Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH-].[Na+]>CN(C)C=O.O.C(N(CC)CC)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([NH:3][CH2:4][C@H:5]([OH:6])[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[O:23])=[CH:18][CH:19]=1
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Br)cc1)NC[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a suspension of (1R)-2-amino-1-(3-pyridyl)ethanol dihydrochloride (2.90 g), 3-(4-bromophenyl)propionic acid (3.30 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.77 g) and 1-hydroxybenzotriazole hydrate (2.92 g) in N,N-dimethylformamide (30 ml) was added triethylamine (4.02 ml) at 4° C. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water (145 ml) and the pH was adjusted to 10 with 24% aqueous sodium hydroxide solution at 4° C. The mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water and dried at 50° C. to give 3-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]propanamide (4.32 g) as a white solid. The filtrate was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave 3-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]propanamide (0.43 g) as a white solid.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:27][S:26](=[O:29])(=[O:28])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:40]([NH:47][CH2:48][CH2:49][CH2:50]Br)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].O>C1COCC1>[N:1]1([C:7]([C:9]2[C:10]3[CH:27]([CH2:50][CH2:49][CH2:48][NH:47][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[S:26](=[O:28])(=[O:29])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC1c2c(C(=O)N3CCOCC3)nn(-c3ccccc3)c2-c2ccccc2S1(=O)=O

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (150 mg; 0.37 mmol; 1 eq.) in THF (3 mL) is added potassium bis(trimethylsilyl)amide (879.19 μl; 0.5 M; 0.44 mmol; 1.2 eq.) and then 3-(boc-amino)propyl bromide (104.68 mg; 0.44 mmol; 1.20 eq.) The reaction mixture is stirred at rt for 2 days. The reaction is not complete even after addition of 2 eq. of 3-(boc-amino)propyl bromide. It is stopped by addition of water. The product is extracted with EtOAc and the combined organic phases are washed with brine, dried over MgSO4 and concentrated under reduced pressure, to afford 217 mg (quant) of the title compound. HPLC (max plot) 83.1%; Rt 4.08 min. MS (ESI−): 565.5.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)c2ccccc2)CC1

Procedure:
L24. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with benzoic acid in analogy to experiment A1 to give (2S,4R)-1-benzoyl-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 458.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[CH:13](O)([CH3:15])[CH3:14].CCCCCC>S(=O)(=O)(O)O>[F:1][C:2]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)O
Reactant: COC(=O)Nc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)Nc1ccc(C(C)C)cc1F
Temperature: 70 °C
Yield: 53.3 %

Procedure:
2-Fluoro-N-methoxycarbonylaniline (1.00 g, 5.92 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (5.00 g) to prepare a solution. Isopropyl alcohol (0.400 g, 6.51 mmol) was added to the solution under a nitrogen atmosphere while stirring and heating the solution at 70° C. The mixture was vigorously stirred for 3 hr. The reaction solution was cooled to room temperature. n-Hexane (10 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer, and this extraction was carried out once again. The organic layers thus obtained were combined, and the combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 666 mg of 2-fluoro-4-isopropyl-N-methoxycarbonylaniline as an oil. The oil was further subjected to separation and purification by column chromatography on silica gel to give 206 mg of 2-fluoro-4-isopropyl-N-methoxycarbonylaniline (yield 17.0%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([N:10]1[CH2:11][CH2:12][CH:7]([NH:6][C:4](=[O:5])[C:3]2[CH:13]=[CH:14][C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)[C:20]([F:23])([F:21])[F:22])=[CH:16][C:2]=2[Br:1])[CH2:8][CH2:9]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in DCM (10.0 mL) was added triethylamine (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at RT. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution and brine solution. The combined DCM layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether/n-pentane to afford the title compound as a white solid (0.054 g, 50%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][SiH2:5][CH:6]=[C:7]([CH3:9])[CH3:8].[I-:10].[Na+]>CC(CC)=O>[I:10][CH2:2][CH2:3][CH2:4][SiH2:5][CH:6]=[C:7]([CH3:9])[CH3:8]
Reactant: CC(C)=C[SiH2]CCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)=C[SiH2]CCCI
Temperature: 75 °C
Yield: 53.6 %

