake on a Parr shaker for 24 h, at which time an additional 20 g of raney nickel catalyst was added. After 6 h under 50 psi of hydrogen, the catalyst was removed by filtration and the solution was concentrated to dryness. To the dry white solid was added ethyl acetate (6 L) and heptane (4 L) and the solution was vigorously stirred with a mechanical stirrer overnight. The white suspension was removed by filtration yielding 530 g (88%) of the desired product as an amorphous powder that was contaminated with approximately one equivalent of NaBr. The compound was used without any additional purification: IR (KBr) 1740, 1215, 1050 cm-1. 1H NMR (DMSO D-6) δ 2.48-2.54 (m, 1H), 2.74-2.87 (m, 2H), 2.91-3.04 (m, 2H), 3.48 (s, 3H), 7.12-7.32 (m, 5H), 13C NMR (75 MHz, D2O/DMSO D-6) δ 38.18, 44.80, 52.67, 52.82, 127.42, 129.13, 129.34, 138.14, 176.84.
Reaction SMILES: [NH2:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl>[OH-].[Na+].O1CCOCC1>[CH2:15]([O:14][C:12]([NH:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(CCC(=O)O)C(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(NC(=O)OCc1ccccc1)C(F)F

Procedure:
To a solution of 2 mmole of 4-amino-4-difluoromethylbutyric acid in 5 ml of 1 N sodium hydroxide at 0° C. are added simultaneously from two syringes 2 mmole of benzyl chloroformate in 1 ml of dioxane and 2 ml of 1 N sodium hydroxide. After 30 minutes at 0° C. the solution is acidified by the addition of 6 N hydrochloric acid, then extracted well with dichloromethane. The organic phase is dried and concentrated to afford 4-benzyloxycarbonylamino-4-difluoromethylbutyric acid which is dissolved in 15 ml of dichloromethane and treated with 2 mmole of thionyl chloride at 25° C. for 1 hour after which 4 mmole of propyl amine is added. The solution is stirred at 25° C. for one hour, then washed with water, dried and concentrated. The residue is treated with 6 ml of a solution of dioxane containing 40% w/w hydrogen bromide and allowed to stand for 30 minutes at 25° C. after which 50 ml of ether is added. The resulting precipitate is collected to afford N-propyl 4-amino-4-difluoromethylbutyramide hydrobromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12]C)=[CH:7]2.B(Br)(Br)Br.ClC(Cl)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Oc1cnc2c(Cl)ccnc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A pressure-resistant vial was charged with 8-chloro-3-methoxy-1,5-naphthyridine (1200 mg, 6166 mmol), boron tribromide (6412 μl, 67825 μmol) and dichloroethane (10277 μl, 6166 μmol). The vessel was sealed and the mixture was stirred at 60° C. for 16 h. The reaction mixture was carefully diluted with DCM, and the solids were filtered.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[N:1]1([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=2)[CH:14]=[N:26][N:25]=[N:24]1
Reactant: CCOC(=O)Cc1ccc(N)nc1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(-n2cnnn2)nc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl (6-aminopyridin-3-yl)acetate (0.55 g, 3.05 mmol), CH(OEt)3 (1.35 g, 9.15 mmol) in AcOH (20 mL) was added NaN3 (0.24 g, 3.7 mmol) at room temperature. The mixture was heated to 80° C. and stirred for 3 hours. The mixture was concentrated under reduce pressure. Water was added, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography via silica gel to give ethyl [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate. 1H-NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 8.44 (s, 114), 8.06 (d, J=8.4 Hz, 1H), 7.94 (dd, J=2.4 Hz, 8.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.72 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+]([CH:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:8][CH:7]=1)([O-])=O.C(O)(=[O:20])C>[Fe]>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:20])[CH3:17])=[CH:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: CC(Cc1ccc(-n2cccn2)cc1)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: CC(=O)Cc1ccc(-n2cccn2)cc1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
A stirred suspension comprising iron (10.7 g, 191.9 mmol) in glacial acetic acid (150 ml) under an inert atmosphere of argon is heated to 40° C. and then treated with a solution of 1-[4-(2-nitro-propyl)-phenyl]-1H-pyrazole (8.8 g, 38.39 mmol) in glacial acetic acid (100 ml). The reaction mixture is heated to 100° C. for 2 hours and then allowed to cool to room temperature. The mixture is poured onto ice-water (200 ml), stirred for 5 minutes and then filtered through celite washing through with DCM (50 ml). The organic portion of the filtrate is separated and the aqueous is extracted with DCM (150 ml). The organic portions are combined, washed with water (3×50 ml), brine (1×25 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a red oil. [MH+ 201.25].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:30]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)[N:31]=[C:32]([C:34]([CH2:38][F:39])([CH3:37])[CH2:35][F:36])[CH:33]=3)=[O:27])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:47].O1CCOCC1>ClCCl>[ClH:47].[F:36][CH2:35][C:34]([C:32]1[CH:33]=[C:29]([NH:28][C:26]([NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)=[O:27])[N:30]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:31]=1)([CH2:38][F:39])[CH3:37]
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1

