Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2F)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(2-fluorophenyl)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 93 mg of 2-(benzamido)-4-(2-fluorophenyl)benzoic acid as white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:3])[NH2:2].C(O)(=[O:13])C>OO>[C:1]([C:4]1[CH:9]=[N+:8]([O-:13])[C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: Cc1cnc(C(N)=O)cn1
Reactant: CC(=O)O
Agent: OO
Product: Cc1cnc(C(N)=O)c[n+]1[O-]
Temperature: 70 °C
Reaction time: 7 h

Procedure:
2-Carboxy-5-methylpyrazine (9.7 g) in dry dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml), keeping the temperature at 0°-5° C. After ten minutes, dioxan (190 ml) saturated with ammonia was added. The mixture was stirred for 3 hours at room temperature, then dioxan was distilled off, and the residue was taken up in saturated aqueous sodium bicarbonate (20 ml). The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), m.p. 204°- 206° C. This amide (7 g) in glacial acetic acid (30 ml) and 35% hydrogen peroxide (20 ml.) was heated with stirring at 70° C for 7 hours. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine 4-oxide (5.5 g), m.p. 206°- 208° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>O1CCOCC1>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]1[O:7][C:15](=[O:16])[NH:9][N:8]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccccc2[N+](=O)[O-])o1
Yield: 86.3 %

Procedure:
A solution of 2-nitrobenzoylhydrazine (9.05 g, 0.05 mol) in dioxane (30 mL) was slowly added to a solution of trichloromethyl chloroformate (4.6 mL, 0.04 mol) in dioxane (30 mL) at room temperature. On completion of the addition the reaction was heated to reflux for 4 hours. The solvent was evaporated off and the residue re-crystallised from 96% ethanol (50 mL) to give 7.15 g of the 5-(2-nitrophenyl)-3H-[1,3,4]oxadiazol-2-one. M.p. 157-158° C. A solution of the nitro compound (2 g, 9.7 mmol) in 96% ethanol (25 mL) was hydrogenated over 5% palladium on charcoal to give desired 1.6 g of the desired amine.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccc(F)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (4-fluorobenzyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.10 (m, 1H), 1.20-1.34 (m, 2H), 1.59 (s, 1H), 1.68 (t, J=12.22 Hz, 4H), 1.87 (s, 3H), 2.23 (s, 3H), 3.86 (d, J=8.87 Hz, 1H), 4.52 (d, J=5.37 Hz, 2H), 7.14 (t, J=8.60 Hz, 2H), 7.33-7.38 (m, 2H), 7.57 (d, J=7.52 Hz, 1H), 8.10 (s, 1H), 12.78 (bs, 1H); MS (ESI) m/z 329.2 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH:4]1[C:5]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccc(Oc2ccc(Br)cc2)cc1

Procedure:
Still other approaches to the preparation of 4,4'-dibromodiphenyl ether involve condensation reactions. Thus, when bromobenzenes were heated with iodyl sulfate and then with concentrated, hydrochloric acid, R2I+Cl- was formed which, on coupling with para-bromophenol in aqueous solution containing sodium hydroxide, gave 4,4'-dibromodiphenyl ether. (Nilsson, C. A., et al., Chemosphere 1977, 6(9), 599-607; C.A. 88: 22273k). Another low yield synthesis of 4,4'-dibromodiphenyl ether utilizes coupling of para-dibromobenzene with phenol. Thus, heating para-dibromobenzene with phenol and potassium hydroxide in the presence of freshly precipitated copper at 180° C. with continuous water removal gave 27 percent yield of para-dibromo diphenyl ether, with somewhat higher yields being obtained at higher temperature. (Bakhvalov, et al., Izv. Akad Nauk SSSR, Ser.Khim. 1970, (1), 143-5;, C.A. 72: 110930x). German Offen No. 2,242,519 describes the synthesis of 4,4'-dibromodiphenyl ether by a soventless Ullmann reaction of halobenzenes with alkali metal phenolates in the presence of cuprous or cupric oxide at 130°-65° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].CC(O)=O.[F:35][C:36]1[CH:43]=[CH:42][C:39](C=O)=[CH:38][CH:37]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)CC1)O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.2 %

