Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C[CH2:2]1.C1(C)C=CC(N=[N+]=[N-])=CC=1.C=CCCCCCCCC.[CH3:24][C:25]12[N:31]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[CH:30]1[CH2:29]CC[CH2:26]2.CC1CCCCC=1>>[CH3:26][C:25]1([CH3:24])[C:30]([CH3:29])([CH3:2])[N:31]1[C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: C1CN1
Reactant: Cc1ccc(N2C3CCCCC32C)cc1
Agent: C=CCCCCCCCC
Agent: CC1=CCCCC1
Agent: Cc1ccc(N=[N+]=[N-])cc1
Product: Cc1ccc(N2C(C)(C)C2(C)C)cc1

Procedure:
Selected control reactions following the method of the General Catalytic Reaction were attempted but without [(Me,EtTCPh)Fe(NCCH3)2](PF6)2. These reactions either gave lower yields for aziridines or almost no isolable aziridine. Two example cases are shown. 2-octyl-1-(ptolyl)aziridine. p-Tolyl azide (0.096 g, 0.72 mmol) and 1-decene (1.853 g, 13.2 mmol) were used in the General Catalytic Reaction described above yielding 0.078 g, 43% yield. 1-methyl-7-(p-tolyl)-7-azabicyclo[4.1.0]heptane. p-Tolyl azide (0.203 g, 1.53 mmol) and 1-methylcyclohexene (4.055 g, 42.2 mol) were used in the General Catalytic Reaction described above yielding 0.007 g, 2% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].NC(N)=[S:32].NCCNCCNCCNCCN>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][SH:32])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: NC(N)=S
Agent: NCCNCCNCCNCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cccc(CCCCCCS)c1CCC(=O)OCC
Yield: 81.1 %

Procedure:
To a solution of 4-[3-(6-Bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (5g, 10.60 mmol) in THF (100 mL), thiourea (0.889 g, 11.68 mmol) was added and heated to reflux overnight. According to HPLC analysis, the starting material was completely consumed. Tetraethylenepentamine (4.02 g, 2.7 mL, 21.23 mmol) was added and the reaction mixture was heated to reflux overnight. At this time, the reaction mixture was diluted with EtOAc (500 mL), washed with 3N HCl (100 mL), water brine and dried over Na2SO4. The solvent was removed in vacuo to afford an oil. FCC (2% EtOAc/Hex) provided an oil (3.65 g, yield 81%). 1H NMR (CDCl3): □ 7.09 (t, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.18-4.08 (m, 4H), 3.99 (t, 2H), 2.95 (t, 2H), 2.64-2.46 (m, 8H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.B(F)(F)F.CCOCC.[CH3:21][C:22]([CH3:35])=[CH:23][CH2:24][CH2:25][C:26]([CH:33]=[CH2:34])=[CH:27][O:28][Si](C)(C)C>C(Cl)Cl>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:34][CH:33]=[C:26]([CH2:25][CH2:24][CH:23]=[C:22]([CH3:21])[CH3:35])[CH:27]=[O:28]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: C=CC(=CO[Si](C)(C)C)CCC=C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)=CCCC(C=O)=CCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 5-trimethylsilyl-3-furanaldehyde (0.444 g, 2.6 mmol) in 5 ml methylene chloride at -60° under argon was added dropwise boron trifluoride etherate (0.33 ml, 2.7 mmol). After one to two minutes a solution of 2-(4-methyl-3-pentenyl)-1-trimethylsilyloxy-1,3-butadiene (0.604 g, 2.7 mmol) in 3 ml methylene chloride was added dropwise. The solution was stirred for 20 hours at -60°, quenched with saturated sodium bicarbonate solution, warmed to room temperature, and taken up in ethyl ether. The organic portion was washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give an orange oil which was complex by TLC. The mixture was purified by flash chromatography (silica, 30% ethyl acetate/hexane). Eluted last was the desired hydroxyaldehyde as an orange oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([Si:14](Cl)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].O>N1C=CC=CC=1>[CH2:12]([Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:11][CH2:10][C:3]([CH2:2][O:1][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH3:13])([CH2:8][O:9][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH3:13])[C:4]([O:6][CH3:7])=[O:5])[CH3:13]
Reactant: COC(=O)C(CO)(CO)CO
Reactant: CC[Si](Cl)(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)OCC(CO[Si](CC)(CC)CC)(CO[Si](CC)(CC)CC)C(=O)OC

