Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:19][OH:20])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]([F:21])([F:22])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH:19]=[O:20])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(N[C@@H]1CCCc2cc(CO)c([N+](=O)[O-])cc21)C(F)(F)F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cc2c(cc1[N+](=O)[O-])[C@H](NC(=O)C(F)(F)F)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (350 mg, 1.1 mmol) in 100 mL of DCM was added portion wise MnO2 (957 mg, 11 mmol). After stirring at RT for 3 h, the reaction mixture was filtered though silica gel with the help of hexane/EtOAc=1:1 to give ((R)-2,2,2-trifluoro-N-(6-formyl-7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]2([CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][Br:17])[C:8](=[O:18])[CH2:7]2)[CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][C:4]2([CH2:7][C:8](=[O:18])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][Br:17])[C:10](=[O:12])[CH2:11]2)[CH2:3]1
Reactant: O=C1CC2(CCC(O)C2)CC(=O)N1CCCCBr
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCC2(C1)CC(=O)N(CCCCBr)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
2-Hydroxy-8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9dione-(15.92 g, 1.00 equiv) was dissolved in 100 mL of CH2Cl2 and added to a solution of PCC (120 g, 11 equiv) in 500 mL of CH2Cl2 and stirred at room temperature for 2 h. The solution was filtered through a bed of celite and the salts were washed with CH2Cl2. The solvent was evaporated in vacuo to give a red-brown sludge which was flash chromatographed in 20% EtOAc/hexane to afford the title compound (15.50 g, 98%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:15]=[N:14][C:13]=1[C:21]#[N:22].Cl.O1CCOCC1>>[NH2:22][C:21]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:12]=2[C:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=2[N:1]=1
Reactant: COC(=O)c1ccc(-c2c(C#N)ncn2CC(C)C)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)nc(N)c1ncn(CC(C)C)c12
Temperature: 25 °C
Yield: 88 %

Procedure:
To 5-(2-amino-4-methoxycarbonylphenyl)-1-isobutyl-1H-imidazole-4-carbonitrile S12 (150 mg, 0.50 mmol, 1.0 equiv) was added 4 N HCl in dioxane (2.0 mL, 8.0 mmol, 16 equiv). The reaction was heated at reflux condition for 15 h then cooled to 25° C. The reaction was concentrated in vacuo and partitioned between 1:9 MeOH/EtOAc (50 mL) and saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with 1:9 MeOH/EtOAc (3×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Purification by flash column chromatography on silica gel (CH2Cl2-1/9 MeOH/CH2Cl2, gradient) afforded the title compound 412 (132 mg, 88%) as an off white solid: 1H NMR (CD3OD, 600 Hz) δ 1.01 (d, J=6.6 Hz, 6H), 2.26 (non, J=7.2 Hz, 1H), 3.96 (s, 3H), 4.43 (d, J=7.8 Hz, 2H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 8.19 (s, 1H), 8.32 (d, J=1.8 Hz, 1H); 13C NMR (CD3OD, 150 Hz) δ 18.4, 28.7, 51.4, 54.2, 117.9, 120.5, 121.8, 127.1, 128.6, 128.8, 132.1, 143.6, 144.3, 152.5, 167.0; MS (APCI+): calcd C16H19N4O2 [M+H]+ 299.2. found 299.2.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:19][CH2:20][CH2:21][CH3:22])[O:24][C:25]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: CCCCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CCCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-butyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20].[N+:21]([O-])([OH:23])=[O:22]>>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:5]([N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])O
Product: O=C1c2ccccc2C(=O)N1c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-Chloro-4-fluoro-5-(phthalimido)phenol (5.0 g, 17.1 mmol) was slowly added with stirring to con. nitric acid (50 ml) at −10° C. Solution was then warned to ambient temperature. and allowed to stir for 0.5 hr. Addition to ice-water resulted in a light yellow precipitate which was separated by filtration to afford the title compound (5.5 g); 1H NMR (CDCl3+CD3OD, 300 MHz) 4.36 (H, br s), 7.61 (1H, d, J=8.6 Hz), 7.88 (2H, dd, J=3.0, 5.5 Hz), 7.99 (2H, dd, J=3.0, 5.5 Hz) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:40])[C:30]2[C:25](=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[C:22]([CH3:40])([CH3:21])[CH2:23][CH2:24]4)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/176722) and 2-(1,1-dimethylindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:29][C:30]([OH:32])=[O:31].Cl>O>[C:30]([CH2:29][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:11][CH2:10]2)[CH2:2][CH2:3]1)([OH:32])=[O:31]
Reactant: O=C(O)CN1CCN(CCN2CCNCC2)CCN(CC(=O)O)CC1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCN(CCN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)CC1
Reaction time: 15 h

