Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13](Br)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1.[NH:19]1[C:23](B(O)O)=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:23]3[NH:19][N:20]=[CH:21][CH:22]=3)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccn[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (5.0 g, 15.0 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added 1H-pyrazole-5-boronic acid (1.70 g, 15.0 mmol), Pd(PPh3)4 (1.75 g, 1.52 mmol), and potassium carbonate (6.3 g, 45.6 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (ethyl acetate:hexane, 50:50) to provide 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid 4-fluoro-benzylamide as yellow solid (3.25 g 68%) MS (M+H)+=317; Rt=1.13 min; HRMS (M+H)+=317.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1cc(Cl)ccc1Cl
Product: O=c1[nH]c2nccc(Nc3cc(Cl)ccc3Cl)c2c2ccccc12
Yield: 32.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,5-di-chloroaniline (105 mg, 0.65 mmol) to provide 199 (50 mg, 32% yield) as a white solid. LC-MS (M+H=356, obsd.=356).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:11]([O:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:14][NH:13][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH2:4]1)=[O:9])[CH3:12].[CH2:11]([O:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:14][NH:13][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH2:4]1)=[O:9])[CH3:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@@H](NNC(=O)OC(C)(C)C)CC1
Product: CCOC(=O)[C@H]1CC[C@H](NNC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of ethyl 4-oxo-cyclohexanecarboxylate (1.00 g, 5.88 mmol), tert-butyl hydrazinecarboxylate (1.16 g, 8.81 mmol) and acetic acid (0.34 ml, 5.9 mmol) in dichloromethane (29 ml) was stirred for 1 h at room temperature and subsequently cooled to 0° C. on an ice-water bath. Sodium triacetoxyborohydride (2.49 g, 11.8 mmol) was added at 0-5° C. The cooling bath was removed after completed addition. Stirring at room temperature for 20 h was followed by quenching with ethanol (5 ml). The reaction mixture was washed with one 50-ml portion of water. The aqueous layer (pH 4) was extracted with two 50-ml portions of dichloromethane. The combined organic layers were washed with one 50 ml-portion of aqueous 2 M sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave cis-4-(N′-tert-butoxycarbonyl-hydrazino)-cyclohexanecarboxylic acid ethyl ester (1.05 g, 62%) and trans-4-(N′-tert-butoxycarbonyl-hydrazino)-cyclohexanecarboxylic acid ethyl ester (0.63 g, 37%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)COCCO>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(Cc2ccc(Cc3ccccc3)cc2)cc1
Temperature: 100 °C
Yield: 97.4 %

Procedure:
In a 4 neck, 1 liter flask fitted with thermocouple, mechanical stirrer, Barrett trap with condenser, nitrogen line, and stopper, was added 1,4-dibenzoylbenzene (90.5 g), hydrazine monohydrate (172.4 g) and diethyleneglycol (400 ml). The reaction mixture was heated at 100° C. for 1.5 hours. The mixture was then heated to 150° C. while collecting water and excess hydrazine hydrate in the Barrett trap. Potassium hydroxide (54.1 g) was slowly added over 0.5 hour while the temperature was slowly increased to 200° C. The temperature was maintained at 200° C. for 1 hour. The reaction was cooled to 80° C. and then poured into 500 ml water. The reactor was rinsed with an additional 550 ml water and combined with the quench solution. The water was extracted 3 times with 250 ml dichloromethane, the combined organic phases were washed with 500 ml water, dried over magnesium sulfate, filtered and the solvent removed on a rotary evaporator to give 1,4-dibenzylbenzene as a white solid (79.5 g, 97.4% yield).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH2:40][CH:41](OC)[O:42]C)[CH3:39])(=[O:37])=[O:36])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:39])[CH2:40][CH:41]=[O:42])(=[O:36])=[O:37])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc3n2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CNCCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC=O)cc3n2C1
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
A solution of (7R or 7S)-14-cyclohexyl-N-{[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-7-{[2-(methylamino)ethoxy]methyl}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide (0.05 M) in DCM was treated with an excess of TFA and H2O (>50 eq of each). The mixture was stirred at 40° C. for 40 min. The solution was allowed to cool to RT and used in the next step. (ES+) m/z 597 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][S:14][C:15]1[N:16]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[O:5][CH2:6][CH2:7][CH2:8][OH:9].CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl>[CH3:49][S:50]([O:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:10]=[C:11]([F:39])[C:12]([CH2:13][S:14][C:15]2[N:16]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:17]([C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=3)([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:52])=[O:51]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a stirred solution of 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propan-1-ol (420 mg, 0.73 mmol) and DIPEA (0.32 mL, 1.83 mmol) in DCM (10 mL) at 0° C. was added dropwise methanesulfonylchloride (113 μL, 1.45 mmol). After stirring 30 min, the reaction mixture was partitioned in DCM (20 mL) and water (20 mL). The aqueous layer was re-extracted with DCM (20 mL×2). The combined organic layers were dried over MgSO4, concentrated and purified by column chromatography (EtOAc/Hex=1:2) to give 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propyl methanesulfonate (470 mg, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8.65 Hz, 1H), 6.87 (dd, J=11.04, 8.48 Hz, 1H), 6.81-6.73 (m, 2H), 6.69-6.66 (m, 1H), 6.58 (dd, J=8.13, 2.23 Hz, 1H), 6.50-6.43 (m, 2H), 6.38-6.31 (m, 1H), 4.42 (t, J=6.04 Hz, 2H), 4.18 (s, 2H), 4.03 (t, J=5.88 Hz, 2H), 3.77 (d, J=5.83 Hz, 2H), 3.68 (s, 4H), 3.10-2.98 (m, 3H), 2.22 (p, J=5.94 Hz, 2H), 1.51 (t, J=4.73 Hz, 5H).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[C:19]([NH:28][CH3:29])=[CH:20][C:21]([N:24]([O:26][CH3:27])[CH3:25])=[N:22][CH:23]=2)=[CH:12][C:11]=1[N+:30]([O-:32])=[O:31].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][C:18]3[CH:23]=[N:22][C:21]([N:24]([O:26][CH3:27])[CH3:25])=[CH:20][C:19]=3[N:28]([CH3:29])[C:4]2=[O:3])=[CH:12][C:11]=1[N+:30]([O-:32])=[O:31]
Reactant: CNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CON(C)c1cc2c(cn1)CN(c1ccc(F)c([N+](=O)[O-])c1)C(=O)N2C
Temperature: 30 °C
Reaction time: 10 h
Yield: 64.6 %

