Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[C:6]([CH:8]1[CH2:10][CH:9]1[C:11]#[N:12])=[O:7].[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[CH:6]([OH:7])[CH:8]1[CH2:10][CH:9]1[C:11]#[N:12]
Reactant: N#CC1CC1C(=O)c1ccc(C(F)(F)F)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
351 mg (9.28 mmol) of sodium borohydride were added to 2.17 g (8.44 mmol) of the compound from Example 129A in 38 ml of ethanol and 16 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 1 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 9/1) to result in 1.59 g (73% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:22]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NC(=O)c1nc(-c2ccccc2)sc1N
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(C(=O)Nc2sc(-c3ccccc3)nc2C(N)=O)cc1OC
Yield: 18.6 %

Procedure:
To a solution of 5-amino-2-phenyl-1,3-thiazole-4-carboxamide (0.3 g, 1.4 mmol) in NMP (1 mL) is added a solution of 3,4-dimethoxybenzoyl chloride (0.41 g, 2.0 mmol) in NMP (3 mL) followed by DBU (0.21 g, 1.4 mmol) and the mixture is stirred at reflux for 4 h. The resulting precipitate is collected by filtration, washed with NMP, acetonitrile, ethanol, ether to give 0.1 g (30%) of the title compound. This is further purified by reverse-phase HPLC: 1H NMR (400 MHz, DMSO-d6) δ [ppm]3.9 (s, 6H); 7.2 (d, J=8.3 Hz, 1H); 7.5 (m, 5H); 8.0 (m, 3H); 8.1 (s, 1H); 12.7 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:21]=2)[C@H:10]([O:39][CH3:40])[CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[CH2:35]([C:19]1[N:18]=[N:17][C:16]([O:15][CH2:14][C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[O:39][CH3:40])=[CH:21][C:20]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:26][CH:27]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@H]2CCNC[C@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.36 mmol, 0.20 g) in DCM (1 mL) was added 4 N HCl in dioxane (1 mL). The solution was stirred for 1 hour. The solvents were removed with reduced pressure and the salt was triturated with diethyl ether and filtered to give (±)-cis-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-methoxy-piperidin-4-ylmethoxy)-pyridazine dihydrochloride (0.17 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([S:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2O)[CH:15]=[CH:16][CH:17]=1)([CH3:11])[CH3:10].[C:26]([O:30]C)(=[O:29])[CH2:27][SH:28].O.[OH-].[Li+]>C(Cl)Cl.O.CO>[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([S:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[S:28][CH2:27][C:26]([OH:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: COC(=O)CS
Reactant: CC(C)(C)c1cccc(S[C@@H]2CCCC[C@H]2O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cccc(S[C@@H]2CCCC[C@H]2SCC(=O)O)c1

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of the title compound of Example 10 (3.6 g, 0.0136 mole) in methylene chloride (5 ml) with stirring. After several minutes, methyl thioglycolate (1.59 g, 0.015 mole) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into methanol (50 ml) containing lithium hydroxide hydrate (12.6 g, 0.30 mole). Water (125 ml) was slowly added to the mixture, and then the mixture was extracted with diethyl ether (100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and extracted twice with 100 ml of diethyl ether. The combined diethyl ether extracts were washed with water (30 ml), 5% sodium bicarbonate (50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator to give the crude product as an oil. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy, and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=O)[N:11]=1)=[O:5].Cl.[NH2:30][OH:31].N1C=CC=CC=1>CCO.C(Cl)Cl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10](/[CH:12]=[N:30]\[OH:31])[N:11]=1)=[O:5]
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nc(/C=N\O)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Into a solution of Compound 67 (180 mg, 0.44 mmol) in 3 mL of EtOH was added hydroxylamine hydrochloride (60 mg, 0.9 mmol) and pyridine (0.5 mL). The solution was stirred at room temperature for 2 hours. The reaction was diluted with 20 mL of CH2Cl2, and the solution was washed with 10 mL of water and dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with 5-100% ethyl acetate in hexane) to give Compound 72 (98 mg, 52%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)C.Cl>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc([N+](=O)[O-])c3)c2c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(N)c3)c2c1
Yield: 37.4 %

Procedure:
N-[3-(3-Aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 49 from 200 mg of N-[3-(3-nitrophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide, 6 ml of ethanol, 73 mg of powdered iron, 100 ml of distilled water and 40 μl of 12 N hydrochloric acid. 70 mg of N-[3-(3-aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of light yellow crystals melting at 154° C. (analysis C20H18N4O4S2 % calculated C, 54.29; H, 4.10; N, 12.66; O, 14.46; S, 14.49. % found C, 53.03; H, 4.26; N, 11.63; S, 13.22).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10](Br)[CH:11]=[CH2:12].[Cl:14][C:15]1[CH:16]=[C:17]2[NH:24][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:22][C:18]2=[N:19][C:20]=1[I:21]>C1COCC1>[CH2:10]([N:24]1[C:17]2[C:18](=[N:19][C:20]([I:21])=[C:15]([Cl:14])[CH:16]=2)[N:22]=[C:23]1[S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=[CH2:12]
Reactant: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Reactant: C=CCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1c(S(C)(=O)=O)nc2nc(I)c(Cl)cc21
Temperature: 60 °C

