Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]1[O:12][CH:11]2[C:8]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:9](=[O:33])[N:10]2[C:13](=[C:30]([CH3:32])[CH3:31])[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[NH:7]1)=[O:5])=[N-].B(F)(F)F.CCOCC.[C:52]([OH:55])(=[O:54])[CH3:53]>>[C:52]([O:55][CH2:3][C:4]([CH:6]1[O:12][CH:11]2[C:8]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:9](=[O:33])[N:10]2[C:13](=[C:30]([CH3:31])[CH3:32])[C:14]([O:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[NH:7]1)=[O:5])(=[O:54])[CH3:53]
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)C=[N+]=[N-])OC12
Reactant: CC(=O)O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)OCC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 0 °C
Yield: 30 %

Procedure:
To a solution of 200 mg of diphenylmethyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-α-isopropylideneacetate in 2 ml of acetic acid is added 0.045 ml of boron trifluoride etherate. After the termination of gas evolution, the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium hydrogencarbonate and then water, dried on sodium sulfate and evaporated. The residue (205 mg) is purified by thin-layer chromatography to yield 65 mg of diphenylmethyl α-(3ξ-acetoxyacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 30% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[O:24]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25]1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:29]([C:26]3[CH:27]=[CH:28][O:24][CH:25]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: O=Cc1ccoc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Product: Nc1cc(Br)cc2nc(-c3ccoc3)nn12

Procedure:
The title compound, MS m/e (%): 281 (M++2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 3-furaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10](O)=[N:9][C:8]2=[O:14])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:10]1[N:11]=[CH:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8](=[O:14])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(O)ncn1Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A toluene solution (25 mL) of 1-(4-chlorobenzyl)-4-hydroxy-1,3,5-triazin-2(1H)-one (600 mg, 2.52 mmol) synthesized in Reference Synthesis Example 10, N,N-diisopropylethylamine (0.52 mL, 4.63 mmol), and phosphorus oxychloride (0.94 mL) was stirred at 70° C. for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and toluene was added, followed by concentrating the resultant mixture under reduced pressure again. To the obtained crude product of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one, chloroform was added and the resultant solution was used in the next reaction as the chloroform solution.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])[CH2:28][CH2:27]1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CN1CCC(C(=O)Cl)CC1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: CN1CCC(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)CC1
Yield: 100 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 1-methylpiperidine-4-carbonyl chloride, the title compound (yield 100%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].[CH2:12]([Li])[CH2:13]CC.CCCCCC.ICC.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:12]([C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1)[CH3:13]
Reactant: [Li]CCCC
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccnn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirred solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide (25.3 g, 144 mmol) in THF (200 mL) at −78° C. was added dropwise 1.6 M n-butyllithium in hexane (99 ml, 159 mmol). After 30 min, iodoethane (12.8 mL, 159 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min and allowed to room temperature slowly. After 1 h, the stirring became difficult by formation of white precipitate. THF (200 mL) was added dropwise to give yellow solution. The stirring was continued for 2 h. Then, the mixture was poured into saturated aqueous NaHCO3 (600 mL) and extracted with EtOAc (400 mL×2), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 30:70 hexane/EtOAc) to afford the title compound (19.8 g, 68%) as colorless liquid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:39][C:40](=[CH2:42])[CH3:41]>C(Cl)Cl>[C:40]([O:32][C:31](=[O:33])[CH2:30][C@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:12]([C@@H:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]1=[O:29])([CH3:42])([CH3:41])[CH3:39]
Reactant: C=C(C)C
Reactant: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 1.14 g (2.3 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) in DCM (21.0 mL) was added sulfuric acid (0.247 mL, 4.63 mmol) followed by isobutylene (4.42 mL, 46.3 mmol) at −78° C. The reaction vessel was sealed and the mixture was slowly warmed to rt and vigorously stirred for 3 days. After cooling to −78° C., the tube was opened and the reaction was quenched with aqueous saturated NaHCO3 to pH 8. The organic solvent was removed under reduced pressure, and the remaining mixture was extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 20 to 35% EtOAc/hexanes) to provide the title compound as a foam.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18](C=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[CH3:28][NH:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].[C:38](=O)([O-])[O-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:28][N:29]([CH3:38])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN(C)CC(=O)OC(C)(C)C)cc2C)ncn1
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 2-(methylamino)acetate hydrochloride (227.1 mg; 1.24 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 2-((4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylbenzyl)(methyl)amino)acetate which was used directly without any further purification. The residue was taken up into DCM (4.5 ml) and TFA (0.5 ml) added. After stirring at RT for 2 hours the solvent was removed in vacuo. The residue was taken up into dilute HCl and precipitated by basification to pH 3-4. The solid was removed by filtration, washed with water and dried to give the title compound as a white solid.
