Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3Cl)[CH:29]=2)=[N:26][CH:27]=1.O>CS(C)=O>[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=3[F:9])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Nc1ccc(O)c(F)c1F
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 4-amino-2,3-difluorophenol (1.59 g, 7.49 mmol) in DMSO (10 mL) was added potassium tert-butoxide (1.1 g, 8.98 mmol), and the reaction mixture was stirred for 2 hours. Chloride 301 (1.6 g, 4.99 mmol) was added and the reaction mixture was heated at 100° C. for 2 hours. The mixture was cooled down then poured into water (150 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was triturated with EtOAc/Hexane (2/1, 100 mL) for 1 h, to afford title compound 302 (1.7 g, 79% yield) as a pale violet solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.70 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.39 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.98 (dd, J=8.1, 2.1 Hz, 1H), 7.10-7.00 (m, 1H), 6.71 (d, J=5.1 Hz, 1H), 6.72-6.61 (m, 1H), 5.90 (s, 1H), 5.64 (s, 2H), 4.16-3.96 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH2:20][CH:21]=O>C(O)(C)C>[F:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]3[N:7]([CH:20]=[CH:21][N:1]=3)[CH:6]=2)[CH:17]=[CH:16][C:11]=1[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)c1ccc(-c2cnc(N)nc2)cc1F
Reactant: O=CCCl
Solvent: CC(C)O
Product: CNC(=O)c1ccc(-c2cnc3nccn3c2)cc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzamide (123 mg, 0.5 mmol) and chloroacetaldehyde (0.318 mL, 2.5 mmol) in isopropyl alcohol (4 mL) was stirred at 90° C. for 4 h. The solvent was removed under vacuum and the residue was triturated with ethyl acetate and hexanes. The solid formed was collected and dried under reduced pressure to give the desired product (120 mg, 88.8%). LCMS: (M+H)=271.0.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([S:1][CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]2)=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(SC2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Methyl 4-mercaptobenzoate (3.00 g, 17.8 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (4.48 g, 17.8 mmol) were dissolved in DMF (30 mL). Cs2CO3 (6.97 g, 21.4 mmol) was added and the mixture was stirred at 90° C. for 3 hours, then cooled to room temperature. EtOAc (50 ml) was added and the solids were filtered off. The filtrate was washed with a saturated aqueous K2CO3 solution (20 mL), dried (MgSO4) and then evaporated. The residue was purified by column chromatography eluting with heptane, EtOAc/heptane (5:95, then 10:90). There was obtained 3.10 g (53%) of 59A as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 3.89 (m, 2H), 3.90 (s, 3H), 4.11 (m, 1H), 4.42 (t, 2H), 7.16 (d, 2H), 7.95 (d, 2H).
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH:11]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:12]>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][CH:11]([C:7]1[N:3]=[CH:4][NH:5][CH:6]=1)[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1cccc(C)c1C(C)Cl
Reactant: C[Si](C)(C)n1ccnc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1C(C)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To a mixture of N-(trimethylsilyl)imidazole (1.4 g) and titanium tetrachloride (1,6 ml) in dry chloroform (20 ml) a solution of 1-chloro-1-(2,6-dimethylphenyl)ethane (1.7 g) in dry chloroform (10 ml) was added. After stirring for 5 h at room temperature the product mixture was poured onto water, washed with ether and neutralized with sodium hydrogen carbonate. Filtration and extraction with methylene chloride gave 4-[(α-methyl)-2,6-dimethylbenzyl]imidazole, yield 33%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[N:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(CN=[N+]=[N-])c1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
To a solution of methyl 3-(bromomethyl)benzoate (1.0 g, 4.4 mmol) in anhydrous DMF (10 mL) was added sodium azide (285 mg, 4.4 mmol). The resulting mixture was heated at 50° C. for 2 h, cooled, diluted with CHCl3 (100 mL), washed with water (5×50 mL), dried (MgSO4) and concentrated under reduced pressure to yield methyl 3-(azidomethyl)benzoate (0.84 g, quant.), which was used without purification. 1H-NMR (CDCl3): δ 8.01 (2H, m), 7.44-7.54 (2H, m), 4.42 (2H, s), 3.94 (3H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>C1COCC1.C(O)C.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(N)cc1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 4-(methylsulfonyl)nitrobenzene (6.26 g, 31.1 mmol) in THF (200 mL) and ethanol (100 mL) was placed in a high pressure reaction vessel and to this solution was added 5% Pd/C (1.6 g). The vessel was shaken for 8 h under an atmosphere of hydrogen (60 psi). The solution was then filtered through diatomaceous earth, partially concentrated in vacuo, and diluted with diethyl ether. The resulting precipitate was filtered and dried in vacuo to give 4.84 g (91%) of a tan solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S)cc1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(SCc2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of 4-(isopropyl)thiophenol (10 g, 65.68 mmol) in N,N-dimethylformamide (200 ml) sodium hydride (3.15 g, 131.35 mmol) was added. The exothermic reaction was allowed to cool down to room temperature. At 15° C. a solution of (4-bromomethyl-phenyl)-acetic acid (15.04 g, 65.68 mmol) in N,N-dimethylformamide (100 ml) was added. After stirring the reaction mixture at room temperature for 16 h the mixture was concentrated, diluted with water, and adjusted to pH=2 by adding HCl (2N). The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (19.5 g, 99%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH3:36])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:18][CH:19]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)OC)cc1
Reaction time: 15 h
Yield: 54.9 %