Procedure:
N,N-diisopropylethylamine (0.69 ml, 3.95 mmol) and allyl bromide (0.32 ml, 3.70 mmol) were added to a stirred suspension of 6-chloro-5-iodo-2-methylsulfonyl-1H-imidazo[4,5-b]pyridine (1.0824 g, 3.03 mmol) in THF (12.0 ml). The reaction mixture was heated to 60° C. for 18 h, then cooled to room temperature. The reaction mixture was partitioned between EtOAc (50 ml) and brine (50 ml). The organic layer was washed with brine (1×50 ml). The combined aqueous layers were extracted with EtOAc (1×50 ml). The organic layers were combined, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the title compound as a yellow foam. This material was a mixture of the allyl regioisomers and was used without further purification. LC-MS: calculated for C10H9ClIN3O2S 396.91 observed m/e: 397.89 (M+H)+ (Rt 1.12 and 1.17/2 min).
Reaction SMILES: [OH:1][C@@H:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[CH3:23][C:24](OC(C)=O)=[O:25]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:1][C@@H:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1)(=[O:25])[CH3:23]
Reactant: C[C@]12CCC(=O)CC1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 6α-hydroxyandrostane-3,17-dione (4.90 g) in pyridine (10 mL) at 0° C., DMAP (94 mg) and Ac2O (4.55 mL) were added. After stirring overnight at room temperature, the solution was evaporated. The residue was treated with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 6α-acetoxyandrostane-3,17-dione (5.57 g, 100%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.66 (m, 1H), 2.47-2.33 (m, 2H), 2.30-2.01 (m, 4H), 2.00 (s, 3H), 1.98-1.08 (m, 12H), 1.05 (s, 3H), 1.00 (m, 1H), 0.84 (m, 1H), 0.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:38][C:37]6[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: COc1ccc(C=O)cc1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: COc1ccc(CN2CCc3[nH]c(-c4n[nH]c5cc(-c6cc(F)c(O)cc6CC(F)(F)F)ccc45)nc3C2)cc1

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 4-methoxybenzaldehyde (63.1 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 22.1% yield, 26 mg.
Reaction SMILES: [Br:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]2[C:9]([CH:15]([CH3:17])[CH3:16])=[CH:10][C:11]([O:13]C)=[CH:12][C:5]=2[S:4]1(=[O:19])=[O:18].B(Br)(Br)Br>>[Br:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]2[C:9]([CH:15]([CH3:16])[CH3:17])=[CH:10][C:11]([OH:13])=[CH:12][C:5]=2[S:4]1(=[O:18])=[O:19]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: BrB(Br)Br
Product: CC(C)c1cc(O)cc2c1C(=O)N(CBr)S2(=O)=O
Temperature: 0 °C
Yield: 124.5 %

Procedure:
A mixture of 2-bromomethyl-4-isopropyl-6-methoxy-l,-2-benzisothiazol-3(2H)-one 1,1-dioxide (44 g, 126.4 mmol) and BBr3 (1.0M in methylene chloride, 164.4 mmol) was allowed to reflux for 48 hours and then poured into ice/water. The mixture was filtered, the aqueous layer was extracted with ethyl acetate, and the mixture of the combined organic layer and the residue (from above filtration) was dried over sodium sulfate and concentrated in vacuo. The solid residue was recrystallized from toluene/cyclohexane (7:2) to afford 52.6 g (96 %) of 2-bromomethyl-4-isopropyl-6-hydroxy-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide as solid, m.p. 167°-169° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[CH:5][CH:4]=1.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@]23CCN(C)C[C@H]2c2ccccc2O3)cc1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CN1CC[C@]2(c3ccc(O)cc3)Oc3ccccc3[C@@H]2C1
Yield: 84 %

Procedure:
A mixture of 3.46 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(4-methoxyphenyl)-2-methyl-benzofuro[3,2-c]pyridine and 3.57 g of lithium thiomethoxide in 30 ml of dry hexamethylphosphoramide was heated under a drying tube at 140° for 41/2 hours. The reaction mixture was diluted with 350 ml of water, and the pH was adjusted to 7 by slow addition of 2N HCl with stirring. As the pH reached neutral, the product precipitated out. The mixture was cooled to 0° and stirred for 30 minutes. The precipitated material was filtered, washed with water and then with a small amount of ether, and dried to give 2.77 g (84.2%) of crystalline solid, m.p. s 209, 215°-217°. Recrystallization from ethanol afforded 2.33 g (70.8%) of crystals, m.p. s 215, 222°-224°.
Reaction SMILES: O=[C:2]([CH3:20])[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[O:17][CH3:18])=[CH:14][C:13]([I:19])=[CH:12][CH:11]=2)=[O:6].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[I:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:5]1[O:6][C:2]([CH3:20])=[CH:3][N:4]=1)=[C:16]2[O:17][CH3:18]
Reactant: COc1c(C(=O)NCC(C)=O)cnc2ccc(I)cc12
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(-c2ncc(C)o2)cnc2ccc(I)cc12
Temperature: 150 °C
Yield: 39.6 %