Reaction SMILES: C(C[C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)#N.[CH2:9]([N:11](CC)CC)[CH3:10].[SH2:16]>N1C=CC=CC=1>[C:9]([NH:11][C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[S:16])[CH3:10]
Reactant: N#CCc1ccc[nH]1
Reactant: S
Reactant: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=S)Nc1ccc[nH]1
Temperature: 0 °C

Procedure:
2-Cyanomethylpyrrole (2.7 g, 25 mmole) was dissolved in 25 ml of dry pyridine. The solution was cooled to 0° C. in a medium pressure glass tube. Hydrogen sulfide was bubbled into the solution for 10 minutes followed by the addition of 1.5 equivalents of triethylamine (5.4 ml). The tube was sealed and heated in a steam bath for 5 hours. After cooling, the tube was opened, venting the excess hydrogen sulfide gas, and the excess pyridine was removed under reduced pressure. Recrystallization from ethyl acetate/hexane yielded 2.2 gm of 2-thioacetamidopyrrole. m.p. 93°-94° C.
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].C([C:12]1[N:13]=[CH:14][C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([N:27]2[CH2:30][C:29]4([CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)[CH2:28]2)[CH2:22][CH2:21]3)=[N:16][CH:17]=1)#N>CCO>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][C:29]2([CH2:28][N:27]([C@H:23]3[C:24]4[C:20](=[CH:19][C:18]([C:15]5[CH:14]=[N:13][C:12]([C:5](=[O:6])[NH2:7])=[CH:17][N:16]=5)=[CH:26][CH:25]=4)[CH2:21][CH2:22]3)[CH2:30]2)[CH2:31][CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4cnc(C#N)cn4)ccc31)C2
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4cnc(C(N)=O)cn4)ccc31)C2
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A round-bottomed flask was charged with water (100 mL) and urea hydrogen peroxide (495 mg, 5.11 mmol). Sodium hydroxide (119 mg, 2.98 mmol) was added and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of tert-butyl 2-((R)-5-(5-cyanopyrazin-2-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (10-1a, 379 mg, 0.85 mmol) in 25 mL EtOH was added dropwise over a period of 30 minutes via the funnel. The reaction was warmed to room temperature and stirred overnight. The resulting white suspension was collected by vacuum filtration. The solids were washed with 50 mL water and air-dried to give 210 mg (53%) of the title compound as an off-white powder. MS (ES+) 464.4 (M+H)+. 1H NMR (DMSO-d6) δ 1.38 (s, 9H), 1.54-1.61 (m, 4H), 1.89 (d, 1H), 2.08 (s, 1H), 2.76-2.80 (m, 2H), 2.99 (d, 3H), 3.11 (d, 2H), 3.19-3.22 (m, 3H), 3.90 (d, 1H), 7.45 (d, 1H), 7.83 (br s, 1H), 8.01 (d, 1H), 8.08 (s, 1H), 8.23 (s, 1H), 9.20 (d, 1H), 9.24 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1Cl)[N:14]([NH:19][CH3:20])[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[C:11]2=[O:24].B(F)(F)O.[OH-].[Na+].[CH3:31]S(C)=O>>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[N:14]([NH:19][CH2:20][CH3:31])[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[C:11]2=[O:24]
Reactant: C1CNCCN1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CS(C)=O
Agent: OB(F)F
Agent: [Na+]
Agent: [OH-]
Product: CCNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Temperature: 110 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 5.18 g of piperazine and 6.37 g of an anhydride of 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and difluoroboric acid formed with 32 ml of dimethyl sulfoxide is stirred at 110° C. for 3 hours. To the reaction mixture 51 ml of a 6 weight/vol % aqueous sodium hydroxide solution are added and the aqueous reaction mixture is stirred under slight boiling for 2 hours. The reaction mixture is filtered, the filtrate is evaporated in vacuo to two-thirds of its volume and the pH of the solution is adjusted to 6.5-7 by adding acetic acid. The reaction mixture is allowed to crystallize in a refrigerator overnight. Next morning the precipitated crystals are filtered, washed twice with 10 ml of water each and with 5 ml of methanol. Thus 5.3 g of 6-fluoro-1-ethylamino-7-piperazino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid are obtained. Yield: 82%. Mp.: 289°-291° C. (decomposition; from dimethyl formamide).