Procedure:
Stir 4-(4-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.1 mmol, 0.6 g) and dissolve in 5 mL of dichloromethane and hydrogen chloride 4.0 M in dioxane (5.3 mmol, 1.3 mL) at room temperature overnight. Concentrate under reduced pressure. Triturate the white solid formed with diethyl ether. LCMS ES+ (m/z) 535 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:20])[C:14](=[O:19])[CH2:15][CH2:16][S:17][CH3:18])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.B1([O-])O[O:22]1.O.O.O.O.[Na+].C([O-])(O)=O.[Na+].ClCCCl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:20])[C:14](=[O:19])[CH2:15][CH2:16][S:17]([CH3:18])=[O:22])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: [O-]B1OO1
Reactant: CSCCC(=O)N(C)c1cnc(-c2cncc(F)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C(=O)CCS(C)=O)c1cnc(-c2cncc(F)c2)s1
Temperature: 65 °C
Yield: 43.6 %

Procedure:
To N-[2-(5-fluoro-pyridin-3-yl)-thiazol-5-yl]-N-methyl-3-methylsulfanyl-propionamide (Compound 30, 44 mg, 0.14 mmol) in glacial acetic acid (1.5 mL) was added sodium perborate tetrahydrate (23 mg, 0.14 mmol), and the mixture was heated at 65° C. for 2 h. The reaction mixture was carefully poured into a separatory funnel containing saturated aqueous NaHCO3 resulting in gas evolution. When the gas evolution had ceased, DCE was added and the layers were separated. The aqueous layer was extracted twice with DCE, and all the organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as white solid (20 mg, 45%): mp 152-154° C.; 1H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 8.59 (s, 0.3H), 8.49 (s, 0.7H), 7.98 (d, J=9.3 Hz, 1H), 7.73 (s, 0.3H), 7.62 (s, 0.7H), 3.64 (s, 2.1H), 3.36 (s, 0.9H), 3.40-2.70 (m, 4H), 2.69 (s, 2.1H), 2.61 (s, 0.9H); ESIMS m/z 328.1 (M+1), m/z 326.1 (M−1).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14]O)[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].S(Cl)([Cl:19])=O.C(Cl)(Cl)Cl>CCCCCC>[Cl:19][CH2:14][CH2:13][N:12]1[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: CCc1nc2ccccc2c(=O)n1CCO
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCc1nc2ccccc2c(=O)n1CCCl
Temperature: 25 °C
Yield: 32.8 %

