Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[CH2:12][C@@:11]2([CH3:14])[O:13][C@@:3]31[C@@H:15]1[C@@H:7]([N:8]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=4)[C:9](=[O:16])[C@H:10]21)[O:6][CH2:5][CH2:4]3.[CH3:29][O:30][C:31](=[O:52])[CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:8]2[C@@H:7]3[C@@H:15]4[C@@H:10]([C@:11]5([CH3:14])[O:13][C@@:3]4([CH2:4][CH2:5][O:6]3)/[C:2](=[CH:32]/[C:31]([O:30][CH3:29])=[O:52])/[CH2:12]5)[C:9]2=[O:16])=[CH:18][C:19]=1[C:25]([F:26])([F:27])[F:28])#[N:22]
Reactant: C[C@@]12C[C@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C1\C[C@@]2(C)O[C@@]13CCO[C@H]1[C@@H]3[C@@H]2C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 72 h
Yield: 70.6 %

Procedure:
To a solution of Example 3 (50 mg, 0.128 mmol) in THF (2 mL) was added methyl(triphenylphosphoranylidene)acetate (51 mg, 0.153 mmol). The reaction mixture was stirred for 3 days and then concentrated in vacuo. The resulting residue was purified by ISCO column (4.0 g column, EtOAc/hexane=0-80%, 10 mL/min) to give Example 103 (40.5 mg, 71%) as a yellow solid.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:13](Cl)(Cl)=[O:14]>CC1CCCCC1>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([O:11][S:13]([C:5]2[CH:6]=[CH:7][C:2]([CH3:12])=[CH:3][CH:4]=2)(=[O:14])=[O:1])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC1CCCCC1
Product: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 50 °C
Yield: 52.3 %

Procedure:
50.0 g (260 mmol) of p-toluenesulphonic acid monohydrate were suspended in 140 g of methylcyclohexane and heated to 50° C. with stirring. 99.9 g (831 mmol, 3.2 equivalents [eq.]) of thionyl chloride were then added dropwise over a period of 75 minutes at such a rate that moderate gas evolution was observed. After addition had ended, the mixture was stirred at 50° C. for a further 1 h. 20.1 g of excess thionyl chloride were then distilled off at a bottom temperature of 96° C. The residue was cooled to 5° C. and stirred at this temperature for 1 h. The precipitated solid was filtered off and washed with 50 ml of methylcyclohexane. After drying under reduced pressure, 22.2 g (52% of theory) of p-toluenesulphonic anhydride were isolated.
Reaction SMILES: [OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([N:26]2[CH2:31][CH2:30][C@:29]([CH2:38][C:39](O)([CH3:41])[CH3:40])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:43])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1.C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([N:26]2[CH2:31][CH2:30][C@@:29]([CH2:38][C:39]([CH3:41])=[CH2:40])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:28][C:27]2=[O:43])[CH3:25])=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.38 g) was added to 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (2.0 g) dissolved in tetrahydrofuran (30 mL) and toluene (15 mL). The resulting solution was stirred at room temperature for 0.5 h and at 75° C. for 1 h. After cooling to room temperature, the solution was concentrated and ethyl acetate was added to the residue. The resulting mixture was washed with aqueous NaHCO3 solution and brine and dried (MgSO4). The title compound was obtained after removal of the solvent. Yield: 1.9 g (quantitative). Mass spectrum (ESI+): m/z=414/416 (Br) [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.O.NN>CCO.C(Cl)Cl.O.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:11][S:12][C:13]2[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(O)nc(SCc2cccc([N+](=O)[O-])c2Cl)n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2cccc(N)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
2-{[(2-chloro-3-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (150 mg, 481 mmol) was dissolved in 1:1 EtOH/DCM (6 mL). Hydrazine hydrate (224 mL, 7.2 mmol) and catalytic amount of Ni-Raney solution in water were added. The mixture was stirred overnight at room temperature. The solid material was filtered on Celite and washed with methanol and ethyl acetate. The filtrate was evaporated. The residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 2-{[(3-amino-2-chlorophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (10 mg, 7% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 5.41 (s, 2H), 5.98 (bs, 1H), 6.70-6.75 (m, 2H), 6.95 (t, J=7.7 Hz, 1H); LRMS (ES+) m/z 282 (100%, M+1), 284 (35%, M+3).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH3:12][CH2:13]O.CCOCC>ClCCCl>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:12][CH3:13])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: CCO
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(C=O)cc1
Yield: 68 %

