Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[C:20]([OH:28])[C:21]([N+:25]([O-])=O)=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>[Pd].CO>[NH2:25][C:21]1[C:20]([OH:28])=[CH:19][C:18]2[C@@H:14]3[C@@H:13]([N:12]([C:10]([C:8]4[CH:7]=[CH:6][C:5]5[NH:1][CH:2]=[N:3][C:4]=5[CH:9]=4)=[O:11])[CH2:17][CH2:16][CH2:15]3)[CH2:24][C:23]=2[CH:22]=1
Reactant: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(O)c([N+](=O)[O-])cc3C[C@@H]21
Agent: [Pd]
Solvent: CO
Product: Nc1cc2c(cc1O)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1H-benzoimidazol-5-yl)-(cis-6-hydroxy-7-nitro-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-methanone (0.56 g), 10% palladium on carbon (50 mg), and methanol (10 mL) is shaken under hydrogen atmosphere (1 bar) at room temperature for 3 h. The catalyst is separated by filtration and the filtrate is concentrated. The residue is chromatographed (dichloromethane/methanol 1:1→7:3) to give the title compound. Yield: 0.32 g (63% of theory); LC (method 1): tR=0.65 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[Br:13]N1C(=O)CCC1=O.C1C(C(OOOC(=O)C2C=CC=CC=2)=O)=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Cl)c1
Agent: O=C(OOOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Cl)c1
Yield: 75 %

Procedure:
Methyl 4-methyl-3-chlorobenzoate (4.5 g, 0.024 mol) was dissolved in carbon tetrachloride (100 ml), and thereto were added N-bromosuccinimide (4.8 g, 0.026 mol) and a catalytic amount of perbenzoic anhydride. The mixture was heated and refluxed under nitrogen atmosphere for 2 hours, allowed to cool, and the precipitate was separated by filtration. The filtrate was concentrated, and separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:20) to give the title compound (4.7 g, 0.018 mol) (yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19]3[N:18]=[C:17]([CH3:16])[CH:22]=[CH:21][N:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccnc(S(C)(=O)=O)n1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: Cc1ccnc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)n1

Procedure:
6-Chloro-N-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-methyl-2-methylsulfonylpyrimidine in a similar manner as described above to give 6 mg (7% yield) of a yellow solid. 1H-NMR (CDCl3): δ 9.05 (s, 1H), 8.23 (d, 1H), 7.45 (m, 1H), 7.17 (d, 1H), 7.07 (dd, 1H), 6.52 (d, 1H), 5.36 (m, 1H), 5.20 (m, 1H), 2.70 (m, 2H), 2.38 (s, 3H), 2.29 (m, 1H), 2.02-1.85 (m, 3H); MS m/z 311 (M−1).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)C
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Product: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OCc2ccccc2)c1