Procedure:
2-ethyl-3-(2-hydroxyethyl)quinazoline-4 (3H)-one (5.00 g; 22.91 mmol) and thionyl chloride (1.672 mL, 22.91 mmol) were added to a 150 mL reactor, together with 60 mL of chloroform. The reaction medium was heated to reflux and for completing the reaction, which was accompanied through CG/MS. After the end of the reaction, 100 mL of hexane were added and the solution was agitated at room temperature in order to precipitate the product. The resulting suspension was vacuum filtered, washed with two portions of hexane and dried, yielding 3-(2-chloroethyl)-2-ethylquinazoline-4 (3H)-one as a white solid (1.78 g; 7.52 mmol; yield: 32.8%).
Reaction SMILES: NN.[OH-:3].[Na+].[C:5]1([C:11]([N:24]=[C:25]=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO.O.C1COCC1>[CH3:25][N:24]1[CH2:11][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:9][OH:3]
Reactant: O=C=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN1CCCC[C@@H]1CO
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Following the known procedure of patent EP 0 429 984 A2 (reference example 8). The resolution was identical to the above given procedure except that 4 rounds of crystallization were performed instead of the two as sited above. To a mixture of (±)-1-methyl-2-piperidinemethanol (77 g, 596 mmol) in EtOH (615 mL) was added dibenzoyl-D-tartaric acid (205 g, 573 mmol). The resulting mixture was slowly heated until a solution was obtained at which time the solution was slowly cooled with gentle stirring. After 12 h the crystals were isolated and dried to afford 131.6 g. This process was repeated: (2) EtOH (533 mL) provided 92.5 g. (3) EtOH (225 mL) provided 68 g (4) EtOH (200 mL) provided 49 g. The resulting salt was treated with 3M HCl (200 mL) which was heated to induce it to dissolve. The still warn solution was poured into a separatory funnel and extracted with ethyl acetate. The remaining aqueous layer was adjusted to pH 10 with K2CO3. The solution was extracted with CH2Cl2, dried (MgSO4) and concentrated to give 12 g of the alcohol. This alcohol (12 g, 92.8 mmol) was suspended in CH2Cl2 (200 mL) and SOCl2 added. After stirring for 12 h, the solvent was removed to provide a crude HCl salt. This salt was dissolved in EtOH (100 mL) and treated with NH2NH2 (89 mL, 1.86 mol) and heated to reflux for 12 h. NaOH (74 g) in H2O (30 mL) was added and stirred for 1 h. Half the solvent was removed and the residue extracted with ether to give a crude oil. After distillation under reduced pressure (50–60° C.) the pure hydrazine product (4.87 g) was obtained. This hydrazine (1.6 g, 11.2 mmol) was dissolved in THF (10 mL) and triphenylmethylisocyanate (3.19 g, 11.2 mmol) was added slowly. The solution was then stirred overnight and filtered to provide 650 mg of the desired product in good purity. 1H NMR (DMSO-d6): δ 1.10 (m, 2H), 1.30–1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71(d, 1H), 3.25 (q, 1H), 3.55(q, 1H), 4.80 (s, 2H), 7.12–7.32 (m, 15 H), 8.02 (s, 1H). ESI-MS m/z 429.2 (100, M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2Br)[CH:7]=[C:6]([NH2:16])[CH:5]=1.[F:18][C:19]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:20]=1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:24]2[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21][C:20]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:19]=2[F:18])[CH:9]=1
Reactant: COC(=O)c1cc(N)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Br)ccc1OCc1ccc(F)cc1F
Product: COC(=O)c1cc(N)cc(C2=C(c3cc(Br)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure 3 but using 3-amino-5-(2-bromocyclopent-1-enyl)benzoic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and 2-(2,4-difluorobenzyloxy)-5-bromophenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A solution of the product of Example 84A (0.63 g, 2.4 mmol), benzaldehyde (0.24 g, 2.3 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) in methanol (10 mL) containing 1% acetic acid was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and the resultant solution was concentrated under vacuum to a yellow solid. The solid was dissolved in ethyl acetate (50 mL), and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum leaving a light yellow oil. The oil was purified by silica gel chromatography eluting with 1% methanol in methylene chloride to provide the title compound (0.63 g, 77%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH3:9])C(=O)C2=CC=CC=C12.O.NN.O>C(O)C>[ClH:22].[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[CH2:7][CH2:6][NH2:5])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(CCN)c1ccc(-c2ccc(Cl)cc2)cc1
Product: Cl
Reaction time: 0.5 h

Procedure:
38.95 g of 1-phthalimido-3-(4'-chloro-4-biphenylyl)-butane are boiled with 12.2 ml of 80% hydrazine hydrate in 400 ml of ethanol for 2 hours, while stirring, water is added, the mixture is cooled and the resulting 1-(3,4-dihydro-4-oxo-1-phthalazinyl-amino)-3-(4'-chloro-4-biphenylyl)-butane (m.p. 195°) is filtered off, dissolved in 450 ml of ethanol and 450 ml of 37% hydrochloric acid and boiled for 30 minutes, while stirring. The solution is concentrated and worked up using sodium hydroxide solution and ethyl acetate to give 3-(4'-chloro-4-biphenylyl)-butylamine. Hydrochloride, m.p. 256°-259°.