Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].O>CN(C)C=O>[CH2:34]([N:36]([CH2:37][CH3:38])[CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])[CH3:35]
Reactant: CCNCC
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and diethylamine (19 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (21 mg, yield 46%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Mg+2].[Br-].[CH3:12][C:13]1([CH:17]=[O:18])[CH2:16][O:15][CH2:14]1.[Cl-].[Na+]>O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH:17]([C:13]2([CH3:12])[CH2:16][O:15][CH2:14]2)[OH:18])[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C=O)COC1
Reactant: COc1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2(C)COC2)c1
Temperature: -70 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
1.0 M Magnesium m-methoxybenzene bromide in tetrahydrofuran (25 ml, 25.0 mmol) was added dropwise to a solution of 3-methyloxetane-3-carbaldehyde (0.5 g, 5.0 mmol) in 8 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred for 4 hours at −70° C. and then allowed to return to 0° C., hydrolyzed with a saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. The residue obtained was purified by chromatography on a cartridge of silica gel (eluted with heptane/ethyl acetate, gradient from 90/10 to 60/40). 0.45 g of product was obtained in the form of a thick colorless oil. Yield=43%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:23][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([N:15]([CH2:17][C@@H:18]([N:20]=[N+]=[N-])[CH3:19])[N:14]=[CH:13]3)=[C:8]2[CH2:7]1)=[O:5])[CH3:2].Cl>CO.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[O:23][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([N:15]([CH2:17][C@@H:18]([NH2:20])[CH3:19])[N:14]=[CH:13]3)=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(ccc3cnn(C[C@H](C)N=[N+]=[N-])c23)O1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C1Cc2c(ccc3cnn(C[C@H](C)N)c23)O1
Yield: 25.3 %

Procedure:
To a solution of the product from Step A (0.13 g, 0.41 mmol) in methanol (20 mL) was added palladium-on-carbon (10%, 0.015 g). This mixture was stirred overnight under an atmosphere of hydrogen (0.4 mL of a 2 N HCl in ethanol was added to protect the ethyl ester). The reaction mixture was filtered and purified by reversed phase HPLC (gradient of acetonitrile in water, 0% to 50% with 0.1% trifluoroacetic acid). The desired fractions were combined, concentrated, treated with 2 N HCl in ethanol (10 mL) and evaporated to a residue which was dried under high vacuum at 78° C. overnight to afford an amorphous solid (0.03 g, 20%): LC/MS (+APCI) m/z 290 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH2:15]([O:22]CC1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>CS(C)=O.C(O)C1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na]
Solvent: OCc1ccccc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 866.3 %

Procedure:
To a solution containing 45.1 g (0.02 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of DMSO was added dropwise at ambient temperature a solution containing 26 g (0.2 mole) of sodium benzyloxide in 75 ml of benzyl alcohol causing the temperature to rise 40° C. After 48 hours at ambient temperature, the reaction mixture was poured into ice water and extracted with ether, and the extract was dried and concentrated to about 200 ml. To the concentrated solution was added 200 ml of hexane and the resulting solution was cooled. Filtration gave 51.5 g (87%) of colorless crystalline solid; m.p. 112°-114° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20](C)[C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[F:32][C:2]([F:1])([F:31])[C:3]([C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 20 h
Yield: 93.1 %