Procedure:
Prepared analogously as described for example D1 using methyl 2-methylproponate and 3-benzyloxy-4-methoxybenzoyl chloride as starting compounds.
Reaction SMILES: [F:1][C:2]1[C:3]([F:23])=[C:4]2[O:9][CH2:8][C@H:7]([CH2:10][F:11])[N:6]3[CH:12]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14](=[O:17])[C:15]([CH:16]=1)=[C:5]23.[N+:24]([O-])([O-:26])=[O:25].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([F:23])=[C:4]2[O:9][CH2:8][C@H:7]([CH2:10][F:11])[N:6]3[CH:12]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14](=[O:17])[C:15]([C:16]=1[N+:24]([O-:26])=[O:25])=[C:5]23
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OC[C@@H]2CF
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OC[C@@H]2CF
Temperature: 0 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl (3R)-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (500 mg, 1.53 mmol) in H2SO4 (5.0 mL), was added KNO3 (216 mg, 2.14 mmol) under cooling with ice, the whole mixture was stirred under cooling with ice for 2 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were washed with water, and dried in vacuo to give ethyl (3R)-9,10-difluoro-3-fluoromethyl-2,3-dihydro-8-nitro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (453 mg, 80%) as a pale brown powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(F)c3)cc2)S1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3cccc(F)c3)cc2)S1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a stirring solution of 5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.62 g, 1.70 mmol) in DCM (15 mL) was added DMSO (0.5 mL) and the solution was cooled to 0° C. Added phosphorus pentoxide (0.49 g, 1.72 mmol) followed by triethylamine (1.1 mL, 7.72 mmol). The reaction mixture was allowed to slowly warm to RT. After 2 hours, HPLC shows that the reaction was complete. Added water and separated phases. The pH of the aqueous phase was adjusted to ca. 7 with 2M NaOH and the aqueous phase was then extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting white solid was chromatographed on a small silica gel column eluting with 10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.25 g (40%) of the title compound as a white solid. MS (ESI−) for C18H14FNO4S m/z 358.0 (M−H)−.
Reaction SMILES: [Cl-].[C:2]1([CH2:8][C@H:9]([NH2+:11][CH2:12][C:13]#[CH:14])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C=O)C.O>[F:20][CH2:19][CH2:18][N:11]([C@H:9]([CH3:10])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][C:13]#[CH:14]
Reactant: FCCBr
Reactant: C#CC[NH2+][C@H](C)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN(CCF)[C@H](C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-aminium chloride (Sigma 100 mg, 0.578 mmol) in dry DMF (2 mL) was added sodium hydride (48.0 mg, 2 mmol). The reaction mixture was stirred at room temperature for 30 min, after which 1-bromo-2-fluoro ethane (0.85 mg, 0.603 mmol) was added. The reaction mixture was stirred over night, diluted with water (10 mL) and extracted with CH2Cl2 (3×15 mL). The organic phase was separated and washed with saturated NaHCO3 (15 ml) and brine (15 ml) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 80:20) and analyzed by NMR, HPLC and LC-MS.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(Cl)Cl.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>O>[CH3:18][S:19]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Into the reaction flask was added tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.80 g, 4.0 mmol), methylene chloride (20 mL), and methanesulfonyl chloride (0.55 g, 4.8 mmol). The mixture was stirred at 0° C. when triethylamine (1.4 mL) was slowly added. The reaction mixture was stirred at rt for 2 h, followed by the addition of water (5 mL). The aqueous layer was extracted twice with methylene chloride. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the desired product (0.85 g crude) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[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[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[Cl:40]>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[Cl:40])[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@@H](OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: Cc1nc2c(ccn2Cc2ccc(F)cc2Cl)c(-c2ccc3c(c2)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 40 °C

Procedure:
The title compound was prepared in a manner similar to that described in Example 1, Step H from (S)-methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-2-chloro-4-fluorobenzene, but purified on a ChiralPak ADH column (250×30 mm i.d., 5 um; ChiralTechnologies, West Chester, Pa.) under supercritical conditions maintained at 40° C., 140 bar, with MeOH modified CO2 (25% Isopropanol, 75% CO2) delivered at a combined flow rate of 90 g/min on a PIC Preplab 200 SFC system (Avignon, France). Triggered collections were made using a Knauer selectable wavelength UV-Vis detector at 230 nm (Rt=5.52 minutes): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.25-7.16 (m, 2 H), 7.14-7.05 (m, 2 H), 6.97-6.88 (m, 2 H), 6.30 (dd, J=3.5, 11.7 Hz, 1 H), 5.71-5.63 (m, 1 H), 5.61-5.52 (m, 2 H), 4.32-4.26 (m, 2 H), 2.96-2.79 (m, 2 H), 2.76 (s, 3 H), 2.08 (dd, J=5.0, 9.5 Hz, 2 H), 1.03-0.90 (s, 9 H); LC/MS (m/z) ES+=537.30 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncn(Cc3ccccc3)c2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Incremental portions of 1.8 g of sodium hydride (50% strength in white oil) is added to a solution of 10.5 g of 4,5-bis(4-methoxyphenyl)imidazole in 50 ml of absolute dimethylformamide. The mixture is agitated for 30 minutes and then 6.75 g of benzyl bromide in 50 ml of dimethylformamide is added dropwise thereto. After 30 minutes, the mixture is poured on ice water, the product is taken up in ethyl acetate, the organic solution dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from ethanol, thus obtaining 13.89 g of 4,5-bis(4-methoxyphenyl)-1-benzylimidazole, mp 165°-167°.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:9]1([CH3:8])[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CC1CCCC1=O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(C)CCCC1=O
Reaction time: 3 h

