Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CO>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:18][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OCc1cccc(F)c1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: N#Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Temperature: 120 °C
Yield: 80.2 %

Procedure:
A mixture of 2-fluoro-5-nitro-benzonitrile (290 m g, 1.74 mmol), 3-flouro-benzyl alcohol (1220 mg, 1.74 mmol) and K2CO3 (219 mg, 2.09 mmol) in DMA (4 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with MeOH(10 ml), filtered and purified by preparative HPLC to give 20A (380 mg, 80%).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([CH:16]=[CH2:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:22]([O:21][C:19]([NH:18][C@H:13]1[CH:14]([CH2:16][CH3:17])[CH2:15][NH:11][CH2:12]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
A 10% palladium carbon catalyst (15 mg) was added to a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine [an isomer mixture of (4S)-form: (4R)-form (1:4)] (230 mg, 0.66 mmol) in ethanol (8 mL), followed by stirring in a hydrogen atmosphere under an ordinary pressure at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:4)) as a colorless oily substance (148 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Mg+2].[Cl-].[Cl-].[CH2:12]=[O:13]>C1(C)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]=[O:13])=[C:4]([OH:8])[CH:3]=1
Reactant: C=O
Reactant: Oc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=Cc1ccc(Br)cc1O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-bromophenol (100.00 g, 0.576 mol) in a mixture of 600 mL of toluene/acetonitile (2:1) was added MgCl2 (110.6 g, 3.68 mol), paraformaldehyde (40.00 g) and the mixture was maintained at 80° C. for 1.5 h while the by-product was distilled off. A second portion of paraformaldenhyde (40.00 g) was added and the mixture was stirred for 2.5 h at 80° C., and the third portion of paraformaldenhyde (30.6 g) was added and stirred for 2 h at 80° C. The reaction was quenched with cool 2.5 N hydrochloride acid, and the mixture was stirred at room temperature for 1 h to afford a biphasic solution. The aqueous phase was extracted with EtOAc. And the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to afford 4-bromo-2-hydroxybenzaldehyde. 1H-NMR (400 MHz, CDCl3) 11.10 (s, 1H), 9.86 (s, 1H), 7.40˜7.43 (d, J=8.4 Hz, 1H), 7.15˜7.20 (m, 2H).
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[S:10]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].[CH3:21][NH:22]CCCCC=C>>[S:10]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].[CH3:21][NH:22][CH2:9][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH3:8]
Reactant: C=CCCCCNC
Reactant: C=CCCCCC(C)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC=CCCCCNC

Procedure:
Compound 32c was synthesized from 7-bromo-octene as a white powder in quantitative yield, following the procedure as described for compound 32a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])=[CH:5][CH:4]=1.[N:25]([CH2:28][CH3:29])=[C:26]=[O:27]>CN(C=O)C>[CH3:24][C:19]1[C:18]([C:10]2[N:11]([C:26]([NH:25][CH2:28][CH3:29])=[O:27])[C:12]3[C:17]([C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)n1c(-c2c(C)noc2C)c(-c2ccc(OC)cc2)c2ccccc21
Temperature: 70 °C