Procedure:
To a solution of diphosgene (1.15 mL, 9.5 mmol) in anhydrous dioxane (100 mL) was added a mixture of 5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine (3.0 g, 9.0 mmol) and Et3N (2.5 mL, 18.0 mmol) in dioxane (200 mL) at 10° C. After addition, the resulting mixture was stirred at 30° C. for 10 h. H2O was added to quench the above reaction and the mixture was neutralized to pH 7 with saturated Na2CO3 solution. The dioxane was removed under reduced pressure and the remaining aqueous solution was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated to give 3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.1 g, 65% yield), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 8.15 (m, 1 H), 7.97 (s, 1 H), 7.80 (m, 1 H), 7.62 (t, J=9.3 Hz, 1 H), 6.58 (s, 1 H), 4.80 (s, 2 H), 3.72 (s, 3 H), 3.27 (s, 3 H), 3.15 (s, 3 H); MS (ESI) m/z: 362.2 (M+H+).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([OH:32])(=[O:31])[CH2:21]NC(C1C=CC=CC=1)=O.C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C.O>[F:17][C:16]([F:19])([F:18])[C:14]1[CH:13]=[CH:12][C:9]2[CH:10]=[C:21]([C:20]([OH:32])=[O:31])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][C:8]=2[CH:15]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Oc1ccccc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)C1=Cc2ccc(C(F)(F)F)cc2Oc2ccccc21
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 10.0 g (37.59 mmol) of 2-phenoxy-4-trifluoromethyl-benzaldehyde, 10.09 g (56.40 mmol) of hippuric acid and 3.70 g (45.10 mmol) of sodium acetate in 38 ml of acetic anhydride is heated at 85° C. for 80 minutes, then cooled to 32° C. 19 ml of water are added and the mixture is heated at 65° C. for 30 minutes. After cooling the mixture to approximately 5° C., 19 ml of concentrated sulfuric acid are added dropwise and the mixture is then heated under reflux (bath: 140° C.) for 2 hours. The brown precipitate that forms on cooling is filtered and washed with 50% acetic acid, washed with water until neutral and dried to yield 7.42 g (24.23 mmol)=65% of 3-trifluoromethyl-dibenz[b,f]oxepine-10-carboxylic acid in the form of beige crystals; melting point: 180° C.; 1H-NMR (CDCl3, 200 MHz): 7.2-7.65 (m, 8H) 8.09 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9](COCC[Si](C)(C)C)[N:8]=1.C(Cl)Cl.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 322.6 %

Procedure:
4-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (111.0 mg, 0.224 mmol) was dissolved in methylene chloride (3.0 mL, 47 mmol). Trifluoroacetic acid (3.0 mL, 39 mmol) was added and the solution was stirred at rt overnight. After the reaction was completed saturated NaHCO3 (1 mL) was added and the reaction was stirred at rt for 20 min. EtOAc (5 mL) was added, the organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 2-20% MeOH in DCM) to give the title compound as a yellow solid (222 mg, 54%). LCMS: (FA) ES+, 307, 309. 1H NMR (400 MHz, d6-DMSO)) δ: 14.5 (s, br, 1H), 8.70-8.72 (dd, J=1.5 Hz, 2H), 8.10 (s, 1H), 7.90-7.94 (dd, J=1.5 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.COCCOC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[C:10]([Cl:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Clc1nccc(-c2cccnc2Cl)n1
Temperature: 90 °C

