Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][NH2:22])=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To an ice-cold solution of tert-butyl N-(3′-benzyloxy-biphenyl-4-ylmethyl)carbamate (0.500 g) in dichloromethane (2.6 mL) was added trifluoroacetic acid (0.976 mL), and the resulting mixture was stirred under ice-cooling for 1 hour. Saturated aqueous sodium hydrogen carbonate (15 mL) was added dropwise and the whole was extracted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate/brine (1/1, 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.367 g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl>[CH3:23][NH:22][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9](=[CH:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH2:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cccc(C2=CCC(=CC3SC(=O)NC3=O)C=C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
2 g (4.7 mmol) of tert-butyl [4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methyl-carbamate and 20 ml of dichloromethane are introduced into a round-bottomed flask. 2.2 ml (28.2 mmol) of trifluoroacetic acid are added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into aqueous bicarbonate solution and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. 1.3 g (85%) of the expected product are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC(C1=NN(c2cccc(C3=CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CC=C(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, cyclopropanesulfonyl chloride (9.3 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 14.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]1[N+:9]([O-:11])=[O:10])[CH3:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:1]([N:3]1[C:7]([CH:8]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][N:5]=[C:4]1[N+:9]([O-:11])=[O:10])[CH3:2]
Reactant: CCn1c(C)cnc1[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Product: CCn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]

Procedure:
By reacting 0.33 g. of 1-ethyl-5-methyl-2-nitroimidazole with benzaldehyde according to the procedure of Example 55, 0.030 g. of 1-ethyl-2-nitro-5-styrylimidazole is obtained, m.p. 154°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH3:9].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15][N:14]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Nc1ncccc1C=O
Reactant: COC(=O)CCCCC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: COC(=O)CCCCc1ccc2cccnc2n1

Procedure:
A mixture of 1-2 (1.4 g, 9.04 mmol), 1-3, 2-amino-3-formylpyridine (552 mg, 4.52 mmol) (for preparation, see: J. Org. Chem., 1983, 48, 3401), and proline (260 mg, 2.26 mmol) in absolute ethanol (23 mL) was heated at reflux for 18 h. Following evaporative removal of the solvent, the residue was chromatog,raphed (silica gel, 80% ethyl acetate/hexane, then ethyl acetate) to give ester 1-4 as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:35])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:35][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=2)(=[O:24])=[O:23])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (104.2 mg, 0.199 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (95.3 mg, 2.3 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. After this time, the reaction mixture was concentrated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (4 mL). The resulting white precipitate was collected by vacuum filtration, washed with water and hexanes, and then further dried under vacuum to afford {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (92.2 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s, 1H), 8.18-8.20 (m, 1H), 8.16-8.18 (m, 1H), 8.07 (s, 1H), 7.97 (t, J=7.80 Hz, 1H), 7.84-7.91 (m, 1H), 7.67 (s, 1H), 7.33 (t, J=9.00 Hz, 1H), 3.92 (br. s., 2H), 3.74 (s, 2H), 3.41-3.70 (m, 2H), 2.57-2.84 (m, 2H), 2.31 (s, 3H), 2.40-2.28 (m, 1H), 1.69 (m, 2H). MS cald. for C25H22F4NO4S [(M−H)−]: 508, obsd. 508.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[CH3:20][NH:21][CH3:22]>O1CCOCC1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[CH:4][CH:5]=1
Reactant: CNC
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)c1ccc(CN(C)C)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
In an atmosphere of argon, 4-chloromethyl-N-(2-methoxyphenyl)benzamide (276 mg, 1.0 mmol) was put into a 25 ml capacity eggplant type flask equipped with a cold finger and dissolved in dioxane (3 ml), followed by the addition of 50% dimethylamine aqueous solution (3 ml) at room temperature. After 2.5 hours of stirring at 80° C. and subsequent removal of dioxane by evaporation, the resulting residue was diluted with ethyl acetate (30 ml). The thus diluted solution was dried on anhydrous sodium carbonate, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ether-ethyl acetate-ethyl acetate:methanol=10:1) to obtain 284 mg (100%) of the title compound in the form of colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]=O)[CH3:2].[CH3:14][NH2:15].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][NH:15][CH3:14])[CH3:2]
Reactant: CN
Reactant: CCc1c(C=O)oc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(CNC)oc2ccccc12
Reaction time: 8 h
Yield: 89 %

