Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C1C=CN=CC=1.O.CN(C)C=O>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([NH:22][CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:25][CH2:24]4)=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Agent: CN(C)c1ccncc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(2,3-dihydro-2-oxo-1H-imidazo-[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g, 7mmol), 4-amino-1-benzylpiperidine (1.59 g, 1.70 mL, 8.4 mmol), triethylamine (1.54 g, 2.12 mL, 15.2 mmol), diphenylphosphoryl azide (2.87 g, 2.25 mL, 10.4 mmol), 4-dimethylaminopyridine (catalytic quantity) and dimethylformamide (40 mL) was stirred at room temperature for 18 hours. The mixture was then diluted with water and the crude free base product collected. After air drying, the free base was suspended in methanol and acidified with a 10% solution of hydrogen chloride in ethanol. The solution was evaporated and the residue dissolved in methanol. Dilution of the methanol solution with diethyl ether gave 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yloxy)-N-[1-(phenylmethyl)-4-piperidinyl]butanamide as the hydrated dihydrochloride salt (3.00 g, 80%), mp. 202°-204 C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[O:20]1[CH2:21][CH2:22][N:17]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:6]=2)=[O:10])[CH2:18][CH2:19]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-nitro-3-trifluoromethylbenzoic acid (10 g), morpholine (3.7 g) in dichloromethane (300 mL) was added DMAP (5.2 g) and 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride (12.3 g). The mixture was stirred at room temperature overnight, washed with 5% aqueous HCl, water and brine and concentrated.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[N:13]=[CH:14][N:15]([C:17]4[CH:22]=[CH:21][C:20](C(=O)C)=[CH:19][CH:18]=4)[CH:16]=3)=[C:10]([CH2:26][O:27]C)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>ClCCl>[C:1]1([C:7]2[C:11]([C:12]3[N:13]=[CH:14][N:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:16]=3)=[C:10]([CH2:26][OH:27])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(C)=O)cc2)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
To a stirred solution of 1-(4-{4-[3-phenyl-5-methoxymethyl-isoxazol-4-yl]-imidazol-1-yl}-phenyl)-ethanone (147 mg, 0.44 mmol) in dry dichloromethane (4 mL) was added slowly boron tribromide (334 mg, 1.33 mmol) at dry ice-acetone bath cooling temperature. After complete addition, the resulting mixture was stirred at −78° C. for 15 min, and then allowed to warm up to room temperature for 35 min. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated, and the aqueous phase was extracted with dichloromethane and ethylacetate. The combined organic solution was dried over sodium sulphate and evaporated. Purification by preparative HPLC afforded the title compound (98 mg, 70%) which was obtained as an off-white solid. MS: m/e=318.0 [M+H]+.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])[OH:4].[O-]S([O-])(=O)=O.[Na+].[Na+].NO.Cl.[F:18][C:19]1[CH:25]=C[C:22]([NH2:23])=[CH:21][C:20]=1[CH3:26]>O.Cl>[NH2:23][C:22]1[CH:21]=[C:20]([CH3:26])[C:19]([F:18])=[CH:25][C:2]=1[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(N)ccc1F
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: NO
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1cc(N)c(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Chloral hydrate (76 g) was dissolved in 1 L water and subsequently 1 kg Na2SO4, 94.1 g H2NOH.HCl, and 51.3 g 4-fluoro-3-methyl aniline in 250 ml 5% aq. HCl were added. The suspension was heated to boiling and kept boiling for 1 minute. After cooling down to room temperature, the solid was filtered off and washed twice with warm water (40° C.). Yield after drying overnight at 60° C. under vacuum was 275 g, which was used without further purification or drying. The 275 g of crude product was slowly poured in 500 ml of concentrated H2SO4 at 50° C., such that the temperature was kept below 75° C. After completion of addition, the dark/purple solution was heated to 85° C. for 15 minutes. After cooling