Procedure:
To a mixture of [4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]phenyl]methanol (0.50 g), methyl 2-(2-hydroxyphenyl)acetate (0.30 g), triphenylphosphine (0.60 g) and tetrahydrofuran (30 mL) was dropwise added a solution (40%, 1.00 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. To the reaction mixture was added ethyl acetate, and washed successively with water, a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.40 g, 56%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:13][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:15])[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(N(CC)CC)C.[Li+].[Br-]>C(#N)C>[C:1]1([CH2:7][C@H:8]([NH:13][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:15])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Dissolve (S)-Methyl 3-phenyl-2-(pyrazine-2-carboxamido)propanoate (57.65 g) in 572 ml of acetonitrile and add 11.7 ml water and 84 ml of triethylamine. Cool the reaction mixture to 0° C. on ice bath and add 175.0 g of LiBr in several portions at vigorous stirring. After 10 minutes of stirring, increase the temperature to ambient temperature. (NB. A HPLC sample showed 99.97% conversion with 98.78% content of the desired product).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].CN.C[CH2:37][N:38](CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:37][NH:38][C:21]([C:5]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:14][CH2:15]2)=[O:9])[N:6]=1)=[O:22]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with methylamine (solution in EtOH), Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 475.2 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([NH:9][C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:14]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][CH:2]([CH3:21])[CH:3]([NH:9][C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:14]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Nc1nnc(-c2ccccc2)o1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(Nc1nnc(-c2ccccc2)o1)C(=O)O
Reaction time: 1 h
Yield: 50 %

Procedure:
Crude ethyl 3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoate (assumed 5 mmol) was dissolved in a mixture of THF (10 ml) and MeOH (2 ml) and then treated dropwise (exothermic) with aqueous 1 N NaOH (6 mL) solution. The reaction was stirred for 1 h, diluted with H2O (50 mL) and then extracted with Et2O (1×50 mL). The aqueous layer was acidified to pH 3 with aqueous 1N HCl solution and then extracted with EtOAc (3×35 mL). The EtOAc extracts were combined, washed with sat. aqueous NaCl solution, dried (MgSO4) and the solvent was removed in vacuo to give 3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoic acid in 50-75% yield over 3 steps in purity >90% as judged by LCMS. MS found: 262 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Brc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(Br)cccc32)nc(N2CCOCC2)cc1=O
Yield: 37.2 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 352 mg of 4-bromoindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 201 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 161 mg of 2-[2-(4-bromo-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3 H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:17])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.C([Li])(CC)C.CON(C)[C:26]([C:28]1([CH3:31])[CH2:30][CH2:29]1)=[O:27].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:26]([C:28]2([CH3:31])[CH2:30][CH2:29]2)=[O:27])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=1
Reactant: CON(C)C(=O)C1(C)CC1
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)C2(C)CC2)c(NC(=O)OC(C)(C)C)c1
Reaction time: 0.75 h
Yield: 65.8 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (2.00 g) in tetrahydrofuran (42 mL) was slowly added dropwise sec-butyllithium (1.08 mol/L hexane-cyclohexane solution, 22 mL) at −45° C., and the mixture was stirred for 45 minutes. Then, a solution of N-methoxy-N,1-dimethylcyclopropane carboxamide (1.33 g) in tetrahydrofuran (4.2 mL) was added dropwise thereto, and the mixture was stirred at −45° C. for 45 minutes, and then stirred at room temperature for 3 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.77 g). 1H-NMR (CDCl3) δ ppm: 0.80-0.89 (2H, m), 1.35-1.44 (5H, m), 1.52 (9H, s), 3.55 (2H, s), 3.80 (3H, s), 6.57 (1H, dd, J=2.8, 8.3 Hz), 6.97 (1H, d, J=8.3 Hz), 7.46 (1H, br s), 7.90-8.28 (1H, br).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:29])[CH:10]([NH:21]C(OC(C)(C)C)=O)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH2:14]([NH:13][C:11](=[O:12])[CH:10]([NH2:21])[C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:29])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NCc1ccccc1)C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(C(=O)NCc1ccccc1)C(=O)NCc1ccccc1
Reaction time: 2.5 h

