Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([N:20]([CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:38](=[O:39])[O:40][CH3:41])=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCOCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(COCC(F)(F)F)C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 12.6 %

Procedure:
In a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(2,2,2-trifluoroethoxymethyl)benzoic acid amide in 10 mL of N,N-dimethylformamide, 0.0825 g of 60% oily sodium hydride was added under cooling with ice and with stirring, and stirred at room temperature for 10 minutes. Then, 0.268 g of methyl chloroformate was added, and continued to stir at the same temperature for 30 minutes. After the completion of the reaction, the reaction was poured in 50 mL of water, extracted with ethyl acetate (50 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.07 g of the aimed product as colorless resinous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]S(C)=O.CI>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H), 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methy iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCI solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (br t, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H, 4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:36]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(S(C)(=O)=O)c3)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(S(C)(=O)=O)c3)nc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetamide 197-7 (30 mg, 0.07 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 183-2 (22 mg, 0.10 mmol), Pd(PPh3)4 (4 mg, 0.003 mmol), Na2CO3 (22 mg, 0.20 mmol), Toluene (0.4 mL), H2O (0.4 mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100° C. overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-methyl-3-(methylsulfonyl)-2,4′-bipyridin-5-yl)acetamide 197. MS m/z 509.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.81 (d, 1H), 8.52 (d, 1H), 8.49 (d, 1H), 7.97 (s, 1H), 7.87 (d, 1H), 7.47 (s, 1H) 7.41 (dd, 1H), 7.37 (dd, 1H), 3.95 (s, 2H), 3.68 (t, 2H), 3.63 (t, 2H), 3.15 (t, 2H), 3.09 (t, 2H), 2.92 (s, 3H), 2.57 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[CH:12]1([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15.6 g (0.1 mol) of 4-fluoro-3-nitro-aniline and 17.9 g (0.11 mol) of cyclohexylcarboxylic acid chloride are dissolved in 250 ml tetrahydrofuran and after the addition of 12.1 g (0.12 mol) of triethylamine the mixture is stirred for 3 hours at ambient temperature. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>>[NH:2]=[C:1]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:30])(=[O:31])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCOCC1
Yield: 31.6 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1 equivalent of morpholine as secondary amine and 0.5 equivalent of DIEA as base. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2S(C2C=CC=CC=2)(=O)=O)=[CH:5][CH:4]=1.[Li]CCCC.[CH:26](=[O:30])[CH:27]([CH3:29])[CH3:28]>C1COCC1>[CH3:28][CH:27]([CH3:29])[C:26]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([S:2][CH3:1])[CH:11]=2)=[O:30]
Reactant: CC(C)C=O
Reactant: CSc1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2cc(C(=O)C(C)C)[nH]c2c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 6-(methylthio)-1-(phenylsulfonyl)-1H-indole (890 mg, 2.93 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen was added n-BuLi (5.86 mL, 14.65 mmol, 2.5 M). After stirring for 30 min, isobutyraldehyde (1.05 g, 14.65 mmol) was added to the formed mixture. The reaction mixture was stirred at 0° C. for 1 h. The mixture was quenched with sat. NH4Cl (10 mL) at 0° C. and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography on silica gel eluted with PE/EtOAc 20:1 to give 2-methyl-1-(6-(methylthio)-1H-indol-2-yl)propan-1-one (440 mg, 64.28% yield) as a colorless oil. LC-MS MS (ESI) m/z 234.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.86 (brs, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.14-7.11 (m, 1H), 7.01 (dd, J1=8.4 Hz, J2=1.6, 1H), 3.42-3.38 (m, 1H), 2.47 (s, 3H), 1.20 (d, J=6.8 Hz, 6H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[C:16](F)[CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([O:19][CH3:20])[CH:13]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: COc1cc(F)cc(Br)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc(OC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL) at 65° C. was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.1 min, M+H+=300.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([O:13][C:14]3[C:19]4[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:38][CH2:39]Cl.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CC(C)=O.CN(C=O)C>[CH:38]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[N:12]=[C:11]([O:13][C:14]3[C:19]4[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[N:8]=2)[CH2:5][CH2:6]1)([CH3:39])[CH3:41]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCCl
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C4=CCNCC4)n3)cccc2s1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C4=CCN(C(C)C)CC4)n3)cccc2s1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a mixture of N-(4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (109 mg, 0.195 mmol, Example 27), acetone (1 mL), 1,2-dichloroethane (6 mL) and DMF (0.5 mL) was added AcOH (one drop), and the mixture was heated at 50° C. with stirring for 10 min. The reaction mixture was left to reach room temperature, sodium triacetoxyborohydride (127 mg, 0.6 mmol, Aldrich) was added, and the stirring was continued for 2 h at room temperature. After the addition of acetone (1 mL) and sodium triacetoxyborohydride (127 mg, 0.6 mmol), the reaction mixture was stirred at room temperature for 1 h and evaporated under reduced pressure. The yellow residue was treated with 1N NaOH (5 mL) and extracted with EtOAc (2×20 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (gradient 0.5-5% (2M NH3 in MeOH) in EtOAc) afforded the title compound as a pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 554 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[Cl:12][C:13]1[CH:14]=[C:15]([OH:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([CH:16]=[C:15]([O:21][C:7]2[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([F:11])[C:2]=2[Cl:1])[CH:14]=1)[C:19]#[N:20]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: N#Cc1cc(O)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(F)nc(F)c2Cl)c1
Temperature: -50 °C