Procedure:
A solution of 1-(2-piperazinoethyl)-4,7-bis-(carboxymethyl)-1,4,7-triazacyclononane (10.7 g, 0.03 mol) in 100 mL of deionized water is adjusted to pH 10 with 1N sodium hydroxide solution. Then bromoacetic acid (4.2 g, 0.03 mol) is added and the solution is heated at 50 C. for 15 hours, keeping the pH between 9 and 10 with 1N sodium hydroxide. After cooling the reaction mixture to 25 C., the pH is adjusted to 4 with 1N hydrochloric acid. The solvent is removed under reduced pressure to give 1-[2-(4-carboxymethylpiperazino)ethyl]-4,7-bis-(carboxymethyl)-1,4,7-triazacyclonane.
Reaction SMILES: [C:1]1([N:11]2[C:15]([S:16][CH2:17][C:18]([OH:20])=O)=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:18](=[O:20])[CH2:17][S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[N:13][N:14]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)CSc1nnnn1-c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CSc1nnnn1-c1cccc2ccccc12)Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
2-{{1-(1-Naphthalenyl)-1H-tetrazol-5-yl}thio}acetic acid (500 mg, 1.75 mmol) and 2-chloroaniline (202 μL, 1.92 mmol) were dissolved in dry pyridine (8 mL). This solution was cooled to 0° C. and POCl3 (0.179 mL) was added dropwise. The mixture was stirred at 0° C. for 1 h, quenched with a few drops of water, and concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (100 mL) and the resulting solution was successively washed with water (2×30 ml) and brine (30 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2:(CH3)2CO, 95:5) to afford the title compound (643 mg, 85% yield) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.[N-:25]=[N+:26]=[N-:27].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][N:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[C:11]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[NH:27][N:26]=[N:25][N:22]=3)=[CH:23][CH:24]=1)[CH:10]=2
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c2c(c3cc(-c4ccc(OCC#N)cc4)ccc31)CCCC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(-c4ccc(OCc5nnn[nH]5)cc4)ccc31)CCCC2

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenoxy]-acetonitrile (0.149 g, 0.471 mmol) was reacted with NaN3 (0.153 g, 2.355 mmol) and NH4Cl (0.126 g, 2.355 mmol) in DMF (5 ml) to give the product (0.060 g, 0.167 mmol, 35%) as a white solid, dec. 205-211° C. 1H NMR (DMSO-d6) δ 1.76-1.81 (m, 2H), 1.86-1.90 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.71 (t, J=5.8 Hz, 2H), 3.61 (s, 3H), 5.51 (s, 2H), 7.11 (d, J=8.7 Hz, 2H), 7.31 (dd, J=1.5, 8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 16.78 (broad s, 1H); IR (solid) 2930, 2850, 1520, 1480, and 1240 cm−1; [ESI(+)], m/z 360 (M+H)+; Anal. Calcd. for C21H21N5O: C, 70.18; H, 5.89; N, 19.48; Found: C, 69.94; H, 5.70; N, 19.67.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (5) (62.013 g, 280 mmol) in 1.4 L of dry MeCN under argon, was added 70 mL (280 mmol) of BSA. The reaction mixture was stirred at room temperature for 15 min to give a clear solution. To this solution were added 1,2,3,5-Tetra-O-acetyl-β-D-ribofuranose (89.096 g, 280 mmol) and then 60 mL (310 mmol) of TMSOTf was added dropwise over 20 min. After the addition had been completed, stirring was continued at room temperature for an additional 30 min. The reaction mixture was diluted with 4 L of EtOAc. The EtOAc solution was washed with 1:1 saturated aqueous NaHCO3 /saturated aquenous NaCl (3×2 L), dried (with Na2SO4, 100 g), decolorized (activated charcoal, 8 g) and filtered through Celite. The filtrate was evaporated and the residue was recrystallized from MeOH to give 116.88 g (3 crops, 87%) of (42) as white needles. The recrystallization was accomplished by heating the crude product in MeOH at reflux on a steam bath for a few minutes and then decanting the supernatant while hot into a clean beaker. Immediate crystallization resulted. A second portion of fresh MeOH was added to the remaining solid and the whole process was repeated until all of the solid was dissolved. MP: 145-146° C. This product was pure by 1H NMR.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]12([CH2:22][NH2:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>C1COCC1>[C:12]12([CH2:22][NH:23][C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[C:1]([OH:6])=[O:11])=[O:5])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
Phthalic anhydride (2.65 g, 17.9 mmol) was dissolved in dry THF (50 ml) and a solution of 1-adamantanemethylamine (2.96 g, 17.9 mmol) in THF (50 ml) was added. The mixture was stirred at room temperature for 16 h and the solution evaporated to dryness. The residue was triturated with hexane and the precipitate formed was filtered, washed with hexane and dried to leave the title compound (5.42 g, 97%), 1H NMR (d6 -DMSO) δ 12.9 (1H, s), 8.2 (1H, t), 7.8-7.4 (4H, m), 2.9 (2H, d), 1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, s).
Reaction SMILES: [NH4+:1].[OH-].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(O)C>[CH:7]1[CH:8]=[CH:9][C:4](/[CH:3]=[N:1]/[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)/[N:1]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: O=Cc1ccccc1
Agent: [OH-]
Solvent: CC(C)O
Product: C(=N/C(/N=C/c1ccccc1)c1ccccc1)\c1ccccc1
Reaction time: 43 h
Yield: 97.5 %

