Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4].Br[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[N:30][CH:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.C(OC(=O)C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:26]3[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])=[N:30][CH:31]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4]
Reactant: CCS(=O)(=O)NCc1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc([Sn](C)(C)C)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)NCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)cn1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(trimethylstannyl)-phenyl)-oxazolidin-3-yl)ethanone (281 mg, 0.66 mmol) and N-((5-bromopyridin-2-yl)methyl)ethanesulfonamide (155 mg, 0.56 mmol) are dissolved in N-Methyl-2-pyrrolidone (40 mL) and purged with nitrogen gas. Pd2(dba)3 (51 mg, 0.055 mmol) and tri-2-furylphosphine (27 mg, 0.11 mmol) are added; the resulting mixture is heated to 80° C. for 18 hours. The reaction mixture is cooled, diluted with ethylacetate, and washed with water. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude material is chromatographed (24 g Redi-Sep column) eluting from 100% hexanes to 90:10 ethylacetate:hexanes to afford the title compound (125 mg): m/z (Cl) M+H 518.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:12])(=O)=O>ClCCl>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([Cl:12])[S:2][CH3:1])[CH3:8]
Reactant: CCOC(=O)CSC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)SC
Temperature: 25 °C

Procedure:
To a Stirred Solution of ethyl (methylthio)acetate (10.8 ml) in dichloromethane (300 ml) cooled to −15° C. is added dropwise sulphuryl chloride (8.1 ml). The mixture is allowed to warm to room temperature over two hours and then concentrated under reduced pressure to give crude chloro-methylsulfanyl-acetic acid ethyl ester as a colourless liquid. The product is used in the next step without further purification. 1H NMR (CDCl3) δ ppm: 5.35 (1H, s); 4.25 (2H, m); 2.30 (3H, s); 1.30 (3H, t).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH:8]=[C:7]2[O:17]C)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH:1]1([CH2:4][CH2:5][C:6]2([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:17])[CH2:3][CH2:2]1
Reactant: COC1=CC(=O)c2ccccc2C1(C)CCC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(CCC2CC2)C(=O)C=C(O)c2ccccc21
Temperature: 95 °C
Yield: 63.9 %

Procedure:
To a solution of Example 157C (1.06 g, 4.10 mmol) in dioxane (10 mL) was added 1 N NaOH (10 mL, 10 mmol) and the reaction mixture heated at 95° C. for 16 hours. After cooling the solution to room temperature, the reaction mixture was diluted with 50 mL of water, the pH adjusted to 2.0 with 1N HCl, and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. The product was purified by flash chromatography on SiO2 eluting with a 10-25% ethyl acetate/hexane gradient yielding the title compound (0.635 g, 64% yield) as a crystalline solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.51 (m, 2 H)-0.02 (m, 2 H) 0.14 (m, 2 H) 0.46 (m, 1 H) 1.16 (s, 3 H) 5.42 (s, 1 H) 7.12 (t, J=7.35 Hz, 1 H) 7.34 (m, 2 H) 7.64 (d, J=7.35 Hz, 1H). MS (ESI+) m/z=243 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17]
Reactant: CC(C)(C)N
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1C1CCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1C1CCC1
Yield: 80.7 %

Procedure:
A solution of 8-bromo-2-chloro-3-cyclobutylquinazolin-4(3H)-one (294.7 mg, 0.94 mmol), tert-butylamine (Aldrich; 1.5 mL, 14.27 mmol), and NMP (0.5 mL) was heated in a sealed microwave vial at 120° C. for 30 min. The reaction mixture was then partitioned between EtOAc (60 mL) and water (40 mL). The organic layer was separated and sequentially washed water (40 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(tert-butylamino)-3-cyclobutylquinazolin-4(3H)-one (266 mg, 0.759 mmol, 81% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (1H, dd, J=7.6, 1.2 Hz), 7.84 (1H, dd, J=7.8, 1.4 Hz), 6.98 (1H, t, J=7.8 Hz), 5.88 (1H, s), 4.47-4.60 (1H, m), 2.54-2.64 (2H, m), 2.06-2.20 (2H, m), 1.56-1.66 (2H, m), 1.52 (9H, s). m/z (ESI, +ve) 349.9/352.0 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([N:21]1[C:26](=[O:27])[C:25]([Cl:28])=[C:24](Cl)[CH:23]=[N:22]1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:28][C:25]1[C:26](=[O:27])[N:21]([CH:18]([CH3:19])[CH3:20])[N:22]=[CH:23][C:24]=1[NH:14][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1
Reactant: CC(C)n1ncc(Cl)c(Cl)c1=O
Reactant: NCc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncc(NCc2cccc(OCc3ccccc3)c2)c(Cl)c1=O
Reaction time: 4.5 h

