Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)=[CH:19][CH:18]=1>CN(C)C=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:10]2[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[C:9]2=[O:13])=[CH:19][CH:18]=1
Reactant: BrCCCCCCCOc1ccc(Br)cc1
Reactant: O=C1NCCN1c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCCOc2ccc(Br)cc2)CCN1c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-chloro-4-pyridyl)-2-imidazolidinone (0.12 g, 0.63 mmol) dissolved in 10 mL dimethylformamide at 0° C. was added NaH (60% dispersion in mineral oil, 27.7 mg, 0.69 mmol). The mixture was stirred at room temperature for 30 minutes; then cooled in ice bath. 1-Bromo-4-[(7-bromoheptyl)oxy] benzene (0.22 g, 0.63 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. A saturated aqueous NH4Cl solution (5 mL) and dichloromethane (10 mL) were added to the residue. The dichloromethane layer was dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 8) as a white solid (0.19 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([C:6](=[O:14])C(=O)[NH:8]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[OH-].[Na+].OO.C(O)(=[O:25])C>O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([NH2:8])[C:5](=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1)[C:6]([OH:14])=[O:25]
Reactant: CC(=O)O
Reactant: COc1c(Cl)cc(C(F)(F)F)c2c1NC(=O)C2=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(Cl)cc(C(F)(F)F)c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
6-Chloro-7-methoxy-4-trifluoromethylisatin (13 mg, 0.046 mmol) was dissolved in NaOH (0.68M, 0.20 mL, 0.13 mmol) and H2O (0.20 mL) and then cooled to +7 C. Hydrogen peroxide (30%, 14 L, 0.14 mmol) dissolved in NaOH (0.68M, 0.49 mL, 0.33 mmol) was added dropwise during 1 min. The reaction mixture was stirred for 1 h 15 min at room temperature. Additional H2O2 (10 L) was added at 7 C. and then stirring was continued at room temperature for 2 h. Acetic acid (54 L, 0.94 mmol) was added, but no precipitation occured. Ethyl acetate (2 mL) was added and pH was raised to 6 with NaHCO3 (aq, sat.). The water phase was washed with EtOAc (3) and the combined organic layers were evaporated and co-evaporated with toluene (2). Purification by flash chromatography (SiO2, gradient EtOAc EtOAc-HOAc 100:1) yielded the title compound (5 mg). 1H NMR (CD3OD): 6.98 (s, 1H), 3.87 (s, 3H). MS (EI, 70 eV): m/z (rel. int.) 271/269 (M+, 17/48).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].C(O)CCC.C1(C)C=CC(S(O[CH2:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])(=O)=O)=CC=1>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OCCC[Si](C)(C)C)cc3)s2)cc1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
0.34 g (1.0 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)-1,3-thiazole, 0.07 g of 85%-KOH and 12 ml of n-butanol were mixed. To the mixture, 0.29 g (1.0 mM) of 3-(trimethylsilyl)propyl p-toluenesulfonate was added dropwise under stirring at 100° C., followed by further stirring for 9 hours at 100° C. After the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, followed by washing with water and drying with anhydrous magnesium sulfate. The magnesium sulfate in the resultant mixture was filtered off and the filtrate was condensed into a solid, followed by purification by silica gel column chromatography (eluent: toluene) and recrystallization from a mixture solvent (ethanol/ethyl acetate) to obtain 0.32 g of 2-(4-hexylphenyl)-5-[4-(3-trimethylsilylpropoxy)phenyl]-1,3-thiazole (Yield: 70.8%). ##STR81##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH3:16])=[CH:10][CH:9]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:28][OH:29])[CH2:15][CH3:16])=[CH:10][CH:9]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(Oc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Agent: Cl
Product: CCC(=NO)c1ccc(Oc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Yield: 83 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}propiophenone was reacted with hydroxylamine hydrochloride to give 4'-{5-fluoro-3-{(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}propiophenone oxime in 83% yield, m.p. 94°-96° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3o2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2oc(Oc3ccc(OC[C@H]4CCCN4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a 20 mL vial which contained a solution of (R)-2-[4-(benzooxazol-2-yloxy)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.1 mmol) in dioxane (0.5 mL) was added HCl (4 N in dioxane 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. Removal of the solvent yielded the title product (28 mg, 80%); LCMS; 75% ESI+, Calcd: 310.4; Found m/z: 311.4 (M+1); 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.75 (m, 1H), 1.85-2.03 (m, 2H), 2.06-2.13 (m, 1H), 3.14-3.26 (m, 2H), 3.79-3.89 (m, 1H), 3.98-4.03 (m, 1H), 4.12 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 6.69-6.72 (m, 2H), 6.78-6.83 (m, 2H), 7.05-7.16 (m, 3H), 7.25-7.30 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27](Br)[CH:28]=3)[CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:34]([O:38][C:39]([N:41]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43][CH:42]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43][CH:42]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:19]5[NH:18][C:17]([CH:12]6[CH2:13][C:14](=[CH2:16])[CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:33])[CH:6]([CH3:8])[CH3:7])=[N:21][CH:20]=5)[CH:23]=4)[CH:28]=3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: C=C1CC(c2ncc(-c3ccc4cc(Br)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CC(C#N)CN7C(=O)OC(C)(C)C)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1

