Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S,4S)-4-Aminopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (7.3 g, 30 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (3 equiv) was added, followed by benzyl chloroformate (1 equiv). The mixture was stirred at room temperature for 3 hours and then diluted with DCM (200 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (10.4 g, 28 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:18][O:19][CH2:20][CH2:21][NH2:22].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:22][CH2:21][CH2:20][O:19][N:18]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: NCCON
Reactant: N#CCCCC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#CCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 6.9 mmol (1.67 g) of 3', 4'-dichloro-4-cyanobutyrophenone (melting point 53°-54° C), 6.9 mmol (1.03 g) of 2-aminooxyethylamine dihydrochloride, 6.9 mmol (0.56ml) of pyridine and 5 ml of absolute ethanol was refluxed for 3.5 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Clc1cccc2cc[nH]c12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 7-chloroindole (0.70 g, 4.6 mmol) and 4-piperidone hydrochloride hydrate (1.4 g, 9.2 mmol). The product was isolated as a yellow solid. Yield 0.80 g (75%). mp 205-208° C. FDMS m/e=234 (M+ of free base).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc(C(F)(F)F)n1
Product: FC(F)(F)c1nccc(Cl)n1

Procedure:
To 2-(trifluoromethyl)pyrimidin-4-ol (2 g, 12 mmol) was added POCl3 (15 mL). It was refluxed overnight. The solvent was removed. 1N NaOH was added to the reaction mixture slowly until pH=10. The mixture was extracted with DCM (3×80 mL). Combined DCM layer dried over Na2SO4 and taken to dryness. The crude product was vacuum distilled. 4-chloro-2(trifluoromethyl)pyrimidine was obtained as a clear oil. (94%). 1H NMR (400 MHz, DCM) δ: 7.60 (d, J=3 Hz, 1H), 8.80 (d, J=3 Hz, 1H),
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2Cl)[CH:8]=[CH:7][N:6]=1)=[O:4].NC1C=CC(O)=C([Cl:28])C=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Cl:28])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1
Product: CNC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-amino-2-chlorophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-3-chlorophenol for 4-amino-2-chlorophenol. 1H-NMR (DMSO-d6) δ 8.76 (m, 1H), 8.47 (d, 1H), 7.35 (s, 1H), 7.15 (s, 1H), 7.06 (dd, 1H), 6.85 to 6.95 (m, 2H), 5.43 (s, 2H), 2.78 (d, 3H); MS LC-MS [M+H]+=278.1 [M+H]+, RT=2.19 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)[C:6]([CH3:25])=[C:5]2[CH:26]=O.Cl.[NH2:29][OH:30].CO>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)[C:6]([CH3:25])=[C:5]2[CH:26]=[N:29][OH:30]
Reactant: NO
Reactant: Cc1c(C=O)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C=NO)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 88 %