Procedure:
To a 3 L 3-necked flask equipped with a mechanical stirrer and a thermometer was added I L of concentrated NH4OH (ca 30%) (14.8 moles). A solution of benzaldehyde (265 g, 2.50 mol) in 500 mL of 2-propanol was added in one portion. The mixture was stirred vigorously at ca 22° C. for 43 hr. The resulting slurry was filtered and the filter cake was washed with water (1 L). After drying in vacuo, 242.4 g of hydrobenzamide was obtained as a white solid (mp 100-102° C.) for a 97.4% yield.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>[OH-].[K+].CO.O.CO>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([CH2:5][CH2:4][C:3]([OH:16])=[O:2])[CH:7]=1
Reactant: COC(=O)CCc1cnc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1cnc2ccccc2c1
Yield: 88.7 %

Procedure:
A solution of 3-quinolinepropanoic acid methyl ester (2.21 g, 10.3 mmol) in 10% KOH/MeOH (48.2 mL), H2O (20 mL) and methanol (134 mL) was stirred at room temperature for 3 h. Upon completion of reaction, the solution was concentrated and the aqueous residue was acidified to pH 5-6 with glacial HOAc. A crystalline solid formed which was filtered, washing with H2O until the filtrate was neutral and dried to give 3-quinolinepropanoic acid (1.84 g, 9.14 mmol) in 89% yield as a solid, mp 180°-181° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[IH:7].[CH3:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1[NH:14][NH2:15]>N1C=CC=CC=1>[IH:7].[CH2:5]([O:4][C:2]([NH:15][NH:14][C:10]1[N:9]([CH3:8])[CH2:13][CH2:12][N:11]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN=C1NN
Agent: I
Solvent: c1ccncc1
Product: CCOC(=O)NNC1=NCCN1C

Procedure:
Ethyl chloroformate (0.95 ml) was added dropwise to a mixture of (1-methyl-4,5-dihydro-1H-imidazol-2-yl)-hydrazine hydroiodide (CAS 49541-82-4) (2 g) and pyridine (40 ml) while stirring, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography. The obtained compound was washed with diethyl ether to obtain the title compound (1.14 g).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[NH:12]CC(O)COC1C2OC(C(=O)C)=CC=2C=CC=1>C(O)C>[NH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CC(=O)c1cc2cccc(OCC(O)CNC3CCc4ccccc4C3)c2o1
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from 2-acetyl-7-(2,3-epoxypropoxy)benzofuran (23.2 g), obtained from 2-acetyl-7- hydroxybenzofuran and epichlorohydrin according to the teaching of Belgian Patent 783,440, and 2-aminotetralin (14.81 g) in ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-acetylbenzofuran-7-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 24 wherein Z is acetyl and the chain bridges position 4 of the Ar group to position 2 of the tetralin moiety).
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[CH3:10][C:8]1([CH3:9])[O:7][C:6]([CH3:11])([CH3:12])[C:5]2[S:13][C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21]([F:20])([F:31])[F:32])=[C:3]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])[C:4]1=2
Reactant: CCCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCCOC(=O)c1c(NC(=O)c2ccccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 62A and commercially available 2-trifluoromethylbenzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 0.90 (t, J=7.5 Hz, 3H), 1.50 (s, 6H), 1.54 (s, 6H), 1.63-1.75 (m, 2H), 4.22 (t, J=6.8 Hz, 2H), 7.79-7.95 (m, 4H), 11.47 (br s, 1H). MS (ESI+) m/z 456 (M+H)+. Anal. calcd. for C22H24F3NO4S: C, 58.01; H, 5.31; N, 3.08. Found: C, 57.97; H, 5.37; N, 3.04.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[C:4]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1.[F:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][N:26]2[CH2:31][C@H:30]([CH3:32])[NH:29][CH2:28][C@H:27]2[CH3:33])=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12]([N:29]2[CH2:28][C@H:27]([CH3:33])[N:26]([CH2:25][C:24]3[CH:34]=[CH:35][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:31][C@H:30]2[CH3:32])=[O:14])=[C:4]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1
Reactant: COc1cc(/C=C/C(=O)O)c(NS(C)(=O)=O)cc1Cl
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(NS(C)(=O)=O)cc1Cl
Yield: 82.7 %

