Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:40])[C@H:13]([OH:39])[C@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:37])[CH2:28][O:29]CC4C=CC=CC=4)=[CH:22][CH:21]=3)[C:15]2=[O:38])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]>CO.CC(O)=O.[Pd]>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:40])[C@H:13]([OH:39])[C@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:37])[CH2:28][OH:29])=[CH:22][CH:21]=3)[C:15]2=[O:38])=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: N=C(N)c1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(NC(=O)COCc4ccccc4)cc3)C2=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(NC(=O)CO)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
To a solution of EXAMPLE 32 (0.12 g) in MeOH—AcOH (20 mL-1 mL), was added 10% Pd—C (20 mg). The reaction mixture was stirred under H2 gas atmosphere at room temperature overnight. The reaction mixture was filtered to remove Pd—C and the filtrate was purified by prep. LC/MS. Before collecting the fractions, conc. HCl was added into each fraction to obtain EXAMPLE 33 (2 mg) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2C(C)=CC=C2C)[N:5]=[C:4]([CH2:15][CH2:16][CH:17]([C:23]([O:25][CH2:26]C)=[O:24])[C:18]([O:20][CH2:21]C)=[O:19])[CH:3]=1.[OH-].[K+].Cl.NO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.CO.O>[NH2:8][C:6]1[N:5]=[C:4]([CH2:15][CH2:16][CH:17]([C:23]([O:25][CH3:26])=[O:24])[C:18]([O:20][CH3:21])=[O:19])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CCOC(=O)C(CCc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Solvent: CO
Product: COC(=O)C(CCc1cc(C)cc(N)n1)C(=O)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 52 %

Procedure:
To a solution of diethyl (2-(4-methyl-6-(2,5-dimethylpyrrol-1-yl)-2-pyridinyl)ethyl)malonate (96 mg, 0.26 mmol) in 1.4 mL of ethanol was added 0.3 mL of water, followed by 105 mg of 87% potassium hydroxide (1.63 mmol). After the mixture had been stirred at room temperature for 7 h., additional water (0.3 mL) was added along with 166 mg (2.39 mmol) of hydroxylamine hydrochloride. The mixture was refluxed 12 h. After removing solvent in vacuo, the residue was dissolved into 10 mL of 2.0 N aqueous hydrochloric acid and washed with 2×10 mL of diethyl ether. The aqueous phase was concentrated and swirled with 3×1 mL of methanol. The methanol extracts were combined, filtered, and evaporated. The residue was dissolved in 5.0 mL of methanol along with 149 mg (0.78 mmol) of p-toluenesulfonic acid and heated to reflux for 16 h. The reaction was cooled and concentrated and the residue was partitioned between 15 mL of saturated aqueous sodium bicarbonate and 30 mL of ethyl acetate. The organic layer was washed with 15 mL of saturated aqueous sodium chloride, dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 10 g of silica gel, eluting with 200 mL of 40% ethyl acetate in dichloromethane and 200 ML of 50% ethyl acetate in dichloromethane to give 36 mg (52% yield) of dimethyl (2-(6-amino-4-methyl-2-pyridinyl)ethyl)malonate.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[F:11][C:12]([F:20])([F:19])[C:13](=O)[CH2:14][C:15](=O)[CH3:16].ClCCl>C(O)C>[CH2:7]([N:9]1[C:15]([CH3:16])=[CH:14][C:13]([C:12]([F:20])([F:19])[F:11])=[N:10]1)[CH3:8]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCn1nc(C(F)(F)F)cc1C