Procedure:
A mixture of 5-fluoro-1-(4-benzyloxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.97 g, 2.7 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol), methanol (25 mL) and pyridine (1 mL) was reacted according to the procedure in Example 3a to afford white solid (88%): mp 183-185° C.; 1H NMR (DMSO-d6): δ 2.30 (3H, s), 5.20 (2H, s) d, 6.94-6.97 (2H, m), 7.23 (2H, d, J=8.9 Hz), 7.37-7.46(5H, m), 7.52(2H, d, J=6.8 Hz), 7.71 (1H, d, J=10.1 Hz), 8.41 (1H, s), 10.72 (1H, s); MS m/z (M+H)+ 375. Anal. for C23H19FN2O2: Calc'd: C, 73.78; H, 5.11 N, 7.48. Found: C, 73.55; H, 5.03; N, 7.35.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:19]=[C:18]([B:29]2[O:33][C:32](C)(C)C(C)(C)[O:30]2)[C:15]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:32]1[O:33][B:29]([OH:30])[C:18]2[CH:19]=[C:20]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:21]=[C:14]([F:13])[C:15]1=2)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)OB(c2cc(OC3CCCCO3)cc(F)c2C=O)OC1(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(F)c21
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a mixture of zinc powder (0.98 g, 15.0 mmol) in anhydrous THF (30 mL) was added TMSCl (0.39 mL, 3.0 mmol) at 40° C. The resulting mixture was stirred at 55° C. for 15 min and then cooled to 37° C. Ethyl 2-bromoacetate (1.35 mL, 12.0 mmol) was added at 37° C. and the reaction mixture was stirred at this temperature for 30 min. To a solution of 2-fluoro-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.05 g, 3.0 mmol) in anhydrous THF (40 mL) was added dropwise above prepared solution at −78° C. The reaction was allowed to stir at room temperature for 1.5 h and quenched by addition of aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/3) on silica gel to give the title compound as a yellow solid. (0.89 g, Yield: 87.9%). MS (ESI) m/z=339 [M+H]+.
Reaction SMILES: [CH:1]([C:5]([CH3:13])([CH:9]([CH3:12])[CH2:10][CH3:11])[C:6](Cl)=[O:7])([CH2:3][CH3:4])[CH3:2].[CH2:14]([CH2:16][NH2:17])[OH:15]>C1C=CC=CC=1>[OH:15][CH2:14][CH2:16][NH:17][C:6](=[O:7])[C:5]([CH:9]([CH2:10][CH3:11])[CH3:12])([CH3:13])[CH:1]([CH3:2])[CH2:3][CH3:4]
Reactant: NCCO
Reactant: CCC(C)C(C)(C(=O)Cl)C(C)CC
Solvent: c1ccccc1
Product: CCC(C)C(C)(C(=O)NCCO)C(C)CC

Procedure:
A solution of 2-sec-butyl-2,3-dimethylpentanoyl chloride (2.0 g) in benzene (10 ml) was added to a stirred solution of ethanolamine (2.0 g) in benzene (100 ml). After 16 hours the benzene solution was washed with dilute hydrochloric acid and water, dried (MgSO4) and concentrated to give a pale yellow syrup. Distillation of this syrup gave N-(2-hydroxyethyl)-2-sec-butyl-2,3-dimethylpentanamide bp. 125°-130°/0.03 mm which slowly solidified on standing.
Reaction SMILES: O([Si:4]([O:7][CH2:8][CH3:9])([CH3:6])[CH3:5])CC.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>CCOCC>[CH2:12]([CH2:9][CH2:8][O:7][SiH:4]([CH3:5])[CH3:6])[CH:11]=[CH2:10]
Reactant: CCO[Si](C)(C)OCC
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCCCO[SiH](C)C
Temperature: -20 °C
Yield: 84 %

Procedure:
In a 1000 ml flame-dried flask equipped with a magnetic stir bar, 250 ml of dry ether and 37 g (250 mmol) of diethoxyldimethylsilane were injected under argon. The solution was vigorously stirred while 250 ml of allylmagnesiumbromide in ether (1.0 M) was added dropewise over 2 hours. The solution was refluxed overnight to complete the coupling reaction. After cooling the mixture to −20° C. and removing the solid by filtration, the solvent was removed by rovaperation. The raw product was subjected to vacuum distillation to obtain 30 g of pure allylethoxyldimethylsilane (colorless liquid) with yield of 84%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A flame-dried 200 mL round bottomed flask was charged with 3-(2-formyl-4-hydroxyphenyl)acrylic acid tert-butyl ester (10.0 g, 40.3 mmol), tert-butylchlorodiphenylsilane (12.6 mL, 48.3 mmol), and dry CH2Cl2 (150 mL). Triethylamine (11.2 mL, 80 mmol) and N,N-dimethylaminopyridine (1.0 g, 1.0 mmol) were added, and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with additional CH2Cl2, washed with brine (2×), dried (Na2SO4), and concentrated to an oil. The crude product was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 5:95) to give a pale yellow oil (18.3 g, 93%). 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 9H), 1.51 (d, J=15.1 Hz, 9H), 6.15 (d, J=5.1 Hz, 1H), 6.87 (dd, J=8.6, 2.7 Hz, 1H), 7.34-7.47 (m, 7H), 7.68-7.73 (m, 5H), 8.28 (d, J=15.6 Hz, 1H), 10.1 (s, 1H). MS (ES) m/e 487 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1)[CH3:2].CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C:27]#[N:28].Cl>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:25][CH2:26][C:27]#[N:28])[N:7]=1)[CH3:2]
Reactant: N#CCCCl
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(CCC#N)c(=O)c2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of ethyl-4-oxo-3-H-phthalazin-1-ylacetate (10.91 g) and dry potassium t-butoxide (5.90 g) in dimethylformamide (50 ml) was added 3-chloropropionitrile (4.92 g) and the resulting solution was stirred for 30 minutes. The solution was then poured onto ice-water (300 ml); sufficient 10% HCl was added to adjust the pH of the resulting mixture to about 4.0 and the precipitated solid was collected and crystallized from methanol (yield: 7.64 g; m.p. 125°-126° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:18]([NH2:25])[C@H:17]1[OH:26]>CCCCO>[Cl:8][C:4]1[N:3]=[C:2]([NH:25][C@@H:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][C@@H:17]2[OH:26])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Temperature: 115 °C
Yield: 54.5 %

