Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([OH:15])=[O:14])[CH2:5][CH2:6][CH2:7]1.S(OC)(O[CH3:20])(=O)=O>>[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([O:15][CH3:20])=[O:14])[CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)C12CCCC1C1CCC2C1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C12CCCC1C1CCC2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
55.0 g (0.275 mole) of a 20% aqueous sodium hydroxide solution was added dropwise to a mixture of 90.0 g (0.5 mole) of tricyclo[5.2.1.02,6 ]decane-2-carboxylic acid (mixture of endo- and exo-compounds) and 69.3 g (0.55 mole) of dimethyl sulfate over one hour under stirring at 50° C. After completion of the addition, stirring was continued at that temperature for 30 minutes. After completion of the stirring, the mixture was allowed to stand at room temperature for a while to form layers. The lower aqueous layer was taken out. The temperature was elevated again to 50° C. 55.0 g (0.275 mole) of sodium hydroxide in a 20% aqueous solution was added dropwise to the remainder over one hour under stirring at 50° C. After completion of the addition, the mixture was stirred at that temperature for 30 minutes. Then, 16.5 g (0.0825 mole) of a 20% aqueous sodium hydroxide solution was added thereto and the whole mixture was stirred at 100° C. for 45 minutes in order to decompose unreacted dimethyl sulfate. The mixture was allowed to cool and divided into layers. After the distillation, 88.3 g (yield 91.0%) of pure methyl tricyclo[5.2.1.02,6 ]decane-2-carboxylate was obtained.
Reaction SMILES: NO.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:17]([NH2:19])[CH3:18])[CH2:14][CH2:15]O)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(O)(=O)C.CCCCCC>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][NH:19][CH:17]2[CH3:18])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(N)C(CCO)c1ccc(C(C)(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1NCCC1c1ccc(C(C)(C)C)cc1

Procedure:
4.2 g (0.018 mol) of the aminoalcohol prepared in (c), 4.69 g (0.018 mol) of triphenylphosphine and 3.1 g (0.018 mol) of diethyl azodicarboxylate were dissolved in 100 mL THF. 2 drops of glacial acetic acid were added and the solution refluxed for two hours. During this time the initially red solution became yellow. On cooling, hexane was added dropwise until precipitation started. The mixture was then cooled in the freezer and the crystalline precipitate filtered off. The solvent was removed under reduced pressure and the residue taken up in chloroform and washed with water. The organic layer was dried with MgSO4, filtered, the solvent evaporated off under reduced pressure and the residue vacuum distilled (130° C. at 2 mm Hg) to afford 3.0 g (77 percent of theoretical) of the crude product in the form of a mobile oil. The NMR and IR spectra of the product were consistent with the expected structure and indicated a mixture of the two possible diastereoisomers were present in a ratio of 3:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C.[OH-].[Na+]>[CH2:31]([O:30][C@@H:16]1[C@@H:15]([CH2:14][NH:13][C:10](=[O:11])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103 mg of the acid) in 2 ml of diethyl ether was added to a solution of 173 mg of 5'-amino-3'-O-benzyl-2',5'-dideoxy-5-ethyluridine in 4.5 ml of 0.11M sodium hydroxide solution. The mixture was shaken vigorously for 10 minutes and then filtered. The solid was recrystallized from ethanol to give 120 mg of 3'-O-benzyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 174°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:16]([F:18])([F:17])[F:19])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][C:32]=3[CH3:33])=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[C:34]([C:36]1[CH:37]=[C:38]([CH:55]=[CH:56][C:57]=1B1OC(C)(C)C(C)(C)O1)[C:39]([N:41]1[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43][CH2:42]1)=[O:40])#[N:35].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:57]2[CH:56]=[CH:55][C:38]([C:39]([N:41]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:43][CH2:42]3)=[O:40])=[CH:37][C:36]=2[C:34]#[N:35])=[N:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[S:29][CH:30]=[CH:31][C:32]=2[CH3:33])=[N:26][N:27]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C#N)c2)CC1
Reactant: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccsc1-c1nnc(-c2nc(-c3ccc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)cc3C#N)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o1
Temperature: 75 °C
Yield: 60.2 %

