Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[N:21]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:34][CH2:35]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see below) and amine 5.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[OH-].[Na+]>CC(O)=O.O.[Pd]>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:35]
Reactant: CCC(CC)C(=O)Nc1ccc(C2=CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC)C(=O)Nc1ccc(C2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of N-{4-[1-(diethylcarbamoyl-phenyl-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenyl}-2-ethyl-butyramide (10 mg, 0.021 mmol) in HOAc (1 mL), H2O (0.1 mL) and 10% Pd/C (2 mg) were added. The mixture was stirred under H2 (1 atm) at 25° C. for 16 h. The mixture was neutralized to pH ˜7 with 1 M NaOH. The mixture was extracted with DCM (2×5 mL), and the organic layer was concentrated and purified by PTLC to provide the title compound (7 mg, 70%). MS: 482.4. 1H NMR (CDCl3): 7.53-7.28 (m, 6H), 7.19-7.03 (m, 3H), 4.26 (s, 1H), 3.50-3.05 (m, 5H), 2.98-2.92 (m, 1H), 2.83-2.75 (m, 1H), 2.44-2.36 (m, 1H), 2.30-1.95 (m, 2H), 1.90-1.47 (m, 8H), 1.08 (t, J=7.0, 3H), 1.04 (t, J=7.1, 3H), 0.91 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:22]=1[C:23]#[N:24].O>CN(C=O)C>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:15][CH2:14][CH:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[O:4][CH3:3])[CH2:13][CH2:12]2)[C:22]=1[C:23]#[N:24]
Reactant: COc1ccccc1CC1CCC(CO)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1CC1CCC(COc2cccc(F)c2C#N)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (0.043 g; 1.1 mmol) in anhydrous DMF (1.4 mL) is added a solution of [4-(2-methoxybenzyl)cyclohexyl]methanol (0.21 g, 0.9 mmol) in anhydrous DMF (1.4 mL) over 11 minutes. After allowing to room temperature over 2 hours, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (0.14 g; 0.99 mmol) in anhydrous DMF (1.4 mL), and allowed to room temperature over 18 hours. The mixture was poured into a water (40 mL) solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to purify by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain 2-fluoro-6-[4-(2-methoxybenzyl)cyclohexylmethoxy]benzonitrile (0.09 g, 28% yield).
Reaction SMILES: O=[Ce:2]=O.[C:4](=[O:7])([O-])[O-:5].[Ce+3].[C:9](=[O:12])([O-])[O-:10].[C:13](=[O:16])([O-])[O-:14].[Ce+3]>C(O)(=O)C>[C:4]([O-:5])(=[O:7])[CH3:9].[Ce+3:2].[C:9]([O-:10])(=[O:12])[CH3:13].[C:13]([O-:14])(=[O:16])[CH3:4]
Reactant: O=[Ce]=O
Reactant: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
High surface area ceria was first prepared following traditional procedures. Five grams of cerium carbonate was slowly mixed with 4.5 ml of glacial acetic acid to produce cerium acetate. The sample was dried in a vacuum over at 100° C., the calcined in air at 425° C. to produce cerium oxide. The ceria was coated with a layer of Al2O3 to act as a template by mixing 2 g of the ceria with 40 ml of a 0.01M Al2O3 sol (diluted from a 20 wt % sol), stirring overnight, then filtering, washing, drying, and calcining in air at 500° C. as above. The zeolite precursor solution was prepared by mixing a solution containing NaOH, dissolved Al foil, and H2O with tetraethylorthosilicate (TEOS) and tetrapropylammonium hydroxide (TPAOH) such that the molar concentrations in the final solution was 4:0.06:571:6:1 NaOH:Al:H2O:TEOS:TPAOH. The solution was stirred at room temperature overnight, then approximately 40 ml was added to 2 g of the Al2O3 coated ceria in an autoclave. The autoclave was heated to 175° C. for 6 hrs under autogenic pressure. After rapid cooling, the sample was filtered, washed, dried, then calcined for 6 hrs in air at 500° C. to remove residual organic compounds. Copper was exchanged with the zeolite film/ceria following the methods listed above for CeO2/Cu-ZSM-5. The final catalyst will be referred to as “Cu-ZSM-5/CeO2”.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)[CH:19]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:37]([O:39][NH2:40])C.N1C=CC=CC=1>C(O)C.CCOC(C)=O>[CH3:37][O:39][N:40]=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:35])[CH:26]=2)[CH:19]=1)[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: CCON
Reactant: Cc1cc(Nc2cccc(C(=O)CCN3CCC(Cc4ccccc4)CC3)c2)c2ccccc2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(CCN1CCC(Cc2ccccc2)CC1)c1cccc(Nc2cc(C)nc3ccccc23)c1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
A mixture of Example 209 (0.40 g, 0.86 mmol), ethoxyamine hydrochloric acid (0.22 g, 2.63 mmol,) and pyridine (0.19 g, 2.47 mmol) in anhydrous ethanol (3.0 mL) was heated under reflux overnight. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL). Upon sequential washings with 1 N NaOH (2×100 mL) and brine (100 mL), the organic solution was dried over Na2SO4 and evaporated to dryness. The resulting residue was purified via flash silica gel chromatography to give the desired product (100 mg, 24%) as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCCCCCc1ccccc1
