Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][NH:3]C(=O)C[Cl:6].[CH3:8][S:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20].S(=O)(=O)(O)O.Cl>C(O)(=O)C.C(O)C>[ClH:6].[NH2:3][CH2:2][C:12]1[CH:13]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:15]=[C:10]([S:9][CH3:8])[C:11]=1[OH:20]
Reactant: O=C(CCl)NCO
Reactant: CSc1cc(C(C)(C)C)ccc1O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CSc1cc(C(C)(C)C)cc(CN)c1O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Pulverized N-hydroxymethyl-2-chloroacetamide (3.32 g., 0.027 mole) is added portionwise over 15 minutes to a solution of 2-methylthio-4-(1,1-dimethylethyl)phenol (5.3 g., 0.027 mole) and conc. sulfuric acid (10 ml.) in acetic acid (150 ml.) cooled in an ice bath. The resulting reaction mixture is stirred at 20° C. for 16 hours and then poured into ice-water (1 l.) whereupon a white gum is deposited. The gum is extracted with ether and the etheral extract, washed well with water and saturated brine. Removal of the solvent under reduced pressure leaves a residual solid which is dissolved in ethanol (30 ml.). The resulting solution is treated with 12 N hydrochloric acid (15 ml.) and heated at reflux for 4 hours. Evaporation in vacuo affords a residual solid which is triturated with ether and collected by filtration to give crude 2-aminomethyl-4-(1,1-dimethylethyl)-6-(methylthio)phenol hydrochloride (5.4 g., 76.4%), m.p. 150°-177° C. Two recrystallizations from ether-ethanol (10:1; v:v) followed by recrystallization from 12 N hydrochloric acid provides analytically pure 2-aminomethyl-4-(1,1-dimethylethyl)6-(methylthio)phenol hydrochloride as colorless crystals, m.p. 180°-181.5° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2].Cl.[NH2:35]O>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:19](=[NH:35])[CH:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[OH:21])[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(Cl)cc4)CC3)cc21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=N)C(O)c4ccc(Cl)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-chlorophenyl)-2-hydroxy-iminoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid was prepared from 1-ethyl-6-fluoro-7-{4-[2-(4-chlorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (0.24 g, 0.5 mmole) and hydroxylamine hydrochloride (0.07 g, 1 mmol) by a method similar to that described for Example 3 (73% yield). 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J=7.0), 2.61 and 3.24 (two m, 8H), 3.44 and 3.73 (two s, 2H), 4.56 (q, 2H, J=7.0), 7.24 and 7.78 (two m, 5H), 7.89 (d, 1H, J=13.4), 8.93 (s, 1H), 11.03 and 11.49 (two s, 1 H), 15.35 (br s, 1H). Anal. Calcd. for C24H24FClN4O4•0.25 H2O: C, 58.66; H, 5.02; N, 11.40. Found: C, 58.48; H, 5.01; N, 11.29.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:16]/[S@@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cccc(Br)c1
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(Br)c1
Temperature: 37 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
3-bromobenzaldehyde, 24-a, (10 g, 53.9 mmol) in dichloromethane (300 ml) were added (R)-2-methylpropane-2-sulfinamide (7.84 g, 64.8 mmol), PPTS (1.97 g, 7.85 mmol) and anhydrous CuSO4 (25.8 g, 161 mmol) and the resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to provide the product, 24-b, (14.4 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].[NH2:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(O)(=O)C>CO>[NH2:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]2[CH3:12])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of 5-methoxy-2-methyl-3-indenylacetic acid (1a) (3.95 g) in 90% methanol (24 ml) containing 85% potassium hydroxide (2.7 g) was added a solution of p-aminosulfonylbenzaldehyde (3.70 g) in 90% methanol (24 ml). The resulting mixture was refluxed under nitrogen for 4-6 hours. A solution of 50% aqueous acetic acid (50 ml) was then added to the reaction mixture during 40 minutes at 50°-60° C. The crystals were collected after aging at 15° C. for 1 hour. The crude product was recrystallized five times from acetone-hexane to give pure Z form of 1-(4-aminosulfonylphenyl) methylene-5-methoxy-2-methyl-1H-3-indenylacetic acid (2a) (4.0 g, 57%): m.p. 224°-225° C.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:20]([F:23])([F:22])[F:21])=[C:12]([N:15]3[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=2)[NH:8][C:7](=[O:24])[C:6]1=[O:25])([OH:3])=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH2:26]([NH:33][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:20]([F:23])([F:22])[F:21])=[C:12]([N:15]3[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=2)[NH:8][C:7](=[O:24])[C:6]1=[O:25])=[O:3])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
2.0 g (6.5 mmol) of 1-carboxymethyl-7-(1-pyrrolyl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione and 0.64 g (5.9 mmol) of benzylamine were dissolved in 50 ml of anhydrous dimethylformamide. At 0° C., 1.6 g (5.9 mmol) of diphenylphosphoryl azide dissolved in a little dimethylformamide, and 1.3 g (12.5 mmol) of triethylamine were successively added dropwise. The mixture was stirred at room temperature for 4 h and then poured into water buffered with sodium bicarbonate. The resulting precipitate was filtered off with suction to yield 1.6 g (62%) of the product. Melting point 241°-242° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1>>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CCCCC
Product: CCCCCCc1ccc(C=O)cc1
Yield: 94.4 %