Procedure:
A mixture of 4-formylbenzoic acid (25 g) conc sulfuric acid (2 ml) and EtOH (19.5 ml) was refluxed gently for 5 days in 100 ml of 1,2-dichloroethane. The solvent was then stripped, and Et2O was added to the residue. The Et2O solution was washed (satd aq NaHCO3) dried (Na2SO4), filtered, and evaporated. Bulb to bulb distillation afforded 20.1 g (68%) of the title ester as a clear liquid, bp 145°-150° (2,900 Pascals, 22 torr).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9].Cl[CH2:16][C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:19][C:17]([CH2:16][NH:9][C:8]1[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:18]
Reactant: NC(=O)CCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCC(N)=O

Procedure:
Add 200 ml dimethylformamide to a mixture of 2,6-dimethylaniline (36.3 g, 0.30 mol), 2-chloroacetamide (74.8 g, 0.80 mol) and potassium carbonate (41.4 g, 0.3 mol). Heat at 120° for 72 hours, allow to cool, and pour into water. Extract with 1:1 ether-ethyl acetate. Wash the organic with 1.0 N HCl. Neutralize the aqueous layer with NaHCO3 and extract it with ethyl acetate. Dry, concentrate, and distill to collect a fraction, b.p. 157°-167°/0.1 mm. Recrystallize from methylene chloride-hexane to give as a solid, m.p. 91°-92°, N-aminocarbonylmethyl-2,6-dimethylaniline.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=[O:9])=[C:6]([F:14])[C:5]=1[F:15].O>CO>[Br:3][C:4]1[C:5]([F:15])=[C:6]([F:14])[C:7]([CH2:8][OH:9])=[C:10]([F:13])[C:11]=1[F:12]
Reactant: O=Cc1c(F)c(F)c(Br)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(F)c(F)c(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Sodium borohydride (1.0 g) was added portionwise over a period of 30 minutes to a stirred solution of 4-bromo-2,3,5,6-tetrafluorobenzaldehyde (8.2 g) in methanol (80 cm3) whilst the temperature was maintained within the range from -5° C. to +5° C., after which the mixture was stirred for 2 hours at the ambient temperature (ca 18° C.). The mixture was poured into water and the precipitated white solid collected by fitration, washed with water and air dried to yield 4-bromo-2,3,5,6-tetrafluorobenzyl alcohol (7.5 g), mp. 60°-62° C.
Reaction SMILES: [CH3:1][Si:2]([CH:5](O)[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.Cl[C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.C1C[O:24]CC1>CCOCC>[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([O:24][CH2:6][CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[N:19]=1
Reactant: C1CCOC1
Reactant: CC(O)[Si](C)(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)CCOc1nccc(Cl)n1
Reaction time: 0.17 h

Procedure:
A solution of trimethylsilylethanol (10 g, 85 mmol) in 30 ml anhydrous THF was cooled to -68° C. in a dry ice/isopropanol bath. A solution of n-butyl lithium (33.8 ml, 2.5M in THF) was added dropwise over 15 min. The solution was stirred for 10 min at this temperature and then added to a solution of 2,4- dichloropyrimidine (12.62 g. 85 mmol) in 75 ml THF at -35° C. to -25° C. The final yellowish solution was allowed to come to room temperature under an argon atmosphere then stirred at this temperature for 1 hr. This solution was diluted with 200 mL of Et2O and washed with cold water (100 ml), sat'd NaHCO3 (100 ml) and brine, then dried over MgSO4, filtered and evaporated to yield a tan syrup. This syrup is crystallized from hexanes at -60° C. to yield the title compound as a light yellow solid, 17.8 g (91%). 1H NMR (CDCl3): δ8.36 (d, 1H, H-6), 6.93 (d, 1H, 5-H), 4.43 and 1.17 (t,t; 4H; CH2CH2), 1.06 (bs, 9H. TMS).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])/[CH:7]=[C:8](\[NH2:10])/[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36](=O)[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(O)C>[C:1]([NH:5][C:6]([C:7]1[CH:15]([C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:36]([CH2:35][O:34][CH2:33][CH2:32][CH2:31][C:23]2[N:22]([CH3:21])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[NH:10][C:8]=1[CH3:9])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: C/C(N)=C/C(=O)NC(C)(C)C
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCCCc1nc2ccccc2n1C
Solvent: CCO
Product: CCOC(=O)C1=C(COCCCc2nc3ccccc3n2C)NC(C)=C(C(=O)NC(C)(C)C)C1c1ccccc1Cl
Yield: 14.3 %

