Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>N1C=CC=CC=1>[CH2:27]([CH2:29][NH2:30])[OH:28].[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: NCCO
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (600 mg) and ethanolamine (600 mg) were added to pyridine (2,500 mg), and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (6 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (603 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28]([NH:22][CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])[CH2:16][CH2:17]2)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN(CCCCCN1CCC(CN)CC1)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(C)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
1H-NMR (CDCl3,ppm) δ: 1.20-1.88(11 H,m), 2.20(3 H,s), 2.63(2 H,t,J=6.8 Hz), 2.60-2.32(4 H,m), 3.78(2 H,s), 7.25-7.36(5 H,m) (3) A suspension of N-benzyl-N-methyl-5-(4-aminomethylpiperidin-1-yl)-pentylamine (3.52 g), 4-amino-5-chloro-2-methoxybenzoic acid (2.34 g), dicyclohexylcarbodiimide (2.39 g), 1-hydroxybenzotriazole (1.57 g) and triethylamine (2.35 g) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 12 hr. The solvent was evaporated, and water was added to the residue, which was followed by extraction with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.86 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(N-benzyl-N-methylamino)pentyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:16]1[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[NH:19][CH:20]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[CH3:25][CH2:26]CCCC>CN(C)C=O>[CH2:3]([C:16]1[CH:17]=[C:18]([C:21]([O:23][CH2:25][CH3:26])=[O:22])[NH:19][CH:20]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Reactant: CCCCCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCc1c[nH]c(C(=O)OCC)c1
Temperature: 25 °C
Yield: 55 %

Procedure:
After washing 140 mg (3.50 mmol) of 60% sodium hydride with hexane, 20 ml of dimethylformamide was added thereto, and then 90 mg (3.38 mmol) of 4-tridecylpyrrole-2-carboxylic acid prepared in Example 2 was further added portionwise under stirring at room temperature. After stirring for 10 minutes, 5.0 g (31.8 mmol) of ethyl idodide was added to the reaction solution followed by heating it at 55° C. for 22 hours. After cooling, an aqueous solution of hydrochloric acid was added to acidify the mixture, and the resulting mixture was then extracted with ethyl acetate, washed with an aquous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to obtain 600 mg (55% yield) of ethyl 4-tridecylpyrrole-2-carboxylate as white crystals, m.p. 59°-60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10](OCC)=[O:11]>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:10]1=[O:11]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)Cl
Product: O=c1[nH]c2ccccc2o1

Procedure:
According to the reaction scheme, o-aminophenol is reacted with ethyl chloroformate, the resulting 3H-benzoxazol-2-one obtained is nitrated with nitric acid, the nitro group of the resulting compound of formula (IX) is reduced with hydrogen in the presence of a hydrogenation catalyst, such as palladium-on-charcoal, the 6-amino-3H-benzoxazol-2-one thus obtained is reacted with 2-methylthioimidazoline, preferably in the form of an acid addition salt such as the hydroiodide, and the resulting compound of formula (XII) is acidified to give 2-(4-amino-3-hydroxyphenylimino)-imidazolidine, which is reacted with formic acid in the presence of acetic anhydride, or with methylsulphonyl chloride, or with a compound NaNCO or R'NCO (wherein R' represents an alkyl radical having from 1 to 4 carbon atoms) to obtain an imidazolidine derivative of general formula (IB).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([N+:26]([O-:28])=[O:27])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:26]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24])[CH2:16][N:6]1[C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3][C:2]1=[O:1])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc2oc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2 g (10.4 mmol) of methyl 2-oxo-2,3-dihydrobenzoxazole-5-carboxylate, 2.97 g (11.4 mmol) of 4-bromomethyl-1,2-dinitrobenzene (prepared in a corresponding manner to DE 3904797) and 5.7 g (41.4 mmol) of potassium carbonate are suspended in 50 ml of acetonitrile, and the mixture is stirred at 80° C. for 1 h. The reaction mixture is poured into 50 ml of water, extracted with 500 ml of MTBE, dried and evaporated to dryness. The residue is purified by column chromatography on silica gel; product: 1.5 g;
Reaction SMILES: [Na].[CH3:2][OH:3].[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([O:3][CH3:2])[CH:15]=[CH:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium (2.49 g, 0.11 mol) was added portionwise to methanol (70 ml) and was stirred at room temperature under a nitrogen atmosphere for 30 minutes. N,N-dimethylformamide (35 ml) was added and the solution was added to 6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (2.8 g, 10.9 mmol) (see reference WO98/30560 Example 33b). The mixture was heated at reflux under a nitrogen atmosphere for 5 days and then was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane (gradient from 0:100 to 4:96) and the material obtained was dried under vacuum to give the title compound (2.54 g).