Procedure:
General procedure G was used to couple 8.1 mmols of 1-hexene to 5.4 mmols of 4-bromobenzaldehyde. 5.1 mmols of the title product was recovered after purification by flash chromatography. Spectral data was consistent with previously described compounds.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1.C(OC(=O)C)C>O.CN(C=O)C.CCCCCC>[F:15][C:13]1[CH:12]=[CH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:1]#[N:2])[C:7]=2[CH:14]=1
Reactant: [C-]#N
Reactant: Fc1ccc2scc(CBr)c2c1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCc1csc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
50% NaCN solution (443 mg, 9.05 mmol) in water (2 mL) was added drop wise to a solution of 3-bromomethyl-5-fluoro-benzo[b]thiophene (I-45a: 1.3 g, 3.32 mmol) in DMF (10 mL) over a period of 5 minutes at 0° C. The resulting reaction mass was stirred at room temperature for 2 hours. The reaction was monitored by TLC (5% ethylacetate in hexane). The reaction mass was quenched with sodium hypochlorite solution and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (6% ethylacetate in hexane) afforded 700 mg of the product (68.89% yield).
Reaction SMILES: [Cl:1][C:2](Cl)([F:11])[C:3](Cl)([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6].ClC(F)C(Cl)OC(F)(F)F>[Zn]>[Cl:1][C:2]([F:11])=[C:3]([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)OC(Cl)(Cl)C(F)(Cl)Cl
Agent: FC(Cl)C(Cl)OC(F)(F)F
Agent: [Zn]
Product: FC(Cl)=C(Cl)OC(F)(F)F
Temperature: -75 °C
Yield: 83 %