Procedure:
To a solution of 2,6-dichloropyrazine (5.0 g, 34 mmol) in n-BuOH (30 mL) was added triethylamine (6.8 g, 9.4 mL, 67 mmol) and (1R,2S)-(+)-cis-1-amino-2-indanol (5.0 g, 34 mmol). The mixture was heated at 115° C. overnight. The solution was cooled to rt and concentrated. Dissolve material in EtOAc (200 mL) and remove insoluble material by vacuum filtration. Wash filtrate sequentially with 4 N NaOH and sat. aq. NaCl. Dry organic extract over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 10% ethyl acetate/hexanes) to afford 4.85 g (57%) of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as a solid: 1H NMR (CDCl3) δ 2.83-2.87, 3.08-3.13, 3.32, 4.54, 5.11, 5.28-5.31, 7.18-7.28, 7.73, 8.12; MS (ESI+) for C13H12ClN3O m/z 262 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14](OS(C)(=O)=O)[C@@H:15]1[CH2:19][C@@H:18]([CH2:20][CH3:21])[C:17](=[O:22])[O:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:15]1[O:16][C:17](=[O:22])[C@H:18]([CH2:20][CH3:21])[CH2:19]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: CC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
7.91 g of sodium azide (122 mmol) was added to a solution of 29.5 g of methanesulfonic acid (R)-2-benzyloxy-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl ester obtained in Example (106d) (86.3 mmol) in N,N′-dimethylpropyleneurea (300 ml) at room temperature, and the mixture was stirred at 60° C. for two days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1) to obtain 23.1 g of the title compound (yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CN(C)CCN
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCN(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and N,N-dimethylethylenediamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>CN(C)C(=O)C>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:7][CH:6]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Nc1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of N-(4-aminophenyl)propanamide (2.00 g, 10.3 mmol) and pyridine (2.50 ml, 30.9 mmol) in N,N-dimethylacetamide (40 ml) was added 2,2,2-trichloroethyl chloroformate (2.13 ml, 15.5 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was poured into ice-water, and 3.41 g (97.4%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][N:20]([CH3:42])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=3)=[C:28]([CH3:41])[CH:27]=2)[N:22]=1>>[CH3:19][N:20]([CH3:42])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:15]4[C:16]5[CH:17]=[C:18]6[C:5]7([CH2:8][O:9][C:10]6=[CH:11][C:12]=5[CH2:13][CH2:14]4)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]7)=[O:39])=[CH:34][CH:33]=3)=[C:28]([CH3:41])[CH:27]=2)[N:22]=1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)O)cc1
Product: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-(5-dimethylamino-1,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (D14) using a procedure similar to that of Example 1 (18%). This was converted to the oxalate salt, which precipitated from acetone/ether as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=2)[CH:27]=1)=O)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:39])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (49 mg).
Reaction SMILES: [CH:1]1([C:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].[Na+].[CH3:12][NH2:13]>CO>[CH3:12][N:13]1[CH:5]2[CH2:4][CH2:3][CH:2]1[C:1]([C:8]#[N:9])=[CH:7][CH2:6]2
Reactant: N#CC1C=CC=CC=C1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C2CC=C(C#N)C1CC2
Temperature: 125 °C
Yield: 70 %