Procedure:
A mixture comprising 8.24 g of 3-benzyloxybenzylamine hydrochloride prepared in Reference Example 2A, 3.11 g of 2-i-propyl-4,5-dichloro-3(2H)pyridazinone, 7.26 g of potassium carbonate, 30 ml of 1,4-dioxane and 90 ml of water was refluxed under stirring for 4.5 hours. The majority of 1,4-dioxane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, and then treated with cerite to remove the precipitate. The organic layer was separated, and washed with water and a saturated sodium chloride aqueous solution, and then dried over sodium sulfate. Then, the solvent was distilled off. The pale yellow oily substance thereby obtained was crystallized from ether-n-hexane to obtain 2.51 g of the above identified compound having a melting point of from 106° to 108° C. as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
50 g (250 mmoles) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are dissolved in 200 ml of acetic anhydride. The solution is cooled to 0° C. and there is slowly added a solution of 10.5 ml (250 mmoles) of nitric acid, 20 ml of acetic acid and 20 ml of acetic anhydride, while maintaining the temperature between 0° and 5° C. The reaction mixture is then stirred for 1 hour at ambient temperature, poured into ice water and filtered. The resulting solid is washed with water. The solid is dissolved in methylene chloride, washed with water and then with a saturated solution of sodium bicarbonate, dried on MgSO4 and evaporated. 45.8 g (74%) of 2-methyl-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 143°-144° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([OH:19])[CH2:12][C@@H:13]([NH:17][CH3:18])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:31]([C:36](O)=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([O:19][C:36](=[O:37])[C@@H:31]([NH:30][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[C@@H:32]([CH3:33])[CH2:34][CH3:35])[CH2:12][C@@H:13]([NH:17][CH3:18])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc([C@H](O)C[C@@H](NC)C(C)C)n1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1csc([C@@H](C[C@@H](NC)C(C)C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 0.1 M solution of N-methyl tubuvaline ethyl ester 35 (0.305 g, 1.06 mmol), 1-hydroxybenzotriazole (HOBt) (0.146 g, 1.08 mmol), and Boc-Ile-OH (0.267 g, 1.11 mmol) in CH2Cl2 (10.6 mL) was cooled in a salted ice-water bath. PS-CCD (1.38 mmol/g, 0.920 g, 1.27 mmol) was added with stirring, and the bath was warmed to rt. Stirring was continued for 14 h, the solution was filtered, and the resin was washed with CH2Cl2. The filtrate was then concentrated, diluted with EtOAc, and washed once with sat. NaHCO3 (aq). The aqueous fraction was back-extracted twice with EtOAc, and the combined organic fractions were dried with Na2SO4, filtered, and concentrated to afford intermediate 36, which was taken on without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:22]>>[NH2:22][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Reactant: N
Product: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Temperature: 130 °C
Yield: 60 %

Procedure:
To a mixture of (5-bromopyridin-3-yl)(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 37, 4.3 g, 12.5 mmol) in aqueous 880 ammonia (65 mL) was added CuSO4.5H2O (936 mg, 3.75 mmol) and the reaction was heated at 130° C. in an autoclave for 18 hours. The reaction was extracted into DCM and the organic layer collected, filtered, dried over sodium sulphate and concentrated in vacuo. The residue was purified through alumina eluting with 1-3% MeOH in DCM to afford the title compound as a white solid (2.1 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11]OC(C)(C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][Cl:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCl)cc1

