Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][OH:18]>C1COCC1>[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:18][C:12](=[O:13])[NH:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C[Si](C)(C)CCO
Reactant: O=C=Nc1cc([N+](=O)[O-])ccc1F
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 50 °C
Reaction time: 11 h
Yield: 75.8 %

Procedure:
To a solution of 1-Fluoro-2-isocyanato-4-nitro-benzene (9.82 g, 54 mmol) in THF (40 ml) at 23° C. under an atmosphere of argon was added 2-Trimethylsilanyl-ethanol (7.72 ml, 54 mmol). The resulting mixture was stirred for 11 hours then heated to 50° C. for 2 hours. The reaction mixture was allowed to cool to 23° C. quenched with saturated NaHCO3 (aq) and extracted with EtOAc (3×100 ml). The pooled ethyl acetate was washed with 1N HCl (aq) (2×90 ml) water (90 ml) and brine (90 ml), dried with Na2SO4, filtered and concentrated to a yellow solid. Silica gel chromatography (2:8 ethyl acetate-hexane) provided (2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (12.3 g, 77%). 1H NMR (300 MHz, CDCl3) δ 9.06 (dd, 1H, J=6.89 Hz, J=2.63 Hz), 7.89 (m, 1H), 7.20 (m, 1H), 6.91 (bs, 1H), 4.31 (t, 2H, J=8.67 Hz), 1.06 (t, 2H, J=8.67 Hz), 0.05 (s, 9H). LCMS (ESI−) [M+H]/z Calc'd 299. found 299.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:33])=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][OH:31].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>N1C=CC=CC=1>[F:1][C:2]1[C:3]([CH3:33])=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][O:31][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(F)c(NCCCO)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(F)c(NCCCOS(C)(=O)=O)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reaction time: 1 h
Yield: 99.7 %

Procedure:
3.96 g (8.57 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-hydroxypropylamino)-7-methyl-4H-1-benzopyran-4-one was dissolved in 100 mL of pyridine under ice-cooling, 1.3 mL (17 mmol) of methanesulfonyl chloride was added and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 4.62 g of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 100%).
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[Cl-].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([C:28]3C=CC=CC=3[P+](C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:11]\[C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=Cc1ccncc1
Reactant: COc1ccc(-c2ccccc2[P+](C)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(/C=C\c2ccncc2)cc1OC1CCCC1
Yield: 11.9 %

Procedure:
A solution of sodium ethoxide [prepared from sodium (0.10 g, 4.50 mmol)] in ethanol (50 ml) was added over 5 min to a stirred mixture of 4-pyridine carboxaldehyde (0.44 g, 4.10 mmol) and (3-cyclopentyloxy-4-methoxyphenyl)-methyltriphenylphosphonium chloride (2.00 g, 4.08 g) in ethanol (30 ml). After 2h, the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (75 ml) and brine (50 ml). The organic layer was separated, then dried (MgSO4) and concentrated in vacuo. A 1H n.m.r. spectrum indicated that the mixture consisted of a 3:2 mixture of (Z): (E)title compound (and triphenylphosphine oxide). A portion (0.6 g) of the mixture was subjected to chromatography (SiO2 ; hexane to EtOAc) to afford pure/Z-title compound (0.14 g) as a pale yellow solid m.p. (Found: C, 77.18; H, 7.16; N, 4.63. C19H21NO2 requires C, 77.26; H, 7.17; N, 4.74%); δH (300 MHz; CDCl3) 1.5-1.55 (2H, br m, cyclopentyl H's), 1.65-1.9 (6H, br m, cyclopentyl H's), 3.83 (3H, s, OMe), 4.44 (1H, br m, OCHCH2), 6.40 (1H, d, J 12.2 Hz, CH=CH), 6.65-6.80 (4H, m, ArH ortho to OMe+2×ArH meta to OMe+CH=CH), 7.15 (2H, ca. d, J 6.0 Hz, pyridine H2, H6); m/z 295 (M+, 22%), 228 (15), 227 (100), 226 (94), 198 (35), 184 (15), 166 (12), 43 (19), and 41 (29).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[C:16]3[N:24](C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:15]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[C:16]3[NH:24][CH:25]=[CH:26][C:15]=23)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC(=O)c1cnc2c(ccn2C(=O)OC(C)(C)C)c1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
1-tert-Butyl 5-methyl 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-1,5-dicarboxylate (0.34 g, 0.74 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added. The reaction was stirred at room temperature for 4 hours and then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid methyl 4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.19 g, 98.9% yield) was collected and dried as the dihydrochloride salt.
Reaction SMILES: [NH2:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11])([O-:21])=[O:20]
Reactant: CCCC1CC(=O)N(CN)C1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)N(CNc2ccccc2[N+](=O)[O-])C1