Procedure:
(E)-3-(4-Chloro-2-methanesulfonylamino-5-methoxyphenyl)-acrylic acid (100 mg; 0.32 mmol), (2R,5S)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (Mavunkel, Babu J. et al., WO 00171535) (73 mg; 0.32 mmol) and EDCl.HCl (75 mg, 0.39 mmol), HOBt (5 mg; 0.03 mmol) were dissolved in DMF (2 ml) and stirred over night. The reaction mixture was evaporated, taken up in 2N Na2CO3 and extracted with EtOAc three times. The combined organic phases were evaporated and purified via chromatography (SiO2 acetone/hexanes 3/7) to yield the title compound as yellow foam (135 mg; 81%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([CH:21]([CH3:23])[CH3:22])[C:12]([NH:14][CH2:15][CH:16](OC)OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>>[CH:21]([C@@H:11]1[C:12](=[O:13])[NH:14][CH:15]=[CH:16][N:10]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])([CH3:22])[CH3:23]
Reactant: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
(R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (335 g, 0.99 mol) was added in portions to a cooled TFA-H2O (temperature <5° C., VTFA/VH2O=7/3, 2 L), and the solution was stirred at rt for 12 h. The solution was added slowly into stirring cooled sat. aq. Na2CO3 (2.5 L) to keep the pH>8. The mixture was extracted with EtOAc (5×2 L). The combined organic layers were washed with brine (2 L), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give (R)-benzyl 2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate as a white solid (259 g, 95.4%), which was used for next step without further purification. LC-MS m/z 274.9 [M+H]+. 1H NMR (CD3OD 300 MHz): δ7.36-7.34 (m, 5H), 6.33-6.30 (m, 1H), 5.79-5.68 (m, 1H), 5.26-5.13 (m, 2H), 4.38-4.29 (m, 1H), 2.01-1.96 (m, 1H), 1.00-0.84 (m, 6H).
Reaction SMILES: [F:1][CH2:2][C:3]1([S:6]([NH:9][C:10]([C@@:12]2([NH:17]C(=O)OC(C)(C)C)[CH2:14][C@H:13]2[CH:15]=[CH2:16])=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[ClH:25]>O1CCOCC1>[ClH:25].[NH2:17][C@:12]1([C:10]([NH:9][S:6]([C:3]2([CH2:2][F:1])[CH2:5][CH2:4]2)(=[O:8])=[O:7])=[O:11])[CH2:14][C@H:13]1[CH:15]=[CH2:16]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(CF)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(CF)CC1
Yield: 72 %

Procedure:
A solution of tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate (11.5 g, 31.7 mmol) in 4 N HCl in dioxane (100 mL) was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether to get crude compound (6 g, 72%). The crude compound was taken to the next step without further purification. MS: MS m/z 263.14 (M++1)
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH2:15][CH2:16]Br)([CH3:14])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2].[CH3:22][NH:23][CH3:24].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH2:15][CH2:16][N:23]([CH3:24])[CH3:22])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCBr)O2
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCN(C)C)O2
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 3.55 g (0.01 mol) of 3,4-dihydro-2-(2- bromoethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-yl acetate and 2.0 g of liquid dimethylamine in 50 ml of dimethylformamide is stirred at room temperature for 40 hours. Water is added and the product is extracted with ethyl acetate and ethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting oil crystallizes from a mixture of ethyl ether and pentane to give 2.05 g of 3,4-dihydro-2-(2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-yl acetate as the free base. The hydrochloride salt prepared by standard methods and recrystallized from isopropanol has m.p. 263°-270° C.