Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][C@H:4]1[CH2:6][OH:7].CO[CH:15](OC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:16]1([CH:15]2[O:7][CH2:6][C@H:4]3[C@:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([CH2:5]3)[CH2:2][O:1]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(OC)c1ccccc1
Reactant: CCOC(=O)[C@]1(CO)C[C@H]1CO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCCCC1
Product: CCOC(=O)[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Temperature: 2.5 °C
Yield: 64.8 %

Procedure:
A solution of ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate (10.5 kg, 60.3 mol) in cyclohexane (105.0 L) was added in a reactor. Then, benzaldehyde dimethylacetal (11.6 kg, 76.4 mol) followed by camphor sulfonic acid (73.0 g) was added into the reactor. The reaction mass was heated to reflux and a portion of solvent was distilled azeotropically. The progress of the reaction was monitored by HPLC. On completion of the reaction, the reaction mass was distilled to remove most of the solvent under reduced pressure below 45° C. To the concentrate, petroleum ether (32.0 L) was added and stirred to precipitate the product. The slurry was cooled to 0-5° C. and stirred for 15 min. The slurry was filtered and washed with cold petroleum ether (11.0 L). The product was dissolved in dichloromethane (210.0 L) and washed with water (52.0 L) followed by brine (53.0 L). The organic layer was dried over sodium sulfate (5.5 kg) and was distilled to remove most of the solvent. Petroleum ether (21.0 L) was added and stirred at 25-30° C. for 30 min to get the complete precipitation of the product. The slurry was further cooled to 0-5° C. and stirred for 60 min. The slurry was filtered and washed with cold petroleum ether (11.0 L). The product was dried in a vacuum tray dryer for 12 hours below 45-50° C. to afford 10.25 Kg (64.5%) of the title compound (4c).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:12]([S:14]([C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH:22]=1)(=[O:16])=[O:15])[CH3:13]>C1COCC1>[F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([O:8][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[CH:22][C:21]=2[C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH2:4][CH2:3]1
Reactant: OC1CCC(F)(F)CC1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3cncn23)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC2CCC(F)(F)CC2)c(-c2cn(C)c(=O)c3cncn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10 mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 minutes. Then the title compound from Step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25° C. for 18 hours. The reaction contents were poured into ice-water (v/v=1/1) (150 mL) and stirred for 20 minutes. The aqueous phase was extracted with EA (40 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (57.35 mg, 22%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, J1=8.8 Hz, J 2=2.4 Hz 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J=7.2 Hz, 2H), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H). LCMS: 452.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1F.[N:14]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][N:14]([CH2:20][CH2:21][OH:22])[CH2:15][CH2:16]2)=[C:4]([F:12])[C:5]([NH2:6])=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(N2CCN(CCO)CC2)c1F
Temperature: 50 °C
Yield: 67.3 %

Procedure:
To a solution of 6.79 g of 4-chloro-2,3-difluoro-6-nitroaniline (which was synthesized following WO9856761 or WO9835977) and 4.70 g of 1-piperazine ethanol in 30 ml of dimethylsulfoxide, 9.23 g of potassium carbonate was added, followed by an hour's stirring at 50° C. After cooling the reaction liquid to room temperature, water was added thereto, followed by extraction with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate, the solvent was distilled off and 6.98 g of the title compound in crude form was obtained as a yellow oily substance.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]1([C:11](Cl)=O)[CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)[O:6][N:5]=1
Reactant: CC1(C(=O)Cl)CC1
Reactant: N=C(CCl)NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(c2nc(CCl)no2)CC1
Temperature: 130 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
2.75 g of 2-chloro-N-hydroxyacetoamidine and 3.0 g of 1-methylcyclopropanecarbonyl chloride were dissolved in 50 ml of N,N-dimethylformamide, and 2.8 g of triethylamine was added dropwise under ice-cooling. After completion of the addition, the mixture was heated to 130° C., stirred for 6 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.97 g of 3-(chloromethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2C2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C=C(c2ccc(F)cc2C2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.2 %