Procedure:
A mixture of 1-aminomethyl-4-propyl-pyrrolidin-2-one a27 (1 eq, 17.09 mmol, 2.67 g), 2-fluoro-nitrobenzene (1 eq, 17.09 mmol, 2.411 g, 1.802 ml) and triethylamine (1.1 eq, 18.8 mmol, 1.902 g, 2.62 ml) in dioxane (20 ml) was refluxed 48 h. After cooling, the crude mixture was filtrated and the dioxane was distilled under vacuum. The residue was purified by preparative chromatography on reverse phase to give (2-nitrophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a28 (2.747 g, 58%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:20]([CH2:21][C:22]([NH:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[CH:11][C:10]=2[N:9]=1>ClCCl>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:20]([CH2:21][C:22]([NH:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])([CH3:23])[CH3:24])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)NC(C)C)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
Isopropyl isocyanate (190 μL, 1.93 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (0.90 g, 1.75 mmol) in dichloromethane (50 mL) at 0° C. After approximately 30 minutes, the solution was allowed to warm to room temperature. A precipitate formed and the mixture was stirred over the weekend. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica gel, gradient elution with 8-10% methanol in dichloromethane) to provide a solid that was dried under vacuum at 60° C. to yield 0.34 g of N-(2-{4-amino-2-(ethoxymethyl)-7-[(6-{[(isopropylamino)carbonyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)-N′-isopropylurea as a tan solid, mp 205-209° C.
Reaction SMILES: Br[C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Br)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[C:32]3[S:31][CH:30]=[CH:34][CH:33]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1cccc2c1Sc1c(Br)cccc1S2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1csc(-c2cccc3c2Sc2c(cccc2-c2cccs2)S3)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 103 %

Procedure:
An airfree tube containing 1,9-dibromothianthrene (187 mg, 0.5 mmole) and Pd(PPh3)2Cl2 (35 mg, 0.05 mmole) was flame dried and filled with Ar. DMF (5 mL) was added to the tube and the tube was heated to 70° C. Tributylstannylthiophene (580 mg, 1.5 mmole) was added and the solution turned black. The reaction mixture was stirred for 2 days and then cooled down to room temperature. It was poured into dichloromethane (50 mL) and the organic layer was washed by water twice, dried by MgSO4. The solvent was removed in vacao. The crude product was further purified by column chromatography (hexane/dichloromethane 6/1) and yield white crystal (196 mg, 92%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[C:8]1[S:9][C:10]([CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=O)=[C:11](CCCC2C=CC(C)=CC=2)[C:12]=1C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)(Cl)Cl.CCOCC>[O:36]1[CH2:37][CH2:38][N:33]([C:28]([CH2:27][C:26]([CH3:31])([CH3:32])[CH2:25][CH2:24][C:10]2[S:9][CH:8]=[CH:12][CH:11]=2)=[O:30])[CH2:34][CH2:35]1
Reactant: Cc1ccc(CCCc2c(CCC(C)(C)CC(=O)O)sc(C)c2C)cc1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(CCc1cccs1)CC(=O)N1CCOCC1
Temperature: 50 °C
Yield: 72 %