Reaction SMILES: [CH3:1][CH:2]([O:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])[CH3:3].Cl[C:22]1[N:27]=[C:26]([NH:28][CH2:29][C:30]2[C:31]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]([C:42]([F:45])([F:44])[F:43])=[CH:24][N:23]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>CO.[Pd]>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[CH3:1][CH:2]([O:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:22]2[N:27]=[C:26]([NH:28][CH2:29][C:30]3[C:31]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=3)[C:25]([C:42]([F:43])([F:45])[F:44])=[CH:24][N:23]=2)[CH:13]=1)(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])[CH3:3]
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: CC(C)OP(=O)(Cc1cccc([N+](=O)[O-])c1)OC(C)C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)OP(=O)(Cc1cccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)c1)OC(C)C
Yield: 34 %

Procedure:
A mixture of triisopropyl phosphite (500 mg, 2.31 mmol) and 1-bromomethyl-3-nitrobenzene (506 mg, 2.43 mmol) was heated at 100° C. under nitrogen for 3 h. The crude dipropan-2-yl(3-nitrobenzyl)phosphonate thus formed was dissolved in MeOH (5 mL) and hydrogenated in the presence of 5% Pd/C (49 mg) for 2 h. The mixture was filtered and concentrated in vacuo and the dipropan-2-yl(3-aminobenzyl)phosphonate residue heated in a microwave reactor at 105° C. under nitrogen for 40 minutes with N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.051 mmol), TFA (12 uL, 0.15 mmol) and 0.5 mL TFE. The mixture was evaporated to dryness and purified by preparative HPLC to afford 11 mg of dipropan-2-yl[3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 35, yield: 34%). 1H NMR (400 MHz, CD3OD) δ=1.19 (d, J=6.1 Hz, 6H), 1.28 (d, J=6.1 Hz, 6H), 3.06-3.12 (m, 4H), 3.12-3.19 (m, 4H), 4.51-4.63 (m, 2H), 4.96 (s, 2H), 7.14 (d, J=7.3 Hz, 1H), 7.21-7.28 (m, 1H), 7.29-7.33 (m, 1H), 7.35-7.43 (m, 2H), 7.76 (d, J=7.6 Hz, 1H), 8.21 (s, 1H), 8.45 (dd, J=4.8, 1.8 Hz, 1H). MS (ES+): m/z 631.27 (100) [MH+]; HPLC: tR=1.03 min (UPLC, purity).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3(O)[CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)=O>CO>[Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]4[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]4)[CH:12]=3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cc3cccc(Br)c3o2)CN2CCC1CC2
Solvent: O=CO
Solvent: CO
Product: Brc1cccc2cc(C3=CN4CCC3CC4)oc12
Yield: 99.3 %

Procedure:
3-(7-Bromo-1-benzofuran-2-yl)quinuclidin-3-ol (600 mg, 1.86 mmol; Intermediate 24, Step 2) was dissolved in methanol (2 mL) and formic acid (40 mL) was added to the flask. The resulting mixture was heated at reflux overnight. Concentration in vacuo furnished 562 mg (99%) of the title product. HPLC purity=90%, m/z=305 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:18]=[N:19][N:20]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:18]=[N:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH:21]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COc1ccc(Cn2cc(CCl)cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(Cn3nc(I)c4c([N+](=O)[O-])cccc43)cn2)cc1
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To 3-iodo-4-nitro-1H-indazole (2.13 g, 7.37 mmol) in DMF (20 mL) was added 4-(chloromethyl)-1-(4-methoxybenzyl)-1H-pyrazole hydrochloride (2.21 g, 8.11 mmol) and K2CO3 (3.06 g, 22.1 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with H2O, and brine, and the filtrate was concentrated under reduced pressure. Silica gel chromatography (hexanes/EtOAc 5:1) provided the desired product (2.88 g).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:20](Cl)=[O:21].C(N(C(C)C)CC)(C)C>ClCCl>[N+:26]([C:25]1[CH:24]=[CH:23][C:19]([C:20]([N:6]2[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])=[CH:18][C:17]=1[CH3:16])([O-:28])=[O:27]