down to room temperature, the solution was poured in 2 L of ice water and was left standing for an half hour. The red solid was filtered and washed twice with cold water. Subsequently, the solid was dried under vacuum at 70° C. Yield: 69.9 g (quantitatively from 4-fluoro-3-methyl aniline) of a mixture of two regio isomers: 5-fluoro and 3-fluoro 3-methyl-isatin in a ratio of about 55:45. The mixture of isatins (69.4 g) was dissolved in 1 L 1N aq. NaOH and subsequently 100 ml of 30% aq. H2O2 was added drop wise, keeping the temperature below 30° C. After completion of addition, the mixture was heated to 45° C. until evolution of gas ceased. The solution was cooled to room temperature, filtered and acidified with glacial acetic acid. The precipitate formed was filtered off, washed twice with water and air-dried 45° C. Yield: 29.4 g of 5-fluoro-4-methyl-anthranilic acid iii.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:32]([C:35]1[C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37][C:36]=1[C:43]([C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][C:54]#[N:55])[CH:48]=[C:49]([CH3:51])[CH:50]=1)=[O:44])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:37]2[C:36]([C:43]([C:45]3[CH:46]=[C:47]([CH:52]=[CH:53][C:54]#[N:55])[CH:48]=[C:49]([CH3:51])[CH:50]=3)=[O:44])=[C:35]([CH:32]([CH3:33])[CH3:34])[C:40](=[O:41])[NH:39][C:38]2=[O:42])[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(CO)cc(Cl)n2)cc1
Reactant: Cc1cc(C=CC#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
To a stirred solution of 2-chloro-6-(p-methoxybenzylamino)-4-pyridine-methanol (278 mg, 1 mmol) in chloroform (10 ml) at 0° C. (ice bath), was added triethylamine (210 μl, 1.5 mmol) followed by methanesulfonyl chloride (90 μl, 1.2 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with 3-[3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (98) (323 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol). Anhydrous DMF (5 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and evaporated in vacuo to give a light yellow foam. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); The fraction of Rf=0.19 was collected.) to afford 323 mg (55%) of a pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[N:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.C(N(CC)CC)C.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6](=[O:11])/[C:5]/2=[N:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=1
Reactant: O=C1Nc2ccc(Br)cc2/C1=N/c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1/C(=N\c2cccc(C(F)(F)F)c2)c2cc(Br)ccc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.2 %

Procedure:
A mixture of (3z)-5-bromo-3-{[3-(trifluoromethyl)phenyl]imino}-1,3-dihydro-2h-indol-2-one (100 mg, 0.272 mmol), copper (II) acetate (54 mg, 0.33 mmol), triethylamine (82.8 mg, 0.817 mmol), and benzene boronic acid (40 mg, 0.325 mmol) in 5 mL of CH2Cl2 was stirred at room temperature for 12 h. The crude mixture was concentrated in vacuo and purified by preparative TLC using EtOAc:hexane (3:7, 1% triethylamine), giving the desired product (22 mg, 20%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:21])[CH2:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8](=[O:21])[CH2:9][CH:10]([OH:20])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(I)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(O)CCc1ccc(I)cc1
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
Sodium borohydride (198 mg, 5.20 mmol) was added in one portion to a stirred solution of 5-(4-iodo-phenyl)-3-oxo-pentanoic acid tert-butyl ester (Intermediate 8, 1.78 g, 4.76 mmol) in methanol (15 mL) at 0° C. The reaction was stirred for 20 minutes then quenched with 1 M HCl (15 mL). The resulting mixture was extracted with diethyl ether (3×20 mL). The organic phases were combined, dried (MgSO4) then the solvent removed by evaporation under reduced pressure to give the title compound (1.46 g, 82%) as a colourless oil. LC/MS: 3.59 min; z/e 394, calcd (M+NH4) 394. 1H NMR (400 MHz: CDCl3): 7.6 (2 H), 6.95 (2 H), 3.95 (1 H), 2.7 (2 H), 2.38 (2 H), 1.73 (2 H), 1.45 (9 H).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[C:45]([NH2:50])[CH:44]=1>C(Cl)(Cl)Cl>[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[C:45]([NH:50][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH3:7])[CH:10]=2)[CH:44]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCCN(CCC)Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1cccc(C(=O)Nc2cc(C(=O)OC)ccc2N)c1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
