Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([CH3:38])[CH:18]([C:21]2[C:22]([CH3:37])=[N:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:25][CH:26]=2)[CH2:19][CH3:20])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:38][N:17]([CH:18]([C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=2)=[CH:25][CH:26]=1)[CH2:19][CH3:20])[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(N(C)C(CC)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(c1ccc(-c2cccc(C(F)(F)F)c2)nc1C)N(C)c1ccc(OCC(=O)O)c2ccccc12
Reaction time: 2 h

Procedure:
0.042 g (0.078 mmol) of the above prepared [rac]-[4-(methyl-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-propyl}-amino)-naphthalen-1-yloxy]-acetic acid ethyl ester was dissolved in 0.84 ml of THF/EtOH=1/1, treated at 0° C. with 0.24 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then neutralized with HCl dil. to pH 7, extracted with AcOEt, the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after crystallization from AcOEt/hekane, 0.033 g of the title compound as yellowish crystals of mp. 76-78° C.
Reaction SMILES: S(O[CH2:12][C:13]12[CH2:20][CH2:19][C:16]([CH3:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)(C1C=CC(C)=CC=1)(=O)=O.[C-:22]#[N:23].[Na+].CS(C)=O>C(Cl)Cl>[CH3:21][C:16]12[CH2:15][CH2:14][C:13]([CH2:12][C:22]#[N:23])([CH2:18][CH2:17]1)[CH2:20][CH2:19]2
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(C)(CC2)CC3)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC12CCC(CC#N)(CC1)CC2

Procedure:
The mixture containing 0.065 mole of 4-methylbicyclo[2.2.2]oct-1-yl methanol tosylate, 0.1 mole of sodium cyanide, and 100 ml. of dimethyl sulfoxide is stirred at 70° C for 4 hours and then poured into 500 ml. of methylene chloride. The organic phase is then washed four times with water, separated and dried with anhydrous magnesium sulfate and filtered. The filtrate is then evaporated under vacuum affording an oil which is then chromatographed on silica gel eluting with 10% ethyl acetate-90%, vol., hexane affording 4-methylbicyclo[2.2.2]oct-1-yl acetonitrile.
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[CH2:14][CH2:13][CH2:12][CH:8]([C:9]([NH2:11])=[O:10])[CH2:7]1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+]>>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:6]2[CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH2:11])=[O:10])[CH2:7]2)=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NC(=O)C1CCCNC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)N2CCC[C@@H](C(N)=O)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
Concentrated sulfuric acid is added to the reaction mixture obtained in Example 4 (amount: 30 g, net weight of (R)-nipecotamide: 3 g) to adjust the pH to 9. To the mixture, p-Methylbenzoyl chloride (8.0 g, 2.2 equivalents) was slowly added dropwise, and the pH of the reaction mixture was kept from 7 to 9 by a 30% aqueous sodium hydroxide solution. After completion of the dropwise addition, the solution was stirred at 15° C. for 3 hours and the precipitated crystal was filtered off. The crystal was dried under reduced pressure to obtain the title compound as white crystal (4.4 g, yield: 760).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:22](N1C=CN=C1)(N1C=CN=C1)=[S:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[C:12]4[N:11]([C:22](=[S:23])[NH:19][C:17](=[O:18])[C:16]=4[CH:15]=[N:14]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(F)c1)=CC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 63.0 g of 7-(3-fluorophenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 6) and 2.5 liters of dry tetrahydrofuran was stirred and cooled to -78° C. in a dry-ice-acetone bath, then 18.0 g of sodium hydride (60% dispersion in mineral oil) was added in one portion. This mixture was stirred at -78° C. for 11/2 hours then 40.0 g of 1,1'-thiocarbonyldiimidazole was added and stirring was continued at -78° C. for 2 hours. The mixture was allowed to warm to room temperature and was stirred for 48 hours, and then the reaction was quenched with 2.5 liters of water, neutralized with 5% aqueous hydrochloric acid. The crystalline solid that formed was collected, washed with ether and dried to give 54.6 g of the desired product as cream-colored crystals, m.p. 298°-300° C.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:7][CH:8]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][CH:26]=1)[CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)c1ccc(C(COc2ncnc3ccccc23)OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(C(O)COc2ncnc3ccccc23)cc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