Procedure:
To a stirred solution of methyl 3-hydroxy-2,2-bis(hydroxymethyl)propanoate (1 equivalent) in pyridine at rt is added triethylsilyl chloride (3-6 equivalents) and the mixture is stirred at temperatures between rt and 60° C. until the reaction is substantially complete as monitored by LCMS or TLC. Water is added and the mixture is extracted with diethyl ether. The combined extracts are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford methyl 3-(triethylsilyloxy)-2,2-bis((triethylsilyloxy)methyl)propanoate.
Reaction SMILES: O=C(NCCC)C(N[C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:18][C:16]=2[CH:17]=1)=[O:12])C1C=CC=CC=1.[Li+].[OH-:46]>C1COCC1.CO.O>[F:38][C:37]([F:39])([F:40])[C:34]1[CH:33]=[CH:32][C:31]([C:26]2[C:25]([C:23]([NH:22][C:19]3[CH:18]=[CH:16][C:15]4[O:14][C:13]([C:11]([OH:12])=[O:46])=[CH:17][C:21]=4[CH:20]=3)=[O:24])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: CCCNC(=O)C(NC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1)c1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
The product from step (c) (8.1 g) was dissolved in THF (100 mL) and methanol (100 mL). Under stirring conditions was added LiOH (2 g) in water (100 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated in vacuo, acidified by adding 1 N HCl solution. The product was extracted with ether (2×300 mL), and combined organic layers were washed with brine (2×50 mL) and then dried over MgSO4. The organic layer was then concentrated in vacuo to give the crude product which was purified by recrystallization from ether/hexane to give 7.1 g of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1OC
Temperature: 75 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of 510 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-iodopyridine, 200 mg of (3R)-3-ethynyl-3-quinuclidinol, 139 mg of tetrakis (triphenylphosphine) palladium (0), 11 mg of cuprous iodide, 0.50 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 281 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[C:24](=O)[CH3:25])=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=3.Cl.[NH2:28][OH:29]>CCO.N1C=CC=CC=1>[Br:1][C:2]1[C:7]2[CH:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[C:24](=[N:28][OH:29])[CH3:25])=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=3
Reactant: COc1cccc2c1-c1ccc(C(C)=O)c(Br)c1C(c1ccccc1)O2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cccc2c1-c1ccc(C(C)=NO)c(Br)c1C(c1ccccc1)O2

Procedure:
A solution of Example 357C (700 mg, 2.03 mmol) and hydroxylamine hydrochloride (2.45 g, 30.4 mmol) in a mixture of EtOH (70 mL) and pyridine (70 mL) was refluxed for 8 hours, cooled and concentrated. The residue was dissolved in EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to provide the desired compound without purifiction.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[H][H].[CH:16](O)(C)C>>[CH:1]1([C:8]2([CH3:16])[CH2:13][CH2:12][O:11][C:9]2=[O:10])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1OCCC1Cc1ccccc1
Reactant: CC(C)O
Reactant: [H][H]
Product: CC1(C2CCCCC2)CCOC1=O
Yield: 92 %

Procedure:
In a 250 mL autoclave a mixture of 2-benzyl-γ-butyrolactone (5.00 g) and Rh-catalyst (5 wt. % Rh on carbon, 0.500 g) in isopropanol (60 mL) was treated with hydrogen (13 bar) at 120° C. for 18 h. Upon completion of the hydrogenation, the mixture was filtered and concentrated on a rotary evaporator to give 4.75 g (92%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:35]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]1=O)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>ClC(Cl)C>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH:45]2[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:43][CH2:44]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
3.3-diphenylpropylamine (5.8 g, 27.5 mmol), sodium triacetoxyborohydride (6.36 g, 30 mmol) and 0.5 ml of acetic acid are added to 5 g (25 mmol) of N-Boc-piperidone in 100 ml of dry dichloroethane. The turbid yellow solution is agitated at ambient temperature for 1 hour. 50 ml of a soda solution (0.1 M) is then added and the mixture is agitated for 30 minutes. The organic phase is washed with a saturated solution of sodium bicarbonate, with sodium chloride, dried over magnesium sulphate, filtered and concentrated in order to produce 10 g of a yellow solid. This solid is purified by flash chromatography on silica gel eluting with a heptane/ethyl acetate mixture (4/1, 3/1, 2/1 then 1/1) then with pure ethyl acetate. The fractions are concentrated under vacuum in order to produce 5.6 g (yield=57%) of a pale yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH:12]=[N:13][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(O)=O.[Na+].C(Cl)[Cl:34]>C(O)(C(F)(F)F)=O>[ClH:34].[ClH:34].[C:1]([C:9]1[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][NH:18]2)[CH:12]=[N:13][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC#Cc1cncc(OC[C@@H]2CCN2)c1
Product: Cl