The compound (300 mg) obtained in Example 18-2, WSCI hydrochloride (365 mg), and HOBt (260 mg) were dissolved in chloroform (6.0 ml), and the whole was stirred for 1 hour. Then, 3,4-diaminobenzoic acid methyl ester (198 mg) was added thereto and the whole was stirred for 2 hours. A solid was precipitated, so DMF (2.0 ml) was added thereto and stirring was continued for additional 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform and washed with a saturated ammonium chloride aqueous solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. Then, the resultant was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (381 mg) as a brown oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].[H-].[Na+]>CN(C=O)C.C1COCC1>[CH3:14][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6]
Reactant: Cc1ccncc1NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccncc1N1CCNC1=O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
1-(2-Chloro-ethyl)-3-(4-methyl-pyridin-3-yl)-urea (I-14a: 8.5 g, 39.96 mmol) in dry DMF (150 mL) was added to a stirred mixture of sodium hydride (2.87 g, 59.94 mmol) in THF (150 mL) at 0° C. The reaction temperature was maintained at room temperature for 30 minutes. The reaction was monitored by TLC. The reaction mixture was quenched with MeOH at 0° C., concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 6.5 g (91% yield) of 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1

Procedure:
569 mg (2.62 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 0.3 ml (2.65 mmol) of 3-chlorobenzaldehyde and 0.03 ml (0.34 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene overnight while water was removed. Ethyl acetate was added to the reaction mixture, and the product was washed with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propene-1-yl)acrylamide. 20 ml of 2-propanol and 260 mg (2.62 mmol) of 4-amino-3-pentene-2-on were added to the product, and they were heated at 80° C. under stirring for 3 days. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([O:16][CH3:17])[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([O:16][CH3:17])[CH:6]=[C:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(OC)nc2c(F)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c2cccc(F)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-Fluoro-2-methoxyquinoline-4-carboxylic acid methyl ester (0.1 82 g) in methanol (10 ml) containing 2N sodium hydroxide (0.41 ml) was stirred at room temperature for 16 h. Solvent was removed at reduced pressure, dissolved in water, and adjusted to pH2 with 2N hydrochloric acid. The precipitated title compound (0.155 g) was collected by filtration and dried. m/z (API−): 222 (MH+). 1H NMR δ: 4.02 (3H, s), 7.44-7.62 (3H, m), 8.31 (1H, d).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH3:15])=[O:6].Cl.[OH-:24].[K+]>CS(C)=O.O>[CH2:14]([N:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[C:3]([O:21][CH3:22])=[C:2]([OH:24])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[CH3:15]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(OC)ccc(Br)c1OC
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCC[C@H]1CNC(=O)c1c(OC)ccc(O)c1OC

Procedure:
(S)-(-)-3-Bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide ×HCl×H2O (1.0 g, 0.0026 mol) was dissolved in 25 ml dimethylsulphoxide. A suspension of crushed potassium hydroxide (1.0 g, 0.018 mol) in 5 ml water was added and the mixture was heated at reflux for 2 h. After cooling 200 ml of water was added and the reaction mixture was neutralized and extracted with chloroform. Drying and evaporation of the solvent gave a residue containing a mixture of several products including the starting material. Separation on silica column with CH2Cl2 -C2H5OH-NH3 (90:9:1) gave 0.05 g of the title compound as a oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