Procedure:
To a stirring solution of chloropropyldimethylvinylsilane (645 g) in ethyl methyl ketone (4.65 L), sodium iodide (1.215 Kg) was added under nitrogen and the mixture heated at 75° C. for 24 hr. The reaction mixture was cooled and added D.M. Water (1.62 L) and separated organic layer. The aqueous layer was re-extracted with ethyl methyl ketone (1.16 L) and the extract combined with the organic layer. The organic layer was dried on sodium sulfate and evaporated to dryness. Orange oil was purified by vacuum distillation to give colourless liquid the title product (540 g).
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][CH2:9][C@H:10]2[O:15][C@@H:14]([O:16][C:17]3[C:26](=[O:27])[C:25]4[C:24]([OH:28])=[CH:23][C:22]([OH:29])=[CH:21][C:20]=4[O:19][C:18]=3[C:30]3[CH:31]=[CH:32][C:33]([OH:37])=[C:34]([OH:36])[CH:35]=3)[C@H:13]([OH:38])[C@@H:12]([OH:39])[C@@H:11]2[OH:40])[C@H](O)[C@H](O)[C@H]1O>O>[CH:31]1[C:30]([C:18]2[O:19][C:20]3[C:25](=[C:24]([OH:28])[CH:23]=[C:22]([OH:29])[CH:21]=3)[C:26](=[O:27])[C:17]=2[O:16][C@@H:14]2[O:15][C@H:10]([CH2:9][OH:8])[C@@H:11]([OH:40])[C@H:12]([OH:39])[C@H:13]2[OH:38])=[CH:35][C:34]([OH:36])=[C:33]([OH:37])[CH:32]=1
Reactant: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Solvent: O
Product: O=c1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Rutin (5 kg) was dispersed in 100 l of water (temperature: 55° C.). To this mixture were added 10 g of naringinase (Amano Enzyme, Inc., trade name: naringinase “Amano”, Japan) and each of the edible components (food additives, food ingredients) listed in Tables 1 and 2. The amount of each edible component added was adjusted that to attain the concentration in the mixture prepared as shown in Tables 1 and 2 (0.5 or 0.05 wt. %). The pH of the reaction mixture was 4.7. The reaction solution was left to stand 24 hours at 72° C., and then cooled to 30° C. The components precipitated by cooling were recovered by filtration. Solid filtrates were washed with water and then dried to obtain isoquercitrin.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:13][C:3]=1[C:4]([O:6][C@@H:7]([CH3:12])[C:8]([O:10]C)=[O:9])=[O:5].Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:13][C:3]=1[C:4]([O:6][C@@H:7]([CH3:12])[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)[C@H](C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: C[C@H](OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl)C(=O)O
Yield: 84.7 %

Procedure:
7.0 g (16 mmol) of methyl (S)-2-[2-chloro-5-(3-methyl-2,6-di-oxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)benzoyl-oxy]propionate from example 3.1 were dissolved in 50 ml of acetic acid, 50 ml of conc. hydrochloric acid were added and the solution was heated under reflux for 4 hours. Most of the acetic acid was distilled off, and the solution that remained was poured onto ice-water. The aqueous phase was extracted three times with ethyl acetate, the organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated to dryness, which gave 5.7 g of (S)-2-[2-chloro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)benzoyloxy]propionic acid.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-])=O)=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1)C1C=CC=CC=1>[Pd].CO>[NH2:27][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=2[OH:8])=[CH:17][C:16]=1[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2O)ccc1N
Yield: 95.2 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(2-benzyloxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (4.14 g), palladium on carbon (10%, 0.41 g) and methanol (60 ml) and the reaction mixture was purified to give the title compound (2.89 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17][CH2:18]O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)nc1Cl
Yield: 85.2 %

