Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH2:7]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O)[CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:13][C:14]1[CH:15]=[C:16](/[CH:17]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: C#CCCCCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 67.8 %

Procedure:
Piperidine (0.26 mL, 2.6 mmol) was added to a suspension of 3-(hex-5-ynyloxy)-4-methoxybenzaldehyde (0.60 g, 2.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.52 g, 2.4 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-(hex-5-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.64 g, 70%) as a pale yellow crystalline solid; mp 135-137° C.; δH (400 MHz, DMSO-d6) 1.62 (p, J=7.2 Hz, 2H, CH2), 1.82 (p, J=7.2 Hz, 2H, CH2), 2.25 (dt, J=7.2, 2.4 Hz, 2H, CH2CCH), 2.78 (t, J=2.4 Hz, 1H, CCH), 3.80 (s, 3H, OCH3), 4.05 (t, J=7.2 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.23 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.37 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 18.1, 25.3, 28.5, 56.3, 68.4, 72.1, 85.0, 112.3, 112.5, 117.3, 120.5, 121.0, 123.3, 127.9, 131.8, 134.7, 141.7, 142.3, 149.0, 151.5, 164.8, 170.1; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1650; vmax 753, 1257, 1512, 1586, 1675, 2941, 3242, 3536 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@:8]([CH2:29][O:30][P:31]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:28])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([N+:25]([O-])=O)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@:8]([CH2:29][O:30][P:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:32])([CH3:28])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:25])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@](C)(CCc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)COP(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@](C)(CCc1ccc(O)c(N)c1)COP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an atmosphere of argon, a solution of [(R)-3-(4-Benzyloxy-3-nitro-phenyl)-1-(di-tert-butoxy-phosphoryloxymethyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (5.36 g, 8.6 mmol) in ethanol (250 mL) was treated with 10% palladium on charcoal (1.22 g). Argon was replaced by hydrogen and the reaction was stirred for 16 hours at RT. After filtration and removal of the solvent in vacuum, the residue was purified by silica gel column chromatography (dichloromethane/methanol 10/1) yielding the title compound as a colorless solid. 1H-NMR (CD3OD): δ=6.61-6.57 (m; 2H), 6.41 (dd; 1H), 6.22 (s; 1H), 4.55 (s; 1H), 4.41/3.93 (2m; 2H), 2.43 (m; 1H), 2.05 (m; 1H), 1.70 (m; 1H), 1.48 (s; 18H), 1.44 (s; 9H), 1.28 (s; 3H); MS (ESI+): 503.4 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](N)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:12][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O>[F:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COc1cc(F)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a mixture of 3,5-dimethoxybenzenamine (6.12 g, 40.0 mmol) and tetrafluoroboric acid (8% solution, 70 mL) was added dropwise a solution of sodium nitrite (2.84 g, 41.2 mmol) in water (10 mL). After stirring at room temperature for 30 min, the reaction mixture was filtered. The solid was collected and washed with water (2×10 mL) and dried under high vacuum. The resulting red solid was suspended in dry hexane (50 mL) and heated to reflux for 2 hr. The mixture was filtered and the filtrate was concentrated to give the crude product as a yellow oil (3.03 g, Yield: 48.5%). MS (ESI) m/z=157 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH:11]([C:13](=[O:18])[NH:14][CH:15]2[CH2:17][CH2:16]2)[OH:12])[CH2:10][CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([CH:11]([OH:12])[C:13]([NH:14][CH:15]2[CH2:16][CH2:17]2)=[O:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)NC2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(O)C(=O)NC2CC2)CC1

Procedure:
A solution of [1-(cyclopropylcarbamoylhydroxymethyl)cyclopropyl]carbamic acid tert-butyl ester in CH2Cl2 (5 mL) and TFA (5 mL) was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and chased with toluene to yield 2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide.
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:25]=[C:26]=[S:27])[CH3:24]>>[CH2:23]([NH:25][C:26]([NH:19][NH:18][C:16](=[S:17])[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:27])[CH3:24]
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCN=C=S
Product: CCNC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The above compound is prepared by a method analogous to that of Example 5 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and ethylisothiocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2([C:10]3([CH3:15])[CH2:12][C:11]3([F:14])[F:13])[CH2:9][O:8]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]([C:10]2([CH3:15])[CH2:12][C:11]2([F:14])[F:13])([OH:8])[CH2:9][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC1(C2(Cc3ccc(F)cc3)CO2)CC1(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C(O)(Cc2ccc(F)cc2)Cn2cncn2)CC1(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 6.3 g (0.026 mol) of 2-(4-fluorobenzyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-oxirane in 5 ml of dimethylformamide is added dropwise with stirring at 80° C. to a mixture of 4.6 g (0.066 mol) of 1,2,4-triazole and 0.5 g (0.0045 mol) of potassium tert.-butylate in 10 ml of dimethylformamide. When the addition is complete, the reaction mixture is stirred for 8 hours at 80° C. The solvent is subsequently stripped off under reduced pressure and the residue which remains is dissolved in ethyl acetate. The organic solution is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using dichloromethane as the eluent. After the eluate has been evaporated, 1.7 g (21% of theory) of 1-(4-fluorophenyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid substance of melting point 114° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[C:11]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)(=[O:15])[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][CH:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:18]=3)[CH2:24][CH2:25]2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCS(=O)(=O)[O-])CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1
Yield: 50.6 %