Procedure:
To a suitable reaction vessel there was added 6.07 g (0.044 mol) of 4-nitroaniline dissolved in 300 ml of methylene chloride. The solution was cooled with vigorous stirring to -65°, giving a suspension of the nitro compound. A solution of 5.75 g (0.055 mol) of t-butyl hypochlorite in 10 ml of methylene chloride was added to form the 4-nitro-N-chloroaniline and subsequently after 3 hr, 7.4 g (0.071 mol) of methylthio-2-propanone in 10 ml of methylene chloride was added, while stirring was continued for 10 hr. to form the azasulfonium chloride salt. The triethylamine, 4.4 g (0.044 mol), dissolved in 10 ml of methylene chloride was added and the solution was warmed to room temperature to form the 2-methyl-3-methylthio-5-nitroindole. A 50-ml portion of water was added and after separation, the organic layer was extracted thoroughly with a 2N aqueous hydrochloric acid. Drying over anhydrous magnesium sulfate and filtration of the organic solution was followed by evaporation, leaving a solid residue that was stirred for several hr with 30 ml of benzene. The remaining precipitate was collected by filtration giving 2.92 g (0.013 mol, 30%) of 2-methyl-3-methylthio-5-nitroindole, mp 197.5°-198.5° (recr. from 95% ethanol); ir (KBr) 3250 cm-1 (NH); pmr (acetone-d6) 1.40 (1H, br, s, NH), 1.02 (1H, d, J=2.0Hz,4-aryl H), 2.02 (1H, dd, J=8.0 and 2.0 Hz, 6-aryl H), 2.57 (1H, d J=9.0 Hz, 7-aryl H) and 7.42 and 7.73 (3H, s, SCH3 and CH3).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][C:11]1[CH:12]=[C:13]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][C:15]1([CH2:17][CH2:16]1)[C:14]2=[N:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25]>CCOCC.C1COCC1.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][C:15]1([CH2:17][CH2:16]1)[C:14]2([C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25]
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2OCC12CC2
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a suspension of activated zinc (3.44 g, 52.5 mmol) in Et2O-THF (50% v/v, 80 ml) under reflux was slowly added a solution of ethyl bromodifluoroacetate (8.00 g, 39.4 mmol) and N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (4.68 g, 13.1 mmol) in Et2O-THF (50% v/v, 80 ml) over 40 minutes, and the mixture was stirred for 4 hours at the same temperature. After cooling, the mixture was filtrated through celite pad and washed with EtOAc. To the filtrate were added saturated aqueous NH4Cl and EtOAc. After separation, the water layer was extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc:hexane=20:80-100:0) to give ethyl {6-bromo-4-[(tert-butylsulfinyl)amino]-4H-spiro[chromene-3,1′-cyclopropan]-4-yl}(difluoro)acetate (6.08 g).
Reaction SMILES: C(OC(C)COC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]([OH:34])(=[O:33])[CH:31]=[CH2:32]>>[CH:22]([CH:32]=[CH:31][C:30]([OH:34])=[O:33])=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COCC(C)OC(C)=O
Product: O=C(O)C=CC=Cc1ccccc1
Reaction time: 2 h

Procedure:
432 g of propyleneglycol monomethyl ether acetate and 13 g of azobisisobutyronitrile were poured into a five-necked reaction vessel having a capacity of one litter. Then, while introducing nitrogen gas into the reaction vessel, the resultant mixture was heated to 80° C. Then, a mixed liquid constituted by 98.9 g of styrene and 9.1 g of acrylic acid was added drop-wise to the above mixture taking two hours. 30 minutes after finishing of the dropping of the mixed liquid, 6.5 g of azoisobutyronitrile was added to the resultant mixture and the mixture thus obtained was heated for 5 hours to obtain a styrene-acrylic acid copolymer. The weight average molecular weight of the styrene-acrylic acid copolymer thus obtained was 3100.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14](/[C:16](=[CH:19]\[CH3:20])/[CH:17]=O)[CH3:15]>C1C=CC=CC=1.O>[CH2:19](/[C:16](=[CH:14]\[CH3:15])/[CH:17]=[CH:5]/[C:3]#[N:4])[CH3:20]
Reactant: C/C=C(/C=O)CC
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C/C=C(/C=C/C#N)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a mixture of sodium hydride (60% in oil, 7.5 g) and dry benzene (200 ml) was added dropwise diethyl cyanomethylphosphonate (30 g) with stirring at 0° C. under dry nitrogen atmosphere. After stirring for 60 minutes at room temperature, a solution of (E)-2-ethyl-2-butenal (16.6 g) in dry benzene was added thereto at 0° C. with stirring. The resulting mixture was allowed to stand at room temperature for 60 minutes and diluted with water and then extracted with ethyl acetate. The extract was washed successively with water and brine, and then dried over magnesium sulfate. Removal of the solvent gave an oil which was purified by distillation under reduced pressure to give (E,E)-4-ethyl-2,4-hexadienenitrile (8.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)[C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(N)c2)cc1
Product: CC(=O)Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(C)cc2)c1
Yield: 97.8 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methylphenyl)benzamide (230.1 mg, 0.50 mmol) and acetic anhydride (0.057 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 245.2 mg (97.8%) of the title compound in a light yellow amorphous form.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[CH:12][C:13](=[O:25])[C:14](=[CH:19][C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:15][C:16]([OH:18])=[O:17].[CH3:26][CH2:27]OC(C)=O.C(=O)(O)[O-].[Na+]>C(O)C>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[CH:12][C:13](=[O:25])[C:14](=[CH:19][C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:15][C:16]([O:18][CH2:26][CH3:27])=[O:17]
Reactant: O=C(O)CC(=Cc1ccco1)C(=O)C=Cc1ccco1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=Cc1ccco1)C(=O)C=Cc1ccco1
Temperature: 25 °C
Yield: 88 %