Procedure:
(±)-(E)-3-[4-Oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 3, 650 mg, 1.85 mmol) was suspended in DCM (100 ml). TEA (0.258 ml, 1.85 mmol) was added and the pH was adjusted to 5 with AcOH. 4-Fluorobenzaldehyde (275 mg, 2.22 mmol) and NaBH(OAc)3 (587 mg, 2.77 mmol) were added and the mixture was stirred for 6 h at RT, then washed with a saturated NaHCO3 solution brine, dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography (eluent DCM/MeOH 99:1) to give (±)-(E)-3-[1′(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (550 mg)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:30])[C:13]3[C:14](=[C:16]([CH2:28][CH3:29])[N:17]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH3:41])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:6][N:5]=1)[CH3:2].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([N:17]2[C:16]([CH2:28][CH3:29])=[C:14]3[N:15]=[C:10]([C:9]4[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[C:7]([S:31]([N:34]5[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH2:39]5)(=[O:32])=[O:33])[CH:8]=4)[NH:11][C:12](=[O:30])[C:13]3=[N:18]2)=[CH:24][CH:23]=1
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccc([N+](=O)[O-])cc3)nc2c(=O)[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccc(N)cc3)nc2c(=O)[nH]1
Temperature: 60 °C

Procedure:
A solution of the title compound from example 63 (100 mg, 0.17 mmol) in methanol (2 ml) was added to a suspension of iron powder (29 mg, 0.52 mmol) in ammonium chloride (45 mg, 0.85 mmol) in water (2 ml), and the reaction heated at 60° C. for 1 hour. The cooled mixture was filtered, and the filtrate evaporated under reduced pressure to give the title compound as a pale brown solid, 93 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=3)=[N:9]2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:53](=[O:54])[C:52]([C:55](O)=[O:56])=[CH:51][CH:50]=[N:49]2)=[CH:44][CH:43]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:55]([C:52]2[C:53](=[O:54])[N:48]([C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)[N:49]=[CH:50][CH:51]=2)=[O:56])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=3)[N:9]=[C:10]([C:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:28][CH:27]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A 50 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 0.0916 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (42.9 mg, 0.183 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (52.7 mg, 0.275 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (37.1 mg, 0.275 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0818 ml, 0.458 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (2 days). The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (38.3 mg, 54.9%). LRMS (APCI pos) m/e 662 (M−99).
Reaction SMILES: [CH2:1]([S:4]([NH2:7])(=[O:6])=[O:5])[CH:2]=[CH2:3].C(N=C=NCCCN(C)C)C.[CH2:19]([NH:23][C:24](=[O:76])[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](NS(CC=C)(=O)=O)=[O:36])[CH:33]=2)[C:28]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[C:27]1[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2[CH:63]=[C:62]([N:64]3[CH2:68][CH2:67][CH2:66][C:65]3=[O:69])[CH:61]=[CH:60][C:59]=2[N:70]2[CH2:75][CH2:74][O:73][CH2:72][CH2:71]2)=[CH:52][CH:51]=1)[CH2:20]C=C>CN(C=O)C.CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH:44]1([C:28]2[C:29]3[CH:30]=[CH:31][C:32]4[C:35](=[O:36])[NH:7][S:4](=[O:6])(=[O:5])[CH2:1][CH:2]=[CH:3][CH2:20][CH2:19][NH:23][C:24](=[O:76])[CH2:25][N:26]([C:34]=3[CH:33]=4)[C:27]=2[C:50]2[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]3[CH:63]=[C:62]([N:64]4[CH2:68][CH2:67][CH2:66][C:65]4=[O:69])[CH:61]=[CH:60][C:59]=3[N:70]3[CH2:71][CH2:72][O:73][CH2:74][CH2:75]3)=[CH:52][CH:51]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: C=CCS(N)(=O)=O
Reactant: C=CCCNC(=O)Cn1c(-c2ccc(OCc3cc(N4CCCC4=O)ccc3N3CCOCC3)cc2)c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)CC=C)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cn2c(-c3ccc(OCc4cc(N5CCCC5=O)ccc4N4CCOCC4)cc3)c(C3CCCCC3)c3ccc(cc32)C(=O)NS(=O)(=O)CC=CCCN1
Yield: 87 %