Procedure:
3-Ethyl-benzofuran-2-carbaldehyde (1.16 g, 6.65 mmol) was added to a solution of methylamine (26 mL of a 2M solution in MeOH, 52 mmol) and the resulting mixture was stirred overnight. The mixture was concentrated under reduced pressure. The residue was taken up in ethanol (20 mL) and then cooled in an ice-bath. NaBH4 (370 mg, 9.90 mmol) was added in one portion. The mixture was concentrated under reduced pressure and the residue taken up in 1 M NaOH. The mixture was extracted with Et2O (3×). The combined organics were washed with brine, dried and concentrated under reduced pressure to give the title compound (1.12 g, 89%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.58 (dd, J=8.4, 6.6 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.30-7.25 (m, 2H), 3.75 (s, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.26 (s, 3H), 2.05 (br s, 1H), 1.21 (t, J=7.5 Hz, 3H); ESI MS m/z 190 (M+H)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:27]>CO>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:27]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C

Procedure:
30 g of Z-Val-Val-OMe (prepared as in Chem. Ber. 103, 788-798 (1970)) are dissolved in 250 ml of methanol and subjected to catalytic hydrogenation at pH 4 after adding methanolic hydrochloric acid and Pd-on-BaSO4. When the reaction is complete, the catalyst is filtered off and the filtrate is concentrated. The resulting oil is triturated with ether. The substance crystallizes after a little time. It is filtered off and rinsed with ether. The substance is hygroscopic and is dried over P2O5 in vacuo. Yield 18.8 g, melting point 153°. [α]D23 =+2.5° (c=1, in methanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18]([NH2:20])=[O:19].CCN(C(C)C)C(C)C>C(#N)C>[C:18]([C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=1)(=[O:19])[NH2:20]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(N2CCC[C@H]2C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 23.6 %

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2.074 g, 10.02 mmol) in acetonitrile (50 mL) was added (S)-pyrrolidine-2-carboxamide (1.150 g, 10.07 mmol) and iPr2NEt (1.92 mL, 11.02 mmol). The mixture was heated at 50° C. overnight and then filtered while still warm. The filter cake was washed with acetonitrile (1×10 mL) then dried under vacuum at 40° C. to give a first batch of (S)-methyl 6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxylate as a tan solid (0.671 g, 2.36 mmol, 24% yield). The filtrate and washes were evaporated in vacuo and triturated with warm acetonitrile (10 mL). The solid was filtered, washed with acetonitrile (2×5 mL), and dried under vacuum at 40° C. to give a second batch of (S)-methyl 6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxylate as a solid (0.849 g, 2.98 mmol, 30% yield). LC/MS: m/z=285.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:11]1([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)c1ccc(C2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(C2CC2)cc1
Temperature: -70 °C

Procedure:
4-Cyclopropyl-benzoic acid ethyl ester (2.46 g, 13 mmol), and THF (250 mL) were combined under nitrogen and cooled in an IPA/dry ice bath to −70° C. Lithium aluminum hydride solution (20 mL, 20 mmol, 1.0M) was added dropwise. After 2 h excess lithium aluminum hydride was quenched by adding EtOAc dropwise. The reaction was warmed to 25° C. then the solvent was removed in vacuo. Water (200 mL) and a few drops of HCl(aq, 6N) were added. The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and filtered. The filtrate was removed in vacuo and the remaining residue was purified by flash column chromatography (hexane:EtOAc 40:60) to give the (4-cyclopropyl-phenyl)-methanol as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:11].[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1>CO.[Pd]>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][CH2:21][CH2:20][C:17]1[CH:18]=[N:19][C:14]([C:13]([F:24])([F:12])[F:23])=[CH:15][CH:16]=1
Reactant: Nc1ccc2c(c1)CCCC2
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCCC3)cn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A solution of 5,6,7,8-tetrahydro-naphthalen-2-ylamine (1.132 g, 6.08 mmol, commercially available) and (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (distilled 166-175° C./2 mb, 0.985 g, 6.69 mmol, prepared as per example 1, step 1) in MeOH (10 mL) was treated with HCO2NH4 (2.301 g, 36.5 mmol) and 10% Pd/C (250 mg) and stirred at 80° C. for 1.5 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (1.333 g, 68%) as an off-white solid. MS m/e: 321.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH2:40][O:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH2:40][O:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: COCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: COCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and 3-[3-(3-methoxymethyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K9) according to the general procedure M. Obtained as a yellow solid (205 mg).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:28]([C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([OH:18])[CH2:20]2)[O:24][CH:25]=1)#[N:29]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C#N)co2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1coc(N2CC(O)C2)n1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-cyano-1,3-oxazol-2-yl)azetidine (0.61 g, 1.51 mmol) (obtained as described in Reference Example 23(1)) in tetrahydrofuran (30 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.5 ml) in an ice bath, and the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-(4-cyano-1,3-oxazol-2-yl)-3-hydroxyazetidine (0.21 g, yield 86%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1COCC1>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 2-phenylbenzyl bromide (4{12}, 5 g, 20.2 mmol, 1 equiv.), piperazine (10.5 g, 121.4 mmol, 6 equiv.), THF (44.2 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{12} (3.92 g, 77%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.55 (dd, 1H, J=1.5, 7.0 Hz), 7.42-7.38 (m, 4H) 7.36-7.32 (m, 2H), 7.30 (dd, 1H, J=1.5, 7.0 Hz), 7.27 (dd, 1H, J=1.5, 7.0 Hz), 3.40 (s, 2H), 2.83 (t, 4H, J=5.0 Hz), 2.33 (br s, 4H), 1.58 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 142.6, 141.4, 135.5, 129.9, 129.8, 129.4, 127.8, 126.9, 126.7, 126.6, 60.3, 54.1, 46.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:24]([O:26]C)=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>CC(O)C>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:24]([OH:26])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)Cc1cc(C(C(=O)O)C2CCCCC2)ccc1OCc1ccc2ccccc2n1