Procedure:
In a 1 l three necked flask, equipped with magnetic stirrer, thermometer, dropping funnel, and connected through a Vigreux column and a condenser to a trap maintained at -75° C., 80.0 g of zinc powder, activated by washing with HCl 3N, 550 ml of DMF and 50 mg of KI were charged under nitrogen atmosphere. The internal temperature was brought to 80° C. and 102.0 g of 1,1,2,2-tetrachloro-1-fluoro-2-trifluoromethoxyethane (377mmoles), were added dropwise. During the addition, the temperature increased up to 90° C. When the addition was over, the reaction mixture was stirred for 1 additional hour at 90° C. In the cold trap 62.8 g (315 mmoles) of 1,2-dichloro-1-fluoro-2-trifluoromethoxyethane (cis/trans 50%/50%) condensed. The 1,2-dichloro-1-fluoro-2-trifluoromethoxyethene (trans+cis) yield was 83%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([CH2:17]N(C)C)[C:11]2=[O:21]>O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([CH2:17][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[C:11]2=[O:21]
Reactant: c1c[nH]cn1
Reactant: CN(C)CC1Oc2ccc(Cl)cc2C1=O
Agent: Cl
Solvent: O
Product: O=C1c2cc(Cl)ccc2OC1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve imidazole (37.44 gms., 550 mmols) in water (200 ml.) and add 5-chloro-2-(dimethylaminomethyl)coumaran-3-one hydrochloride (25 gms., 55 mmols). Stir the reaction mixture overnight at room temperature, then add water (2 liters) and extract with chloroform (1 liter). Wash the chloroform solution with another 2 liter portion of water, dry over anhydrous magnesium sulfate, filter and evaporate in vacuo to give 5-chloro-2-(1'-imidazolylmethyl)coumaran-3-one.
Reaction SMILES: C(OC([N:6]1[CH2:15][CH:14]([CH3:16])[C:13]2[C:12]3[CH2:17][CH2:18][CH:19]([C:20]([F:23])([F:22])[F:21])[C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH3:16][CH:14]1[C:13]2[C:12]3[CH2:17][CH2:18][CH:19]([C:20]([F:23])([F:21])[F:22])[C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][NH:6][CH2:15]1
Reactant: CCOC(=O)N1CCc2sc3c(c2C(C)C1)CCC3C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC1CNCCc2sc3c(c21)CCC3C(F)(F)F
Temperature: 70 °C

Procedure:
The product of step (e) (diastereomer 1 and diastereomer 2, separately, 20 mg, 0.06 mmol) was dissolved in 3 mL CHCl3 and treated with TMSI (40 μL, 0.29 mmol). After heating to 70° C. overnight, the reaction was quenched with MeOH (5 mL) and 1 M NaOH (2 mL). The title compound was extracted into CHCl3 (2×10 mL) and subsequently purified by preparative HPLC-MS.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].C[O-].[Na+].[Na].Cl>CO>[C:1]([NH:4][CH:5]1[CH2:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C=C[C@H](NC(C)=O)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CCC(NC(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111 %

Procedure:
(±)-cis-Methyl 4-acetamido-2-cyclopentene 1-carboxylate [S. Daluge and R. Vince, J. Org. Chem. 1978. 43, 2311](3.90 g, 21.3 mmol) was dissolved in dry methanol (25 mL) and added to a solution of sodium methoxide prepared from sodium (0.98 g, 43 m.equiv.) and dry methanol (150 mL). This solution was stirred at 25° C. for 2.0 hours and then neutralized with 1 N hydrochloric acid. The solution was concentrated to 40 mL and extracted with chloroform (3×75 mL). The chloroform was dried (MgSO4) and evaporated to colourless glass (3.9 g). Chromatography on silica gel with 1-2% methanol-chloroform gave title compound as white crystals (4.33 g, 82%); m.p. 72-74° C [Lit. Can. J. Chem. 1985 63, 2787; m.p. 75-76° C. Sublimation of such a sample at 100°/0.2 mm gave white crystals, m.p. 72-74° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH2:8])[CH2:4][CH2:3]1.N1(CCC[C:18]2[CH:19]=[C:20]([NH:28][C:29](=[O:31])[CH3:30])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)CCCCC1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:18]2[CH:19]=[C:20]([NH:28][C:29](=[O:31])[CH3:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=2)[CH2:4][CH2:3]1
Reactant: C=C1CCN(C)CC1
Reactant: CC(=O)Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Product: CC(=O)Nc1cc(CC2CCN(C)CC2)cc(C(F)(F)F)c1

Procedure:
N-[3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-acetamide was prepared from 1-Methyl-4-methylene-piperidine similar to that described in the preparation of N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:29](Br)(Br)([F:31])[F:30].O>C1COCC1>[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][C:25](=[C:29]([F:31])[F:30])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(C(=O)OCc2ccccc2)CC1
Reactant: FC(F)(Br)Br
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(OCc1ccccc1)C1CCC(=C(F)F)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 9.5 %