Procedure:
To prepare a starting compound of Formula III, 12 g of levulinic acid (0.104 mol, 1.0 eq) was first dissolved in 66 mL of water. A solution of 15.4 g of sodium carbonate (0.146 mol, 2.8 eq of base relative to levulinic acid) was slowly added. The resulting suspension was stirred for 30 minutes at room temperature. The reaction mixture was heated to 90° C., and a solution of 25 g of furfural (0.260 mol, 2.5 eq) in 25 mL of ethanol was added dropwise. The reaction mixture was stirred at 90° C. until complete, as determined by thin layer chromatography (TLC) (sys 9:1 CHCl3/HOAc). The reaction mixture was cooled to room temperature, and the pH was carefully adjusted to pH=2 with concentrated HCl. The solids were removed by filtration and dissolved in ethyl acetate twice (400 ml). The ethyl acetate was treated with activated carbon, filtered and washed with ethyl acetate. Hexanes were added to the filtrate. The resulting slurry was filtered and washed with hexanes to give 6-(furan-2-yl)-3-(furan-2-ylmethylene)-4-oxohex-5-enoic acid as a brown solid (11.7 g, 41.3%, HNMR). A solution of 2 mL of sulfuric acid in 2 mL of ethanol was added to 10 g of 6-(furan-2-yl)-3-(furan-2-ylmethylene)-4-oxohex-5-enoic acid (0.0367 mol, 1.0 eq) in 100 mL of ethanol. The mixture was heated to reflux and stirred until complete, as determined by TLC (sys: 100% EtOAc). The reaction mixture was cooled to room temperature and poured slowly into a saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, washed with saturated brine, treated with activated carbon and dried with sodium sulfate. The filtrate was evaporated to dryness to give ethyl 6-(furan-2-yl)-3-(furan-2-ylmethylene)-4-oxohex-5-enoate as an oil (9.7 g, 88% yield, HNMR, carbon nuclear magnetic resonance (13CNMR)).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:19])[CH:15]=[CH:16][CH:17]=[O:18].C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>>[CH3:12][O:13][C:14](=[O:19])[C@@H:15]([C:4]1[CH:5]=[CH:6][C:1]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:2][CH:3]=1)[CH2:16][CH:17]=[O:18]
Reactant: c1ccc(N2CCCC2)cc1
Reactant: COC(=O)C=CC=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Product: COC(=O)[C@H](CC=O)c1ccc(N2CCCC2)cc1

Procedure:
This example describes a Friedel-Crafts alkylation reaction of 1-phenyl-pyrrolidine and 4-oxo-butenoic acid methyl ester, catalyzed by the hydrochloride salt of (1), to provide (R)-4-oxo-2-(4-pyrrolidin-1-yl-phenyl)-butyric acid methyl ester.
Reaction SMILES: [ClH:1].C1C2=C3C(C4C2=CC=CC=4)=CC=CC3=C(CNC(C)(CO)CO)C=1.[CH:26]1[C:40]2=[C:41]3[C:33]([C:34]4[C:35]([CH:42]=O)=[CH:36][CH:37]=[CH:38][C:39]=42)=[CH:32][CH:31]=[CH:30][C:29]3=[CH:28][CH:27]=1.[NH2:44][C:45]([CH3:50])([CH2:48][OH:49])[CH2:46][OH:47]>>[ClH:1].[CH:26]1[C:40]2=[C:41]3[C:33]([C:34]4[C:39]2=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42][NH:44][C:45]([CH3:50])([CH2:48][OH:49])[CH2:46][OH:47])=[CH:32][CH:31]=[CH:30][C:29]3=[CH:28][CH:27]=1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1cccc2c1-c1cccc3cccc-2c13
Agent: CC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2
Agent: Cl
Product: CC(CO)(CO)NCc1cccc2c1-c1cccc3cccc-2c13

Procedure:
Using the reductive amination procedure outlined in 1D, 7-fluoranthenecarbaldehyde (1B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-((7-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 204°-206° (dec), (CH3OH/Et2O), (C,H,Cl,N).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[F:21][C:22]([F:33])([F:34])[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[O:32])=[CH:28][CH:29]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
1-(4-trifluoromethoxy-phenyl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-urea was prepared starting from intermediate D and 4-trifluoromethoxy-phenylisocyanate. MS calcd. for C24H8ClF3N3O3 [(M+H)+] 488.1, obsd. 488.0.
Reaction SMILES: ClC1C=C(C=CC=1Cl)C([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=O.[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:9]1)=[O:36]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 3 (40 mg), 2-methoxy-4-nitro-benzoic acid (47 mg), triethylamine (0.07 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg) in dry tetrahydrofuran (3 ml) was stirred at 20° C. for 18 h under a nitrogen atmosphere. The mixture was then partitioned between potassium carbonate solution and dichloromethane. The organic phase was passed through a hydrophobic frit and evaporated. The residue was purified on a silica gel SPE cartridge. Elution with dichloromethane, then with dichloromethane:ethanol:0.880 ammonia; 400 then 200:8:1 gave an oil which was triturated with diethyl ether giving the title compound as a colourless solid (51 mg).