Procedure:
A solution of 25.0 g (grams) (167 mmol) (millimoles) of ethylhydrazine oxalate in 50 mL (milliliters) of ethanol was added to a solution of 25.0 g (162 mmol) of 1,1,1-trifluoro-2,4-pentanedione in 200 mL of ethanol at ambient temperature with stirring. The mixture was heated to reflux with stirring for 18 hours and was then allowed to cool. The volatile components were removed by evaporation under reduced pressure and the residue obtained was taken up in 150 mL, of dichloromethane. The resulting solution was washed twice with 100 mL portions of water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 19.1 g (66 percent of theory) of the title compound as an amber oil
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:23][CH2:22][N:9]2[C:10]3[C:15]([C:16]([C:17](=O)[C:18](Cl)=[O:19])=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].Cl.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][C:36](=[NH:38])[OH:37])=[CH:27]1>>[C:1]([O:4][CH2:5][CH:6]1[CH2:23][CH2:22][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:19])[NH:38][C:36](=[O:37])[C:35]=4[C:28]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:26]([CH3:25])[CH:27]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: Cn1cc(CC(=N)O)c2ccccc21
Reactant: CC(=O)OCC1CCn2c(c(C(=O)C(=O)Cl)c3ccccc32)C1
Agent: Cl
Product: CC(=O)OCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c3ccccc32)C1

Procedure:
In a manner analogous to that described in Example 1, 333 mg (1 retool) of [8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]glyoxylyl chloride were treated with 266 mg (1 mmol) of isopopyl 1-methyl-3-indoleacetimidate hydrochloride in different solvents and at various temperatures to give 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl ]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione. The results obtained are compiled in Table I:
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][N:14]=[CH:13][C:9]=3[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1COCC1>[CH3:19][N:20]([CH:22]=[C:10]1[C:9]2[CH:13]=[N:14][CH:15]=[CH:16][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:11]1=[O:12])[CH3:21]
Reactant: O=C1Cc2cnccc2Nc2ncccc21
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=C1C(=O)c2cccnc2Nc2ccncc21

Procedure:
A solution of 6,11-dihydro-5H-dipyrido[2,3-b:3′,4′-f]azepin-5-one (0.440 g, 2.08 mmol, Intermediate D-6) and 1,1-dimethoxy-N,N-dimethylmethanamine (2.49 mL, 18.7 mmol) in THF (30 mL) was stirred for three days under an atmosphere of nitrogen. The mixture was concentrated in vacuo to give the desired product as an orange solid which was used directly for the next step. LC/MS: 267 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].Cl.[NH:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:25]3[CH:26]=[C:27](N)[CH:28]=[CH:29][C:24]=3[CH2:23][N:22]([C:31]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)=[O:32])[CH2:21][CH2:20]2)[N:15]=[CH:14]1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[ClH:11].[ClH:11].[NH:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:25]3[CH:26]=[C:27]([NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:28]=[CH:29][C:24]=3[CH2:23][N:22]([C:31]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)=[O:32])[CH2:21][CH2:20]2)[N:15]=[CH:14]1
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2cc(NS(=O)(=O)c3ccccc3)ccc2C1
Reaction time: 16 h

Procedure:
Benzenesulphonamide (0.024 g, 0.13 mmol) was added to a solution of Example 26 (0.50 g, 0.12 mmol) and triethylamine (0.019 mL, 0.13 mmol) in CH2Cl2 (1 mL). After stirring for 16 hr, the reaction was diluted with CHCl3 (10 mL) and NaHCO3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCl3 (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was treated with HCl/ether, a yellow solid was formed which was triturated with ether several times and dried under vacuum to afford Example 54 (0.64.2 g, 83%) as a light brown solid.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>C(O)(=O)C>[Br:1][C:12]1[CH:13]=[C:8]([S:5]([CH2:4][Cl:3])(=[O:6])=[O:7])[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: O=S(=O)(CCl)c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=S(=O)(CCl)c1ccc(O)c(Br)c1
Temperature: 45 °C
Yield: 64.8 %