Procedure:
Combine N,N′-dibenzyl-2-(t-butoxycarbonylamino)malonamide (0.415 g, 1.04 mmol) and dichloromethane (7 mL). Add trifluoroacetic acid (1.0 mL). After 2.5 hours, evaporate in vacuo dry under high vacuum to give the title compound.
Reaction SMILES: N#N.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([I:25])C(=O)C1.CCO>CCOC(C)=O>[I:25][C:15]1[N:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=3)=[CH:10][C:11]2=[N:17][CH:16]=1
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Reactant: O=C1CCC(=O)N1I
Agent: N#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: Ic1cnc2cc(-c3ccncc3)ccn12

Procedure:
Charge a 250 μL round bottom flask equipped with: a magnetic stirrer, temperature controlled heating mantle, N2 atmosphere, with 7-pyridin-4-yl-imidazo[1,2-a]pyridine (3.35 g, 17.2 mmol), NIS (3.8 g, 16.8 mmol), EtOH (3A). Heat the reaction to 65° C. for 1 hour. This can be followed by SiO2 TLC (100% EtOAc). Add more NIS (3.8 g, 16.8 mmol) and heat the reaction to 65° C. for 1 hour. Mix the reaction while cooling in an ice bath for 30 minutes then filter and rinse the solids with MeOH. Air dry the solids and vacuum oven dry at 40° C. to afford 4.59 g (83%). Additional product can be obtained from the filtrate. MS (ES), m/z 322 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:22])=[CH:12][CH:13]=1
Reactant: CCC(C)NCc1ccc(Cl)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCOCC
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=S)Nc1ccccc1
Yield: 89.1 %

Procedure:
20 g of N-(4-chlorobenzyl)-N-sec.-butylamine were dissolved in 500 ml of ether. To the resulting solution, a solution of 14 g of phenyl isothiocyanate in 50 ml of ether was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and the solution was then stirred at room temperature for about 10 hours. The crystals which had been formed were separated by filtration. After recrystallization with a solvent mixture of hexane and ethyl alcohol, 30 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylthiourea were obtained. Yield: 91%. Melting point: 134°-134.5° C.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[C:5]=1[O:21][CH3:22]
Reactant: CC(C)(CO)CBr
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 7.9 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (100 mg, 0.31 mmol) in acetonitrile (10 mL) was added potassium carbonate (128 mg, 0.930 mmol) and 3-bromo-2,2-dimethyl-propan-1-ol (155 mg, 0.930 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC to afford title compound as a solid (10 mg, 8%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[NH3:23]>C(O)CO.O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:23])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Reactant: N
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(N)cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
Into a 10 mL sealed tube, was placed 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (150 mg, 0.40 mmol). To this was added Cu2O (30 mg, 0.21 mmol), followed by a saturated solution of NH3 in ethylene glycol (4 ml). The resulting solution was stirred at 70° C. for 3 hours, then diluted with 30 mL of H2O and extracted three times with 20 mL of EtOAc. The organic layers were combined and dried over Na2SO4. Removal of the volatile components under reduced pressure afforded the product 5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v) (50 mg, yield 40%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.ClCCCl.S(Cl)(Cl)=O.Cl.[NH2:39][C:40]1([C:43]([N:45]([O:51][CH3:52])[CH2:46][C:47]([F:50])([F:49])[F:48])=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:52][O:51][N:45]([CH2:46][C:47]([F:48])([F:49])[F:50])[C:43]([C:40]1([NH:39][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6](/[CH:5]=[CH:4]/[CH:3]([C:19]3[CH:20]=[C:21]([Cl:27])[C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=3)[C:2]([F:28])([F:29])[F:1])=[CH:7][C:8]=2[C:15]([F:18])([F:16])[F:17])[CH2:42][CH2:41]1)=[O:44]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: CON(CC(F)(F)F)C(=O)C1(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CON(CC(F)(F)F)C(=O)C1(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.2 %

Procedure:
A 25 mL rb flask was charged with (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (150 mg, 0.31 mmol) and DCE (5 mL). Thionyl chloride (41.1 mg, 0.35 mmol) was added neat in one portion and the resulting reaction mixture was heated at reflux for 1.5 h. After which time, reaction mixture was allowed to cool and concentrated to give a brown oil which was used without further purification. The crude acid chloride was taken up in anhydrous DCM (2 mL) and was added drop wise to a cold solution containing crude 1-amino-N-methoxy-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide hydrochloride (78 mg, 0.31 mmol), TEA (66.7 mg, 0.66 mmol) and DCM (10 mL). The reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted with DCM and washed with 0.1N HCl, aqueous NaHCO3, dried over MgSO4, filtered and evaporated to give an oil. The residue was chromatographed on a silica gel column eluting with 10% EtOAc/hex to afford the title compound (17 mg, 8.%): 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=14.1, 1.6 Hz, 1H), 7.59 (dd, J=8.0, 1.8 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.41 (s, 2H), 6.62 (d, J=15.9 Hz, 1H), 6.53 (s, 1H), 6.44 (m, 1H), 4.29 (q, J=8.5 Hz, 2H), 4.12 (m, 1H), 3.78 (s, 3H), 1.62 (m, 2H), 1.29 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −58.81, −68.59, −69.22; ESIMS m/z 671.3 ([M−H]−).