Procedure:
A mixture of tert-butyl 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-piperidin-4-yl(methyl)carbamate (3.19 mmol, 1.5 g), dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred for 20 hours. Purification by SCX chromatography gave the title compound (1.1 g). MS (ESI) m/z 371.4 [M+H]+
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][C@H:21]1[C@@H:25]([CH3:26])[CH2:24][N:23]([C:27]2[C:35]([F:36])=[CH:34][C:30]([C:31]([OH:33])=O)=[C:29]([F:37])[C:28]=2[CH3:38])[CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:39]([O:45][CH2:46][CH3:47])(=[O:44])[CH2:40]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([NH:20][C@H:21]1[C@@H:25]([CH3:26])[CH2:24][N:23]([C:27]2[C:35]([F:36])=[CH:34][C:30]([C:31](=[O:33])[CH2:40][C:39]([O:45][CH2:46][CH3:47])=[O:44])=[C:29]([F:37])[C:28]=2[CH3:38])[CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1c(F)c(C(=O)O)cc(F)c1N1C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(N2C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(C)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
1,1′-carbonyldiimidazole (1.46 g, 9.00 mmol) was added to a solution of 4-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoic acid (2.20 g, 6.30 mmol) in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 3 hours. Separately, a magnesium salt was prepared potassium ethyl malonate (3.40 g, 20.0 mmol), magnesium chloride (2.38 g, 25.0 mmol), and triethylamine (4.18 mL, 30.0 mmol), and the salt was dissolved in ethyl acetate (40 mL). The reaction mixture was added dropwise to the solution under cooling with ice, followed by stirring at an external temperature of 50° C. for 16 hours. Under cooling with ice, a 10% aqueous citric acid solution was added thereto, and the resultant mixture was extracted with ethyl acetate (200 mL×2), washed by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield the title compound (2.58 g, 93.0%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:15]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)(C)(C)C.C(=O)[C:26]1[C:27](=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:28].Cl>O1CCCC1>[C:21]([O:20][C:18]([O:17][C:15]1[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=1[CH:27]=[O:28])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
350 mg (2.8 mmol) of N,N-dimethylaminopyridine and 8.1 ml (46.9 mmol) of N,N-diisopropylethylamine are added to a solution containing 20.9 g (95.7 mmol) of di(tert-butyl)dicarbonate in 150 ml of tetrahydrofuran under a stream of nitrogen. 10 ml (93.8 mmol) of salicylaldehyde are added dropwise. After stirring at ambient temperature for 2 hours, the medium is treated with a 1N aqueous hydrochloric acid solution and then extracted with a heptane/ethyl acetate 1/1 mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. 21.5 g of 2-(tert-butoxycarbonyloxy)benzaldehyde are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:12][CH2:13][NH:14]1
Reactant: COC(=O)c1ccnc(Cc2cc(F)ccc2F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2cc(F)ccc2F)C1
Reaction time: 5 h
Yield: 95.6 %

Procedure:
A mixture of methyl 2-(2,5-difluorobenzyl)isonicotinate (6.8 g, 25.83 mmol) and platinum(IV) oxide (0.293 g, 1.29 mmol) in acetic acid (68 mL) was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 5 h. More PtO2 (190 mg) was added and the hydrogenation continued at room temperature and 5 bar for additional 80 min. The reaction mixture was filtered through Celite and the catalyst was washed with methanol. The filtrate was concentrated, the residue was dissolved in DCM, washed with satd NaHCO3 and the organic layer was dried using a phase separator. The solvent was evaporated under reduced pressure. The residue was dissolved in iso-hexane/ether and filtered. The solvents were evaporated in vacuo to yield methyl 2-(2,5-difluorobenzyl)piperidine-4-carboxylate (6.65 g, 96%). MS m/z 270 (M+H)+
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][O:11][C:12](=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
To a stirred solution of [2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid 2-tert-butoxycarbonylamino-ethyl ester 4 (5.3 g, 0.01 mol) in DCM (50 mL) was added TFA (5.3 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 h. Reaction was monitored by TLC. After completion, reaction mixture was concentrated under reduced pressure. The residue was neutralized with aq sodium bicarbonate and extracted with DCM (2×50 mL). Combined organic layer was dried over anhy Na2SO4 and evaporated under reduced pressure. Crude compound was purified by silica gel column chromatography using methanol and DCM (5:95) to get 1.0 g (24.4% Yield) Compound-5 as a brown solid; Mass: 339.0 (M++H).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)[C:6]([O:8]CC)=[O:7])C.[OH-].[K+]>C(O)C.O>[CH:12]1([CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:16])=[O:3])[CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C(CC1CCC1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CC1CCC1)C(=O)O
Temperature: 110 °C
Yield: 34.6 %

Procedure:
A solution of 2-cyclobutylmethyl-malonic acid diethyl ester (4.68 g, 20.5 mmol) in ethanol (45.4 mL) was treated with a solution of potassium hydroxide (3.45 g, 61.5 mmol) in water (11.4 mL). The reaction was then heated to 110° C. overnight. After this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with water (50 mL) which was then acidified with a 2N aqueous hydrochloric acid solution and then extracted with a 90/10 methylene chloride/methanol solution (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-cyclobutylmethyl-malonic acid (1.22 g, 34.7%) as a tan solid. This material was used without further purification.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[O:38][CH3:39]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[C:31]([O:38][CH3:39])=[CH:32][CH:33]=[C:34]([F:37])[C:35]=3[F:36])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: COc1ccc(F)c(F)c1CBr
Product: COc1ccc(F)c(F)c1Cn1ccc2c(-c3ccc(C)cc3)c(C(OC(C)(C)C)C(=O)O)c(C)nc21