Procedure:
160 g (1 mole) of bromine were added dropwise at room temperature to a solution of 206.5 g (1 mole) of 4-chloromethylsulfonylphenol in 500 ml of glacial acetic acid; the mixture was stirred for a further hour at 45° C and, when it has cooled, was poured onto 1.5 l of ice-water. The product which had precipitated was filtered off and recrystallized from toluene. 185 g (65% of theory) of 2-bromo-4-chloromethylsulfonylphenol were thus obtained as a colorless powder of melting point 158°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[S:21][CH2:20][C:19]([O:23][CH3:24])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: COC(=O)CS
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CSC(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of 4,4'-dimethoxybenzhydrol (Aldrich) (300 mg, 1.23 mmol) and methyl thioglycolate (123 mg, 1.35 mmol) in 6 mL of 10% methanolic HCl is heated at reflux for 45 minutes. The reaction is cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. The product is concentrated in vacuo to give methyl [[bis-(4-methoxyphenyl)methyl]thio]acetate as a colorless oil in 73% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1.Cl>ClCCl.O>[C:1]([O:5][C:6]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([OH:21])=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(SCCCN(CCc2ccccc2)C(=O)OC(C)(C)C)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCSc1nc2ccccc2n1CC(=O)O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-[3-(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor J-01b, 12.7 mg, 0.025 mmol) is suspended in an aqueous 0.2 M NaOH solution (0.67 ml). After addition of THF (1.3 ml) the resulting solution is allowed to stir overnight at rt. It is then treated with 1 M aqueous HCl (3.35 ml), water (2 ml) and dichloromethane (3 ml). The phases are separated and the dichloromethane is removed under reduced pressure. Drying under high vacuum yields the pure title compound: tR=2.12 min (LC-2), ESI-MS (neg.): m/z 470.47 [M−H]+; 1H-NMR (DMSO-d6): δ 1.31 (s, 9H, tBu), 1.88 (quint., 2H, SCH2CH2), 2.73 (m, 2H, CH2Ph), 3.24 (t, 2H), 3.28-3.36 (m, 4H), 4.94 (s, 2H, CH2CO2), 7.13 (m, 5Harom), 7.23 (t, 2Harom), 7.42-7.50 (m, 2Harom).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]2[O:13]CCCO2)[CH:7]=1.[CH2:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:7]=1)[CH:8]=[O:13])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNCCCC
Reactant: COc1ccc(Br)cc1C1OCCCO1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
2-(5-Bromo-2-methoxy-phenyl)-[1,3]dioxane (40 mmol), di-n-butylamine (48 mmol), Pd2(dba)3 (0.2 mmol, 1 mol % Pd), P(o-tol)3 (0.6 mmol) and Na-t-OBu (68 mmol) was stirred in degassed toluene (60 mL) at 80° C. for 18 h. The darkbrown mixture was poured into icecold hydrochloric acid (1 M, 200 mL) and stirred vigorously for 2 hours at 25° C. The solution was cooled to 0° C. and pH was adjusted to 9 using 6M NaOH(aq) and extracted with Et2O (4×100 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure. The resulting crude oil purified by flash chromatography using EtOAc/n-heptane (1:4, v/v) as eluent. The product was isolated as yellow oil in 46% yield.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:47]1([C:53]2[O:57][C:56]([C:58]([NH2:61])([CH3:60])[CH3:59])=[N:55][N:54]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([NH:61][C:58]([C:56]3[O:57][C:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[N:54][N:55]=3)([CH3:60])[CH3:59])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(N)c1nnc(-c2ccccc2)o1
Reactant: CC1(COc2cc(C(=O)O)ncc2C2CC2)COC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(COc2cc(C(=O)NC(C)(C)c3nnc(-c4ccccc4)o3)ncc2C2CC2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of the acid 5-cyclopropyl-4-((3-methyloxetan-3-yl)methoxy)picolinic acid (20 mg, 76.0 μmol) in dichloromethane (1 ml) was added DIPEA (24.5 mg, 33.2 μl, 190 μmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (23.1 mg, 83.6 μmol). The reaction is stirred for 30 minutes at room temperature followed by addition of 2-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-amine (CAN 68176-04-5, 15.4 mg, 76.0 μmol) and the reaction mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane (5 mL) and washed with a 0.2M aqueous solution of hydrochloric acid (3×10 mL) and brine (15 mL). The organic phase is dried over magnesium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to yield the title compound (24.3 mg, 71%). MS (ESI, m/z): 449.7 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CN2CCCCC2)C1
Yield: 50 %

Procedure:
To a suspension of 3-methanesulfonyloxymethylazetidine-1-carboxylic acid tert-butyl ester (0.36 g, 1.40 mmol) in toluene (2 mL) was added piperidine (0.7 mL, 7.00 mmol) and the resultant mixture was heated to 110° C. in a sealed tube for 18 h. The solution was concentrated in vacuo, the crude residue dissolved in DCM and washed with 0.5 N KOH (aq.) (1×) and brine (1×). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The resultant oil was purified by chromatography on silica gel with MeOH:DCM (1:19, v/v) as eluent to afford 3-piperidin-1-ylmethylazetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.70 mmol, 50%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=O)=[C:10]([CH3:17])[N:9]2[CH3:18])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[CH:36]=2)=[C:28]([F:48])[CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(OCC)(=O)C.O1CCCC1>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:26]([NH:25][C:14]([C:11]5[C:12](=[O:13])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]([CH3:18])[C:10]=5[CH3:17])=[O:16])=[CH:27][C:28]=4[F:48])=[CH:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n(-c2ccc(F)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1130 mg, 4.5 mmol) in tetrahydrofuran (75 mL) were added N,N-dimethylformamide (6 drops) and oxalyl dichloride (780 μL, 9.1 mmol), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in N,N-dimethylacetamide (10 mL). The solution was added to a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (1230 mg, 3.8 mmol) in N,N-dimethylacetamide (30 mL), and the mixture was stirred at room temperature for 4 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (1640 mg, 67%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[C:21]([NH2:24])=[N:22][CH:23]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[C:21]([NH2:24])=[N:22][CH:23]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Nc1ncc(-c2cc(Cl)nc(Cl)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
To a microwave vial charged with 2,4,6-trichloropyrimidine (300 mg, 1.64 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (518 mg, 1.80 mmol) and cesium carbonate (1.07 g, 3.27 mmol) in acetonitrile/water (4:1, 30 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (60 mg, 0.05 mmol) under nitrogen. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, and resulting residue was purified by flash column chromatography (15% ethyl acetate in petroleum ether to 50% ethyl acetate in petroleum ether) to provide 5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (300 mg, 59.3% yield). LCMS (ESI): [MH]+=308.7.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+].[Na+].[Na+].[Mg+2].[Cl-].[Cl-]>>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
Moreover, a sample of this concentrated solution (155 mg/ml, pH 4.5) was taken for addition of sodium citrate buffer of pH 4.5 to a foreseen final buffer concentration of 17.5 mM. But already after the addition of the first droplets (of 1 M sodium citrate buffer pH 4.5), E25 aggregated immediately and the solution became white turbid, turning soon into a white solid gel. If 1 M MgCl2 (instead of 1 M sodium citrate pH 4.5) is added to the final concentrated solution of Example 14 (to a final MgCl2 concentration of 50 mM), the solution remains clear.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][O:10][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1noc2cc([N+](=O)[O-])ccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1noc2cc(N)ccc12
Yield: 49.6 %

Procedure:
Ethyl 6-nitrobenzo[d]isoxazole-3-carboxylate (12.7 mmol), iron (53.6 mmol), and ammonium chloride (56.1 mmol) were combined and diluted with ethanol (150 mL) and water (20 mL). The resulting suspension was heated at reflux, with vigorous stirring, for 2 h. The reaction mixture was filtered through Celite, diluted with brine (200 mL), and the resulting solution was extracted with ethyl acetate (200 mL). The organic layer was washed with of brine (3×200 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (20/1 petroleum ether/ethyl acetate) to provide ethyl 6-aminobenzo[d]isoxazole-3-carboxylate 49.6% yield as a orange solid
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=1[CH2:5][SH:6].CS(O[C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([C:34](=[O:36])[CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C:26](=[CH:27][C:28](=[O:37])[CH:29]=[CH:30]1)[CH2:25][CH2:24]3)(=O)=O>C(O)C>[Cl:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=1[CH2:5][S:6][C@@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([C:34](=[O:36])[CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C:26](=[CH:27][C:28](=[O:37])[CH:29]=[CH:30]1)[CH2:25][CH2:24]3
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: SCc1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccc(Cl)cc1Cl

Procedure:
To 1.04 gm. of sodium metal dissolved in 80 ml. of ethanol is added 5.55 ml. of 2,4-dichlorobenzylmercaptan followed by 1.5 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat at reflux for 76 hours under an atmosphere of nitrogen. In a manner similar to that described in Example 1E, isolate the title compound.