Procedure:
In 2 ml of methanol was dissolved 0.5 g (4.27 mmol) of 2,4,6-cycloheptatriene-1-carbonitrile (4: CHT-CN). A solution of 171 mg (4.27 mmol) of sodium hydroxide in 5 ml of methanol and then 3 ml (about 38 mmol) of 40% methanolic solution of methylamine were added thereto, and the resulting mixture was stirred with heating at 125° C. for 10 hours in a sealed vessel. After standing at room temperature, the methanol was evaporated and the residue was adjusted to pH 2 with 1N sulfuric acid solution, followed by extraction with chloroform (No. of run: 1) or ether (No. of run: 2 to 5) (separation into an organic layer 1 and an aqueous layer 1). The aqueous layer 1 was neutralized with 4N sodium hydroxide solution, followed by extraction with chloroform (No. of run: 1) or ether (No. of run: 2 to 5) (separation into an organic layer 2 and an aqueous layer 2). The organic layer 2 was dried and then the solvent was evaporated therefrom to obtain 0.458 g of a brown oil (1RS)-AECG-CN (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=O.[C:13]([NH2:17])(=[O:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[NH:17][C:13](=[O:16])[CH2:14][S:15]1
Reactant: O=CCOc1ccc(Cl)cc1Cl
Reactant: NC(=O)CS
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1CSC(COc2ccc(Cl)cc2Cl)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.1 %

Procedure:
To a solution containing 5.25 g (0.025 mole) of (2,4-dichlorophenoxy)acetaldehyde and 5.0 g (0.055 mole) of thioglycolamide in 100 ml of anhydrous ether was added 14.2 g (0.10 mole) of boron trifluoride etherate. The resulting solution was stirred at ambient temperature for 6 hours, washed with water, dried (MgSO4), and concentrated to dryness. The residual solid was purified by silica chromatography to give 1.4 g of 2-(2,4-dichlorophenoxymethyl)-4-thiazolidinone as a white crystalline solid melting at 134°-136°.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[O:9]
Reactant: O=CCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC(Br)c1ccccc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a solution of phenyl-acetaldehyde (1 g, 8.3 mmol) in CH2Cl2 (3 mL) was added dropwise a solution of Br2 (1.3 g, 8.3 mmol) in CH2Cl2 (3 mL) at −10° C. over 30 min. The resulting solution was allowed to warm to rt and then heated to reflux overnight. Aqueous NaHCO3 was added to the cooled mixture and the solution was extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford crude bromo-phenyl-acetaldehyde (1 g, 5.05 mmol, 61%) as a green liquid which was taken to the next step directly. Anal. Calcd. for C8H7BrO m/z 198.0, found: 198.0 GC-MS (M)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][NH2:25])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][NH:25][C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: Clc1nc2c(Br)cccn2n1
Product: CC(C)(C)OC(=O)N1CCCC1CNc1cccn2nc(Cl)nc12

Procedure:
2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (475.0 mg, 2.372 mmol) in a manner analogous to Example 2d. Product isolated as a yellow viscous oil (0.411 g, 54%). MS=374, 376 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
3-Chlorophenol (1.9 g) was stirred with 4-fluoro-benzaldehyde (1.8 g) and sodium hydride (0.46 g of an 80% suspension in oil) in dimethylformamide (50 ml) at 110° C. under an atmosphere of nitrogen for 16 hours. The solution was diluted with water and extracted with diethyl ether. The ethereal extract was dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:9) to give the title compound as a colourless oil.