Procedure:
4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (15 mg, 0.06 mmol) and isocyanatoethane (40 μl) were mixed 1 ml dry DMF under nitrogen. The mixture was heated at 70° C. for 3 h. 100 μl isocyanatoethane were added and the heating at 70° C. continued over night. The crude reaction mixture was purified by prep HPLC. 8.0 mg 2-(3,5-dimethylisoxazol-4-yl)-N-ethyl-3-(4-methoxyphenyl)-1H-indole-1-carboxamide was obtained.
Reaction SMILES: [Br:1]Br.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=2[O:11][CH2:10][CH:9]=1.ClCCl>C(N(CC)CC)C>[NH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=2[O:11][CH2:10][CH:9]1[Br:1]
Reactant: BrBr
Reactant: COc1cccc2c1OCC=C2CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1OCC(Br)C2=CCCN
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3.02 kg of bromine is added during 35 minutes to a mixture of 4.83 kg of 4-(3-aminopropyl)-8-methoxy-2H-[1]-benzopyran hydrochloride and 58 l of dichloromethane at 16°-23°, and once addition is complete the reaction is stirred for 3.5 hours at room temperature. 5.8 kg of triethylamine is added to yield 4-(3-aminopropylidene)-3-bromo-8-methoxy-2H-[1]-benzopyran. The reaction is heated at 60° for 4 hours and then stirred overnight at room temperature. The mixture is washed five times with 12 l water each and 8 l of brine, dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated at reduced pressure to give an oil. This is dissolved in 12 l of isopropanol, treated with 400 g of charcoal, and the mixture is filtered. The filtrate is cooled at 10°, treated with 1.8 l of 10N ethanolic hydrogen chloride and stirred for 1 hour at 5°-10°. The suspension is filtered; the product is washed three times with 4 l isopropanol each and dried 72 hours at 40°/400 Pa to give 7-methoxy-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 195°-198° (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:31][C:28]1[CH:27]=[CH:26][C:25]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([CH3:17])[CH2:19][CH2:20]2)=[CH:30][CH:29]=1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Yield: 26 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.15 g, 0.54 mmol) and [4-(4-methyl-1,4-diazepan-1-yl)phenyl]amine (0.11 g, 0.54 mmol) were stirred in N,N-dimethylformamide (3 mL) with triethylamine (0.3 mL). The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol. The crude material is dissolved in a minimum of 5% methanol in chloroform and then passed through a Florisil plug, eluting with 5% methanol in chloroform. The filtrate is concentrated under reduced pressure to give and then dried under vacuum to give (4Z)-6-bromo-4-({[4-(4-methyl-1,4-diazepan-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (64 mg, 26%) as a rust colored powder.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][C:20]=3[CH:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2o1
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-6-carboxylic acid (110 mg, 0.252 mmol) in THF (5.0 mL) at RT is treated with NaBH4 (19 mg, 0.505 mmol). The resulting mixture is stirred for 1 h and is quenched with water (1.0 mL) and extracted with EtOAc (3×30 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (105 mg, 95%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][C:23]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52]Br)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:22][C:23]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52][N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCN1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCBr)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCN(CCc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-Ethylpiperazine (0.065 mL) and potassium carbonate (0.042 g) were added to an acetone (1.2 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethyl)benzamido)-4-phenylbenzoate (0.060 g), followed by stirring at room temperature for 6 hours. 1-Ethylpiperazine (0.065 mL) was added to the reaction mixture, followed by stirring at room temperature for 9 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.062 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[CH:15]1([P:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([SH:23])=[S:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([P:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([S:23][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:14])[CH3:1])=[S:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: CC(C)CCCCCCCCCCBr
Product: CC(C)CCCCCCCCCCSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
11-Methyldodecyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain isotridecyl dicyclohexylphosphinodithioate, a viscous colorless liquid, which on testing lasted 750 hours longer than the control. The total number of hours required to reach failure was 2.6 times that of the control.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8][C:7]=2[CH:14]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH:10]1[CH2:9][CH2:8][C:7]2[CH:14]=[C:3]([O:2][CH3:1])[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]=2[CH2:12][CH2:11]1
Reactant: COCCN
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCC(=O)CC2
Product: COCCNC1CCc2cc(OC)c([N+](=O)[O-])cc2CC1

Procedure:
(2-Methoxyethyl)-(2-methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)amine was prepared from 2-methoxy-3-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one and 2-methoxyethylamine in a analogous manner to Example 881a. Product was isolated as a brown film. 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.53 (t, 1H, J=14 Hz), 3.37 (s, 6H), 2.83-2.92 (m, 5H), 2.71 (m, 2H), 2.12 (m, 2H), 1.39 (m, 2H).
Reaction SMILES: [NH4+].[Cl-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[CH2:13][N:14]([CH3:16])[CH3:15]>CCO.[Fe]>[CH3:16][N:14]([CH2:13][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[F:3])[NH2:10])[CH3:15]
Reactant: CN(C)Cc1cc([N+](=O)[O-])ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)Cc1cc(N)ccc1F
Temperature: 55 °C
Yield: 72.8 %

Procedure:
A mix of satd. NH4Cl (5.19 mL) in EtOH (8 mL) was treated with 1-(2-fluoro-5-nitrophenyl)-N,N-dimethylmethanamine (494 mg, 2.49 mmol), followed by iron powder (1.39 g, 24.93 mmol) and heated at 55° C. overnight. The mixture was cooled to RT, the solids removed via filtration through diatomaceous earth and washed with 10% MeOH/DCM. The filtrate was concentrated to dryness, the residue treated with DCM, sonicated and the resulting solid collected via filtration, washed with THF and dried to afford 3-((dimethylamino)methyl)-4-fluoroaniline (305 mg, 72% yield). MS (ESI) m/z: 169.1 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=O)[CH2:2][CH2:3][CH3:4].[OH2:30].[O-]Cl.[Na+]>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCCc1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
3-butyryl-4-(2-chlorophenylamino)-8-(3-methylthiopropoxy)quinoline (0.31 g, 0.72 mmol) was dissolved in methylene chloride (10 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride:methanol 95:5 as the eluent gave 0.104g (32%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[CH:22][C:21]=2[O:34]CC2C=CC=CC=2)[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[NH2:10][C@H:11]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2[OH:34])[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 18 h
Yield: 97.7 %

