Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:18])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2cc(F)ccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2cc(F)ccc2c1

Procedure:
6-Fluoro-2-naphthoic acid (228 mg, 1.2 mmol) was dissolved in dichloromethane (15 mL) and N,N-dimethylformamide (0.1 mL), and in an ice bath oxalic chloride (228 mg, 1.8 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was moved to react at room temperature for 3 hours, and concentrated under reduce pressure to obtain a white solid, i.e. 6-fluoro-2-naphthoyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH:11]4[O:18][CH:14]3[CH2:13][CH2:12]4)[C:9]2=[O:19])=[C:4]([CH2:20][CH3:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+].ClCCl>COCCOC>[CH2:20]([C:4]1[C:5]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH:11]4[O:18][CH:14]3[CH2:13][CH2:12]4)[C:9]2=[O:19])=[CH:6][CH:7]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:3]=1)[CH3:21]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCc1cc(Br)ccc1C1C(=O)C2C3CCC(O3)C2C1=O
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: ClCCl
Product: CCc1cc(-c2ccc(F)cc2)ccc1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 80 °C

Procedure:
A mixture of (1RS,2SR,6RS,7SR)-4-(4-bromo-2-ethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione (200 mg, 0.57 mmol), 4-fluorophenylboronic acid (112 mg, 0.80 mmol) and cesium fluoride (260 mg, 1.71 mmol) are stirred together in degassed 1,2-dimethoxyethane (5 ml) at room temperature under an atmosphere of nitrogen for 40 minutes at room temperature. [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (74 mg, 0.09 mmol) is added, and the reaction mixture is heated to 80° C. for 20 hours. The mixture is cooled to room temperature, filtered through a plug of diatomaceous earth, washing with 2M aqueous hydrochloric acid and dichloromethane. The organic phase is collected, and the aqueous phase is extracted with dichloromethane. The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column choramtography on silica gel to give (1RS,2SR,6RS,7SR)-4-(3-ethyl-4′-fluorobiphen-4-yl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [BH3:1].C1COCC1.[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.O1CCCC1>O1CCCC1>[CH:7]1([BH:1][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1=CCCCC1
Reactant: B
Solvent: C1CCOC1
Product: B(C1CCCCC1)C1CCCCC1
Temperature: 0 °C

Procedure:
A 250 ml, three-necked round-bottom flask was sparged with nitrogen and equipped with a 50 ml dropping funnel, a thermometer, a stir bar, and a septum. The flask was charged with 38.38 ml (38.38 mmol) BH3.THF adduct and cooled to 0° C. in an ice bath. The dropping funnel was charged with 7.78 ml (76.7 mmol) cyclohexene and 36 ml tetrahydrofuran (THF). The cyclohexene/THF mixture was added dropwise over 45 min. A white solid (dicyclohexylborane) formed. The reaction mixture was stirred for one hour at 0° C. The dropping funnel was then charged with 13.0 g (202.0 mmol) poly(methylvinyl)silazane, [(MeSiHNH)0.8 (MeSiViNH)0.2 ]x and 36 ml THF and added to the reaction mixture over 30 min. After the polysilazane addition was complete, the reaction mixture was stirred for 30 min at 0° C. and then warmed to room temperature. The white solid disappeared and a clear solution was formed. The boron-substituted polysilazane, Polymer III, contained about 2.1 wt % boron bound to the polymer backbone. This solution was used in the following example.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]CCCC)=O)=[CH:4][CH:3]=1.[NH3:15]>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1ccc(Cl)nn1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)nn1
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of the chloro pyridazine compound from the previous step (51 g, 0.238 mole) in THF (375 ml) was treated with methanolic ammonia (saturated, 80 ml). The reaction was allowed to stand at ambient temperature overnight. The precipitate was filtered and dried to give 6-chloropyridazine-3-carboxamide as a pink solid (18.2 g, 49%). [Further material could be obtained by evaporating the filtrate (at reduced pressure) and treating the residue with THF (100 ml) and methanolic ammonia (40 ml). The product was isolated as before to give a pink solid (17.4 g). Total yield (35.6 g, 95%)].
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3cccnc3)cc1)n2C)c1ccccn1
Yield: 40 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and nicotinic acid chloride. Yield: 40% of theory, C32H30N8O4 (590.7); Rf value: 0.47 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=591; (M+H+Na)++=307; (M+Na)+=613.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@@:8]1([C:14]([OH:16])=[O:15])[C@H:12]([CH3:13])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:18]([N:10]1[CH2:11][C@@H:12]([CH3:13])[C@@:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])([C:14]([OH:16])=[O:15])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccccc2)C[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 40 °C