Procedure:
tert-Butyl N-[5-bromo-3-[5-(3-methyl-2-thienyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (13.52 g, 25.12 mmol) and tert-butyl 4-[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1,4-diazepane-1-carboxylate (11.44 g, 25.12 mmol) were taken up in DMF (160 mL) and Na2CO3 (37.68 mL of 2 M, 75.36 mmol) (4:1 mixture) and reaction mixture degassed with nitrogen and Pd (tBu3P)2 (1.027 g, 2.010 mmol) added in one portion. The resulting mixture was heated at 75° C. 2.5 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic extracts were washed with water (1×100 mL) and brine (1×100 mL) and then the aqueous layers back extracted with ethyl acetate (3×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The material was passed through a silica pad eluting with 50-100% EtOAc/Petroleum ether. The material was purified further by column chromatography on silica (500 mL) eluting with 30-100% EtOAc/petroleum ether. Product fractions were combined and concentrated in vacuo to leave the product as a yellow solid (11.9 g, 55% yield)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11](Br)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[C:20]([Cl:21])[CH:19]=3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(Br)c2ncccc2c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CCc1cc(-c2ccc(Cl)c(Cl)c2)c2ncccc2c1

Procedure:
6-ethyl-8-bromoquinoline and 3,4 dichlorobenzene boronic acid can be combined to form 6-ethyl-8-(3,4-dichlorophenyl)quinoline,
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]OS(C5C=CC(C)=CC=5)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=O.Cl.[C:56]1([CH:62]2[CH2:66][CH2:65][NH:64][CH2:63]2)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][N:64]5[CH2:65][CH2:66][CH:62]([C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:63]5)=[CH:28][CH:29]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN4CCC(c5ccccc5)C4)cc3)cc21
Reaction time: 2 h

Procedure:
A solution of 0.350 g of benzyl 3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[2-(toluene-4-sulphonyloxy)ethoxy]phenyl}piperidinecarboxylate (Example 267c) in 5 ml of N,N-dimethylformamide is admixed with 0.112 g of 3-phenylpyrrolidine hydrochloride, 0.199 g of potassium carbonate and 0.018 g of tetrabutylammonium iodide. The reaction mixture is subsequently stirred at 80° over 2 hours. The reaction mixture is cooled and poured onto 10 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (2×20 ml). The organic phase is washed with 20 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (95:5 dichloromethane-methanol); Rt=5.03.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[Cl:13][C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:13][C:14]1[C:19]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=2)=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2nccnc2Cl)cc1
Temperature: 70 °C

Procedure:
To a solution of 4-hydroxybenzoic acid ethyl ester (55.21 g, 332.3 mmol) and 2,3-dichloropyrazine (49.50 g, 332.3 mmol) in DMSO (300 mL) was added cesium carbonate (129.9 g, 398.7 mmol). The mixture was heated to 70° C. until the starting material was consumed. The mixture was cooled to RT, diluted with water and DCM, the layers were separated and the aqueous layer was extracted with DCM (2×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was washed with copious amounts of methanol and dried to give ethyl 4-(3-chloropyrazin-2-yloxy)benzoate.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:29][CH2:30][O:31][CH2:32][CH2:33]6)=[N:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound, white solid (122 mg, 94%), MS (ISP) m/z=521.5 [(M+H)+], mp 231° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 6-morpholin-4-yl-nicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:23]#[C:24][CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:23][CH2:24][CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:6][CH:7]=1
Reactant: CSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CSCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 4 h

Procedure:
A mixture of N-[(4-Chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-1-propynyl]-3-quinolinecarboxamide from Example No. 126 (0.07 g) and Pd/C (10%, 0.120 g) in 3:1 CH2Cl2 /MeOH (20 mL) was placed on a Parr hydrogenator under 45 psi of H2 and shaken for 4 h. Another 0.08 g of Pd/C was added, and the resulting mixture is shaken for 2 h. The reaction mixture is then filtered through Celite, 0.120 g of fresh catalyst was added, and the resulting mixture was shaken under H2 for 6 h. The reaction mixture is then filtered through Celite and concentrated in vacuo. Crystallization from EtOH gave 0.015 g of the title compound as a solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:12][CH:11]=1>C(O)(=O)C>[Cl:1][C:12]1[CH:11]=[C:10]([F:9])[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[C:13]=1[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)NCCCc1ccc(F)c2c1CCO2
Solvent: CC(=O)O
Product: CC(=O)NCCCc1c(Cl)cc(F)c2c1CCO2
Reaction time: 72 h