Procedure:
A sample of 5-octynyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 63a in CH2Cl2 (3 mL) and TFA (2 mL) was stirred for 30 minutes at 0° C. The residue was neutralized with NaHCO3 to pH 8, then extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2 :MeOH 10:5 to 10:11 to afford the free base of the title compound (178 mg). MS (CI/NH3) m/z 273 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.90 (m, 3H), 1.32 (m, 4H), 1.45 (m, 2H), 1.62 (m, 2H), 2.40 (m, 2H), 2.53 (m, 2H), 3.80 (m, 1H), 3.96 (m, 1H), 4.19 (m, 2H), 4.62 (m, 1H), 7.22 (m, 1H), 8.20 (m, 2H). The base was converted to the salt by treatment with hydrogen chloride saturated EtOH to give the title compound. mp 88-90° C. MS (CI/NH3) m/z 273 (M+H)+. 1H NMR (D2O, 300 MHz) δ0.90 (m, 3H), 1.33 (m, 4H), 1.46 (m, 2H), 1.64 (m, 2H), 2.50 (t, J=2.9 Hz, 2H), 2.71 (m, 2H), 4.05-4.22 (m, 2H), 4.49 (d, J=4.4 Hz, 2H), 4.98 (m, 1H), 7.99 (m, 1H), 8.34 (s, 1H), 8.39 (d, J=2.6 Hz, 1H). Anal. Calcd for C17H24N2O·2.8 HCl: C, 54.53; H, 7.21; N, 7.48. Found: C, 54.25; H, 7.12; N, 7.63. [α]25D=-9.64° (c 2.08, MeOH).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[ClH:19].CC(C)=O.N([O-])=O.[Na+]>O>[Cl:19][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: Cl
Reactant: Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)n[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
3-(4-Amino-3-trifluoromethylphenyloxy)-5-methylpyrazole (2.00 g, 7.8 mmol) was added to a mixed solution of concentrated hydrochloric acid (2.1 ml) and acetone (20 ml) at room temperature, and the mixture was stirred at room temperature for 20 minutes. After the mixture was cooled below 0° C., a solution of sodium nitrite (0.54 g, 7.8 mmol) in water (3 ml) was dropwise added, and the mixture was stirred at an ambient temperature for 30 minutes. Then, cuprous chloride (0.85 g, 8.6 mmol) was little by little added at 0° C., and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml×2). An organic layer was washed with water (50 ml×3), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish viscous substance of 3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole (2.12 g, yield: 98.7%). 1H-NMR (CDCl3, TMS, ppm): δ 2.25 (s, 3H), 5.64 (s, 1H), 7.23 (dd, J=3.0 and 8.8 Hz, 1H), 7.31-7.46 (m, 2H), 10.56 (br s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10]>O1CCCC1>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:9](=[O:10])[C:8]([F:15])([F:14])[F:7]
Reactant: NCC(O)CO
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCC(O)CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
15 g of 3-aminopropan-1,2-diol (164.6 mmol) were solubilized in 100 ml of tetrahydrofuran in a round-bottomed flask provided with a magnetic bar. The reaction mixture was then cooled to 0° C. on an ice bath and 21.5 ml of ethyl trifluoroacetate (181.1 mmol) were gradually added. The reaction mixture was stirred for 2 hours at room temperature. The crude reaction product was then evaporated to dryness. 29 g of a pure colorless oil were thus obtained (yield: 95%), that product was used without further purification.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH2:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:26][S:31]([CH3:30])(=[O:33])=[O:32])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 69 mg (0.16 mmol) of (3S,5R,6S)-3-allyl-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 28, Step B from the non-racemic precursor described in Example 19, Step A) in 1.6 mL of DCM was added methanesulfonyl chloride (13.7 μL, 0.175 mmol) and pyridine (38.7 μL, 0.478 mmol) successively at 0° C. After being stirred at rt for 14 h the reaction mixture was acidified with 10% aq. citric acid and extracted (2×DCM). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase HPLC (40 to 90% MeCN/H2O in 45 min, 2 injections, tR=25.94 min) provided the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH2:17])[CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>ClCCCl>[CH3:1][O:2][C:3]([C:4]1([CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][O:24]1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C(=O)OC)C(F)CCCCc1ccccc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: COC(=O)C1(C(F)CCCCc2ccccc2)CO1
Reaction time: 8 h