Procedure:
To 2,4-dichloropyrimidine (2.00 g, 13.4 mmol), 2-choropyridine-3-boronic acid (3.16 g, 20.1 mmol) and Pd(PPh3)4 (1.55 g, 1.30 mmol), was added DME (30.0 mL) and 1 M NaHCO3 (13.0 mL). The resulting mixture was heated to 90° C. for 17 hours, then diluted with EtOAc and extracted with saturated sodium carbonate, water, and brine. The organics were dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether and dried to yield the desired product. MS m/z=226 [M+H]+. Calc'd for C9H5Cl2N4: 225.12.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15](C(O)=O)[CH2:14]2)=[CH:9][CH:8]=1.C[N:26]1CCOCC1.[Cl:32]C(OCC(C)C)=O.[N-]=[N+]=[N-].[Na+]>O1CCOCC1.O>[ClH:32].[NH2:26][C@@H:15]1[CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[C:17](=[O:18])[CH2:16]1
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CN1CCOCC1
Reactant: CC(C)COC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cl
Product: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: -8 °C
Reaction time: 0.08 h

Procedure:
A solution of 61 mmol of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid in 300 ml of dioxane was treated with 61 mmol of N-methylmorpholine. Thereafter, the reaction mixture was cooled to −8° C., and 61 mmol of isobutyl chloroformate was added. After stirring for 5 min, a solution of 121 mmol of sodium azide in 40 ml water was added while the temperature rose to 0° C. After stirring for 70 min at 0° C., the suspension was filtered over Dicalite®. The filtrate was diluted with 700 ml of toluene and transferred into a separatory funnel. The organic layer was separated, then washed twice with 250 ml of a saturated solution of sodium hydrogencarbonate and twice with 200 ml of a saturated solution of sodium chloride. Thereafter, the organic layer was dried over sodium sulfate and, after addition of 400 ml of toluene, the solvent and the residual isobutylalcohol were evaporated to end with a volume of about 350 ml. The solution was heated gradually to 80° C. and kept at this temperature for 70 min. After cooling, the solution of the intermediate isocyanate was concentrated to about 300 ml and was added dropwise to a solution of 25.4 ml of hydrochloric acid (37%) in 100 ml of dioxane while heating to 45° C. Finally, after complete addition, the temperature was raised to 60° C. for 1 hour and the hydrochloride already started to precipitate. The mixture was cooled to 0° C., and the solid material formed was collected on a filter funnel. After washing with tert-butylmethylether, the product was dried under high vacuum. There was obtained (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride as a white solid. MS: m/e=301 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[OH-].[Na+].[CH2:10]([NH2:12])[CH3:11]>>[O:4]1[CH2:5][CH2:6][O:7][CH:3]1[CH2:2][NH:12][CH2:10][CH3:11]
Reactant: CCN
Reactant: ClCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1OCCO1
Reaction time: 18 h

Procedure:
A 40% by weight aqueous solution of ethylamine (100 ml) and 2-chloromethyl-1,3-dioxolane (35 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture is stirred for a period of about 18 hours. After this time sodium hydroxide (18 grams) is added with stirring over a period of about 4 hours. Stirring is then continued for an additional period of about 16 hours. The organic phase of the reaction mixture is then separated, washed with aqueous potassium carbonate and dried over anhydrous magnesium sulfate. The dried product is then distilled under reduced pressure to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-N-ethylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:4][CH:3]=1.[Br:30]N1C(=O)CCC1=O.[O:38]1CCO[CH2:40][CH2:39]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:30][CH2:40][C:39]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:10][N:11]2[C:12](=[O:21])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])=[CH:4][CH:3]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1,1-dimethylethyl {(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (5 mol %) were stirred in anhydrous dioxane (300 mL) at 100° C. for 3 h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400 mL) and treated with N-bromosuccinimide (108.8 mmol) and stirred at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL) and precipate formed upon addition of hexanes (350 mL). The precipitate was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+H]+: 502.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[CH:37][O:36][N:35]=2)=[CH:30][C:29]=1[F:39].O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[CH:37][O:36][N:35]=3)=[CH:30][C:29]=2[F:39])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Fc1cc(-c2ncon2)ccc1CBr
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1F)[C@@H]1CCCC[C@H]1CO
Yield: 23.7 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (200 mg, 0.66 mmol), cesium carbonate (257 mg, 0.79 mmol), and 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (204 mg, 0.79 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (75 mg, 24%). 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 1H), 7.91 (dd, J=8.06, 1.51 Hz, 1H), 7.81 (t, J=7.81 Hz, 1H), 7.76 (d, J=10.20 Hz, 1H), 7.74 (d, J=8.60 Hz, 2H), 7.49 (d, J=8.60 Hz, 2H), 4.61 (d, J=15.86 Hz, 1H), 4.40 (d, J=15.61 Hz, 1H), 3.54-3.73 (m, 2H), 3.08 (dd, J=11.96, 1.64 Hz, 1H), 2.64 (br. s., 1H), 1.56-1.78 (m, 3H), 1.49 (ddd, J=12.21, 9.44, 9.32 Hz, 2H), 0.97-1.21 (m, 4H). Analytical HPLC R.T.=23.76 min. MS [M+H]+=480; [M+Na]+=502. HRMS [M+H]+ calcd 480.1160, found 480.1157.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCC(O)CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 4-hydroxypiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.09 minutes; C21H20Cl2N4O3 (447.32); mass spectrum: (M+H)+=447.2.