Procedure:
2 g (0.0157 mol) of oxalyl chloride dissolved in 10 ml of CHCl3 are placed in a 100 ml single-necked flask. After having brought the mixture to 0° C. with an ice bath, 3.9 g (0.0105 mol) of 2,3-dimethyl-4-(3-p-methylphenylpropyl)-5-(4-carboxy-3,3-dimethylbutyl)thiophene (see above, paragraph B of the synthesis of the starting materials) are added. The reaction mixture is then stirred at room temperature and subsequently at 50° C. until the evolution of gas has ceased. The solvent is distilled off at a temperature below 50° C. The acid chloride prepared above dissolved in 60 ml of ether, and 1.82 g (0.021 mol) of morpholine dissolved in 60 ml of ether, are simultaneously poured into a 500 ml three-necked flask while stirring. The morpholinium hydrochloride precipitates instantaneously. After one hour's stirring, the solid is removed by filtration. The filtrate is washed with water, dried over MgSO4, rendered colourless with carbon black and concentrated to dryness. The crude product obtained is purified by chromatography on silica (eluant: CH2Cl2 /CH3COOC2H5 -95/5, then CH2Cl2 /CH3OH-98/2). 3.31 g of 2,3-dimethyl-4-3-p-methylphenylpropyl)-5-(4-morpholinocarbonyl-3,3-dimethylbutyl)thiophene are obtained in the form of a colourless oil, yield: 72%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:7][CH:8]=1.[H][H]>CO.[Ni]>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:7][CH:8]=1
Reactant: Cc1ccc(-n2ccc3nc(COc4ccccc4)cn3c2=O)nc1
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: Cc1ccc(N2CCc3nc(COc4ccccc4)cn3C2=O)nc1
Yield: 5 %

Procedure:
A 1.25 M solution of HCl in MeOH (3 mL) was added to a stirred solution of 6-(5-methyl-pyridin-2-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.3 mmol) in MeOH (10 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickel cartridge, 30° C., full hydrogen mode, 4 cycles) and then (1 mL/min, 30 mm Raney nickel cartridge, RT, full hydrogen mode, 1 cycle). The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 100/0 and then 7 M solution of ammonia in MeOH in DCM with a gradient of 0/100 to 2/98). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by RP HPLC (C18 XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% ACN) to yield 6-(5-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (5 mg, 5% yield). 1H NMR (500 MHz, CDCl3) δ ppm 2.35 (s, 3H), 3.24 (t, J=6.6 Hz, 2H), 4.35 (t, J=6.6 Hz, 2H), 5.03 (s, 2H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 6.99-7.05 (m, 2H), 7.27-7.33 (m, 2H), 7.57 (dd, J=8.5, 2.2 Hz, 1H), 7.59 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 8.25 (dd, J=1.6, 0.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9](OCC)=[O:10])=[C:4]([Cl:14])[CH:3]=1.[NH3:15]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:15])=[O:10])=[C:4]([Cl:14])[CH:3]=1
Reactant: CCOC(=O)c1[nH]c(=O)c(Br)cc1Cl
Reactant: N
Solvent: CCO
Product: NC(=O)c1[nH]c(=O)c(Br)cc1Cl
Temperature: 45 °C
Reaction time: 2 h