Procedure:
HMPT (7.40 ml, 39.5 mmol) was added to a solution of 4-oxo-cyclohexanecarboxylic acid benzyl ester (1.50 g, 6.59 mmol) and CF2Br2 (1.8 ml, 19.8 mmol) in THF (30 ml) at 0° C., and the reaction mixture was stirred at room temperature for 22 hours. Water was added, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→75/25) to give 4-difluoromethylene-cyclohexanecarboxylic acid benzyl ester (166 mg, 9%).
Reaction SMILES: C1(C(C)C)C=CC=CC=1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:11]>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[CH2:11])=[CH:13][CH:14]=1
Reactant: CCc1ccc(C)cc1
Solvent: CC(C)c1ccccc1
Product: C=Cc1ccc(C)cc1

Procedure:
This example illustrates the dehydrogenation of cumene and p-ethyltoluene using a diluent comprising steam and nitrogen. Three and three-tenths of the catalyst prepared in Example I, ground to 18 to 40 mesh, was employed in the reactor described in Example I. Initially p-ethyltoluene was flowed into the reactor at 0.38 liquid hourly space velocity, 11:1 diluent to p-ethyltoluene ratio (8:1 steam and 3:1 nitrogen) at 588° C. yielding a relatively poor conversion and selectivity. The catalyst was decoked with 5% oxygen and nitrogen for about 1 hr. Cumene was then run at 0.38 liquid hourly space velocity, 11:1 diluent ratio (8:1 steam and 3:1 nitrogen) at 588° C. providing 40% conversion to alphamethylstyrene and 88% selectivity. The feed was then switched from cumene to p-ethyltoluene using the same diluent dilution and conditions providing 22% conversion to p-methylstyrene and 93% selectivity. Conditions were then changed to 0.72 liquid hourly space velocity, 10:1 diluent ratio for the p-ethyltoluene (8:1 steam and 2:1 nitrogen) at 598° C. yielding 40% conversion and 92% selectivity to p-methylstyrene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=1)=[O:21]>Cl.O>[NH2:11][C@@H:8]([C:5]1[C:4]([F:19])=[C:3]([C:20]([C:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=2)=[O:21])[C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(OC)nc2)c1F
Agent: Cl
Solvent: O
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(=O)[nH]c2)c1F
Yield: 86.7 %

Procedure:
Step 2 Tert-butyl N-[(1R)-1-{4-chloro-2-fluoro-3-[(6-methoxypyridin-3-yl)carbonyl]phenyl}-propyl]carbamate (90.0 mg, 0.21 mmol) was dissolved in 6M HCl in water (5.0 mL) and the reaction was heated at reflux for 8 h. Complete conversion. Mixture was quenched with NaOH (5M) until pH˜5, then extracted with 4:1 CHCl3:IPA (3×20 mL). Combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give 5-({3-[(1R)-1-aminopropyl]-6-chloro-2-fluorophenyl}carbonyl)-1,2-dihydropyridin-2-one (56.2 mg, 88% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH:20]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2/[CH:20]=[CH:23]/[C:24]([OH:26])=[O:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a solution of 0.41 g of 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carbaldehyde in 3 mL of pyridine, 0.35 g of malonic acid and 0.02 mL of piperidine were added, and the resulting mixture was stirred at 80° C. for 3 hours. After the solution was allowed to cool, 50 mL of water and concentrated hydrochloric acid were added to adjust the pH to pH3, and the precipitated solid was collected by filtration and washed with ethanol to obtain 0.29 g of (2E)-3-{1-[(4-bromophenyl)sulfonyl]-1H-indol-2-yl} acrylic acid as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:10](=[O:25])[N:9]([CH2:26][C:27]([OH:29])=[O:28])[N:8]=2)C[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30]C1C=CC=CC=1C(C1C=CC=CN=1)=O.NC1C=CC=CC=1C(C1CCCCC1)=O>>[CH3:22][C:20]([CH3:21])([CH3:23])[C:19](=[O:24])[CH2:18][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][N:30]=2)=[N:8][N:9]([CH2:26][C:27]([OH:29])=[O:28])[C:10]1=[O:25]
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Reactant: Nc1ccccc1C(=O)c1ccccn1
Agent: Nc1ccccc1C(=O)C1CCCCC1
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21