Procedure:
10.2 g (0.0236 mol) of the compound of Example 80 are taken up in 70 ml of 2-propanol and the solution is heated to boiling point overnight with 50 ml of 1N sodium hydroxide solution. After the mixture has become cold it is neutralised with 50 ml of 1N hydrochloric acid. The precipitate obtained is filtered off with suction, washed and dried and then recrystallised from diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[H-].[Na+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydro-1-oxo-isoquinoline, Sall and Grunewald, J. Med. Chem. 1987, 30, 2208-2216 (0.39 mmol) and NaH (0.17 g, 0.43 mmol, 60% oil dispersion) in THF (5 mL) is heated to reflux for 1 h and then allowed to cool to RT. Ethyl chloroacetate (0.43 mmol) is added and the mixture is allowed to stir for 1 h. The mixture is quenched with H2O (10 mL) and washed with EtOAc. The organic layers are combined, washed with H2O (10 mL) and concentrated to an oil which is purified by (silica gel, gradient, 10-33% CH3OH/CH2Cl2) to afford the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH:29][C:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:15]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: CC(C)n1cc(C(=O)O)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(NC(=O)c2cn(C(C)C)c3ccccc23)c(Cl)c1
Temperature: -15 °C
Yield: 91.1 %

Procedure:
To a solution of 1-isopropylindole-3-carboxylic acid (159.6 mg, 0.785 mmol) in methylene chloride (3.5 ml) was added oxalyl chloride (101.0 μl, 1.178 mmol) under stirring at −15° C. The reaction mixture was stirred for 2.5 hours at room temperature and then distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (3.5 ml), followed by the addition of a solution of methyl 3-chloro-4-aminophenylacetate (164.6 mg, 0.824 mmol) in methylene chloride (3.5 ml) and triethylamine (0.35 ml, 2.474 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was dissolved in chloroform. The resulting solution was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetate (275.3 mg, 91%) was obtained as a brown solid. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH:12]=O.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CO.[BH4-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=CCc1ccc([N+](=O)[O-])cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CCNCc2ccc(F)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
2-(2-Chloro 4-nitro-phenyl)acetaldehyde (3.0 g, 15.03 mmol) and 4-fluorobenzylamine (1.88 g, 15.02 mmol) were added to methanol (45 mL) at RT and stirred for 15 minutes. The reaction mixture was cooled to 0° C. and acetic acid (15 mL) followed by solid NaBH4 (0.56 g, 15.0 mmol) were added. The reaction mixture was allowed to warm to RT and stirring continued for 2 hours. The volatiles were then removed under reduced pressure. Dichloromethane (60 mL) and water (60 mL) were added and the mixture was stirred for 15 minutes. The separated organic layer was washed with water (60 mL), brine (60 mL), dried (Na2SO4) and the solvents removed under reduced pressure to afford the title compound (3.1 g, 67%) which was used in the next step without further purification.