Procedure:
A mixture of (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 1i (1.8 g, 7.4 mmol), benzaldehyde (1.51 ml, 14.8 mmol), acetic acid (0.635 ml, 11.1 mmol), sodium triacetoxyborohydride (3.14 g, 14.8 mmol) and methanol (35 ml) was heated at 40° C. for 38 hours and 30 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (ODS silica gel, elution solvent: water/methanol) to give the title compound as Lot A (584 mg) and Lot B (708 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH:10]=[CH:11][CH2:12][C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:13]([CH2:12]/[CH:11]=[CH:10]/[C:9](=[O:16])[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[O:15])=[CH:27][CH:26]=1
Reactant: O=C(O)CC=CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CNC(=O)C/C=C/C(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 4-(3,4-dichlorophenyl)-4-oxo-2-butencarboxylic acid (2.0 g, 8.16 mmol) and oxalyl chloride (0.84 ml, 9.79 mmol) in chloroform (25 ml), was maintained at room temperature under nitrogen atmosphere for 3 hours. The solvent was removed under vacuum and the residue evaporated twice from toluene with the rotary evaporator to remove traces of oxalyl chloride. The thus obtained acid chloride was dissolved in methylene chloride (15 ml) and cooled at -78° C., under inert atmosphere. TEA (1.25 ml, 9.79 mmol), 4-DMAP (0.1 g, 0.816 mmol) and 4-methoxy benzylamine (1.12 g, 8.16 mmol) were added while magnetic stirring was continued at -78° C. for 4 hours. The reaction mixture was allowed to warm at room temperature and then diluted with methylene chloride (100 ml); the organic phase was washed with 1N HCl (3×10 ml), saturated potassium bicarbonate (3×10 ml), brine (3×15 ml), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography, using cyclohexane/ethyl acetate 0÷5 as eluent. The title compound was obtained as a light yellow solid (1.84 g, 62w) (m.p. 169°-170° C.).
Reaction SMILES: I[C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCO.C([O-])(O)=O.[Na+]>C(COC)OC.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>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1c[nH]c(=O)c(I)c1
Reactant: CC1(C)OB(c2ccc(Cl)c(OCc3ccccc3)c2)OC1(C)C
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: CCO
Solvent: COCCOC
Product: COC(=O)c1c[nH]c(=O)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Temperature: 90 °C

Procedure:
Stir a solution of 4 g (14.35 mmol) of methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate and 6.42 g (18.64 mmol) of 2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a mixture of 160 mL of dimethoxyethane (DME), 80 mL of EtOH and 120 mL of a saturated aqueous solution of NaHCO3 for 15 minutes under argon, then add 662 mg of Pd(PPh3)4 and heat the reaction mixture for 4 h 30 min at 90° C. After concentration under reduced pressure, distribute the residue obtained in a mixture of 200 mL of DCM and 10 mL of water. Extract the aqueous phase again with 100 mL of DCM, combine the organic phases, dry over MgSO4, filter and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 2% of methanol. After concentration under reduced pressure, solidify the residue in a 5/95 methanol/ether mixture, then filter and wash with ether. We thus obtain 1.99 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylate in the form of a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([N:13]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH2:46]>C(Cl)Cl.N1C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH:46][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:13]([CH:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Yield: 83.7 %