Procedure:
A solution of sodium tert.-amylate in toluene (70 ml, 0.1 mole) is added dropwise with stirring under an atmosphere of nitrogen to a solution of 2-methylcyclopentanone (9.8 g, 0.1 mole) and ethyl bromoacetate (16.7 g, 0.1 mole) in dry benzene (100 ml). The reaction is exothermic, a precipitate is formed, and the mixture turns yellow-orange. Stirring is continued for 3 hrs. at room temperature, the solution is washed with 1% HCl, cold water, and brine, dried over anhydrous magnesium sulfate and the solvent evaporated to yield 1-methyl-2-oxocyclopentane acetic acid ethyl ester as a pale yellow oil which is used without further purification in the subsequent step and which is identical with the same compound described in Example 5.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2
Reactant: Cc1cc(C)c2c(c1)NC(=O)C2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(c(C)c1[N+](=O)[O-])C(=O)C(=O)N2
Temperature: 0 °C
Yield: 77.2 %

Procedure:
The method of Cheesman, G. W. H.; J. Chem. Soc. 1170 (1962), was adapted. 4,6-Dimethylisatin (89 mg, 0.50 mmol) was dissolved in concentrated H2SO4 (1.0 mL) at 0° C. for 30 min with stirring, then KNO3 (55 mg, 0.55 mmol, Baker) was added to this solution. The mixture was stirred at 25° C. for 24 h. It was then poured into ice water (5 g). The resulting precipitate was collected by filtration. The precipitate was dissolved in 1N KOH (5 mL) and the small amount of solid was removed by filtration, then the filtrate was acidified to pH 2 with 4N HCl (~1 mL) to give a yellow precipitate. The solid was collected by filtration and was washed with water (2×1 mL), then it was dried in the air at 50° C. for 4 h affording pure (by NMR) title compound (85 mg, 77%) as a yellow powder. Crystallization from acetone/water gave crystals. Mp 278°-80° C. (dec.). IR (KBr, cm-1): 3452, 3225, 2931, 1780, 1742, 1635, 1608, 1535. 1H NMR (DMSO-d6): δ 11.357 (s, 1H), 6.771 (s, 1H), 2.389 (s, 3H), 2.305 (s, 3H). Purity >97.5% by HPLC.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Reaction time: 0.58 h
Yield: 81.2 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. 1-Propanesulfonyl chloride (0.184 mL, 1.64 mmol) was added. The solid immediately dissolved. The mixture was stirred 35 minutes, and then it was diluted with dichloromethane and washed with brine (1×50 mL). The organic phase was collected, dried on MgSO4 and the volatiles were evaporated under reduced pressure, yielding the product as a pale yellow solid (628.3 mg, 1.33 mmol, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:14]=2)[C@H:9]([N:29]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])[CH2:8][C@@H:7]1[CH3:49])=[O:5])[CH3:2].[OH-].[Li+]>C1COCC1.CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:14]=2)[C@H:9]([N:29]([CH2:34][C:35]2[CH:36]=[C:37]([C:45]([F:47])([F:48])[F:46])[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=2)[C:30]([O:32][CH3:33])=[O:31])[CH2:8][C@@H:7]1[CH3:49])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCOc1cc2c(cc1OC)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)C[C@H](C)N2C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(OCCCCCC(=O)O)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
Prepared by treating a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-(5-ethoxycarbonyl-pentyloxy)-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 163) (27 mg, 0.04 mmol) in 0.6 mL THF and 0.2 mL methanol with an aqueous 1M lithium hydroxide solution (0.2 mL, 0.2 mmol) at room temperature. After 45 minutes, acidification with 1N HCl and extraction with ethyl acetate, drying the organic extracts over sodium sulfate, and concentration under reduced pressure provided 25 mg of the title compound. MS m/z 697 (M+ +19), 378 (M+ -300); 1H NMR (CDCl3) δ 6.39 (C5, s, 1H), 3.79 (C6-OMe, s, 3H), 1.16 (Me, d, 3H, J=6.1 Hz).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])[CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][CH:21]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:32]=[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]1[C:23]1[CH:22]=[CH:21][C:20]([NH:19][CH2:2][C:3]([N:5]2[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]([C:13]3[S:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[O:12])[CH2:6]2)=[O:4])=[CH:25][CH:24]=1
Reactant: O=C(N[C@@H]1CCN(C(=O)CBr)C1)c1ccc(Cl)s1
Reactant: Nc1ccc(-n2ccccc2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCN(C(=O)CNc2ccc(-n3ccccc3=O)cc2)C1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.7 %