Procedure:
To a solution of 4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine-1-carboxylic acid t-butyl ester (245 mg, 0.59 mmol) produced in Example (106f) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL), followed by stirring for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give 220 mg of a crude product of the title compound as a light yellow solid.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[F:16][C:17]1[N:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[CH:19][CH:18]=1.Cl.[CH3:27][O:28][NH:29][CH3:30]>C(Cl)Cl>[CH3:27][O:28][N:29]([CH3:30])[C:23]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[N:22]=1)=[O:25]
Reactant: O=C(O)c1cccc(F)n1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)n1
Reaction time: 17 h
Yield: 19.6 %

Procedure:
Add N-methylmorpholine (6 mL, 52 mmol) and isobutylchloroformate (3.5 mL, 26.9 mmol) to a solution of 6-fluoropyridine-2-carboxylic acid (3.8 g, 26.9 mmol) in methylene chloride at 0° C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) and N-methylmorpholine (3 mL, 26.9 mmol). Stir the reaction at 0° C. for 15 minutes and then room temperature for 17 hours. Dilute the reaction with methylene chloride and wash sequentially with water (1×50 mL), 10% aqueous citric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodium bicarbonate (1×50 mL), and brine (1×50 mL). Dry the resulting organic solution with Na2SO4, filter, and purify by flash column chromatography (Silica Gel, 20% acetone/hexanes) to provide the title compound 0.97 g (18% from 2-fluoro-5-methylpyridine) as a clear, yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:29][CH2:28]3)=[C:23]([CH:30]=O)[CH:22]=2)=[C:17]([F:32])[CH:16]=1>COCCOC.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:28][CH2:29]3)=[C:23]([CH:30]=[C:5]3[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]3=[O:7])[CH:22]=2)=[C:17]([F:32])[CH:16]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2F)ccc1C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91920 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (8.40 g, 0.059 mol) in anhydrous 1,2-dimethoxyethane (75 ml) is added sodium methoxide (3.60 g, 0.066 mol) in one portion, and the mixture is stirred at this temperature for 30 minutes. A solution of 4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-carbaldehyde (14.80 g, 0.054 mmol) is then added dropwise over 20 minutes, maintaining temperature below 10° C. The reaction mixture is stirred at this temperature for 1 hour, then allowed to warm to room temperature before diluting with diethyl ether and distilled water. The two phases are separated, and the aqueous phase is extracted again with diethyl ether (×2). Organic fractions are combined, washed with brine, then dried over magnesium sulfate. The suspension is filtered and the filtrate concentrated in vacuo to afford 4-[1-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (19.80 g) which is of sufficient purity to use directly in the next step.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3](Cl)=[O:4].[CH3:9][NH2:10]>C(Cl)Cl.O>[Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([NH:10][CH3:9])=[O:4]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CN
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C(Br)CCBr
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
2,4-Dibromobutanoyl chloride (CAS no. 82820-87-9) (16.9 g, 64 mmol) in DCM (20 mL) was added dropwise to a solution of methylamine (20 mL) in water (30 mL) and DCM (30 mL) at 10-15° C., then warmed to 30° C. and stirred for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with DCM (2×10 mL), the combined organic layers were washed with brine (20 mL), dried (MgSO4) and evaporated to afford the product (16.3 g, 98%). 1H NMR δ (400 MHz, CDCl3) 2.35-2.45 (m, 1H), 2.57-2.67 (m, 1H), 2.81 (d, 3H), 3.44-3.54 (m, 2H), 4.46 (q, 1H), 6.34 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][NH:30]1>>[CH2:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][N:30]1[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: c1ccc2c(c1)CNC2
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3Cc4ccccc4C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with isoindoline via General Procedure E to give 10.7 mg of 276 following reverse phase purification. MS (Q1) 481.2 (M)+
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15].C(NCC)C>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:16][CH2:13][C:14]#[C:15][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCNCC
Product: CCOC(=O)c1ccc(C#CCO)cc1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
2.5 g of tetrakis(triphenylphosphine)palladium (0) was added to 50 ml of a solution of 10 g of ethyl p-bromobenzoate in benzene at room temperture. The obtained mixture was stirred at that temperature for one hour, followed by the addition thereto of 2.5 g of propargyl alcohol, 0.84 g of cuprous iodide and 19 g of diethylamine. The obtained mixture was stirred at room temperature for 26 hours and filtered through Celite. Water (50 ml) was added to the filtrate and the obtained mixture was extracted with ethyl acetate. The organic phase was washed with a 10% aqueous solution of hydrochloric acid and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 20% ethyl acetate/n-hexane) to give 3.1 g of the title compound as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].ClCl.S(Cl)([Cl:14])(=O)=O>>[Cl:14][C:6]1[CH:5]=[C:3]([OH:4])[C:1](=[CH:8][CH:7]=1)[OH:2]
Reactant: Oc1ccccc1O
Reactant: O=S(=O)(Cl)Cl
Agent: ClCl
Product: Oc1ccc(Cl)cc1O