Procedure:
In a 25 ml round-bottomed flask, 1.23 g of {(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl}carbamic acid benzyl ester are dissolved in ml of methanol and also 15 ml of ethyl acetate in the presence of 0.25 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered. The residue is chromatographed on silica gel (95/5 dichloromethane/methanol). 0.625 g of (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one is obtained. Yield=64%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C@H:16]1[C@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:29]([CH2:39][OH:40])[O:28][C@@H:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@@H:17]1[N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:40][CH2:39][C@H:29]1[O:28][C@@H:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@H:17]([N:41]2[C:42](=[O:51])[C:43]3=[CH:50][CH:49]=[CH:48][CH:47]=[C:44]3[C:45]2=[O:46])[C@@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:30]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(O[C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2N2C(=O)c3ccccc3C2=O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 20 h
Yield: 85 %

Procedure:
Under nitrogen gas atmosphere, acetic anhydride (200 ml) and DMAP (catalytic amount) were added to a solution of Compound 21 (10.5 g, 17.6 mmol) in pyridine (200 ml), and the mixture was stirred for 20 hours. Ethanol was added to the reaction mixture, and it was stirred for 20 minutes. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=4:1) to obtain Compound 22 (9.6 g, 85%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:15])=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22]>>[C:1]([NH:4][C:5]1[C:13]([N+:21]([O-:23])=[O:22])=[C:9]([C:8]([Cl:14])=[CH:7][C:6]=1[Cl:15])[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)O)c(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 81 %

Procedure:
5-Acetamido-2,4-dichlorobenzoic acid 1-4 (40.0 g, 0.161 mol) was added in portions to a cooled mixture of concentrated H2SO4 (400 mL) and concentrated nitric acid (400 mL) at 5° C. After stirring for 2 h concentrated H2SO4 (100 mL)/concentrated nitric acid (100 mL) was added. After another 90 min concentrated H2SO4 (400 mL)/concentrated nitric acid (200 mL) was added and stirring was continued for a further 2 h. The reaction mixture was cautiously poured onto ice resulting in the formation of a yellow precipitate. The product was collected by filtration then extracted into EtOAc. The combined organic layers were washed with H2O, brine, dried over Na2SO4, filtered and concentrated to provide the nitro compound 1-5 as a yellow/orange solid (38.1 g, 81% yield). 1H NMR (400 MHz, d6-DMSO) δ1.99 (s, 3H), 8.21 (s, 1H), 10.27 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14](F)[CH:13]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([S:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)c(SCCc2ccccc2)c1
Temperature: 75 °C

Procedure:
Phenylethylmercaptan (2.14 ml, 16 mmol) was added to a stirred suspension of 4-cyano-2-fluorobenzaldehyde (2.23 g, 15 mmol) and potassium carbonate (2.21 g, 16 mmol) in dimethylformamide (10 ml) at room temperature under nitrogen atmosphere. The mixture was heated to 75° C. for 1 hour, then cooled and diluted with water (15 ml). A yellow solid precipitated and was filtered, washed with water and then crystallised from cyclohexane (250 ml) to give pale needles of 4-cyano-2-(2-phenylethylthio)benzaldehyde, m.p. 89° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH:27]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: O=CCCCC1CC(c2ccccc2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCNCC1CCCCC1CC(c2ccccc2)=NO1
Yield: 74.5 %

Procedure:
4-(3-Phenyl-4,5-dihydroisoxazol-5-yl)butanal (20.9 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 25.5 mg (69.2%) of the target compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]>>[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1F
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3F)cc2)cc1

Procedure:
Prepared as described in Example 36, Step 6 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-fluoro-phenyl)-ethyl ester and 2-(4-bromo-phenyl)-2-methyl-propionic acid ethyl ester; purification by preparative HPLC was utilized.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(N)cc1F
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: COc1ccc(N2CCC(C(=O)O)C2=O)cc1F
Yield: 91.5 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) 3-fluoro-4-methoxyaniline (0.628 g; 4.36 mmol) in ethanol (3 mL). 1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.336 g (91%) was obtained as a white solid.