Procedure:
A mixture of 6-iodo-4-methoxy-quinoline-3-carboxylic acid (2-oxo-propyl)-amide (example 16b) (1.3 g, 3.38 mmol) and Burgess Regent ((methoxycarbonylsulfamoyl)-triethylammonium hydroxide, inner salt) (2.0 g, 8.5 mmol) in THF was heated to 150° C. for 15 min by microwave. The solvent was removed by rotary evaporator. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-50% ethyl acetate in hexanes in 30 min) afforded 6-iodo-4-methoxy-3-(5-methyl-oxazol-2-yl)-quinoline (0.49 g, 40%) as a white solid. LC-MS m/e 367 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>N1C=CC=CC=1>[CH2:18]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
In 10 ml of pyridine was dissolved 2.3 g of benzyl p-hydroxybenzoate, a solution of 3 g of p-decyloxybenzoic acid chloride in 15 ml of pyridine was added to the above solution, and a reaction was carried out at room temperature overnight. The reaction liquid was put in ice-cooled dilute hydrochloric acid and the formed precipitate was recovered by filtration, dried and purified by the silica gel chromatography to obtain 4 g of benzyl 4-(4'-decyloxybenzoyloxy)benzoate. This ester was dissolved in 20 ml of ethyl acetate and 0.4 g of Pd/C was added. Catalytic reduction was carried out under a hydrogen pressure of 2 kg/cm2 overnight. The catalyst was removed by filtration, and ethyl acetate was evaporated from the reaction liquid to obtain 3.2 g of 4-(4'-decyloxybenzoyloxy)benzoic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][C:52]1[C:57]([O:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:56][CH:55]=[CH:54][N:53]=1>CN(C=O)C.O>[CH3:51][C:52]1[C:57]([O:58][CH:59]2[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:61][CH2:60]2)=[CH:56][CH:55]=[CH:54][N:53]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ncccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 45.3 %

Procedure:
DIPEA (193 mg, 1.5 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (127 mg, 0.5 mmol) in DMF (2 mL) followed by HOBt (67 mg, 0.5 mmol) and EDCI.HCl (105 mg, 0.55 mmol). After 2 minutes 2-methyl-3-(piperidin-4-yloxy)-pyridine hydrochloride (100 mg, 0.5 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, and the solid was collected. Purification of the solid by washing with 10% MeOH in CHCl3 afforded 95 mg (47.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-methyl-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 420, 96.7%. 1H NMR (300 MHz, DMSO-d6): δ 8.3 (m, 1H), 8.2 (b, 1H), 8.0 (m, 1H), 7.8 (m, 2H), 7.6 (m, 1H), 7.5 (m, 2H), 7.4 (m, 1H), 7.2 (b, 1H), 4.9 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2H), 2.5 (m, 3H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:22]3[CH2:23][NH:24][CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:22]3[CH2:23][NH:24][CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCNC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc3n(n2)CCNC3)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A mixture of 205f (165 mg, 0.28 mmol) and lithium hydroxide (67 mg, 2.80 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at room temperature for 1 h. The mixture was evaporated in vacuo and diluted with water (4 mL). It was then extracted with ethyl acetate (10 mL×2). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 205 (70 mg, 46%) as a white solid. MS-ESI: [M+H]+ 541.2. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=5.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J=5.5 Hz, 1H), 6.90 (s, 1H), 5.70 (s, 1H), 5.01 (s, 1H), 4.64-4.61 (m, 1H), 4.50 (s, 1H), 4.34 (s, 1H), 4.16-3.99 (m, 6H), 3.89-3.87 (m, 1H), 3.71 (s, 3H), 3.30 (t, J=5.5 Hz, 2H), 2.63-2.57 (m, 4H), 1.92-1.89 (m, 2H), 1.80-1.78 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1cn[nH]c1
Product: C[C@@H](n1cccn1)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (569 mg) and pyrazole, (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-pyrazol-1-yl)ethyl]oxirane (166 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)=[CH:57][CH:58]=2)[CH:53]=[CH:52]1>CN(C=O)C>[CH3:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:61]=[C:62]([NH:66][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=3)=[CH:57][CH:58]=2)[CH:53]=[CH:52]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Cn1ccc2cc(-c3cccc(N)c3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(ccn5C)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 47.1 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-indol-5-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.013 g of product in 46% yield: LCMS (ESI) m/z 425 (MH+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[N+](C1C=C(S(O[CH2:26][C@:27]2([CH3:30])[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(N(CC)CC)C>ClCCl>[CH3:26][C@@:27]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][O:28]1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(CON2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
A mixture of N-hydroxypthalimide (5.3 g), [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (5.9 g) and triethylamine (10.6 ml) in dichloromethane (15 ml) was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was poured onto a silica column and eluted with dichloromethane to give the sub-title compound as a colourless solid (3.1 g).