4-(2-tetrahyropyranyloxy-2-(4-tert-butylphenyl) ethoxy) quinazoline (0.25 g, 0.615 mmol) is dissolved in 5 ml ethanol and pyridinium-p-toluenesulfonate (15.4 mg, 0.061 mmol) is added to it. The solution is heated to 55° C. and stirred at that temperature for 4 hours. The ethanol is removed and the crude is purified by flash chromatography (silica gel; ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:25])([F:24])[F:23])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[N:26]([O-])=[O:27].[Na+]>Cl.O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:24])([F:23])[F:25])[CH:11]=[CH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([N:26]=[O:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=N[O-]
Reactant: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCN3)C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=NN1CCc2cc(C=CC(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5° C., was added slowly NaNO2 in water and the reaction was allowed to stir at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J=8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm−1.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19].[OH2:23]>ClCCl>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Br:16][C:17]([CH3:22])([CH3:21])[C:18]([O-:19])=[O:23]
Reactant: O
Reactant: CC(C)(Br)C(=O)Br
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Br)C(=O)[O-]
Reaction time: 0.75 h

Procedure:
N-Hydroxysuccinimide (11.51 g, 0.1 mol) was dissolved in anhydrous dichloromethane (100 ml) with triethylamine (28.1 mL, 0.2 mol) under nitrogen in a 250 ml round-bottomed flask equipped with a magnetic stirrer. The flask was cooled to 0° C. with an ice bath before the dropwise addition of 2-bromo-2-methylpropionyl bromide (13.9 mL, 0.11 mol). Next the mixture was stirred for 45 minutes and allowed to reach room temperature. After this the reaction mixture was poured into an excess of cold water and extracted with diethyl ether (3×50 mL). The organic layer was subsequently washed with a saturated aqueous solution of sodium carbonate (3×50 mL), acidified water (pH=4.5, 3×50 mLl), and again the saturated aqueous solution of sodium carbonate (3×50 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. Finally the solvent was removed under reduced pressure by using the rotary evaporator in order to isolate the title compound in quantitative yield as a white solid. 1H NMR (CDCl3) δ (ppm) 2.08 (s, 6H, C(CH3)2Br), 2.87 (s, 4H, Hcycl). 13C NMR (CDCl3) δ (ppm) 26.03 (2C, Ccycl), 31.09 (2C, C(CH3)2Br), 51.60 (1C, (CH3)2Br), 167.89 (1C, C═O), 169.02 (2C, Ccycl═O). IR (solid, ATR cell) ν (cm−1) 1803, 1772 (Ccycl═O), 1728 (C═O), 1394, 1359, 1197, 1121, 1071, 996, 924, 856, 811, 731, 648. Mass spectroscopy (+EI, m/z) 266, 265, 156, 151, 149, 123, 121, 116, 115, 91, 87, 70, 69. Elem. Anal. Theoretical for C8H10NO4Br: C, 36.39; H, 3.82; N, 5.30; Br, 30.26. Found: C, 36.35; H, 3.82; N, 5.03; Br, 30.17. Melting point 72-74° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O1CCOCC1.[CH:13]1([NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:27])[CH:19]=2)[CH2:15][CH2:14]1.[N-:29]=[N+:30]=[N-:31].[Na+]>O.C1(C)C=CC=CC=1>[CH:13]1([N:16]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:27])[CH:19]=3)=[N:31][N:30]=[N:29]2)[CH2:15][CH2:14]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nnnn2C2CC2)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 71 %

Procedure:
6.3 g (30 mmol) of phosphorus pentachloride was added to a mixture of 40 ml of toluene and 4 ml of dioxane containing 4.7 g (21 mmol) of N-cyclopropyl-3-methyl-4-nitrobenzamide and the mixture was heated to reflux for three hours. The reaction mixture was concentrated under reduced pressure, then dissolved in 30 ml of DMF and slowly added dropwise to a DMF solution containing 2.8 g (43 mmol) of sodium azide. The reaction mixture was stirred for five hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was filtered and washed with ether to obtain 3.7 g of the desired compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([OH:47])=O)([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH2:52]([OH:59])[C:53]([NH2:58])([CH2:56][OH:57])[CH2:54][OH:55].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:47])[NH:58][C:53]([CH2:56][OH:57])([CH2:54][OH:55])[CH2:52][OH:59])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NC(CO)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NC(CO)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and tris(hydroxymethyl)aminomethane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](=O)[C:13]([OH:15])=[O:14])=[CH:2]1.[NH2:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19].C([BH3-])#N.