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCCCCCc1ccccc1)CCc1ccc(C#N)cc1

Procedure:
A solution of 127 mg (0.32 mmol) of ethyl (7E)-6-[2-(4-cyanophenyl)ethyl]-8-(2-hydroxyphenyl)oct-7-enoate in 10 ml of acetonitrile is mixed with 88.42 mg (0.39 mmol) of (5-bromopentyl)benzene and 67.25 mg (0.49 mmol) of potassium carbonate and stirred under reflux for 12 hours. After cooling, the mixture is concentrated. The residue is taken up in ethyl acetate and extracted with water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The resulting residue is purified by preparative HPLC. 128 mg (0.24 mmol, 73.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:27])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:28](C[Sn])=[N+:29]=[N-:30]>O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[NH:30][N:29]=[N:28][N:2]=4)[CH:4]=3)=[O:27])[CH2:14][CH2:15]2)=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1
Reactant: [N-]=[N+]=NC[Sn]
Solvent: O
Product: O=C(Nc1cccc(-c2nnn[nH]2)c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(3-cyano-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-2-oxo-acetamide (Example 14) and azidomethyltin (Aldrich) according to the method described in Example 71. Melting Point: 107-112° C. (water)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[SH:30][CH2:31][C:32]([NH:34][CH3:35])=[O:33]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([S:30][CH2:31][C:32]([NH:34][CH3:35])=[O:33])=[N:3][C:4]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CNC(=O)CS
Product: CNC(=O)CSc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.4 g) and 2-mercapto-N-methylacetamide (0.1 g). The intermediate product containing the SEM (2-[trimethylsilyl]ethoxymethyl) group was purified by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.05 g.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH:14]=[O:15])=[CH:9][C:8]=1[O:16][CH3:17])(=O)=O.CCOC(C)=O.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:26]#[N:27])=[C:8]([O:16][CH3:17])[CH:9]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: COc1cc(C=O)c(C)cc1OS(=O)(=O)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(C)cc1C#N
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate (35.0 g, 117 mmol), zinc cyanide (55.1 g, 469 mmol) and tetrakis triphenylphosphine palladium (0) (20.34 g, 17.60 mmol) in DMF (300 mL) were stirred at 110° C. under nitrogen atmosphere for 8 hr. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxy-5-methylbenzonitrile. 1H NMR (CDCl3, 500 MHz) δ 10.39 (s, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 4.02 (s, 3H), 2.66 (s, 3H); LC/MS: (IE, m/z) [M+1]+=176.06; tR=2.71 min.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:18])[C:6]2=[O:17].C([O-])([O-])=O.[Na+].[Na+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:13]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH:5]([CH3:18])[C:6]2=[O:17])=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(C(C)(C)C)cc2c(c1Br)CC(C)C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)C2=O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a mixture of 46.7 g (0.150 mol) of 4-bromo-6-tert-butyl-5-methoxy-2-methylindan-1-one, 44.5 g (0.420 mol) of Na2CO3, 22.0 g (0.180 mol) of PhB(OH)2, 570 ml of DME, and 195 ml of water 0.674 g (3.0 mmol) of Pd(OAc)2 and 1.58 g (6.00 mmol) of PPh3 were added. The resulting mixture was refluxed for 12 h, cooled to room temperature, and then DME was evaporated on Rotavap. To the residue 1 liter of cold water was added, and the crude product was extracted with 3×300 ml of dichloromethane. The combined organic extract was dried over K2CO3 and then evaporated to dryness. The residue after evaporation was extracted with hot hexane (500 ml, then 3×250 ml) and this extracts while hot were passed through a short pad of silicagel, evaporated on Rotavap to yield 45.1 g (98%) of 6-tert-butyl-5-methoxy-2-methyl-4-phenylindan-1-one as a slightly yellowish crystalline solid which was further used without an additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:12]=[C:11]([CH:23]=[O:24])[CH:10]=1.[Cl:25]N1C(=O)CCC1=O.O>O1CCCC1.CN(C)C=O>[Cl:25][C:12]1[N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[CH:10][C:11]=1[CH:23]=[O:24]
Reactant: O=Cc1cc(-c2c(F)cccc2F)n(S(=O)(=O)c2cccnc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-c2c(F)cccc2F)n(S(=O)(=O)c2cccnc2)c1Cl
Reaction time: 15 h
Yield: 58.2 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.06 g) and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-yellow oil (yield 160 mg, 58%).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH2:3][CH3:4].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][NH2:26].C(O)(=O)C.[OH-].[Na+]>ClCCCl.C(Cl)Cl>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][NH:26][CH2:8][C:7]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:6]=1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:18][CH3:19]