Procedure:
4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid (3.62 g, 10 mmol) and oxalyl chloride (3.8 mL, 30 mmol) were stirred in DCM dry (120 mL) and a few drops of dry DMF at room temperature for 2 hours Volatiles were evaporated and the residue dissolved in dry pyridine (50 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (2 gr, 7.72 mmol) in dry pyridine (20 mL) was added to the cooled reaction mixture under nitrogen atmosphere. The resulting mixture was allowed to react overnight at room temperature, then the solvent removed under reduced pressure. The residue was taken-up with EtOAc and washed with aqueous NaHCO3 sat. sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using AcOEt/Hexane 7:3 as the eluant, affording 3.9 g of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>O.CCO>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
To a mechanically stirred solution of 5.0 g NaOH in 35 ml H2O and 25 ml EtOH at 15° C. was added 12.0 g (0.100 mole) of acetophenone and 12.4 g (0.100 mole) of 4-fluorobenzaldehyde. After a brief exotherm to 25° C., the temperature returned to 15° C., and the cooling bath was removed. The reaction mixture was stirred at room temperature for 1.5 hour, and the thick slurry was transferred to a beaker to cool overnight at 10° C. This mixture was filtered, and the solids were washed with distilled H2O until the washings were neutral to litmus. Upon drying in vacuo, 20.8 g of a pale yellow solid was obtained, m.p. 86°-87° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@H:12]([CH2:14]N3CCN(C(C(OCC4C=CC=CC=4)=O)CC(OCC4C=CC=CC=4)=O)CC3)[O:11][C:10]2=[O:43])=[CH:5][CH:4]=1.ClCC1C=CC(N)=CC=1.[O:53]1CC1CO.ClC1C=CC(NCC(O)CO)=C(C)C=1.C(=O)(OCC)OCC.CC(C)([O-])C>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][OH:53])[O:11][C:10]2=[O:43])=[CH:7][CH:8]=1
Reactant: OCC1CO1
Reactant: O=C(CC(C(=O)OCc1ccccc1)N1CCN(C[C@@H]2CN(c3ccc(CCl)cc3)C(=O)O2)CC1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cc1cc(Cl)ccc1NCC(O)CO
Agent: Nc1ccc(CCl)cc1
Solvent: CCOC(=O)OCC
Product: O=C1OC(CO)CN1c1ccc(CCl)cc1

Procedure:
1.1 g of 3-(4-chloromethylphenyl)-5(R)-[4-(1,2di-benzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one [obtainable by reaction of 4-chloromethylaniline with 2,3-epoxypropan-1-ol to give N-(4-chloro-methylphenyl)-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-(4-chloromethylphenyl)-5-hydroxymethyl-oxazolidin-2-one, subsequent esterification with methanesulfonyl chloride and reaction with 1-(1,2-dibenzyloxycarbonylethyl)piperazine], dissolved in 30 ml of DMF, are treated at room temperature with 0.9 g of freshly prepared guanidine, dissolved in 10 ml of DMF, and the mixture is stirred for two hours. After removal of the solvent and customary working up, 3-(4-guanidinylmethylphenyl)-5(R)-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH:23]=[C:22]([C:24](O)=[O:25])[N:21]=[N:20]2)[CH2:15][CH2:14]1)=[O:11].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:12][C@H:13]1[CH2:14][CH2:15][C@@H:16]([N:19]2[CH:23]=[C:22]([C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:25])[N:21]=[N:20]2)[CH2:17][CH2:18]1)=[O:11]
Reactant: O=C(Cc1c(F)cccc1Cl)N[C@H]1CC[C@@H](n2cc(C(=O)O)nn2)CC1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1c(F)cccc1Cl)N[C@H]1CC[C@@H](n2cc(C(=O)N3CCCCC3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution under Ar of 1-{cis-4-[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-cyclohexyl}-1H-[1,2,3]triazole-4-carboxylic acid (100 mg) in DMF (4 ml) were added piperidine (22 mg), TBTU (93 mg) and DIPEA (0.13 ml). The solution was stirred 1 h at RT before partitioning it between EtOAc (50 ml) and H2O (50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2 to CH2Cl2 5% MeOH) afforded the product (112 mg, 95%). Off-white solid. MS 448.1 (100, [M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.P(OCC)(OCC)OCC.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[H-].[Na+]>O.COCCOC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrCc1cccc(Br)c1
Agent: CCOP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 51.5 %