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (10-1; 1.0 g; 5.39 mmol) and Compound 1-4 (0.83 g; 5.39 mmol) were dissolved in DMF and the solution cooled to −50° C. under a nitrogen atmosphere, after which potassium carbonate (1.12 g; 8.09 mmol) was added and the mixture allowed to slowly warm to 25° C. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic extract was concentrated and purified on a silica column eluted with ethyl acetate:hexane to give the title product 10-2 as a clear oil. Rf=0.6 (EtOAc:hx, 5:95). 1H NMR (CDCl3): δ 7.50 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]N)=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(=O)[CH3:21]>>[N+:17]([C:11]1[CH:10]=[C:9]([O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=[C:13]2[C:12]=1[NH:15][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:21]2)([O-:19])=[O:18]
Reactant: NNc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(=O)c1ccccn1
Agent: Cl
Product: O=[N+]([O-])c1cc(Oc2ccccc2)cc2cc(-c3ccccn3)[nH]c12
Yield: 12.3 %

Procedure:
(4-Phenoxy-2-nitrophenyl)hydrazine hydrochloride (10 g, 49 mmol) and 2-acetylpyridine (5.5 ml, 49 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (2 g, Yield 16%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH3:2].CN(C(O[N:31]1[N:39]=N[C:33]2[CH:34]=CC=[N:37][C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:47]1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN1C=CC(N)=N1>CN(C=O)C>[CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:10]([NH:37][C:32]2[N:31]([CH3:47])[N:39]=[CH:34][CH:33]=2)=[O:12])=[CH:8][N:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cn1ccc(N)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccnn2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To an ice-cold solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 91 mg, 0.24 mmol, 1.50 eq) followed by HOBt (N-hydroxybenzotriazole, 32 mg, 0.24 mmol, 1.50 eq), DIPEA (31 mg, 0.24 mmol, 1.50 eq) and finally the 1-methylpyrazol-3-amine (0.24 mmol, 23 mg, 1.50 eq). The resulting reaction mixture was stirred overnight at room temperature. The reaction mass was then poured onto the ice-cold water followed by extraction with EtOAc (3×20 mL). The reaction mass was then poured onto the ice-cold water followed by extraction with EtOAc (3×20 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (60-120 M, 1-2.5% MeOH-DCM) to obtain Compound 10 (15 mg, 25%). 1H NMR (300 MHz, DMSO-d6): δ 10.31 (br s, 1H), 9.97 (br s, 1H), 9.14 (br s, 1H), 8.64 (s, 1H), 7.85 (m, 1H), 7.40 (m, 3H), 7.27 (m, 3H), 7.17 (m, 1H), 6.23 (s, 1H), 3.71 (s, 3H), 3.13 (m, 2H) and 1.07 (m, 3H); [M+H]+ m/z=380.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH:12]2N3[CH2:18][CH2:19][CH:14](C(=O)C3)[CH2:13]2)C[N+]([O-])=O)C=1.[CH2:21](O)C>[Ni]>[CH3:21][CH2:18][CH2:19][CH2:14][CH2:13][CH2:12][CH2:7][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CN2CCC1CC2C(C[N+](=O)[O-])c1cccnc1
Reactant: CCO
Agent: [Ni]
Product: CCCCCCCCCCC
Reaction time: 48 h
Yield: 67 %