Procedure:
N-t-Butyl-3-aminocrotonamide (0.63 g), 2-chlorobenzaldehyde (0.56 g) and ethyl 4-[3-(1-methylbenzimidazol-2-yl)propoxy]-3-ketobutanoate (1.27 g) were dissolved in ethanol (16 ml) and stirred under reflux for 15 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The residue was chromatographed on silica eluting with 3% methanol in ethyl acetate. The fractions containing the product were combined and evaporated. Recrystallisation of the resulting foam from ethanol yielded the title compound as a white solid (0.33 g, 14%), m.p. 202° C. Found: C, 66.17; H, 6.92; N, 9.48. C32H39ClN4O4 requires C, 66.36; H, 6.79; N, 9.68%.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])[CH3:4].[CH3:17]I>CO>[CH3:4][C:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])[CH2:2][S:1][CH3:17]
Reactant: CC(C)(CS)NC(=O)OCc1ccccc1
Reactant: CI
Solvent: CO
Product: CSCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 17 h
Yield: 65 %

Procedure:
To a pressure tube was added a solution of benzyl 1-mercapto-2-methylpropan-2-ylcarbamate in methanol (5 mL), TEA (2.35 mL, 1 equiv) and methyl iodide (1.05 mL, 1 equiv). The tube was sealed and the reaction stirred for 17 h. The solvent was removed in vacuo and the crude material was purified on an ISCO purification system. The desired fractions were pooled and concentrated under reduced pressure to give a pale yellow oil (2.78 g, 65%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI+) for C13H19NO2S (253.1); Found: 254 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.O.[OH-].[Na+].[H][H]>[Pd].C(O)CCC>[Cl:1][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: Clc1ccccc1N(Cl)Nc1ccccc1
Yield: 78.2 %

Procedure:
630 g o-chloronitrobenzene, 615 g water and 185 g sodium hydroxide (corresponding to a 23.1 wt. % aqueous solution), 0.9 g naphthalenediol-1,4, 535 g n-butanol and 1.0 g palladium on alumina (5% Pd) (the quantitative ratio of palladium metal to o-chloronitrobenzene used being 0.00008:1) are hydrogenated at a hydrogen pressure of 6 bars and at 55° to 65° C. for 4 hours and worked up as described in Example 1. 396 g pure 2,2'-dichlorohydrazobenzene of a purity of better than 98% is obtained in a yield of 78% of theory. In addition, 37 g o-chloroaniline is obtained which after the n-butanol has been drawn off is distillable under vacuum and thus may be recovered pure. When the distillation residue is mixed with 65 g n-butanol of 60° C., a second fraction of 61 g 2,2'-dichlorohydrazobenzene of a purity of from 97 to 98% crystallizes out on cooling. The total hydrazobenzene yield thus is 89.8%. In addition, 7.3 wt. % o-chloroaniline is obtained.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:21]([C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=1)[CH:27]=[C:28]([C:36]([CH3:38])=O)[C:29]([O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1)=[O:30])([O-:23])=[O:22].[NH3:42]>C(O)C>[CH3:38][C:36]1[NH:42][C:3]([CH3:5])=[C:2]([C:1]([O:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:11])=[O:6])[CH:27]([C:26]2[CH:39]=[CH:40][CH:41]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:28]=1[C:29]([O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1)=[O:30]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC1CC1
Reactant: N
Reactant: COc1ccc(CN(C)CCOC(=O)CC(C)=O)cc1
Solvent: CCO
Product: COc1ccc(CN(C)CCOC(=O)C2=C(C)NC(C)=C(C(=O)OCC3CC3)C2c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 7 h
Yield: 46.7 %