Procedure:
The mixture of 1-bromo-3-(bromomethyl)benzene (6.2 g, 24.8 mmol) and triethyl phosphite (4.53 g, 27.28 mmol) was heated at 90° C. for 12 hours, cooled to 0° C., added DME (40 ml) and tert-butyl 4-oxopiperidine-1-carboxylate (5.73 g, 28.8 mmol) and sodium hydride (1.19 g, 49.6 mmol) and stirred at RT for 2-3 hours. Diluted with water and extracted with ether to afford 4.5 g (51.5% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 10% ethyl acetate in hexane as eluent. MS: m/z=353.2 (M+1).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:23])[CH2:19][CH2:20]2)=[CH:16][C:15]=1[C:24]([OH:26])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][N:3]([CH3:4])[C:24]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:14]=1[O:13][CH3:12])[CH2:20][CH2:19][C:18]2=[O:23])=[O:26]
Reactant: COc1cc2c(cc1C(=O)O)C(=O)CC2
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1C(=O)N(C)C)C(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of Dimethylamine hydrochloride (2.22 g, 27.24 mmol) and triethylamine (7 ml, 54.48 mmol) in CH2Cl2 (30 ml) was added 6-Methoxy-3-oxo-indan-5-carboxylic acid (2 g, 9.08 mmol), HOBt (2.45 g, 18.18 mmol), EDCI (3.48 g, 18.18 mmol) at 0° C. in order. The mixture was stirred at room temperature for 3 hrs and washed with 8% NaOH, water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product (1.69 g, 80% yield). LC-MS: m/e 234 (MH+)
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[NH2:19][C:20]1[CH:25]=[C:24]([C:15]2[CH:16]=[CH:17][C:12]([C:2]([F:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck flask [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.53 mmol, prepared in example 1), 3-aminobenzene boronic acid (188 mg, 0.76 mmol), potassium carbonate (104 mg, 0.76 mmol) and tetrakis(triphenyl phosphine)palladium(0) (41 mg, 0.036 mmol) were combined in dioxane/water (20 mL, 3:1). The mixture was heated at 100° C. under stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated and washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (276 mg) as a dark oil. The resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Hexane/Ethyl Acetate 1:1 to yield the title compound (164 mg, 90%) as a viscous oil. Ion spray M.S. 351.4 (M*+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: CC(C)n1cc(Br)cn1
Reactant: COC(=O)c1ccnc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1ccnc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 2-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-isonicotinic acid methyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[CH:54]=[C:53]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[C:52]2[C:47](=[CH:48][C:49]([C:61]([F:64])([F:63])[F:62])=[CH:50][CH:51]=2)[N:46]=1>CN(C=O)C>[CH2:9]([CH:3]([CH2:1][CH3:2])/[CH:4]=[CH:5]/[C:6]([N:58]1[CH2:59][CH2:60][N:55]([C:53]2[C:52]3[C:47](=[CH:48][C:49]([C:61]([F:64])([F:62])[F:63])=[CH:50][CH:51]=3)[N:46]=[C:45]([CH3:44])[CH:54]=2)[CH2:56][CH2:57]1)=[O:8])[CH3:10]
Reactant: CCC(/C=C/C(=O)O)CC
Reactant: Cc1cc(N2CCNCC2)c2ccc(C(F)(F)F)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(/C=C/C(=O)N1CCN(c2cc(C)nc3cc(C(F)(F)F)ccc23)CC1)CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 320 %

Procedure:
(E)-4-Ethyl-hex-2-enoic acid (21.3 mg, 0.15 mmol) was dissolved in DMF (350 μl), diisopropylethylamine was added (26 μl, 0.15 mmol) followed by HATU (57 mg, 0.15 mmol dissolved in 0.25 ml DMF). The mixture was stirred at room temperature for 15 minutes, then 2-methyl-4-piperazin-1-yl-7-(trifluoromethyl)quinoline (44 mg, 0.15 mmol, dissolved in 1 ml DMF) was added and stirring was continued overnight. The mixture was evaporated under reduced pressure, the residue was dissolved in dichloromethane, the solution was washed with 5% sodium bicarbonate solution and water, evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 20.3 mg (0.48 mmol, 32.3%) of a solid.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([C:31]#[N:32])[C:29]#[N:30])=[CH:23][CH:22]=1>>[NH2:32][C:31]1[N:12]2[N:13]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:11]2[CH:10]=[C:27]([C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)[C:28]=1[C:29]#[N:30]
Reactant: N#CC(C#N)=Cc1ccncc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: N#Cc1c(-c2ccncc2)cc2nc(-c3ccco3)nn2c1N

Procedure:
The title compound, MS m/e (%): 303 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 4-pyridinylmethylen-propanedinitril.