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(N([CH2:43][CH3:44])CC)C.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[C:43]1([CH3:44])[CH:50]=[CH:49][C:48]([S:51]([N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[CH2:6][N:7]([CH2:14][C:15]2[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:8][C:9]2[N:13]([S:51]([C:48]3[CH:49]=[CH:50][C:45]([CH3:55])=[CH:46][CH:47]=3)(=[O:53])=[O:52])[CH:12]=[CH:11][N:10]=2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3S(=O)(=O)c3ccc(C)cc3)Cc3nccn3S(=O)(=O)c3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound (50.8 mg) obtained in Example 19-3 was dissolved in anhydrous chloroform (2.0 ml). The solution was added with triethylamine (0.049 ml) and then added with p-toluenesulfonyl chloride (manufactured by Kanto Kagaku) (57.2 mg), followed by stirring at room temperature for 16 hours. After completion of the reaction, chloroform (3.0 ml) was added to the solution, and the whole was washed with water. The organic layer was dried with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate), thereby obtaining the subject compound (15.2 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2O)=[C:4]([F:13])[CH:3]=1.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC([O-])=O>C1COCC1>[CH:22]([O:21][C:19]([C:17]1[N:16]([CH:9]2[C:10]3[C:5](=[C:4]([F:13])[CH:3]=[C:2]([Br:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)[CH:15]=[N:14][CH:18]=1)=[O:20])([CH3:24])[CH3:23]
Reactant: OC1CCCc2c(F)cc(Br)cc21
Reactant: CC(C)OC(=O)c1c[nH]cn1
Agent: COC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCc2c(F)cc(Br)cc21
Reaction time: 1 h

Procedure:
To a solution of 7-bromo-5-fluoro-3,4-dihydro-2H-naphthalen-1-ol (0.280 g, 1.10 mmol) and isopropyl 4-imidazolecarboxylate (0.121 g, 0.77 mmol), which can be prepared as described in Example 1, in THF (6 mL) at 0° C. is added triphenylphosphine (0.291 g, 1.10 mmol) and methyl azodicarboxylate (40% in toluene, 0.41 mL, 1.10 mmol). After 1 hour, the cooling bath is removed and after another hour, the mixture is diluted with ethyl acetate and washed with half-saturated brine, dried over magnesium sulfate, filtered, t and concentrated. The resulting residue is purified by semi-preparative reverse phase HPLC (5 to 100% acetonitrile/water w/0.1% TFA) to furnish affords a pale yellow oil. After free-basing, 3-(7-bromo-5-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester is obtained; MS: (ESI) m/z 381.1, 383.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, J=6.3 Hz, 3 H), 1.39 (d, J=6.3 Hz, 3 H), 1.71-1.81 (m, 1 H), 1.83-1.92 (m, 1 H), 2.07-2.24 (m, 2 H), 2.72 (dt, J=17.7, 6.8 Hz, 1 H), 2.87 (dd, J=17.7, 5.8 Hz, 1 H), 5.22 (sept, J=6.3 Hz, 1 H), 6.29 (t, J=5.2 Hz, 1 H), 6.94 (br. s, 1 H), 7.18 (dd, J=8.8, 1.8 Hz, 1 H), 7.22 (s, 1 H), 7.79 (s, 1 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[H-].[Na+].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:35]I.C(OC)(C)(C)C>CN(C)C=O.O>[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:35][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