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
A mixture of 1.17 g of 6,11-dihydro-5H-dibenz[b,e]azepine, 1.20 g of 3-methyl-4-nitrobenzoyl chloride, 0.80 ml of diisopropylethylamine in 25 ml of dichloromethane is stirred 18 hours at room temperature. The mixture is washed with water and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and diluted while hot with hexane to give 1.40 g of crystals. Recrystallization from dichloromethane-hexane gives 1.26 g of crystals, m.p. 179°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccccc1-c1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
tert-Butyl 4-(5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.045 g, 0.11 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give 5-(2-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.034 g, 81% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClC(Cl)C>[Cl:15][CH2:16][C:17]([C:7]1[C:2]([F:1])=[CH:3][C:4]([F:9])=[CH:5][C:6]=1[F:8])=[O:18]
Reactant: Fc1cc(F)cc(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1c(F)cc(F)cc1F
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a mechanically stirred solution of 1,3,5-trifluorobenzene (6.0 mL, 58 mmol) in dichloroethane (14.0 mL) was added gradually AlCl3 (15.5 g, 116 mmol) in a period of 15 min with caution. Violent bumping and HCl gas evolution was observed. The mixture was carefully heated to reflux, and chloroacetyl chloride (5.5 mL, 69 mmol) was added drop wisely in a period of 45 min. The reaction mixture was heated at reflux for additional 6.0 h. The solution was cooled, carefully poured onto an ice/water slush (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ethereal layers were washed with 10% aqueous HCl (2×30 mL), 1.0 N aqueous NaOH (3×30 mL), and brine (25 mL). The solution was dried over MgSO4 and concentrated under reduced pressure to give 2-chloro-1-(2,4,6-trifluorophenyl)ethanone (5.28 g) as yellow solids in 51% yield: 1H NMR (500 MHz, CDCl3) δ 6.79-6.76 (m, 2 H), 4.50 (s, 2 H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[C:25](O)=[O:26])[CH:22]=[CH:21][S:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]([F:37])([F:36])[C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[C:25]([NH:35][C:32]2[S:33][CH:34]=[C:30]([C:29]([F:37])([F:36])[F:28])[N:31]=2)=[O:26])[CH:22]=[CH:21][S:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OC1CCCC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 4 (200 mg, 0.520 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (105 mg, 0.624 mmol) in the presence of EDCI hydrochloride (200 mg, 1.040 mmol) and DMAP (159 mg, 1.300 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 86 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.62 (m, 4H), 1.76-1.79 (m, 4H), 3.81 (s, 3H), 4.85 (br s, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.43-7.49 (m, 2H), 7.82 (d, J=16.2 Hz, 1H), 8.06-8.10 (m, 2H), 12.99 (br s, 1H); ESI-MS (m/z) 535.11 (MH)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:13]2=[O:28])=[N:9][C:8]=1[CH3:29])=O.O.[NH2:32]N>C(O)C>[CH3:29][C:8]1[N:9]=[C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[C:13]2=[O:28])[S:11][C:7]=1[C:5]1[CH:4]=[CH:3][NH:2][N:32]=1
Reactant: NN
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1-c1cc[nH]n1
Yield: 72 %

Procedure:
To a solution of (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one (0.44 g, 1.00 mmol) in ethanol (10 mL) was added hydrazine monohydrate (0.12 mL, 1.58 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a colorless solid in 72% yield (0.30 g): mp 212-213° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3& CD3OD) δ 7.54-7.20 (m, 5H), 6.24 (s, 1H), 4.39 (s, 2H), 3.98-3.89 (m, 2H), 3.35-3.30 (m, 2H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3 & CD3OD) δ 156.9, 155.8, 139.8, 130.2, 129.8, 129.3, 128.2, 125.6, 125.5, 122.0, 103.8, 47.2, 41.9, 41.8, 15.7; MS (ES+) m/z 408.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[O:22])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.Cl.C(OCC)C>O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[O:22])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reaction time: 0.08 h