Procedure:
Esterification of 2,6-dichloronicotinic acid (25.5 g, 0.1328 mmol) in EtOH (200 proof, 200 mL) catalyzed with 96% H2SO4 (1.7 g) at refluxing temperature for 40 h under N2 gave the desired ethyl 2,6-dichloronicotinate as grey solid (24.89 g, 0.1131 mmol, yield 85.2%) after a normal work-up.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[CH2:21](O)[CH3:22]>O>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:21][CH3:22])=[O:10])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-nitropyrazol-3-carboxylic acid (19.9 g) in ethanol (200 mL) was added dropwise thionyl chloride (9.7 mL) over a period of 5 minutes and the mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethanol (50 mL) and to the mixture was neutralized with sodium hydrogencarbonate (54 g). The mixture was filtered and the residue was washed with ethanol. The filtrate and the washings were combined and concentrated in vacuo. The residue was azeotropically distilled with ethanol and the residue was dissolved in ethyl acetate, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and to the residue was added isopropylether. The precipitates were collected by filtration and washed with ethyl acetate/diisopropylether (1/2) to give ethyl 5-nitropyrazol-3-carboxylate (20 g, yield: 85%) as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[NH3:12].CO>>[S:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:2][NH2:12]
Reactant: ClCc1cc2ncccc2s1
Reactant: N
Solvent: CO
Product: NCc1cc2ncccc2s1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2-(Chloromethyl)thieno[3,2-b]pyridine (C-5) (183 mg, 1 mmol) was dissolved in NH3/methanol (7 N, 10 mL). The resulting mixture was stirred at 50° C. for 16 hours and concentrated. The residue was purified by chromatography. MS (m/z): 165 (M+1)+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
Methyl 3-cyclohexyl-1H-indole-6-carboxylate (500 mg, 1.94 mmol) was added to a suspension of NaH (85.5 mg of 60% dispersion in mineral oil, 2.14 mmol) in DMF (5 mL), and the reaction mixture stirred at RT for 15 min. Methyl 5-bromovalerate (0.305 mL, 2.14 mmol) was then added and the reaction mixture stirred at RT overnight, after which the reaction was quenched with ice and extracted with ethyl acetate (2×50 mL). The extracts were then combined, washed with 1N HCl solution, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using hexanes to 25% ethyl acetate in hexanes as eluant to give the title compound as a colorless thick oil (0.41 g, 57% yield). MS m/z 372(MH+). 1H NMR (300 MHz, CDCl3) δ ppm 1.23 (m, 1 H) 1.35-1.48 (m, 5 H) 1.62 (m, 2 H) 1.69-1.89 (m, 6 H) 2.03 (m, 2 H) 2.29 (t, J=7.32 Hz, 2 H) 2.78 (m, 1H) 3.62 (s, 3 H) 3.90 (s, 3 H) 4.11 (t, J=6.95 Hz, 2 H) 6.97 (s, 1 H) 7.60 (d, J=8.42 Hz, 1 H) 7.72 (d, J=9.51 Hz, 1 H) 8.00 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:14].S(Cl)(Cl)=O.CO.N1C=CC=C[CH:31]=1>C(Cl)CCl>[CH3:31][O:14][C:13]1([C:3]2[CH:4]=[CH:5][C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:7][C:2]=2[CH3:1])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[O:19])[O:18]1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: c1ccncc1
Solvent: CO
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)c1ccc(C2(OC)OC(=O)c3ccccc32)c(C)c1

Procedure:
Proceeding in a manner similar to that described in Example 1 above, 5.2 g of 2-(2-methyl-4-diethylaminophenyl)carbonylbenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of pyridine to obtain 2.5 g of 3-methoxy-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula II: R0 =R=R1 =R2 =H; R4 =R4' =C2H5 ; R5 =Y=CH3 ; X=O), a yellow-colored oil. A significant infrared maximum appeared at 1770 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was concordant with the assigned structure. Analysis by mass spectrum showed m/e peaks at 325 (M+) and 294 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a yellow-colored image.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([C:19]3([CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[OH:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([C:19]3([CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC1(C(O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCC1(C(=O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.9 %