50 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate are dissolved in 0.5 ml of dimethylformamide and 22 mg of NaH (60%) are added. After 30 min of stirring, 112 mg of 5-methyl-2-p-tolyloxazol-4-yl-methyl iodide are added at room temperature. The mixture is placed in an ultrasonic bath for 10 min and then stirred at room temperature for 3 h. 10 ml of methyl tert-butyl ether and 10 ml of water are then added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether and the organic phases are dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 5/1->1/1). 60 mg of the crude tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionate are obtained as a yellow oil. C27H39NO5 (457), LCMS(ESI): 458 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2OCC[O:28]2)[CH:22]=1.C1(C)C=CC=CC=1.CCOC(C)=O>CC(O)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C3OCCO3)c2)c1N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 5 (Example 8, 1.14 g, 2.6 mmol) was suspended in aqueous AcOH (10 mL, 1.5 M in H2O). Glacial AcOH was added dropwise until a clear solution was obtained. The reaction mixture was stirred at room temperature overnight. Evaporation of the solvent under reduced pressure to give a residue. Toluene and EtOAc were added and the mixture was concentrated again to give the crude product that could be purified by silica gel chromatography (hexanes/EtOAc: 1/4). The desired 3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 6 was obtained as a yellow foamy solid (0.91 g, 89%). MS m/z 389.1 [M+H]+; 1H NMR (300 MHz, CDCl3) 0.61 (m, 2H), 0.85 (dd, J1=6.9 Hz, J2=12.4 Hz, 2H), 2.25 (s, 3H), 2.87 (m, 1H), 5.95 (brs, 2H), 6.57 (brs, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.67-7.78 (m, 4H), 8.07 (s, 1H), 8.09 (d, J=1.3 Hz, 1H), 8.31 (s, 1H), 10.12 (s, 1H) ppm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[O:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=1.[Br:29]C(Br)(Br)Br>O1CCCC1>[Br:29][CH2:21][C:22]1[O:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)o1
Temperature: -10 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
38 g (145 mmol) triphenylphosphine were added to a solution of 15 g (121 mol [sic]) of 5-hydroxymethyl-2-cyanofuran in 250 ml of tetrahydrofuran. The mixture was cooled to -10° C., and a solution of 48 g (145 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was allowed to warm to room temperature and was stirred at this temperature for 3 hours. The mixture was concentrated in a rotary evaporator under water pump vacuum and the residue was purified by column chromatography (mobile phase petroleum ether:dichloromethane 1:1, Rf =0.5). 11.5 g of the title compound were obtained. 1H-NMR (250 MHz, d6 -DMSO): δ=4.8 (m, 2H), 6.7 (d, 1H), 7.7 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([CH3:42])=[N:18][C:19]([CH3:41])=[C:20]([C:29](=[O:40])[NH:30]CCCC3C=CC=CC=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:44](F)(F)[C:45]([O-])=O>ClCCl>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:20]([CH2:23][CH2:22][CH2:27][C:45]3[CH:44]=[CH:20][CH:21]=[CH:16][CH:14]=3)([C:29]([NH2:30])=[O:40])[CH:19]([CH3:41])[N:18]=[C:17]([CH3:42])[C:16]=2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: Cc1nc(C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1
Solvent: ClCCl
Product: CC1=NC(C)C(CCCc2ccccc2)(C(N)=O)C(c2cccc(Cl)c2)=C1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
619 mg (1.05 mmol) of 4-[4-(3-chlorophenyl)-2,6-dimethyl-5-(3-phenylpropylcarbamoyl) pyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester was dissolved in 30 ml of dichloromethane. 15 ml of trifluoroacetate was added and stirred at room temperature for 2 hours. After concentration under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. By adding hexane to the residue, the solid substance was precipitated, filtered and dried under reduced pressure to obtain the title compound.