Procedure:
For example, chlorination of catechol with either chlorine or sulfuryl chloride, Berichte 44, 2182 (1911), C.A. 5, 3433 (1911) gives 4-chlorocatechol as the major product, whereas excess halogen yields the 4,5-dichlorocatechol. ##STR14##
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([O:7][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@:3]1([CH3:26])[OH:25].[Cl:27][C:28]1[C:35]([CH3:36])=[C:34](F)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:27][C:28]1[C:35]([CH3:36])=[C:34]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@H:4]([OH:7])[C@:3]2([OH:25])[CH3:26])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@@H](N)[C@]1(C)O)(c1ccccc1)c1ccccc1
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H]2CC[C@H](O)[C@@]2(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
The title compound is prepared by essentially following the procedure described in Example 1, using rel-(1S,2R,5 S)-2-amino-5-(tert-butyl(diphenyl)silyl)oxy-1-methyl-cyclopentanol (409 mg, 1.1 mmol, Preparation 43) and 2-chloro-4-fluoro-3-methyl-benzonitrile (142 mg, 0.84 mmol). A 0.2 M solution of the crude product in THF is treated with tetrabutylammonium fluoride (1.3 mL, 1.3 mmol, 1.0 M in THF) and stirred at room temperature for 16 h. The mixture is treated with water, concentrated in vacuo and extracted with EtOAc. The organic extracts are dried over magnesium sulfate, filtered, and concentrated. The resulting material is purified on silica gel (25-100% EtOAc/hexanes) to give the title compound as a pale yellow oil (15 mg, 6%). The relative stereochemistry is determined by NMR studies. 1H-NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 5.60-5.57 (m, 1H), 4.98 (d, J=4.2 Hz, 1H), 4.68 (s, 1H), 3.73-3.70 (m, 2H), 2.12 (s, 3H), 2.09-2.09 (m, 2H), 1.69-1.67 (m, 1H), 1.52-1.49 (m, 1H), 1.07 (s, 3H). LC-ES/MS m/z 281 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCCC1>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[O:14])=[CH:21][CH:22]=1
Reactant: O=C1CCCN1C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCCN1C(=O)c1ccc(O)cc1

Procedure:
2.0 g. of 1-(p-benzyloxybenzoyl)-2-pyrrolidinone are hydrogenated in 20 ml. of absolute tetrahydrofuran and 20 ml. of absolute methanol over 300 mg. of palladium/carbon (5%) under atmospheric pressure and at room temperature. The catalyst is filtered off, the filtrate is concentrated and the residue is triturated with diethyl ether. After filtration, there is obtained 1-(p-hydroxybenzoyl)-2-pyrrolidinone, having a melting point of 179°-182° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[N:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:28][CH2:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: NCc1ccc(C(F)(F)F)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Yield: 86 %