In 69.2 g of pyridine was dissolved 33.27 g of 2-benzyloxy-ethanol, and to this solution was then added with stirring 45.9 g of p-tosyl chloride at an inner temperature in the range of 5°- 10° C. The resulting mixture was stirred at a temperature of 15° C for 2 hours. After completion of the reaction, a mixture solution of 130 ml of conc. hydrochloric acid and 450 ml of ice-water was added to the resulting reaction mixture and then subjected to extraction with benzene. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Upon evaporation of the solvent from the extract, there was obtained 66.9 g of 2-benzyloxy-1-(p-toluenesulfonyloxy)ethane as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]3=[O:11])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: O=C1CCCCN1CCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1CCCN1CCN(c2ccc(F)cc2)CC1
Reaction time: 14 h

Procedure:
A mixture of 1-chloro-3-[2-oxopiperidin-1-yl]propane (2.1 g, 12 mmol), 1-(4-fluorophenyl)piperazine (2.16 g, 12 mmol), anhydrous Na2CO3 (0.618 g, 6.2 mmol) and Nal (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 800 .English Pound. for 14 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHCl3 (2×35 ml). The extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl)piperazin-1-yl]-3-[2-oxopiperidin-1-yl]propane as an oil which was purified by column chromatography over silica gel using chloroform as eluent, yield 2.40 g (63.0%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH3:33][C:34]([CH3:45])([NH2:44])[CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:44][C:34]([CH3:45])([CH3:33])[CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(N)CCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NC(C)(C)CCCc2cccnc2)c2ccc(OC)cc2)cc1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.73 g) and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred for 20 hours at room temperature and then at reflux for an additional 24 hours to complete the reaction. After the usual work up, the crude amide was crystallized from ethyl acetate-hexane (2x) to furnish 1.55 g of (E)-5,5-bis(4-methoxyphenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 144°-145° C. Anal. Calculated for C30H34N2O3 : C, 76.57; H, 7.28; N, 5.95 Found: C, 76.70; H, 7.48; N, 6.20.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([C:10](=[O:22])[NH:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:14]=2[F:21])[N:7]([C:23](=[O:37])[NH:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([C:34](=[O:36])[NH2:35])[CH:26]=2)[CH2:6]1)=[O:4].CCOCC.C[Si](C)(C)[O-].[K+]>C1COCC1.CCOC(C)=O.O>[C:34]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([NH:24][C:23]([N:7]2[C@H:8]([C:10](=[O:22])[NH:11][CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:14]=3[F:21])[CH2:9][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[O:37])=[CH:26]1)(=[O:36])[NH2:35]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)NCc2c(F)ccc(Cl)c2F)N(C(=O)Nc2cn(C(N)=O)c3ccccc23)C1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: NC(=O)n1cc(NC(=O)N2C[C@@H](C(=O)O)C[C@H]2C(=O)NCc2c(F)ccc(Cl)c2F)c2ccccc21
Temperature: 25 °C
Reaction time: 1.3 h

Procedure:
To a solution of (3S,5S)-1-(1-carbamoyl-1H-indol-3-ylcarbamoyl)-5-(3-chloro-2,6-difluoro-benzylcarbamoyl)-pyrrolidine-3-carboxylic acid methyl ester Example 353 (50 mg, 0.094 mmol) in THF (0.3 mL)/Et2O (3 mL)/H2O (0.3 mL) was added potassium trimethylsilanolate (19.5 mg, 0.2 mmol) and the resulting suspension was stirred at RT for 1.30 h. The reaction was diluted with EtOAc (15 mL) and H2O (3 mL), and the biphasic mixture was vigorously stirred for 5 min. The layers were separated, and the aqueous one was extracted with EtOAc (×2). The aqueous layer was acidified by addition of 1N HCl and extracted with EtOAc, the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give, after lyophilization of the purified fractions the title compound as a white solid. MS (LC-MS): 518.4 [M−H]−, 520.1 [M+H]+, 1039.3 [2M+H]+; tR (HPLC conditions f): 1.70 min.