Procedure:
In a round bottom flask containing ethyl 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4, 75.0 g, 267.38 mmol) was added liquid ammonia (150.0 mL, 267.38 mmol) in ethanol (100 mL) at 0° C. The reaction mixture was stirred at 45° C. for 2 h. At this time the mixture was concentrated to remove the ethanolic ammonia. The crude solids were washed with diethyl ether (500 mL) and dissolved in refluxing methanol (1 L) and filtered hot. The filtrate was concentrated under reduced pressure until ⅓ of solvent volume remained. Diethyl ether was added until all solids precipitated. The solid was filtered and dried under vacuum to afford 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (5) as a light brown solid. Yield: 45 g, 69%; MS (ESI) m/z 248.9 [M−1]−; 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.82 (m, 1H), 7.61-7.59 (m, 1H), 7.36 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)Cc1ccccc1CNS(C)(=O)=O)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 8a in dichloromethane (0.1 M) at 0° C. under nitrogen was added triethylamine (3.5 eq) and methanesulfonyl chloride (1.1 eq). The reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane) to afford the product. (41%) 1H NMR (400 MHz, CDCl3) δ 7.16-7.46 (m, 9H), 6.79 (m, 1H), 6.12 (m, 1H), 4.32 (m, 2H), 4.03 (m, 1H), 3.70 (m, 1H), 3.36-3.17 (m, 1H), 2.90 (s, 2H), 2.47-2.83 (m, 6H), 1.74 (m, 6H), 1.25 (m, 1H). Mass Spectral Analysis m/z=430.3 (M+H)+ tR=3.70 min (96%)
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1)NO
Reaction time: 23 h
Yield: 54 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (34 mg, 0.08 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 23 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:6) to furnish IV as a colourless oil (18 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][C:25](=[O:27])[NH:24][CH2:23]4)=[O:21])=[C:16]([C:28]([F:31])([F:30])[F:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C)C=O.[Cl-].[Na+].O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:33])([F:35])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][C:25](=[O:27])[N:24]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:23]4)=[O:21])=[C:16]([C:28]([F:31])([F:30])[F:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1CC(F)(F)F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)imidazolidin-4-one (300 mg, 0.56 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), sodium hydride (26 mg, 1.08 mmol, 2.00 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (260 mg, 1.12 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 20° C. The resulting solution was diluted with 50 mL of brine. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 58.8 mg (17%) of 1-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)-3-(2,2,2-trifluoroethyl)imidazolidin-4-one as a off-white solid. (ES, m/z): [M−H]− 620; 1H NMR (300 MHz, CDCl3) δ: 8.01-8.03 (m, 2H), 7.53 (s, 3H), 7.47 (s, 1H), 5.20 (s, 1H), 4.65 (s, 1H), 4.32 (s, 1H), 4.17 (s, 1H), 4.02-4.11 (m, 2H), 3.73-3.84 (m, 2H)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 95 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (400 mg, 1.91 mmol) and trans-4-aminocyclohexanol (220 mg, 1.91 mmol) are dissolved in dimethylsulfoxide (10 mL) and the reaction is then heated at 95° C. for 3.5 hours. After cooling to room temperature, the mixture is diluted with dichloromethane (15 mL) and washed with water (3×10 mL). The organic phase is collected and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is recrystallised from petrol ether. The desired product is finally isolated as a yellow solid (84% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].CN(C=O)C.[H-].[Na+].I[CH:21]([CH2:23][CH3:24])[CH3:22]>O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH:21]([CH2:23][CH3:24])[CH3:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(S)n1
Reactant: CCC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(SC(C)CC)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.25 g, 1.3 mmol) was added with DMF (7 mL), and the mixture was cooled to 0° C. NaH (0.065 g, 1.56 mmol) was added thereto, and the mixture was stirred for 30 minutes. 2-Iodobutane (0.2 mL, 1.56 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was added with water and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and purified by column chromatography to obtain the title compound (0.17 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:18][N:17]=2)[N:3]=1.[OH-].[K+].[F:30][C:31]([F:35])([F:34])[CH2:32]I>CS(C)=O.C(OCC)(=O)C>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[C:26]([O:27][CH2:32][C:31]([F:35])([F:34])[F:30])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:18][N:17]=2)[N:5]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3O)n2)n1
Reactant: FC(F)(F)CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3OCC(F)(F)F)n2)n1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 2-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-pyridin-3-ol (prepared in an analogous manner to Intermediate 58, 85 mg, 0.23 mmol) in DMSO (5 mL) was added potassium hydroxide (77 mg, 138 μmol) and 1,1,1-trifluoro-2-iodo-ethane (159 mg, 760 μmol). The resultant solution was heated at 120 C for 12 h, allowed to cool to room temperature, diluted with ethyl acetate (10 mL) and washed with brine (3×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by prep HPLC (Method A) to give the title compound as a cream solid (58 mg, 57%).
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH3:46])[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH2:43]([O:42][CH:38]([O:39][CH2:40][CH3:41])[C@@H:37]([N:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[C:23](=[O:24])[C@@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:20])[CH3:46])[CH3:45])[CH3:44]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 115 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.