Procedure:
100 mg (0.75 mmol) of 2-methyl-1H-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 286 mg (0.75 mmol) of 3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propylmethanesulfonate and 310 mg (2.25 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH2Cl2) to obtain 159 mg (yield 51%) of the title compound.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:13][CH2:14][C@:15]1([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:21][C@@H:20]2[C@H:16]1[CH:17]=[CH:18][CH:19]2[CH2:22][CH3:23]>C1C=CC=CC=1>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[NH2:13][CH2:14][C@:15]1([CH2:24][C:25]([OH:27])=[O:26])[CH2:21][C@@H:20]2[C@H:16]1[CH:17]=[CH:18][CH:19]2[CH2:22][CH3:23]
Reactant: CCC1C=C[C@@H]2[C@H]1C[C@]2(CN)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC1C=C[C@@H]2[C@H]1C[C@]2(CN)CC(=O)O

Procedure:
p-Toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol) was added to a benzene solution (20 mL) of tert-butyl(±) [(1S,5R,6S)-6-(aminomethyl)-2-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate (2.75 g, 10.4 mmol), and the mixture was refluxed for 1 hour. The mixture was allowed to cool, and the deposited solid was then washed with methylene chloride to obtain the compound of interest as a gray solid (3.17 g, 80%, Major/Minor=3/1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1])(=[O:9])=[O:8])=[O:16]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: O=S(=O)(Cl)c1sccc1Br
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1sccc1Br

Procedure:
N-[(tert-Butoxy)carbonyl]3-bromothiophene-2-sulfonamido 2,2-dimethylpropanoate (58) is synthesised from 3-bromothiophene-2-sulfonyl chloride (synthesised according to the method detailed in Bioorganic and Medicinal Chemistry Letters 1996, 6, 2651-2656), sodium hydride and [(tert-Butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. (0.2 g, 12%), 1H NMR (500 MHz, DMSO-d6) δ ppm 8.25 (1H, d, 5.2 Hz), 7.44 (1H, d, 5.2 Hz), 1.39 (9H, s), 1.29 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)/[C:7]([CH3:23])=[C:6]2[CH2:24][C:25]([OH:27])=O.C(Cl)(=O)C([Cl:31])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)/[C:7]([CH3:23])=[C:6]2[CH2:24][C:25]([Cl:31])=[O:27]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)/C2=C/c1ccc(S(C)(=O)=O)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccc(S(C)(=O)=O)cc1