Yield: 203.1 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (1.86 g, 4.0 mmol) was treated with 10 mL of 4 N hydrochloric acid in dioxane at room temperature. After 5 minutes, the solid went into solution and the mixture was stirred for 1 hr and 25 mL of ethyl ether was added to precipitate the product. The solids were collected by filtration and were washed with hexane. The resulting hydroscopic and gummy solids were dissolved in 50 mL of methanol and concentrated. After drying under high vacuum, 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt (1.64 g, 97%) was obtained as a light yellow solid, mp 158-161° C.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]12([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:24](Cl)=[O:25])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>N1C=CC=CC=1>[C:11]12([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:24]([S:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:25])[CH2:12][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:19]3)[CH2:18]1)[CH2:20]2
Reactant: COCCOCOc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(S)cc1
Solvent: c1ccncc1
Product: COCCOCOc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.54 g (10 mmol) of 4-mercaptobenzoic acid and 40 ml of pyridine were introduced into a round-bottomed flask. A solution of 3.75 g (10 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoyl chloride prepared in Example 10(c) was added dropwise and the mixture was stirred at room temperature for six hours. The mixture was evaporated to dryness, the residue was taken up in water and ethyl ether. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The solid obtained was recrystallized from a diisopropyl ether/methanol mixture, filtered off and dried. 2.94 g (59%) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxybenzoylthio]benzoic acid, having a melting point of 187°-8° C., were recovered.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:30]([C:31](Cl)=O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[C:30]([C:31]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccnc2Cl)n1
Temperature: 150 °C
Yield: 34.2 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-3-pyridinecarbonyl chloride (0.186 g, 1.10 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.047 g (40% yield) of pure product: MS (ES) m/z 445 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])[CH3:17]>C(OCC)C.CCCCCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:24]2([OH:27])[CH2:23][CH2:22][N:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:26][CH2:25]2)=[C:3]([F:10])[CH:4]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)N1CCC(O)(c2cc(F)c(Br)cc2F)CC1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
A solution of 16.55 g (60.85 mmol) 1,4-dibromo-2,5-difluorobenzene in 400 ml of ethyl ether stirred at -75° C. under an argon atmosphere was treated dropwise with 24.3 ml of 2.5 M n-butyl lithium in hexane. The mixture was let warm to -50° C. and treated dropwise with a solution of 11.00 g (64.33 mmol) 1-ethoxycarbonyl-4-piperidone in 100 ml ethyl ether. After stirring a further 0.25 hour, the mixture was let warm to room temperature and extracted with ammonium chloride solution. The organic layer was dried (MgSO4), evaporated and the crude product chromatographed on a silica gel column and crystallized from toluene hexane to afford the title compound, mp 133°-136° C.