Procedure:
To a solution of intermediate 12-4 (438 mg, 0.622 mmol) and prop-2-ene-1-sulfon-amide (151 mg, 2 eq), synthesized as described in Journal of Enzyme Inhibition, 16(6), 475, 2001, in dry DMF (10 mL), were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCI; 193 mg, 2 eq) and 4-dimethylaminopyridine (DMAP; 152 mg, 2 eq) at room temperature, under N2. After completion, the reaction mixture was poured into 200 mL of brine, and extracted with a mixture of ethyl acetate and THF (several times). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The obtained residue was triturated in diethylether and filtered off to afford 436 mg (87% yield) of the desired product N-but-3-enyl-2-[3-cyclohexyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-6-(prop-2-ene-1-sulfonylaminocarbonyl)-indol-1-yl]-acetamide 12-5 as an off-white solid; m/z=809 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:31][CH2:32][OH:33])=[C:20](OCC4C=CC=CC=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]4[O:33][CH2:32][CH2:31][C:19]=4[C:17]=3[O:18]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(OCc4ccccc4)c(CCO)c3O2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(c3O2)CCO4)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2.3 g (4.9 mmole) of [(2R)-7-(benzyloxy)-8-(2-hydroxyethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 100 mL of methanol was added to a slurry of 0.40 g of 10% palladium on carbon in 30 mL of methanol in 500 mL Parr hydrogenation bottle. The mixture was treated with 50 psi of hydrogen on a Parr shaker for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to 1.72 g of a yellow oil. The oil was dissolved in 100 mL of benzene, 2.1 g (8.0 mmole) of triphenylphosphine and 1.6 g (8.0 mmole) of diisopropylazodicarboxylate added and the mixture stirred at room temperature for 3 days. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant to give 1.25 g of the (R)-enantiomer of the title compound as a white solid, m.p. 95-96° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[O:4][N:3]1[CH2:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[CH3:30])[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.[CH2:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([NH2:41])[CH2:36]1)[CH3:34].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].C(Cl)(Cl)Cl>C1COCC1.CO>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[O:4][N:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:41][CH:37]4[CH2:38][CH2:39][CH2:40][N:35]([CH2:33][CH3:34])[CH2:36]4)=[O:29])=[CH:23][C:22]=3[CH3:30])[CH:18]=[CH:19][CH:20]=2)=[CH:31][CH:32]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1
Reactant: CCN1CCCC(N)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCN1CCCC(NC(=O)c2ccc(-c3cccc(COc4ccc(Cn5oc(=O)[nH]c5=O)cc4)c3)c(C)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
3′-({4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10.8 mg) was dissolved in a THF-methanol [1 ml, 4:1 (v/v)] mixed solution, and the solution was added to 1-ethylpiperidine-3-amine (5.8 mg). DMT-MM (12 mg) was added, followed by overnight stirring at room temperature. Thereafter, chloroform was added to the reaction liquid, and the organic layer was washed with water. The organic layer was concentrated, and the residue was purified by a fractional HPLC (Waters, product name: Waters SunFire™ Prep C18OBD™ (19×100 mm, 5 μm)) to obtain 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-N-(1-ethylpiperidin-3-yl)-2-methylbiphenyl-4-carboxamide (3.4 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cc1ccncc1[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
The title compound is prepared following the procedures of WO, 00 55159 as follows. A solution of 2-(3-nitropyridin-4-yl)malonic acid dibenzyl ester (1.58 g, 5.6 mmol), lithium chloride (250 mg, 10.6 mmol), dimethylsulfoxide (35 mL) and water (95 mL) is heated at reflux for 8 hr. After cooling to room temperature, the reaction is diluted with water and extracted with ethyl acetate. The combined extract is extracted with water, with brine, dried, filtered and concentrated to yield (3-nitropyridin-4-yl)acetic acid benzyl ester (1.13 g, 99% yield) as a yellow-orange oil. The material is purified by chromatography eluting with pentane-20 to 30% ethyl acetate to afford the product as a pink oil. MS 273 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:46][CH3:47])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[O:21][CH:22]1[CH2:39][CH:38]2[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]3[C:35]([C:41]([OH:43])=O)([NH:36][C:37]2=[O:40])[CH2:34]3)[CH2:23]1)[CH3:2].[CH:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH2:1]([C:3]1[C:4]([O:46][CH3:47])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[O:21][CH:22]1[CH2:39][CH:38]2[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]3[C:35]([C:41]([NH:54][S:51]([CH:48]4[CH2:50][CH2:49]4)(=[O:53])=[O:52])=[O:43])([NH:36][C:37]2=[O:40])[CH2:34]3)[CH2:23]1)[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCc1c(OC)ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc12
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: CCc1c(OC)ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc12