Procedure:
(Z)-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 35 ml) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19]Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[S:33])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1COCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:34]=[C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)[S:33][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Reactant: COc1cccc(NC(N)=S)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC(c2ccc(-c3csc(Nc4cccc(OC)c4)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of {4-[4-(2-bromoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (100 mg, 0.272 mmol) in EtOH/THF (4:1 v/v, 5 mL) is added 3-methoxyphenylthiourea (99.6 mg, 0.272 mmol) and Na2CO3 (58 mg, 0.545 mmol). The reaction mixture is allowed to stir at 50° C. for 3 h. The reaction mixture is used directly in the next step: (M+H)+451.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:29])=[CH:25][NH:26]2)=[CH:22][CH:21]=1)=[O:19].O>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:25]1[NH:26][C:27]2[C:23]([C:24]=1[CH3:29])=[CH:22][CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:28]=2)=[O:9]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(C)c(C(=O)c3ccc(Cl)cc3Cl)[nH]c2c1
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
Aluminium chloride (1.72 g) is suspended in methylene chloride (50 ml), to which are added 2,4-dichlorobenzoyl chloride (1.35 g) and then 6-(methoxycarbonyl)-3-methylindole (1.00 g), and stirred at room temperature for 16 hours and then at 40° C. for 2.5 hours. The reaction mixture is poured into water with ice, and then extracted with ethyl acetate (150 ml). The organic layer is washed three times with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and then with a saturated saline solution, and thereafter dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting crystal is washed with methyl t-butyl ether and dried to obtain 2-(2,4-dichlorobenzoyl)-6-(methoxycarbonyl)-3-methylindole (71) (1.48 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH2:25][CH3:26].C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH:21][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Reaction time: 16 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-amino-2-pyridinyl)amino]piperidine (EXAMPLE 204B, 6.37 g, 20.56 mmol) and propionaldehyde (1.63 ml, 22.6 mmol) are dissolved in 50 ml methanol and cooled to 0°. Sodium cyanoborohydride (1.42 g, 22.6 mmol) is added and the mixture is warmed to 20°-25°. Twice more propionaldehyde (22.6 mmol) and sodium cyanoborohydride (22.6 mmol) are added, cooling the mixture to 0° before and warming to 20°-25° after each addition. The mixture is stirred 16 hr, then poured into 1N sodium hydroxide and extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, 300 g; ethyl acetate/hexane (25/75)), gives the title compound, NMR (400 MHz, CDCl3) 7.72, 7.30, 6.91, 6.78, 4.79, 3.49, 3.14, 3.04, 2.87, 1.98, 1.73, 1.63, 1.01 and 0.86δ.
Reaction SMILES: OO.[CH2:3]([C:5]1[N:6]=[N+:7]([O-:20])[C:8]2[C:17]3[CH2:16][N:15]([CH3:18])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[N:19]=1)[CH3:4].C(O)(C(F)(F)F)=[O:22]>C(Cl)Cl.N>[CH2:3]([C:5]1[N:6]=[N+:7]([O-:20])[C:8]2[C:17]3[CH2:16][N:15]([CH3:18])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[N+:19]=1[O-:22])[CH3:4]
Reactant: CCc1nc2ccc3c(c2[n+]([O-])n1)CN(C)CC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCN(C)C3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
H2O2 (70%, 0.5 mL, ca. 5 mmol) was added dropwise to a stirred solution of TFM (0.7 mL, 5 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 264 (120 mg, 0.5 mmol) and TFA (0.19 mL, 2.5 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (20 mL) and extracted with DCM (4×100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-8%) of MeOH/DCM, to give 1,4-dioxide 265 (24 mg, 19%) as a red solid: mp 117-121° C.; 1H NMR δ 8.35 (d, J=8.8 Hz, 1H, H-5), 7.70 (d, J=8.8 Hz, 1H, H-6), 4.41 (s, 2H, H-10), 3.18 (q, J=7.5 Hz, 2H, CH2), 3.12 (br t, J=5.8 Hz, 2H, H-7), 2.74 (t, J=5.8 Hz, 2H, H-8), 2.58 (s, 3H, NCH3), 1.42 (t, J=7.5 Hz, 3H, CH3); MS (APCI) m/z 261 (MH+, 100%); HRMS (FAB+) calcd for C13H17N4O2 (MH+) m/z 261.1352, found: 261.1354.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(C(=O)O)CC1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
96 g (0.448 mol) of 4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylic acid (mixture of cis and trans isomers) was dissolved in CH2Cl2 (1 L). To this solution, oxalyl chloride (76 mL, 0.885 mol) was added dropwise. The reaction was stirred at room temperature for 2 hours and then concentrated. CH2Cl2 (1 L) was added to the residue and the solvent was stripped off. The process was repeated. Next, the residue was dissolved in CH2Cl2 (1 L) and Et3N (94 mL, 0.672 mol) was added. The solution was cooled to 10° C. and benzyl alcohol (56 mL, 0.537 mol) was added dropwise. The reaction was allowed to warm to room temperature and stir at room temperature for 12 hours. Next, the solvent was removed and toluene (1 L) was added. The volume of solvent was reduced to 500 mL and the solids were removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (0 to 20% EtOAc/heptanes) to afford benzyl trans-4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylate.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)=[CH:29][CH:28]=1>>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:35]2[CH2:36][CH2:37][CH:33]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:25])([F:38])[F:39])=[CH:28][CH:29]=3)[CH2:34]2)=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)phenyl]pyrrolidine oxalate (18.3 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.5 mg). Calcd for C22H16F6N2O2: 454.1116, found 454.1116.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:10][CH:9]=1)[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:5]([CH3:6])[CH2:4][OH:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
48 g of ethyl-α-[4-(2,4-dichlorophenoxy)phenoxy]propionate was dissolved in 80 ml of anhydrous diethyl ether and the solution was added dropwise to a dispersion of 5 g of lithium aluminum hydride in 200 ml of anhydrous diethyl ether while cooling. After completion of the addition, the mixture was allowed to stand for 12 hours at room temperature and then heated under refluxing for 1.5 hours to complete the reaction. The reaction mixture was poured into an appropriate amount of ice water, and the ethereal layer was separated. The ethereal layer was again extracted with diethyl ether and the extract was dried over anhydrous sodium sulfate. The ether was removed by distillation from the dried extract, and the residue was distilled under reduced pressure to obtain 40 g of the desired product having a boiling point of 201° to 205° C/2 mmHg.
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[Cl:29][C:30]1[S:34][C:33]([CH2:35][O:36][NH2:37])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[S:34][C:33]([CH2:35][O:36][NH:37][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:32][CH:31]=1
Reactant: NOCc1ccc(Cl)s1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Product: O=C(NOCc1ccc(Cl)s1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by the same method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(5-chloro-thiophen-2-ylmethyl)-hydroxylamine (see preparation 64).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])c(O)c1

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde (5 g) in toluene (50 ml) was added carbethoxymethylenetriphenylphosphorane (8.96 g), and the mixture was heated under reflux for 2 h. The mixture was then concentrated and the residue was purified by column chromatography eluting with cyclohexane:ethyl acetate (6:4) to give the title compound. (6.2 g) as a solid, m.p. 95°.