Procedure:
7.2 A solution of 250 mg 5-chloro-thiophene-2-carboxylic acid [(R)-1-(2-bromo-acetyl)-pyrrolidin-3-yl]-amide in 2 ml DMF was treated with 110 mg 1-(4-amino-phenyl)-1H-pyridin-2-one (CAS 13143-47-0), 0.12 ml TEA and 110 mg tetrabutylammonium iodide. The reaction mixture was stirred at r.t. for 2 days, then quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and filtrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2 to CH2Cl2/MeOH 95:5) to give 72 mg 5-chloro-thiophene-2-carboxylic acid ((R)-1-{2-[4-(2-oxo-pyridin-1-yl)-phenylamino]-acetyl}-pyrrolidin-3-yl)-amide. MS 457.5 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(C)cc(Br)cc1C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (10 g), ethyl chloroformate (5.4 g) and potassium carbonate (10.4 g) were mixed in tetrahydrofuran (100 mL) and heated to reflux for 16 hours, cooled, filtered and concentrated in vacuo. Heptane (200 mL) was added to the crude product, which was stirred for 30 minutes at 70° C. The mixture was filtered and concentrated in vacuo to furnish 12 g (88% yield) of the title compound as a solid. LC-MS (m/z) 273 (MH+); tR=2.95, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, CDCl3): 1.31 (t, 3H), 2.24 (s, 6H), 4.19 (q, 2H), 5.92 (b, 1H), 7.22 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13][CH3:14])=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22].C([BH3-])#N.[Na+]>C(O)(=O)C>[OH:1][C:2]1[C:16]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:15][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13][CH3:14])=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CSc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1nccn1NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.04 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-methylmercaptoimidazole are dissolved in 20 ml of glacial acetic acid and treated portionwise within 30 minutes with 0.43 g of 90% sodium cyanoborohydride. The reaction mixture is stirred at room temperature overnight, whereupon the solvent is removed by evaporation in a vacuum and the residue is taken up with 20 ml of water. Saturated sodium carbonate solution is added up to an alkaline reaction and the mixture is extracted three times with 15 ml of methylene chloride each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The residue is recrystallized from methanol/water and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-2-methylmercaptoimidazole of m.p. 110°-113°.
Reaction SMILES: [I:1]Cl.[CH2:3]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]#[N:16])=[N:6]1)[CH3:4].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:3]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:12])[CH3:13])=[C:8]([I:1])[C:7]([C:15]#[N:16])=[N:6]1)[CH3:4]
Reactant: ClI
Reactant: CCn1nc(C#N)cc1CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCn1nc(C#N)c(I)c1CC(C)(C)O
Reaction time: 18 h

Procedure:
A solution of iodine monochloride in dichloromethane (10.8 mL of 2 M, 21.6 mmol) was added to a mixture of 1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (2.0 g, 10.3 mmol), dichloromethane (17 mL) and freshly ground potassium carbonate (2.9 g, 22 mmol). The reaction was stirred for 18 hours. The work-up and purification procedures described in Part D of Example 588 were followed to provide 1.8 g of 1-ethyl-5-(2-hydroxy-2-methylpropyl)-4-iodo-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: O=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([CH2:14][NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:8]1([CH2:7][N:6]2[CH2:2][CH2:3][CH:4]([CH2:14][NH:15][CH2:16][C:17]([F:20])([F:18])[F:19])[CH2:5]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CC(CNCC(F)(F)F)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)CNCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8.50 g (28.3 mole) of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine in 100 ml tetrahydrofuran was added dropwise to 3.22 g (84.9 mmole) of lithium aluminum hydride in 50 ml tetrahydrofuran. The reaction was refluxed two hours, then stirred at room temperature overnight. The reaction was cooled in an ice bath and 3.2 ml of water, 3.2 ml of 15% sodium hydroxide, and 9.6 ml of water were added. The precipitated salts were filtered and washed with hot ethanol. The combined filtrates were concentrated under reduced pressure. The residue was taken up in dichloromethane, filtered, and dried over magnesium sulfate. The solvent was removed at reduced pressure to give 7.15 g of 1-(phenylmethyl-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine.