Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([OH:29])=O)=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([NH:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[O:29])=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: Nc1nnn[nH]1
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2C(=O)Nc2nnn[nH]2)cc1

Procedure:
2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(methoxymethyl)imidazole (1.0 g) was first converted to the corresponding acid chloride and then coupled to 5-aminotetrazole by the procedure in Example 78, Part C to yield 0.87 g of a yellow glass. Flash chromatography in 100% ethyl acetate over silica gel yielded 77.1 mg of a white solid; m.p. 169°-173°. NMR (200 MHz, CDCl3, DMSO-d6)δ12.0 (br s, 1H); 7.73-7.30 (m, 6H); 7.00 (d, 2H, J=7 Hz); 5.18 (s, 2H); 4.23 (s, 2H); 2.55 (t, 2H, J=7 Hz) 1.63 (t of t, 2H, J=7,7 Hz); 1.31 (t of q, 2H, J=7,7 Hz); 0.84 (t, 3H, J=7 Hz). Anal. Calcd. for C24H26ClN7O2 · (H2O)2 : C, 55.87; H, 5.86. Found: C, 56.01; H, 6.01.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:29])([F:28])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:26][NH2:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:27][CH2:26][C:20]1([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:29])([F:28])[F:12])=[N:15][CH:16]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.17
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:13]4(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14]4)([CH2:5]3)[CH2:3]1)[CH2:9]2.N1C=CC=CC=1.[F:26][C:27]([F:40])([F:39])[S:28]([O:31]S(C(F)(F)F)(=O)=O)(=[O:30])=[O:29].[Cl-].[Na+]>C(OCC)(=O)C>[CH3:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([C:13]4[CH:14]=[CH:15][C:16]([O:31][S:28]([C:27]([F:40])([F:39])[F:26])(=[O:30])=[O:29])=[CH:17][CH:18]=4)([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(C1(O)C=CC=CC1)(C3)C2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC12CC3CC(C)(C1)CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)(C3)C2
Temperature: -15 °C
Yield: 88 %

Procedure:
Into a 100 ml four-necked flask equipped with a thermometer, an inlet for nitrogen gas and a stirrer, 4.0 g (0.0157 moles) of 4-(1-(3,5-dimethyladamantyl)phenol obtained above and 20 ml of pyridine were placed. A stream of nitrogen gas was introduced into the flask, and a solution was prepared under stirring. The obtained solution was cooled at −15° C. in an ice/methanol bath. Using a dropping funnel, trifluoromethanesulfonic acid anhydride was added dropwise. After the addition was completed, the obtained mixture was stirred at the room temperature for 2 hours. To the reaction fluid, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium chloride were added, and the obtained mixture was transferred to a separation funnel. The layer of ethyl acetate was taken out and washed twice with 100 ml of a saturated aqueous solution of sodium chloride. Then, ethyl acetate was removed by distillation under a reduced pressure using a rotary evaporator, and 5.4 g of 1-(1-(3,5-dimethyladamantyl)-4-trifluoromethane-sulfonyloxybenzene was obtained (the yield: 88%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[NH:14][C:15](=[O:16])[CH2:17][CH2:18]3)=[O:8])[CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(C(=O)c3cccnc3)ccc2N1

Procedure:
A mixture of 1.42 g of nicotinoyl chloride (a compound of Formula A2), 6 g of aluminum trichloride and 1 g of 3,4-dihydrocarbostyril were reacted in the same manner as in Preparation 1. The product was isolated similarly giving 6-(3-pyridylcarbonyl)-3,4-dihydrocarbostyril, m.p. 195°-202° C.
Reaction SMILES: [CH2:1]1[NH:15][C:4](=[C:5]2[CH:11]=[C:10]([N+:12]([O-])=O)[C:8](=[O:9])[CH:7]=[CH:6]2)[NH:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:12][C:10]1[CH:11]=[C:5]([C:4]2[NH:15][CH2:1][CH2:2][N:3]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: O=C1C=CC(=C2NCCN2)C=C1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cc(C2=NCCN2)ccc1O
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A mixture of the cyclic amidine 35 (490 mg, 2.36 mmol), ammonium formate (1.5 g, 23.6 mmol) and 10% Pd on carbon (50 mg) in methanol was heated at reflux for 4 hrs. After cooling to room temperature, the catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo. The residue was triturated with hexane and the resulting solid was collected to yield 309 mg (74%) of the desired product 37. 1H NMR (600 MHz, DMSO-d6) δ 7.07 (d, 1H, J=1.8 Hz), 6.94 (dd, 1H, J=7.8, 1.8 Hz), 6.64 (d, 1H, J=7.8 Hz), 5.46 (br s, 2H), 4.69 (br s, 1H), 2.64 (s, 4H). MS: m/z Calcd 177.2 Found MH+ 173.3
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[OH-].[Na+]>O>[OH:8][CH2:7][C@H:5]([NH:6][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:4]([O:3][CH3:2])=[O:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Yield: 95 %

Procedure:
To a solution of 24.01 g L-serine-methylester hydrochloride in 130 ml of water were added at 0° C. 29.8 g of benzyl chloroformate. The pH was kept at 6-7 by adding a 40% aqueous solution of sodium hydroxide. After 3 h at 0° C. the mixture was extracted with 5 portions of ethyl acetate, the combined extracts were dried and evaporated to give 37.12 g (95%) of pure methyl 3-hydroxy-(S)-2-benzyloxycarbonylamino-propionate. IR (neat): 3380 m (NH, OH), 1720 s, br. (C=O), 1540 s (amide II).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C@:52]1([C:61]2[CH:62]=[C:63]([C:67]3[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]=[CH2:74])[CH:68]=3)[CH:64]=[CH:65][CH:66]=2)[CH2:56][NH:55][C@H:54]([C:57]([O:59][CH3:60])=[O:58])[CH2:53]1>C(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([N:55]1[CH2:56][C@:52]([O:51][CH3:50])([C:61]2[CH:62]=[C:63]([C:67]3[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]=[CH2:74])[CH:68]=3)[CH:64]=[CH:65][CH:66]=2)[CH2:53][C@H:54]1[C:57]([O:59][CH3:60])=[O:58])=[O:12])=[O:7])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1cccc(-c2cccc([C@@]3(OC)CN[C@H](C(=O)OC)C3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2cccc(-c3cccc(C=C)c3)c2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
(S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (255 mg, 1.111 mmol), DIEA (0.40 mL, 2.223 mmol) and HATU (310 mg, 0.815 mmol) were added to a solution of (2S,4R)-methyl 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-2-carboxylate (250 mg 0.741 mmol) in DCM (3 mL). The reaction was stirred at r.t. for 2 hrs. The reaction was evaporated and purified by flash chromatography on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-2-carboxylate (277 mg, 0.505 mmol, 68% yield) as a white foam. LCMS: rt=2.31 min. [M+H]+=549; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent 13=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min, inj. vol.=5 uL; wavelength=220.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[N:16]1([CH:22]=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][C:5]1[C:6]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8][C:7]=2[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH:22]=[O:23])[CH2:17][CH2:18]2)=[N:3][N:4]=1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: O=CN1CCNCC1
Product: Cc1nnc(N2CCN(C=O)CC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of piperazinecarboxaldehyde at 150° C. gave the title compound as the free base, which was purified by flash chromatography (silica gel, 1 to 20% methanol:ethyl acetate) and converted to the dihydrochloride salt (MeOH/etheral HCl/diethyl ether), mp 325° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:33]=[CH:32][C:20]([CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH2:25]3)=[CH:19][CH:18]=1>C1COCC1>[O:31]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][CH:30]=[C:22]([CH2:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])=[CH:33][CH:32]=3)[CH:23]=2)[NH:27]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1ccc(Cc2ccc3c(c2)CC(=O)N3)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)CC(=O)N3)cc1
Temperature: 79 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.168 g, 1.09 mmol) and thionyl chloride (4 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by distillation. The crude acid chloride was cooled to 65° C., and then dissolved in THF (5 mL). 5-(4-Amino-benzyl)-1,3-dihydro-indol-2-one (0.200 g, 0.840 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. Subsequently, the reaction mixture was allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a pale yellow precipitate. The pale yellow solids were filtered to afford the pure product (0.141 g, 0.377 mmol, 34.5%).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[C:24]([NH:29][C:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH3:38])[CH:33]=3)=[O:31])[CH:25]=[C:26]([CH3:28])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[C:24]([NH:29][C:30]([C:32]4[N:36]([CH3:37])[N:35]=[C:34]([CH3:38])[CH:33]=4)=[O:31])[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)cn3c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
A mixture of N-{3-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (3.20 g, 5.82 mmol), trifluoroacetic anhydride (20 mL) and dichloromethane (30 mL) was stirred at room temperature for 4 hr. The reaction solution was concentrated under reduced pressure, ethanol (30 mL), water (15 mL) and 8N aqueous sodium hydroxide solution (15 mL) were added to the residue, and the mixture was stirred at room temperature for 60 hr. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with diethyl ether to give the title compound (1.22 g, 56%) as a pale-brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13](=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-hydroxy-3,4-dihydro-2(1H)-quinolinone (90.8 g, 0.56 mol, 1 equiv) in CH3CN (2 L) was added potassium carbonate (230.67 g, 1.67 mol, 3 equiv). The mixture was stirred for 1 h at 25° C., then Mel (75 g, 0.53 mol, 0.95 equiv) was added and the mixture was maintained at 60° C. for 12 hours. The mixture was filtered and the filtrate was taken to a residue under reduce pressure. The crude 6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone was directly use to the next step. (128 g, crude) 1H NMR (400 MHz, DMSO) δ, 2.34-2.38 (m, 2 H), 2.79 (t, 2 H, J=7.2 Hz), 3.65 (s, 3 H), 6.67 (m, 1H), 6.72-6.75 (m, 2 H), 9.86 (br, 1 H). This procedure was reproduced multiple times to prepare >300 g quantities of 6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone.
Reaction SMILES: O=[C:2](O)[C@@H:3]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]1[OH:5].[NH2:13][C:14]1[C:19]([NH2:20])=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=1>>[C@@H:3]1([C:2]2[NH:20][C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[N:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]1[OH:5]
Reactant: Nc1ncnc(N)c1N
Reactant: O=C(O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1ncnc2nc([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[nH]c12

Procedure:
Hydrolysis of this product yielded 2,5-anhydroallonic acid and reaction of this acid with 4,5,6-triamino pyrimidine, after cyclization, yielded the nucleoside, 8-β-D-ribofuranosyl adenine.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:18]([NH:20][S:21](Cl)(=[O:23])=[O:22])[CH3:19].CCN(CC)CC>C(Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][S:21]([NH:20][CH2:18][CH3:19])(=[O:23])=[O:22])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CCNS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To 5.18 g (20 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)aniline and 3.44 g (24 mmole) N-ethylsulfamoyl chloride in 30 ml CHCl3, add 2.18 g (24 mmole) Et3N in 20 ml CHCl3 and stir for 16 hours. Dilute with CHCl3 and wash with 1N HCl. Dry, concentrate and recrystallize from Et2O-hexane to yield the product; m.p. 178°-179° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl.[CH3:36][CH:37](O)[CH3:38]>ClCCl.[K].[Fe]>[F:1][C:2]([F:34])([F:33])[C:3]([C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:23]=[C:24]([NH:28][C:20]([NH:17][C:37]4[CH:38]=[CH:15][N:14]=[CH:13][CH:36]=4)=[O:21])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)O
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: [Fe]
Agent: Cl
Agent: [K]
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1cccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)(3-nitrophenyl)methanone (1.730 mmol, 850 mg) and iron powder (17.30 mmol, 966 mg) in 2-propanol was added a small volume of hydrochloric acid (37%). The reaction was refluxed for 1 hour then was allowed to cool to room temperature. The reaction was diluted with dichloromethane and solid potassium carbonated was added. The reaction was stirred for 1 hour then was filtered through celite washing with dichloromethane. The filtrate was concentrated under reduced pressure. The crude material was chromatographed on silica eluting with ethyl acetate to give the title compound (440 mg). MS (ESI) m/z 462.2 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:1][CH2:2][CH:3]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:49][CH2:50][C:51]2[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=2[CH3:57])=[O:17])=[CH:18][CH:19]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C(CO)Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(CO)Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.8 %

Procedure:
The 4-(2-hydroxy-1-phenoxyethyl)benzoic acid (100 mg, 0.3870 mmol), was dissolved into dichloromethane (20 mL), and then N-hydroxybenzotriazole (0.5814 mmol, 80 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5814 mmol, 112 mg), triethylamine (1.69 mmol, 2 mL) was added to the mixture. After the mixture was stirred at room temperature for 10 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.387 mol, 58 mg) was added. The mixture was stirred at room temperature for 18 hours. Then washed with water (20 mL), extracted with dichloromethane (20 mL). The organic layer were concentrated and subjected to column chromatography (silica gel, dichloromethane/menthol=15:1) to give 4-(2-hydroxy-1-phenoxyethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (30 mg, 15%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20]C)=O)=[N:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH3:22]>CO>[NH2:1][C:2]1[C:3]([C:18]([NH2:22])=[O:20])=[N:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2cccc3ccccc23)cnc1N
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(-c2cccc3ccccc23)cnc1N
Temperature: 85 °C
Yield: 79 %

Procedure:
A solution of methyl 3-amino-6-naphthalen-1-ylpyrazine-2-carboxylate (80 mg, 0.29 mmol) in methanol (30 mL) was saturated with ammonia gas at 0° C. in a high-pressure test tube. The reaction tube was tightly sealed and heated to 80-90° C. for 4h. Reaction cooled to room temperature and evaporated at reduced pressure to afford 3-amino-6-naphthalen-1-ylpyrazine-2-carboxamide (59 mg, 79% yield) as yellow product: 1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 8.10 (d, 1H), 7.90 (d, 2H), 7.58 (m, 6H); MS (EI) for C15H12N4O: 265 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26]O)=[CH:5][C:4]=1[CH3:28].C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:30][CH2:26][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:28])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CBr)cc1C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a 100 ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added {5-[2-(4-Methoxy-3-methyl phenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol (0.708 g, 1.74 mmoles, 1 eq), CH2Cl2 (20 ml), carbon tetrabromide (0.634 g, 1.91 mmoles, 1.1 eq) and triphenylphosphine (0.501 g, 1.91 mmoles, 1.1 eq) in that order. The reaction was stirred overnight at which time it was diluted with CH2Cl2 and washed with H2O, brine, dried over Na2SO4, concentrated in vacuo and purified via silica gel chromatography to yield 573 mg (70%) of product.
Reaction SMILES: [CH:1]1([CH2:4]/[C:5](=[N:7]/[S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])/[CH3:6])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.CO>ClCCl>[CH:1]1([CH2:4][CH:5]([NH:7][S:8]([C:10]([CH3:11])([CH3:13])[CH3:12])=[O:9])[CH3:6])[CH2:2][CH2:3]1
Reactant: C/C(CC1CC1)=N\S(=O)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(CC1CC1)NS(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 41.3 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-methyl-propane-2-sulfinic acid [2-cyclopropyl-1-methyl-eth-(E)-ylidene]-amide (120 mg, 0.596 mmol) and dichloromethane (2 ml) under an argon atmosphere. The reaction mixture was cooled in a −78° C. bath. DIBAL-H (0.80 ml, 0.800 mmol) was added slowly dropwise. The reaction mixture was allowed to stir for 45 min after which the cooling bath was removed. The reaction mixture was stirred for 15 min at room temperature, after which the reaction mixture was returned to the cooling bath. The reaction was quenched with MeOH (0.08 mL, 1.98 mmol). The reaction mixture was diluted with dichloromethane (8 mL) and 1.0 M aqueous Na+K+ tartrate solution (5 mL). After stirring at room temperature overnight, the mixture was extracted with dichloromethane. The organic layer was concentrated to afford 50 mg of 2-methyl-propane-2-sulfinic acid (2-cyclopropyl-1-methyl-ethyl)-amide which was used in the next step directly without purification.
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[N:7][C:6]=2[C:5]2=[C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])[C:17](=[O:19])[CH2:18][CH:4]2[CH2:3]1.O=S(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:26][CH:2]1[C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[N:7][C:6]=2[C:5]2=[C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])[C:17](=[O:19])[CH2:18][CH:4]2[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: C[Si](C)(C)C1=C2c3nc4ccccc4cc3C(O)CC2CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)C1=C2c3nc4ccccc4cc3C(Cl)CC2CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The 5-hydroxy-1-trimethylsilanyl-3,3a,4,5-tetrahydro-2H-cyclopenta[c]acridin-2-one (323 mg, 1.00 mmol) is dissolved in 10 ml of freshly distilled DCM under an argon atmosphere at 0° C. SOCl2 (182 μl, 2.5 mmol) is then added dropwise to the reaction medium, which is stirred at 0° C. for 15 min. The reaction medium is then run into a saturated aqueous solution of NaHCO3, the aqueous phase is extracted with DCM and the resulting organic phase is rinsed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and evaporated. The residue obtained is purified by flash chromatography.