Procedure:
To a stirred solution of 5-[(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-yl)-hydroxy-methyl]-indole-1-carboxylic acid tert-butyl ester (0.460 g, 1.00 mmol) in DCM (10 mL) at 0° C. under nitrogen was added DMP (0.652 g, 1.54 mmol) in a single portion. The reaction mixture warmed to ambient temperature and stirred for 90 minutes, then diluted with DCM, washed with a 1:1 mixture of 10% aqueous Na2S2O5 and NaHCO3, followed by brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil. Purification by chromatography (silica, 0 to 80% EtOAc in hexanes) gave 5-(1-tert-butoxycarbonyl-2-propyl-pyrrolidine-2-carbonyl)-indole-1-carboxylic acid tert-butyl ester (0.132 g, 0.289 mmol, 29%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH:12]2[CH2:14][CH:13]2[CH3:15])[N:7]=[C:6]([N:23]([CH3:30])[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:41]([C@:48]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:51])[CH:49]=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[CH2:41]([C@:48]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:51])/[CH:49]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]([N:23]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:25])=[O:26])[CH3:30])[N:7]=[C:8]([N:10]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH:12]2[CH2:14][CH:13]2[CH3:15])[CH:9]=1)=[O:3])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=O)Cc1ccccc1
Reactant: CC(=O)c1cc(N(Cc2ccccc2)CC2CC2C)nc(N(C)S(=O)(=O)C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CC1CN(Cc1ccccc1)c1cc(C(=O)/C=C/[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(C)S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of N-(4-acetyl-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylpropane-2-sulfonamide (100 mg, 0.23 mmol) from Step B in 1.5 mL dry THF was added lithium bis(trimethylsilyl)amide (244 μL, 0.49 mmol, 2M solution in THF), and the resulting mixture was allowed to stir for 15 min. To this mixture was added a solution of tert-butyl (1R) -1-benzyl-1-methyl-2-oxoethylcarbamate (61 mg, 0.23 mmol, prepared according to preparation of intermediate III up to step C) dissolved in 1 mL dry THF. The solution was allowed to slowly warm to rt and then allowed to stir for an additional 16 h, at which time it was quenched with a saturated solution of ammonium chloride (15 mL) and extracted with ethyl acetate (2×25 mL). The combined organics were dried over sodium sulfate and concentrated. Purification by reverse-phase chromatography afforded tert-butyl (1R,2E)-1-benzyl-4-{2-{benzyl[(2-methylcyclopropyl)methyl]amino}-6-[(isopropylsulfonyl)(methyl)amino]pyridin-4-yl}-1-methyl-4-oxobut-2-enylcarbamate, intermediate n, as an orange oil. LCMS [M+H]=675.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.S(=O)(=O)(O)O.[Cl:18]Cl.[OH-].[K+]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:18])=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1ccc(C(F)(F)F)c(Cl)n1
Reactant: ClCl
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(Cl)c(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 200 ml four necked flask equipped with a thermometer, a stirrer and a reflux condenser were placed 7 g of 2-amino-5-trifluoromethyl-6-chloropyridine, 10 ml of carbon tetrachloride and 70 ml of 20% sulfuric acid to give a homogeneous solution. Chlorine gas was introduced thereinto while cooling the flask at 0° C., and the reaction was carried out for 4 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction product was poured into ice water and neutralized with a potassium hydroxide solution. 50 ml of methylene chloride was added thereto, followed by washing with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated off. The solid thus obtained was washed with n-hexane to obtain 6.7 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:14])[C:4]=1[F:15])#[N:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[Cl-].[Li+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:14])[C:4]=1[F:15])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: COC(=O)C(=CN(C)C)c1ccc(C#N)c(F)c1C
Temperature: 10 °C
Yield: 62.8 %

Procedure:
Combined methyl 2-(4-cyano-3-fluoro-2-methylphenyl)acetate (10.0 g, 48.3 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (17.25 g, 145 mmol), and solid lithium chloride (0.205 g, 4.83 mmol) and heated to 105° C. for 1.5 h. The mixture was cooled to 10° C. and water (210 mL) was added slowly. The solid was collected by vacuum filtration, dissolved in DCM and was purified by column chromatography to afford the title compound (7.95 g, 63%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (d, J=2.53 Hz, 3H) 2.54-2.86 (m, 6H) 3.50 (s, 3H) 7.10 (d, J=7.83 Hz, 1H) 7.62 (s, 1H) 7.63-7.66 (m, 1H). ESI-MS m/z [M+H]+ 263.2.