Procedure:
The title compound was prepared from 17-[8-ethyl-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carboxylic acid (70) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (56): m/z=764 (M+H)+.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 45.3 %

Procedure:
Nicotinoyl chloride hydrochloride (122 mg, 0.685 mmol, commercially available product) and triethylamine (250 μl, 1.79 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (152 mg, 0.622 mmol), obtained as described in Referential Example 1-2. The resulting mixture was warmed to room temperature and stirred for 16.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15 g, hexane/ethyl acetate=1.5/1-1/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]nicotinamide (GIF-0343) (98.4 mg, 45.3%) was yielded as a colorless solid.
Reaction SMILES: O1CCOCC1.[C:7]([C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]#[N:15])#[N:8].C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>>[CH3:23][N:24]([CH3:28])[C:25]([N:10]1[C:9]([C:7]#[N:8])=[C:13]([C:14]#[N:15])[N:12]=[CH:11]1)=[O:26]
Reactant: N#Cc1nc[nH]c1C#N
Reactant: CN(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1cnc(C#N)c1C#N
Temperature: 25 °C

Procedure:
To 50 ml of dry 1,4-dioxane 6.0 g (0.05 mole) of 4,5-dicyanoimidazole, 5.0 g (0.05 mole) of triethylamine and 6.0 g (0.055 mole) of dimethylcarbamoyl chloride are added in succession at room temperature. This mixture is stirred and refluxed for 3 days, cooled to room temperature and evaporated to dryness. The residue is stirred in 50 ml of ethyl acetate and 50 ml water. The organic layer is separated, washed, dried and evaporated to give 8 g. (85%) of white product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:4]([NH:11][C:12]([C:14]2[C:15](=[O:31])[N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[N:17]=[C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:19]=2[OH:20])=O)[CH:3]=1.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]2[S:7](=[O:10])(=[O:9])[N:8]=[C:12]([C:14]3[C:15](=[O:31])[N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[N:17]=[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[C:19]=3[OH:20])[NH:11][C:4]=2[CH:3]=1
Reactant: CC(C)CCn1nc(-c2cccs2)c(O)c(C(=O)Nc2cc(Cl)sc2S(N)(=O)=O)c1=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1nc(-c2cccs2)c(O)c(C2=NS(=O)(=O)c3sc(Cl)cc3N2)c1=O
Temperature: 140 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a solution of the amide intermediate (15a) (54 mg, 0.11 mmol) in anhydrous pyridine (1.5 mL) in a sealed tube, 1,8-Diazabicyclo[5,4,0] undec-7-ene (DBU) (20 μL) was added and then stirred at 140° C. (oil bath temperature) for 24 hrs. The reaction mixture was cooled to room temperature and solvent was removed in vacuo, and then the residue was further dried in high vacuum for 2 hrs. The crude material was purified by flash chromatography on silica gel using hexane and EtOAc to give the desired product (5m) (8.0 mg, 15%) as a yellow solid. LC-MS (ESI+): m/e=485.21 [M+1]+ (exact ms: 484.01); 1H NMR (400 MHz, DMSO-d6): δ 7.86 (dd, 1H, J=3.2, 1.2 Hz), 7.52 (dd, 1H, J=5.2, 0.8 Hz), 7.46 (s, 1H), 7.07 (dd, 1H, J=5.2, 3.2 Hz), 4.03 (m, 2H), 1.60 (m, 3H), 0.93 (d, 6H, J=6.4 Hz).