Procedure:
A solution of 500 mg (2.0 mmol) of β-fluoro-α-methylenebenzeneheptanoic acid methyl ester in 50 ml of 1,2-dichloroethane is treated with 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol). The mixture is heated to reflux and maintained under nitrogen for 10.5 hours. An additional 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol) is added and reflux is continued for 8 hours.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=O)(=[O:3])[CH3:2].CC([O-])=O.[Na+].Cl.[NH2:24][OH:25]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=[N:24][OH:25])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-(3,5-dichloro-2-formylphenoxy)ethyl acetate (1.48 mmol) in 2.5 mL DMF was cooled to 0° C. and NaOAc (1.62 mmol) followed by hydroxylamine HCl (1.62 mmol) were added. The ice bath was removed and the reaction mixture was stirred at RT for 1.5 h. The mixture was diluted with EtOAc and washed once with water and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept and EtOAc gives the desired compound as white solid.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]=2[OH:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23]O>>[C:6]1([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([O:18][CH3:23])=[O:17])[C:14]=2[OH:22])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Cc2ccccc2)c1O
Yield: 46 %

Procedure:
To a solution of the acid (0.47 g, 2.1 mmol) in dry methanol (40 ml) was added conc. Sulfuric acid (0.47 g) and the solution heated to reflux for 96 h. Upon cooling the the methanol was removed and the residue taken up in water (50 ml), and extracted with dichloromethane (3×30 ml). The combined extracts were dried (Na2SO4), and the solvent removed. The residue was eluted through a silica column using 5% ethyl acetate in petroleum spirit to yield a colorless oil (0.23 g, 46%). 1H-NMR (CDCl3, 300 MHz): δ 3.94 (s, 3H), 4.03 (s, 2H), 6.81 (t, 1H, J=8 Hz), 7.20-7.32 (m, 6H), 7.73 (dd 1H, J=8 Hz, 1.5 Hz), 11.10 (s, 1H).
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([F:33])=[C:21]([CH:32]=2)[O:22][CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28]C)=[O:27])=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([F:33])=[C:21]([CH:32]=2)[O:22][CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([OH:28])=[O:27])=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)c(OCCC(C)(C)C(=O)O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of Methyl 4-(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenoxy)-2,2-dimethylbutanoate in MeOH/THF (1 mL/1 mL) was added excessive LiOH (1N aqueous solution). The reaction mixture was stirred at r.t. for overnight. The reaction was quenched by adding 6N HCl to PH 2. The mixture was concentrated under reduced pressure to remove MeOH and THF. DCM was added. The reaction mixture was washed with brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford pure product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[CH:19][CH:20]1[CH:22]([C:23]([OH:25])=[O:24])[C:21]1([CH3:27])[CH3:26])#[N:17].C(N(CC)CC)C.O>CN(C)C=O>[C:16]([C:18]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[CH:19][C@H:20]1[C@H:22]([C:23]([O:25][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[O:24])[C:21]1([CH3:27])[CH3:26])#[N:17]
Reactant: Cc1ccc(C(C#N)=CC2C(C(=O)O)C2(C)C)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C#N)=C[C@H]2[C@H](C(=O)OCc3cccc(Oc4ccccc4)c3)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
m-Phenoxybenzylbromide (3.68 g; 0.014 mole) is added to a solution of 3-(β-cyano-p-methylstyryl)-2,2-dimethyl-cyclopropanecarboxylic acid (3.19 g; 0.0125 mole) and triethylamine (1.27 g; 0.0125 mole) in dry dimethylformamide and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture, containing some precipitated salts, is poured into water and extracted with ether (2×75 ml). The combined ether extracts are washed several times with water, then with sodium bicarbonate solution and saturated sodium chloride solution. Evaporation of the ether solution yields 3.42 g (62.5%) of a yellow oil. Purification of this yellow oil by dry column chromatography (silica gel; eluent: 1:1 methylene chloride:hexane) affords 0.96 of the trans isomer and 0.6 of the cis isomer.