Procedure:
A mixture of 8.8 g (30 mmol) of 2-[N-(4-methoxybenzyl)-N-methylamino]-ethyl acetoacetate, 8.5 g (30 mmol) of cyclopropylmethyl 2-(3-nitrobenzylidene)acetoacetate, 2.5 ml of 28% aqueous ammonia and 50 ml of ethanol was stirred at the reflux temperature for 7 hours, and then the solvent was removed under reduced pressure. The residue was chromatographed on silica gel column to afford 3-cyclopropylmethyl 5-[2-[N-(4-methoxybenzyl)-N-methylamino]ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (7.8 g, 46.7%) as yellow oil. Treatment of this oil with 1 equivalent of fumaric acid in ethanol gave the corresponding fumarate.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12](=[CH2:15])[C:13]#[N:14].CO>O.C(O)(=O)C>[Cl:11][CH:12]([CH2:15][S:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9])[C:13]#[N:14]
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(Cl)C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: N#CC(Cl)CS(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
Benzenesulfinic acid sodium salt (9.4 g, 57 mmol) was dissolved in a mixture of water (18.3 mL) and acetic acid (9.1 mL). 2-Chloroprop-2-enenitrile (4.6 mL, 57 mmol) was added, followed by MeOH (18.3 mL). The resulting mixture was allowed to stir for 10 minutes before the solid product was collected by filtration and rinsed with minimal water. The majority of the solid filtered through with the rinse and so all material was rinsed through the filter. The filtrate was extracted with DCM (2×) and the combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2-chloro-3-(phenylsulfonyl)propanenitrile as a crude residue. Crude 2-chloro-3-(phenylsulfonyl)propanenitrile (6.1 g, 27 mmol) was dissolved in chloroform (41 mL) cooled in an ice-salt bath and stirred before adding TEA (3.7 mL, 27 mmol) dropwise. The mixture was allowed to stir at 0° C. for 20 minutes. The reaction mixture was then washed sequentially with dilute 1N aqueous HCl, followed by saturate aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford (2E and 2Z)-3-(phenylsulfonyl)prop-2-enenitrile as a crude residue. The crude residue (4.9 g, 25 mmol) and (buta-1,3-dien-2-yloxy)(trimethyl)silane (4.2 g, 29 mmol) were refluxed together in benzene (63.8 mL) under nitrogen for 16 hours. The reaction mixture was then concentrated in vacuo to afford an oily mixture of the intermediate adducts. The residue was dissolved in aqueous acetic acid (80%) and allowed to stir. After 1 hour at ambient temperature, the mixture was diluted with water and extracted with DCM (2×). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DCM. A solid precipitated from the solution and was collected by filtration to afford the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 30% overall yield. FDMS m/e=369 (M+ of free base). α[D]589 =-2.49 (c=0.24, methanol).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:28]=[CH:29][C:21]=12.C([N-]C(C)C)(C)C.[Li+].[I:48]I>O1CCCC1>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:28]([I:48])=[CH:29][C:21]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(Cl)cnc32)cc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)c(Cl)cnc32)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (4.85 mL, 34.1 mmol) in tetrahydrofuran (50 mL) at −10° C. under nitrogen was added dropwise 2.5M n-butyllithium in hexane (13.62 mL, 34.1 mmol) and the mixture was stirred at −10° C. for 30 minutes. A solution of Example 229A (8.3 g, 24.33 mmol) in tetrahydrofuran (220 mL) cooled to −78° C. was treated with the lithium diisopropylamide solution dropwise over 20 minutes and the mixture was stirred for 50 minutes at −78° C. A solution of iodine (8.64 g, 34.1 mmol) in tetrahydrofuran (30 mL) was added and the mixture was stirred for 20 minutes at −78° C. and allowed to warm to room temperature. The reaction was quenched with saturated aqueous sodium thiosulfate and extracted with ethyl acetate (150 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 30-60% ethyl acetate in hexanes. The solid was triturated with 100 mL 15% ethyl acetate/hexane, filtered and dried under vacuum to afford the title compound. MS (ESI+) m/z 466.7 (M+H)+.
Reaction SMILES: [Na].[O:2]([CH:9]([CH3:13])[C:10](=[O:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[O:20])[CH2:11][C:10](=[O:12])[CH:9]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:13])[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C(C)Oc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C(C)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
Sodium (82 mg, 3.55 mmol) was added to EtOH absolute (9.8 mL) at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then (rac)-3-phenoxy-butan-2-one (530 mg, 3.23 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes. Then diethyl oxalate (0.44 mL, 3.23 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent evaporated in vacuo. The residue was diluted with water, the mixture acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM 100%) to yield (rac)-2,4-dioxo-5-phenoxy-hexanoic acid ethyl ester (566 mg, 58% yield) as an orange oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:28]=[O:29])C.O>C1COCC1>[CH:28]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1)=[O:29]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C=O)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of tert-butyl 4-bromonaphthalen-1-ylcarbamate (29) (3.00 g, 9.31 mmol) in THF (100 mL) at −78° C. under nitrogen was added n-BuLi (1.6M in hexane, 20.4 mL, 32.6 mmol) and the reaction mixture was stirred at −78° C. for 1 hr. Neat DMF (4.50 mL, 58.1 mmol) was added and the reaction mixture was stirred at −78° C. for 1 hr, then warmed to RT and stirred for a further 1 hr. Water (5 mL) was added and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was triturated with isohexane to afford the title compound (30) as a beige solid (2.20 g, 87%): m/z 272 (M+H)+ (ES)+.