Procedure:
Two 20 mL microwave vials were each charged with a half portion of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.62 g, 21.6 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanamine (5.0 g, 28 mmol), N,N-diisopropylethylamine (7.6 mL, 44 mmol) and acetonitrile (10 mL), and the mixture was subjected to a microwave irradiation at 200° C. for 3.5 h. LC-MS analysis showed the reaction was complete for both samples. The samples were combined, and partitioned between CH2Cl2 (150 mL) and 0.5M NaH2PO4 (pH 4; 120 mL). The organic layer was extracted with 2M HCl (60 mL, 30 mL). The combined acid extracts were basified with 50% KOH (25 mL), extracted with CH2Cl2 (2×100 mL), dried (Na2SO4), filtered and concentrated to yield a light brown oil, which was absorbed on silica (40 g) and purified by column (120 g silica gel, 0-7.5% MeOH/CH2Cl2) to afford a light yellow foam (7.42 g, 86%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:27]I.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(Cc3cn(C)c4ncccc34)CC2)cc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Sodium hydride (80% dispersion in oil; 0.13 g, 4.3 mmol) was added to a solution of 3-(4-(4-methoxyphenyl)piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (1.06 g, 3.29 mmol) in dimethylformamide (30 ml) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for an hour. Methyl iodide (0.22 ml, 3.53 mmol) was added and the reaction mixture stirred for 2 h at room temperature. The mixture was poured into water (300 ml), extracted with ethyl acetate (2×150 ml), and the extracts washed with brine (150 ml). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. Purification by flash chromatography, eluting with 5% then 7.5% methanol in dichloromethane, gave the title compound (0.87 g, 79%). Recrstallisation from ethyl acetate/petrol (60°-80° C.) gave fine needles, m.p. 92°-94° C.; (Found: C, 71.25; H, 7.18; N, 16.49. C20H24N4O requires C, 71.40; H, 7.19; N, 16.65%); δH (CDCl3) 2.65 (4H, m, 2×piperazinyl CH2), 3.09 (4H, m, 2×piperazinyl CH2), 3.74 (2H, s, CH2N), 3.75 (3H, s, ArOCH3), 3.87 (3H, s, N--CH3), 6.85 (4H, m, ArH), 7.05 (1H, dd, J 7.8, 4.7 Hz, 5-H), 7.15 (1H, br s, 2H), 8.04 (1H, dd, J 7.8, 1.5 Hz, 4-H), and 8.33 (1H, dd, J 4.7, 1.5 Hz, 6-H); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O-:10])=[O:9])([O:5][CH3:6])=[O:4].[K+].Br[CH2:13][N:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([Cl:23])[C:16]([C:24]#[N:25])=[C:15]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>CN(C)C=O.O>[CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][CH2:13][N:14]1[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:16]([C:24]#[N:25])[C:17]([Cl:23])=[C:18]1[C:19]([F:22])([F:20])[F:21])=[O:9])([O:5][CH3:6])=[O:4]
Reactant: N#Cc1c(Cl)c(C(F)(F)F)n(CBr)c1-c1ccc(Cl)cc1
Reactant: COP(=O)(CC(=O)[O-])OC
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COP(=O)(CC(=O)OCn1c(-c2ccc(Cl)cc2)c(C#N)c(Cl)c1C(F)(F)F)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A solution of potassium (dimethylphosphono)acetate (0.69 g, 4 mmol) in N,N-dimethylformamide is treated with 1-(bromomethyl)-4-chloro-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (0.79 g, 2 mmol), stirred at room temperature for one hour, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain a brown oil. The oil is chromatographed using silica gel and a 1:1 hexanes/ethyl acetate mixture to give the title product as a viscous yellow oil (0.41 g) which is identified by 13C and 19FNMR spectral analyses.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([Cl:41])[CH:40]=1)[C:35](Cl)=[O:36]>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([Cl:41])[CH:40]=1)[C:35]([N:9]([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:8])=[O:36]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1cc(Cl)cc(Cl)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 350 μl (2.5 mmol) of 3,5-dichlorobenzoyl chloride, and after purification, 400 mg (50%) of 3,5-dichloro-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylbenzamide are obtained in the form of a white solid with a melting point of 106° C.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:38])[C@H:24]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:38])=[O:22])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to Nε-Boc-lysine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.