Procedure:
[1-(3,3-Dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid was prepared using steps a-d of the method employed in the preparation of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d), except that (2-amino-phenyl)-pyridin-2-yl-methanone (G. Semple, et. al. Synth. Commun., (1996), 26, 721) was used in step a instead of (2-amino-phenyl)-cyclohexyl-methanone. 1H NMR (DMSO-d6) 12.50 (1H, br s), 8.57 (1H, m), 7.94 (2H, m), 7.50 (2H, m), 7.16 (3H, m), 4.78 (2H, s), 4.25 (2H, br s), 1.15 (9H, s).
Reaction SMILES: [Mg].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[F:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:29]2[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH2:22][C@H:19]3[CH2:18][CH2:17][C@H:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:21][CH2:20]3)[CH2:27][CH:28]=2)[C:3]=1[F:2]
Reactant: CCCCC[C@H]1CC[C@H](CCCCC2CCC(=O)CC2)CC1
Reactant: Fc1cccc(Br)c1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCCCC2CC=C(c3cccc(F)c3F)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
Under nitrogen gas stream, 52.3 g (2150 mmol) of magnesium was added in 100 ml of THF, and a solution of 378 g (1960 mmol) of 2,3-difluoro-1-bromobenzene in 4.0 l of THF was added by drops thereto so that the reaction temperature was maintained at about 50° C. Further, after stirred at room temperature for 1 hour, a solution of 500 g (1630 mmol) of 4-(4-(trans-4-pentylcyclohexyl)butyl)cyclohexanone in 5.0 l of THF was added by drops to the solution and stirred at 50 to 60° C. for 2 hours, and then 1.0 l of saturated aqueous ammonium chloride solution was added to the solution to terminate the reaction. The reaction mixture was filtered with Celite, the solvent was distilled off under a reduced pressure, and then it was extracted with 2.0 l of toluene. The organic layer was washed with 1.0 l of water thrice and dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was removed by filtration, 23.7 g of p-toluenesulfonic acid monohydrate was added to the filtrate and heated to reflux for 4 hours. The organic layer was washed with 1.0 l of water thrice and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 436 g of a crude 1,2-difluoro-3-(4-(4-(trans-4-pentylcyclohexyl)-butyl)cyclohexene-1-yl)benzene.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H]([O:15][C:16]3[CH:17]=[C:18]([OH:36])[C:19]4[C:25](=[O:26])[CH2:24][C@@H:23]([C:27]5[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=5)[O:22][C:20]=4[CH:21]=3)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O.C1C=CC(CCC(C2C=CC=CC=2O)=O)=CC=1>Cl>[OH:36][C:18]1[CH:17]=[C:16]([OH:15])[CH:21]=[C:20]([OH:22])[C:19]=1[CH:25]([OH:26])[CH2:24][CH2:23][C:27]1[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=1
Reactant: COc1ccc([C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)cc3O2)cc1O
Agent: Cl
Agent: O=C(CCc1ccccc1)c1ccccc1O
Product: COc1ccc(CCC(O)c2c(O)cc(O)cc2O)cc1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Neohesperidin is a glycoside of dihydrochalcone. A total weight of 100 mg of neohesperidin was suspended in 10 ml of 1 N HCl and heated at 80° C. for 2 hours. The hydrolyzed product (10) was cooled down and extracted with ethyl acetate (3×10 ml). The ethyl acetate layers were combined, evaporated to remove ethyl acetate and dissolved in 1-propanol (5 ml). Sodium borohydride (25 mg) was added to the propanol solution and stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was separated on a pre-packed C18 column eluting with a MeOH/H2O gradient to provide 1-(2,4,6-trihydroxyphenyl)-3-(3′-hydroxy-4′-methoxyphenyl)-1-propanol (11).