Procedure:
(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (202 mg, 0.392 mmol), 4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (181 mg, 0.392 mmol), Pd[PPh3] (45.6 mg, 0.0392 mmol), potassium carbonate (108 mg, 0.784 mmol) were heated in DME (3 mL)/water (0.4 mL) at 120° C. for 20 minutes under microwave conditions. The volatiles were removed in vacuo and the crude was partitioned between EtOAc and brine/aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate. Filtration and evaporation of solvents yielded the crude material, which was purified via flash chromatography on silica gel to yield the product. (161 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:17]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][N:46](C)[C:47](=O)OC(C)(C)C)=[CH:41][C:40]=3[CH3:55])[CH:35]=2)=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=O)(C)(C)C>ClCCl>[CH:31]([S:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[N:18]=[C:17]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:44]=[CH:43][C:42]([CH2:45][NH:46][CH3:47])=[CH:41][C:40]=4[CH3:55])[CH:35]=3)[C:16]([NH2:15])=[N:21][CH:20]=2)=[CH:27][CH:26]=1)(=[O:29])=[O:30])([CH3:33])[CH3:32]
Reactant: Cc1cc(CN(C)C(=O)OC(C)(C)C)ccc1-c1cc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)on2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
TFA (556.9 mg, 376.3 μL, 4.884 mmol) was added to a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]-3-methyl-phenyl]methyl]-N-methyl-carbamate (190 mg, 0.2442 mmol) in dichloromethane (4.750 mL) and the resulting yellow solution stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue taken up in methanol (2 mL) and dichloromethane (1 mL) and passed through an SCX cartridge and the product eluted with 2M ammonia in methanol and concentrated in vacuo. The filtrate was purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (96.4 mg, 69% yield); 1H NMR (400.0 MHz, DMSO) d 1.18 (d, 6H), 2.61 (s, 3H), 2.62 (m, 3H), 3.48 (m, 1H), 4.20 (m, 2H), 7.24 (br s, 2H), 7.48-7.52 (m, 2H), 7.63 (s, 1H), 7.84 (m, 1H), 7.93 (m, 2H), 8.37 (m, 2H), 8.81 (br s, 2H) and 8.97 (s, 1H) ppm; MS (ES+) 478.3
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[Cl:10][CH2:11][CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:24][C:18]=3[C:17]([N+:29]([O-:31])=[O:30])=[CH:16][C:15]=2[N:14](C(=O)C(F)(F)F)[CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].CO>O>[Cl:10][CH2:11][CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][C:23]([S:25]([NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:26])=[O:27])=[CH:24][C:18]=3[C:17]([N+:29]([O-:31])=[O:30])=[CH:16][C:15]=2[NH:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
t-Butyl carbazate (86 mg, 0.65 mmol) was added to a solution of 116 (107 mg, 0.23 mmol) in ThF (5 mL) and the mixture was stirred at room temperature for 16 h. Cs2CO3 (150 mg, 0.46 mmol) and MeOH (2 mL) were added and the mixture was stirred for a further 2 h. The mixture was diluted with water and extracted with CH2Cl2 (×2). The combined extracts were dried and evaporated and the residue was purified by chromatography, eluting with EtOAc/petroleum ether (1:4 then 2:3). The product was recrystallised from EtOAc/petroleum ether to give tert-butyl 2-{[1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}hydrazinecarboxylate (119) (72 mg, 67%) as an orange crystalline solid: mp 179° C. (dec.); 1H NMR [(CD3)2SO] δ 9.60 (br s, 1H), 9.18 (v br s, 1H), 8.54 (d, J=1.4 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.75 (s, 1H), 7.74 (dd, J=8.9, 1.8 Hz, 1H), 6.74 (s, 1H), 4.29-4.22 (m, 1H), 3.94-3.85 (m, 2H), 3.80 (dd, J=11.0, 8.0 Hz, 1H), 3.74 (dd, J=10.5, 3.0 Hz, 1H), 1.10 (br s, 9H). HRMS (FAB) calcd. for C18H2135ClN4O6S (M+) m/z 456.0870, found 456.0877.
Reaction SMILES: C([N:8]([CH2:30][C@H:31]([OH:41])[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1>CO.[Pd]>[OH:41][C@H:31]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:30][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1cccc(CCCOCCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(O)c(CO)c2)c1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)c1cccc(CCCOCCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 87.3 %