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-3,4-difluoro-1-methoxybenzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.64 (d, J=7.0 Hz, 1 H), 7.43-7.38 (m, 1 H), 7.34 (d, J=7.4 Hz, 2 H), 7.12 (d, J=3.5 Hz, 1 H), 7.00 (dd, J=9.2, 10.1 Hz, 1 H), 6.73 (dd, J=6.4, 11.9 Hz, 1 H), 6.24 (d, J=3.5 Hz, 1 H), 5.54 (s, 1 H), 5.48 (d, J=6.0 Hz, 2 H), 3.86 (s, 3 H), 2.78 (s, 3 H), 2.47 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=509 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([CH2:12][CH:13]=[CH2:14])[C:5]=1[OH:15].[Li+].[Cl-]>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Cu+2].Cl[Pd]Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:15][C:13]([CH3:14])=[CH:12][C:6]=2[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:16]
Reactant: C=CCc1cc(OC)cc(C(=O)OC)c1O
Agent: Cl[Pd]Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc2cc(C)oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of 3-allyl-2-hydroxy-5-methoxy-benzoic acid methyl ester (4b) (1.48 g, 6.66 mmol) in DMF (30 mL) was added Cu(OAc)2 (3.63 g, 19.98 mmol), LiCl (847 mg, 19.98 mmol) in H2O (1 mL) and PdCl2 (24 mg, 0.133 mmol). The reaction mixture was stirred at RT for 3 h, quenched with H2O (100 mL) and NH4OH (5 mL) and extracted with EtOAc (100 mL). The organic layer was washed with H2O (100 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 10-15% EtOAc/hexane to give colorless oil (1.48 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.53 Hz, 1 H) 7.17 (d, J=2.53 Hz, 1 H) 6.36 (s, 1 H) 4.00 (s, 3 H) 3.87 (s, 3 H) 2.51 (s, 3 H)
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:26]=O>C(O)(=O)C>[C:18]([N:17]1[CH2:16][CH2:15][C:12]2[C:11](=[CH:10][C:9]([C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:8])=[CH:14][CH:13]=2)[CH2:26]1)(=[O:20])[CH3:19]
Reactant: C=O
Reactant: CC(=O)NCCc1ccc(C(=O)c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc(C(=O)c3ccccc3)cc2C1
Temperature: 0 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
N-[2-(4-Benzoylphenyl)ethyl]acetamide (16.46 mmol, 4.40 g) was introduced into glacial acetic acid (20 ml). Concentrated sulfuric acid (25 ml) and then formalin (49.29 mmol, 4.00 g) were slowly added thereto at 30° C. The mixture was stirred for 2 days and poured into ice-water, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with aqueous sodium carbonate solution, dried and concentrated. The residue was stirred with diethyl ether and the solid resulting therefrom was filtered off with suction. 1.6 g of the title compound were obtained as a beige-colored solid with a melting point of 110-113° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-]#N.[Na+].Cl>CS(C)=O.C(Cl)Cl.O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH3:15])=[N:17][CH:18]=1
Reactant: COc1ccc([C@@H](C)NC(=O)Cc2ccc(C(C)C)cc2)nc1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(O)cn2)cc1
Temperature: 175 °C
Reaction time: 16 h