[Na+]>>[C:13]([CH:12]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)([OH:15])=[O:14]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1c[nH]c2ccccc12)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 24, 4-(3-indolyl)-2-oxobutyric acid and L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-[1-carboxy-3-(3-indolyl)propyl]L-alanyl-L-proline. The mass spectrum of the trisilyated material shows a molecular ion at 603 m/e and a M+ -15 peak at 588 m/e.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:5]1([CH:4]([C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[NH:1][CH:26]2[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][CH2:25]2)[OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccccc1C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
2-Aminobenzhydrol from Step 1 above (1.0 g, 5 mmol), N-Boc-4-piperidone (2.0 g, 10 mmol), and acetic acid (0.86 mL, 0.9 g, 15 mmol) were combined in methanol (10 mL). Sodium cyanoborohydride (0.79 g, 12.5 mmol) was added in portions, and the mixture was stirred at ambient temperature for 42 hours. The mixture was concentrated in vacuo. Ethyl acetate (100 mL) was added to the residue and the resulting mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel eluted with 1:9 then 15:85 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give phenyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16]N(C=O)C.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in CH2Cl2 (250 mL) at 0° C. was added DMF (0.100 mL) followed by (COCl)2 (2M in CH2Cl2, 36.23 mL, 72.46 mL) over a period of 10 min. The reaction was stirred at 0° C. for 1 h and then at room temperature for 30 min. The reaction solvent was removed under a reduced pressure, dried under high vacuum and again suspended in CH2Cl2 (250 mL). The solution was cooled to 0° C., were added pyridine (4.8 mL, 48.03 mmol) followed by McOH (10 mL, excess) and stirred overnight. The extractive work-up with CH2Cl2 gave the expected 2-methoxycarbonyl-5-nitrobenzofuran (R926609). 1H NMR (CDCl3): δ 8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: ret. time: 26.94 min.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH:9]([CH3:21])[CH2:10][O:11][CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].[NH2:22][C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1.[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>C(O)C>[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]1[C:24]2[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:23]=2[NH:22][C:13]([CH2:12][O:11][CH2:10][CH:9]([N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH3:21])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCCc1nccn1C(C)COCC(=O)CC(=O)OCC
Reactant: NC1=CC(=O)CCC1
Reactant: O=Cc1ccccc1Cl
Solvent: CCO
Product: CCCc1nccn1C(C)COCC1=C(C(=O)OCC)C(c2ccccc2Cl)C2=C(CCCC2=O)N1
Reaction time: 8 h
Yield: 21.7 %

Procedure:
Ethyl 4-[2-(2-n-propylimidazol-1-yl)propoxy]-3-ketobutanoate (590 mg), 3-aminocyclohex-2-enone (220 mg) and 2-chlorobenzaldehyde (281 mg) were stirred in refluxing ethanol (8 ml) for 8 hours. The solvent was removed under reduced pressure. The crude product was chromatographed over silica eluting with a mixture of diethylamine and ethyl acetate (1:49). The solvents were removed in vacuo and the residue rechromatographed over silica eluting with a mixture of methanol and ethyl acetate [1:9]. The solvents were removed in vacuo. The resulting foam was stirred in ether overnight, the solid filtered and dried in vacuo yielding the title compound as a white solid 220 mg (22%). M.p. 127-131° C.
Reaction SMILES: Br.[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[C:20](=[CH:25]N(C)C)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>CCO>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]2[N:9]=[C:8]([N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[N:10]=[CH:25][C:20]=2[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N=C(N)N1CCOCC1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2nc(N3CCOCC3)ncc2C1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a 500 ml round bottom flask charged with anhydrous EtOH (150 ml) under nitrogen at 0° C. are added morpholine-4-carboxamidine hydrobromide (10.50 g, 50 mmol), tert-butyl-3-[(dimethylamino)methylene]-4-oxo-1-piperidinecarboxylate (12.7 g, 50 mmol, 1.0 eq.), and potassium t-butoxide in t-butanol (11.0M, 100 ml, 100 mmol, 2.0 eq.). The resulting mixture is stirred at 75° C. for 16 hr. The solvent is evaporated under reduced pressure, and the residue is taken up in DCM (300 ml), washed with water and brine, dried (Na2SO4) and concentrated. The residue is purified by silica gel chromatography (Hexane/EtOAc 1:1) to give the title compound. MS (+VE) m/z 321.1 (M++1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH2:40])[C:33]=1[C:42]([OH:44])=[O:43])(=[O:29])[CH3:28]>O1CCCC1.O>[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH:40][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:33]=1[C:42]([OH:44])=[O:43])(=[O:29])[CH3:28]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=C(O)CCCn1cccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCn3cccc3)C2SC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