Procedure:
N-Chlorosuccinimide (47.7 mg) was added to a solution of N-[3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propyl]-acetamide (77 mg) in glacial acetic acid (5 ml) at room temperature under nitrogen and the mixture stirred for 72 h. The solution was evaporated and the residue partitioned between sodium carbonate (2N; 10 ml) and ethyl acetate (10 ml). The combined organic extracts were washed with brine (10 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by column chromatography. Eluting with dichloromethane/methanol 50:1 gave the title compound as a colourless gum which crystallised on standing (67 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13](C3C4C(=CC=C(C(F)(F)F)C=4)NN=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][C:30]=3[Cl:29])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc(C(F)(F)F)cc23)[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.1 %

Procedure:
To a mixture of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (1 g, 4.9 mmol) (Example 55) and 2-chloro-4-nitro-benzoyl chloride (1.5 g, 6.8 mmol) (Aldrich, Milwaukee, Wis.) in benzene (10 mL) at room temperature, was added a solution of tin (IV) chloride (1.4 mL). After stirring at room temperature for 5 hours and the usual work-up, the residue was purified on a silica gel column to give 135 mg of 5-(2-chloro-4-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide as a white solid.
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>O1CCOCC1>[N+:13]([C:12]1[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:3]([CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:15])=[O:14]
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: C1CCNCC1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-chloro-3-nitro-5-trifluoromethylbenzoate (4.2 g; 1 eq.) in dioxane (40 ml) is added piperidine (3.9 ml; 2.1 eq.). After stirring for 18 hours at room temperature, the medium is poured into water (50 ml) and the product is extracted with ethyl ether. The organic phase is washed with water, dried and concentrated. 4.9 g of ethyl 3-nitro-2-piperid-1-yl-5-trifluoromethylbenzoate are obtained in the form of a colourless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27]>C(#N)C>[CH2:26]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:16])([F:17])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1)[CH3:27]
Reactant: Oc1c(OC(F)(F)F)cccc1C1CCNCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(OC(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethoxy)phenol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethane (0.01 g). MS m/z (relative intensity, 70 eV) 289 (M+, 45), 288 (20), 275 (15), 274 (bp), 84 (26).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) and pyrrolidine in DMSO at 23° C. according to the general procedure C. Obtained as a yellow solid (6.65 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]([CH3:17])[CH3:16].O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:15]([CH3:17])[CH3:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at 10° C. to a mixture of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methylpropyl]carbamoate (0.202 mol) in pyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H2O (75 ml) was added at 10° C. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated, yielding 49 g of (±)-1,1-dimethylethyl [1-[[[(4-methylphenyl)-sulfonyl]oxy]methyl]-2-methylpropyl]carbamate (68%) (interm. 13).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCc1ccccc1
Reactant: COc1cccc(C2CCCN2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (1.04 g) in dry acetonitrile (30 ml) was added 2-bromoethylbenzene (0.96 ml) followed by milled potassium carbonate (1.78 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 48 hrs, warmed under reflux for 2 hrs, and cooled to ambient temperature. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated and the residue was purified by flash column chromatography (silica gel, dichloromethane/0-100% ether). The appropriate fractions were collected and concentrated to afford 1.2 g (72%) of 2-(3-methoxyphenyl)-1-(2-phenylethyl)pyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][C:15]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2N)CC1
Yield: 102.6 %

Procedure:
A solution of 1.75 g (4.71 mmol) of (5′-methanesulfonyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in a 1:1 mixture of ethanol:ethyl acetate (150 mL) is shaken over 1.0 g (0.94 mmol) of 10% palladium on carbon under an atmosphere of hydrogen overnight. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 1.65 g (100%) of (3′-amino-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester as a brown solid.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:33])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])[CH:14]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:19][C:15]1[CH:14]=[C:13]([CH2:12][C:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:33])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 20 h

Procedure:
To a solution of the title B compound, (R)-1-{2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acetyl}-pyrrolidine-2-carboxylic acid ethyl ester (1.3 g, 2.9 mmol) in 25 mL of methanol at RT is added 1 N aqueous sodium hydroxide (8.7 mL). The mixture is stirred for 20 h and washed with ethyl acetate. The aqueous layer is acidified with 1 N aqueous hydrochloric acid (HCl), extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated to give an oil. The crude product is purified by flash chromatography (silica gel) eluting with ethyl acetate→ethyl acetate:acetic acid (2:1) to give (R)-1-{2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acetyl}-pyrrolidine-2-carboxylic acid as a foam: MS m/z 419.1 [M−1]−.