Procedure:
2-(4-Isopropylphenyl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide (3.8 g, 12.2 mmol) (Example 11) was dissolved in DMSO (20 mL) and transferred to a sealed tube. To this solution was added NaCN (3.6 g, 73.0 mmol) and the mixture was stirred at 175° C. for 16 h. The mixture was cooled to room temperature and diluted with CH2Cl2 (200 mL) and water (100 mL). The pH of the aqueous layer was brought to neutral by the addition of 2N HCl and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL), concentrated, and purified by normal phase chromatography (2-10% MeOH/CH2Cl2) to give N-[(1R)-1-(5-hydroxypyridine-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 8.06 (t, J=1.65 Hz, 1H), 7.17 (m, 4H), 7.02 (m, 2H), 6.67 (d, J=7.50 Hz, 1H), 5.03 (quint., J=6.96 Hz, 1H), 3.53 (d, J=2.20 Hz, 2H), 2.88 (sept., J=6.69 Hz, 1H), 1.38 (d, J=6.77 Hz, 3H), 1.23 (d, J=6.95, 6H); MS (Electrospray): m/z 299.3 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:16].CS(C)=[O:19]>>[ClH:16].[NH2:1][CH:2]([CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:19])[C:13]([OH:15])=[O:14]
Reactant: CS(C)=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Product: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.2 Grams of L-tryptophane was suspended in 7.8 g of dimethyl sulfoxide, then 16.6 ml of concentrated hydrochloric acid was added all at once in the suspension, and the mixture was stirred at a room temperature overnight. The crystals formed in the reaction mixture were collected by filtration, then washed with acetone and dried to obtain 9.8 g of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride. [α]D20 +22.5° (C=1, methanol)
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].[Br:11][CH2:12][CH2:13][C:14](Cl)=[O:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:11][CH2:12][CH2:13][C:14]([NH:5][C:4]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])=[O:15]
Reactant: CCc1cccc(C)c1N
Reactant: O=C(Cl)CCBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cccc(C)c1NC(=O)CCBr
Reaction time: 0.5 h

Procedure:
In a glass-stoppered bottle, a solution of 2-ethyl-6-methylaniline (15.0 g, 0.111 mole) in glacial acetic acid (95 ml) was cooled to 13° C. and 3-bromo-propionyl chloride (21.1 g, 0.122 mole) was added. The mixture was mixed and was combined immediately with a cooled (3° C.) solution of sodium acetate trihydrate (36.9 g) in water (150 ml). The mixture was shaken vigorously for 30 min. The white product that formed was filtered off, washed carefully with water, and dried. This product, i.e., 3-bromo-2'-ethyl-6'-methylpropionanilide (27.4 g, 91%), melted at 149°-150° C. and was sufficiently pure for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:24])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:24])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)O
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Methoxy-4-(1-acetyl-4-piperidyloxy)benzoic acid (0.546 g, 1.86 mmol) in THF (10 ml) was stirred under nitrogen and treated with thionyl chloride (0.27 ml, 0.44 g, 3.7 mmol). The mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo to give 2-methoxy-4-(1-acetyl-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:31]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 16 μL (0.11 mmol) 2-methoxybenzoyl chloride. NMR was consistent with the proposed compound. Electrospray Mass Spectrum: M+1=495.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH:15]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(C(=O)C=Cc2ccccc2)c(Cl)c1Cl
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To a stirred suspension of [2,3-dichloro-4-(1-oxo-ethyl)phenoxy]acetic acid (15.78 g 0.06 mole) in 75 ml ethanol was added benzaldehyde (7.95 g, 0.075 mole) with stirring under nitrogen, followed by NaOH (8.0 g, 0.20 mole) in 16 ml of water. An additional 150 ml of ethanol was added and stirring was continued. The reaction mixture was heated at reflux for 11/2 hours, poured into ice water and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate and methylene chloride, washed with dilute hydrochloric acid, then brine, dried over magnesium sulfate and concentrated under reduced pressure to give 8.7 g of [2,3-dichloro-4-(1-oxo-3-phenyl-2-propenyl)phenoxy]acetic acid which melted at 190°-191° C. after recrystallization from acetonitrile.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[N:6][CH2:7][CH:8]=[CH2:9])[CH:2]=[CH2:3].[N:10]#[C:11][NH2:12]>ClCCCl>[CH2:1]([NH:4][C:5]([NH:6][CH2:7][CH:8]=[CH2:9])=[N:12][C:11]#[N:10])[CH:2]=[CH2:3]
Reactant: C=CCN=C=NCC=C
Reactant: N#CN
Solvent: ClCCCl
Product: C=CCNC(=NC#N)NCC=C

Procedure:
A solution of 0.7 g N,N'-bis(allyl)carbodiimide in 10 ml of 1,2-dichloroethane is reacted with 0.27 g of cyanamide and the reaction mixture is worked up as described in Example 4. Recrystallisation from diethyl ether yields a crystalline product which melts at 66.5°-67.0° C.