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
2-(Butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (6.5 g), 3,5-bis-trifluoromethyl-benzylamine (7.52 g), acetic acid (2.04 ml) are dissolved in 1,2-dichloroethane (50 ml), and thereto is added triacetoxy sodium borohydride (10.1 g) at room temperature and the mixture is stirred for 2 hours. To the reaction solution are added 1N-aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine and dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (10.48 g). MS (m/z): 501 [M+H]+
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32](/[CH:36]=[CH:37]/[C:38]([O:40]CC)=[O:39])[O:33][C:34]=3[CH3:35])=[C:26]([O:45][CH3:46])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32](/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39])[O:33][C:34]=3[CH3:35])=[C:26]([O:45][CH3:46])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3/C=C/P(=O)(OCC)OCC)cc2OC)c(C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(/C=C/C(=O)O)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a mixture of ethyl (2E)-3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoate (0.62 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give (2E)-3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoic acid as colorless crystals (0.50 g, yield 85%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH:28]([C:30]1[O:31][CH:32]=[CH:33][CH:34]=1)=[O:29]>O1CCCC1.CCCCCC.[Cl-].[Na+]>[Cl:13][C:14]1[C:26]([CH:28]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)[OH:29])=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)cc1Cl
Reactant: O=Cc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Cl)c(C(O)c2ccco2)c1Cl
Temperature: -75 °C
Reaction time: 12 h

Procedure:
At -20° C., 4.0 g (39.6 mmol) of diisopropylamine in 80 ml of tetrahydrofuran are treated for 15 min with 19 ml (30.4 mmol) of 1.6 M n-butyllithium solution in hexane. After cooling to -75° C., a solution of 7.5 g (30.4 mmol) of tert-butyl 2,4-dichlorobenzoate in 20 ml of tetrahydrofuran is added dropwise and the mixture is stirred at room temperature for 12 h. The reaction mixture is admixed with a solution of 2.9 g (30.2 mmol) of 2-formylfuran in 15 ml of tetrahydrofuran and stirred at room temperature for a further 12 h. The mixture is taken up in 300 ml of saturated aqueous sodium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. Yield: 9.2 g; 1H-NMR, δ [ppm], (CDCl3): 1.6 (s), 3.6 (d), 6.2 (m), 6.3 (m), 7.4 (m), 7.7 (d), 7.4 (m), 7.5 (d)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:27])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCc1cccnc1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1cccnc1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([O-:12])([OH:11])=[O:10].[N:13]#[C:14][NH2:15]>CCO>[N+:9]([O-:12])([OH:11])=[O:10].[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[NH:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc(F)cc1
Yield: 47 %

Procedure:
A solution of 4-fluoroaniline (25 mmol, 2.80 g) in EtOH (10 mL) was cooled on an ice bath. Nitric acid (69% aq. soln.; 1.8 mL) was added dropwise. Then cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 21 h. The solvent was evaporated to dryness. The solid residue was washed with EtOH and dried under high vacuum overnight to afford the title compound as a purple powder (2.54 g, 47%). This material was used for subsequent reaction without further purification.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH:12]1(C2C=CC(N)=CC=2)[CH2:17][CH2:16]C[CH2:14][CH2:13]1>>[ClH:1].[CH:9]1([C:7]2[CH:6]=[CH:5][C:4]([NH:10][NH2:11])=[CH:3][CH:8]=2)[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1
Reactant: Cc1ccc(NN)c(Br)c1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: Cl
Product: NNc1ccc(C2CCCCC2)cc1

Procedure:
4-Cyclohexylphenylhydrazine hydrochloride (35.6 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 4-cyclohexylaniline as starting material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[C:5]([O:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.Cl.[Sn](Cl)(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[O:8][CH2:9][C:10](=[O:11])[NH:15][C:4]=2[CH:3]=1
Reactant: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1COc2ncc(Br)cc2N1
Temperature: 65 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Ethyl [(5-bromo-3-nitropyridin-2-yl)oxy]acetate (intermediate 212) (4.3 g, 14.1 mmol) was dissolved in anhydrous THF (10 mL) and concentrated HCl (10 mL) was added at 0° C. Tin chloride (5.0 g, 26.4 mmol) was added in small portions. The reaction was stirred for 1 hr and heated at 65° C. overnight. The reaction mixture was concentrated under reduced pressure, extracted with chloroform, dried over magnesium sulfate and concentrated. Chromatography on silica gel with methanol/chloroform gave the product as a light pink solid (1.2 g, 37% yield).