Procedure:
3-(3-{[7-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide (87.2 g) in methanol (800 ml) was hydrogenated over 5% Pd/C catalyst (28 g, 50% wet) at atmospheric pressure and ambient temperature. The catalyst was removed by filtration through a Hyflo pad and the filtrate concentrated in vacuo to give the title compound (64.4 g)-LC RT=3.46 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH:14]=[O:15])=[CH:5][CH:4]=1.[CH3:18][O:19][Si](C)(C)C.[CH3:24][Si](OS(C(F)(F)F)(=O)=O)(C)C>C(Cl)Cl>[CH3:24][O:15][CH:14]([O:19][CH3:18])[C:10]1[N:11]=[CH:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Reactant: CO[Si](C)(C)C
Solvent: ClCCl
Product: COC(OC)c1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of Example 52B (1.26 g, 5.22 mmol) in CH2Cl2 (5 mL) was cooled to −78° C. after which the starting material was observed to precipitate. Methoxytrimethylsilane (1.44 mL, 10.5 mmol) and trimethylsilyltrifluoromethane sulfonate (0.047 mL, 0.261 mmol) were added and the reaction mixture was allowed to proceed for 24 hr with gradual warming to ambient temperature. The reaction was quenched with saturated aq NaHCO3 solution (10 mL), then diluted with EtOAc (50 mL) and H2O (30 mL). The separated aqueous phase was extracted with EtOAc, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The result was 1.42 g (95%) of the title compound as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.98 (d, J=8.7, 2H), 7.87 (d, J=8.4, 2H), 5.55 (s, 1H), 3.34 (s, 6H). MS (DCI+) m/z 288 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:48][C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=3)=[O:19])=[CH:16][N:17]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.8 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 2-amino-5-chloropyridine (29 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane and washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (27 mg, 0.051 mmol, 27%) as a white powder.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:17][Si:18]([C:21]#[C:22][C:7]1[CH:8]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(S(N)(=O)=O)c1
Yield: 85.3 %

Procedure:
A dimethylformamide (30 mL) solution of 3-bromobenzenesulfonamide (13.7 g), trimethylsilylacetylene (5.18 g), copper(I) iodide (65 mg), bis(triphenylphosphine)palladium(II) dichloride (400 mg), triphenylphosphine (300 mg) and triethylamine (15.0 mL) was stirred at 80° C. for 6 hours. Thereafter, the reaction solution was added to water, and the obtained solution was then extracted with ethyl acetate. The organic layer was successively washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel 60 N, hexane:ethyl acetate=4:1 to 3:1), so as to obtain the title compound (11.4 g) in the form of a light brown solid.
Reaction SMILES: C([O:3]/[CH:4]=[CH:5]\[C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)C.O1CCOCC1.O.Cl>O1CCOCC1>[CH3:35][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:15]([C:12]2[N:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH:4]=[O:3])=[CH:7][C:8]3=[N:14][CH:13]=2)=[O:16])[N:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:21]=1
Reactant: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.7 %

Procedure:
A solution of (Z)-7-(2-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (82.8 mg, 0.177 mmol) in 1:1 dioxane/water (2 mL) was treated with 45 equivalents of 4.0 M hydrochloric acid in dioxane solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 1.5 hours, quenched with saturated aqueous sodium bicarbonate solution, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography on silica with a 10% MeOH in DCM solution as eluent to afford 37 mg of the impure desired product as a yellow solid. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][OH:16])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1
Reactant: O=Cc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(CO)cc12
Yield: 100 %

Procedure:
1-(3-Chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.18 g, 0.4 mmol) was dissolved in THF and treated under nitrogen with the excess of sodium borohydride (0.2 mmol). After 1 hr the reaction mixture was diluted with water and the product extracted with methylene chloride to afford after evaporation of the solvent the title compound as a colorless solid (0.18 g, 0.4 mmoles).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[F:15][C:16]([F:48])([F:47])[S:17]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:32]1)(=[O:19])=[O:18]>C(Cl)Cl>[F:48][C:16]([F:15])([F:47])[S:17]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:32]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1C1N[C@@H](c2ccccc2)Cc2ccccc21)C(F)(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2ccccc2c1C1=N[C@@H](c2ccccc2)Cc2ccccc21)C(F)(F)F
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
Powdered 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (908 mg, 4.0 mmol) was added to a solution of 5 (2.033 g, 4.21 mmol) in CH2Cl2 (20 mL) at rt. After 20 minutes, the mixture was filtered through a short pad of silica gel using CH2Cl2 as the eluant. The solvent was evaporated and the residue was purified by column chromatography on silica gel (9:1 hexanes/EtOAc) to yield the title product 6 (1.65 g, 86% yield) as a solid. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.03-7.93 (m, 2H), 7.54-7.12 (m, 12H), 6.86-6.79 (m, 1H), 5.04-4.94 (m, 1H), 3.29-3.06 (m, 2H); HRMS calcd for C26H19F3NO3S+1 (M+1): 482.1038. found: 482.1032.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1n[nH]cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 64.4 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.77 g), 4-iodo-3-trifluoromethyl-1H-pyrazole (0.99 g) and potassium carbonate (0.63 g) were stirred in DMF (10 ml) at 60° C. for 1 hour. After cooling, the reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (1.0 g).