Procedure:
6-(1-(3-Pyridinyl)-2-nitroethyl)-1-azabicyclo[2.2.2]octan-3-one (14.0 g, 0.046 mol) was dissolved in ethanol (200 mL), and then Raney nickel was added under nitrogen. The mixture was subjected to hydrogenolysis (40 psi H2) for 48 h and then filtered through Celite and concentrated by rotary evaporation to a crude brown residue. The residue was purified by column chromatography, using chloroform/methanol/ammonia (80:20:1, v/v) as eluent, to yield 3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane as a yellow oil (8.0 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].CC([O-])=O.[Na+].[I:17]Cl.O>C(O)(=O)C>[I:17][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(I)cc([N+](=O)[O-])c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a mixture of 2-methyl-6-nitroaniline (106.5 g, 0.7 mol) and NaOAc (63.2 g, 0.77 mol) in acetic acid (525 mL) was added a solution of ICl (125 g, 0.77 mol) in acetic acid (350 mL). The mixture was heated at 80° C. for 50 min and poured into H2O (2100 mL). After stayed at the room temperature for 16 h, the mixture was filtered to furnish yellow solid that was washed with H2O (3×350 mL). Drying under reduced pressure at 40° C. for 48 h afforded the title compound (191 g, 98%). 1H NMR (CDCl3) δ 2.22 (s, 3H), 6.20 (br s, 2H NH), 7.53 (s, 1H), 8.34 (s, 1H). ESI-MS m/z 279 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:7]([OH:9])=O.[NH2:20][C:21](=[N:39][OH:40])[C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[C:24]([F:38])[CH:23]=1>>[F:38][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:7]([C:6]3[CH:10]=[CH:11][C:12]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=3)[O:9][N:39]=2)[CH:37]=[CH:36][C:25]=1[C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27].[F:38][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:7]([C:6]3[CH:10]=[CH:11][C:12]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=3)[O:40][N:39]=2)[CH:37]=[CH:36][C:25]=1[C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27]
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Product: CCOC(=O)CCNC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(COC)c3)n2)cc1F
Product: COCc1cc(-c2nc(-c3ccc(C(=O)NCCC(=O)O)c(F)c3)no2)ccc1N1CCCCC1C

Procedure:
Ethyl N-(2-fluoro-4-{5-[3-(methoxymethyl)-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}benzoyl)-beta-alaninate was prepared following the general procedure 3 starting from Intermediate 2 and Intermediate 6. It was hydrolyzed following general procedure 9 to afford the title compound as a pale yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 12.3 (brs, 1H), 8.56 (m, 1H), 8.18 (m, 1H), 8.06 (m, 1H), 7.97 (m, 1H), 7.90 (dd, J=8.0 Hz, 1H), 7.81 (t, 1H, J=7.6 Hz), 7.38 (d, J=8.5 Hz, 1H), 4.54 (m, 2H), 3.47 (m, 2H), 3.40 (s, 3H), 3.23 (m, 1H), 3.02 (m, 1H), 2.56-2.47 (m, 3H), 1.88-1.30 (m, 7H), 0.85 (d, J=6.2 Hz, 3H). LC/MS (Method B): 497.4 (M+H)1, 495.4 (M−H)−. HPLC (Method A) Rt 3.01 min (Purity: 97.2%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16]Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl-:23].[NH4+].CN(C)[CH:27]=[O:28]>O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C@@:6]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][O:28][C:27]2[CH:9]=[CH:8][C:7]([Cl:23])=[CH:6][CH:5]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: [Cl-]
Reactant: CN(C)C=O
Reactant: CC(=O)N[C@](C)(CCc1ccc(C#CCBr)o1)COC(C)=O
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N[C@](C)(CCc1ccc(C#CCOc2ccc(Cl)cc2)o1)COC(C)=O
Yield: 93 %

Procedure:
Subsequently, to the reaction mixture was added a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(3-bromoprop-1-ynyl)furan-2-yl]butane (0.3050 g, 0.82 mmol) obtained in Example (22b) in N,N-dimethylformamide (4 ml) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 30 minutes. After stirring, saturated aqueous ammonium chloride solution was added to the reaction mixture to quench the reaction, and then the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and acetone (10:1) as the eluent to afford the title compound (0.3188 g, yield: 93%).