4-(1-Pyrryl)butanoic acid (0.05 mole) is dissolved in 50 ml of tetrahydrofuran (THF) and 0.05 mole of triethylamine is added. This mixture is cooled to -10° C. and 0.05 mole of isobutylchloroformate is added. The mixture is stirred for 0.5 hours at -5° C. and then 0.05 mole of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 0.075 mole of triethyl amine in 50 ml of THF (precooled) is added. The mixture is stirred at 0° C. for 1 hour and then warmed to room temperature. The mixture is diluted with water and extracted with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate. The ethyl acetate extracts are combined, dried, filtered, and the solvent evaporated to give the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:21])=[CH:7][C:8]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11].Cl>CO.C1COCC1>[CH3:3][O:4][C:5]1[C:6]([CH3:21])=[CH:7][C:8]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(OC)c(C)cc1-c1ncccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)c(-c2ncccn2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1M aq. NaOH (4 mL) was added to a rt suspension of methyl 5-methoxy-4-methyl-2-(pyrimidin-2-yl)benzoate (503 mg, 1.95 mmol) in MeOH (5 mL) and THF (5 mL) and stirred at rt for 2 days. The residue was acidified with 25% aq. HCl, washed with DCM and concentrated in vacuo to yield the title compound A-1-16 as a off-white solid as its HCl-salt. LC-MS A: tR=0.63 min, [M+H]+=245.06.
Reaction SMILES: C(OC(=O)[CH2:5][CH:6]1[CH2:11][N:10]([CH2:12]C2C=CC=CC=2)[CH2:9][CH:8]([CH2:19][C:20]([O:22]CC)=O)[N:7]1[CH3:25])C.C(O)(C(F)(F)F)=[O:28].[C:34]([O:38][K])([CH3:37])([CH3:36])[CH3:35]>CO.C1(C)C=CC=CC=1>[C:34]([O:38][C:12]([N:10]1[CH2:11][CH:6]2[N:7]([CH3:25])[CH:8]([CH2:19][C:20](=[O:22])[CH2:5]2)[CH2:9]1)=[O:28])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)CC1CN(Cc2ccccc2)CC(CC(=O)OCC)N1C
Reactant: CC(C)(C)O[K]
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Solvent: Cc1ccccc1
Product: CN1C2CC(=O)CC1CN(C(=O)OC(C)(C)C)C2
Reaction time: 24 h

Procedure:
(4Benzyl-6-ethoxycarbonylmethyl-1-methylpiperazin-2-yl)acetic acid ethyl ester (Patent WO 92/05174) (71.0 g, 0.196 mol) was dissolved in MeOH (400 mL). TFA (77.8 mL, 1.02 mol) was added and the flask was purged with nitrogen. Pd/C (10%, 50% moisture, 3.6 g) was added. The flask was closed and purged with hydrogen (3×). After 1 day, the mixture was filtered through celite and washed with MeOH. The solvent was removed under reduced pressure and the foamy residue (92.7 g) was dried under high vacuum. A sol. of tBuOK (117.2 g, 1.04 mol) in toluene (3.07 L) was heated to reflux. A sol. of the crude piperazine formerly obtained, dissolved in THF (300 mL), was added dropwise over 50 min.
Reaction SMILES: F[C:2]1(F)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([F:14])([F:13])[C:5]([F:16])([F:15])[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.Cl.C(O)(=[O:25])C>>[F:16][C:5]1([F:15])[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[C:2](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]1([F:14])[F:13]
Reactant: CC(=O)O
Reactant: FC1(F)c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Agent: Cl
Product: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A solution of 989 mg. (0.00328 mole) of 10,11-dihydro-5,5,10,10,11,11-hexafluoro-5H-dibenzo[a,d]cycloheptene in 13.2 ml. of glacial acetic acid - 3.5 ml. of 6 N hydrochloric acid is held at room temperature for approximately 20 hours, heated in a 65° C. bath for 3 hours, again held at room temperature for about 20 hours, and finally heated in a 65° C. bath for 3 hours. The solution is concentrated under reduced pressure and the residue partitioned between benzene and water. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Sublimation of the residue at 80° C. and 0.1 mm. yields the crude product as an oily solid. Purification is effected by column chromatography on silica gel, the product being eluted with carbon tetrachloride. The fractions that show one sport of Rf 0.1 on a silica thin layer plate developed with carbon tetrachloride are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, m.p. 76°-78° C.