Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:27]1([CH2:36][C:37](O)=[O:38])[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:37](=[O:38])[CH2:36][N:27]1[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2cc(Cl)ccc2Cl)s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2cc(Cl)ccc2Cl)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(2,5-dichlorophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.27 (s, 0.6H), 11.25 (s, 0.4H), 9.13 (brs, 1H), 8.26 (d, 0.4H), 8.25 (d, 0.6H), 7.81–7.74 (m, 2H), 7.32 (s, 0.6H), 7.23 (s, 0.4H), 4.63 (s, 1.2H), 4.47 (s, 0.8H), 4.32 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (q, 1.2H), 4.04 (s, 1.2H), 3.55 (t, 1.2H), 3.45–3.38 (m, 2H), 3.25 (t, 0.8H), 1.73 (s, 3H), 1.22 (t, 1.2H), 1.16 (t, 1.8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH2:27][CH2:25][OH:26])=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCCO
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 72 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (68 mg, 0.21 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (55 mg, 72%) which was obtained as an off white solid. MS: m/e=372.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1)([O-:12])=[O:11].CC(N=C=NC(C)C)C>CN(C=O)C>[Cl:9][C:3]1[C:2]2[NH:1][C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=3)=[N:8][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: Nc1ccnc(Cl)c1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2nc3ccnc(Cl)c3[nH]2)cc1
Reaction time: 6 h
Yield: 82.9 %

Procedure:
3.1 A solution of 0.72 g of 3,4-diamino-2-chloropyridine, 0.9 g of 4-nitrophenyl isothiocyanate and 0.78 ml of N,N-diisopropylcarbodiimide in 30 ml of DMF is stirred at room temperature for 16 hours, then at 500 for 6 hours. The solvent is separated off, and the residue is crystallised from methanol, giving 1.2 g of 4-chloro-2-(4-nitrophenylamino)-3H-imidazo-[4,5-c]pyridine (“6”).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)O)=[CH:23][CH:22]=1.[ClH:38]>C(O)C>[ClH:38].[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:1][C:2]3[N:6]([C:28]=2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=3[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:25][CH:26]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C(c1ccc(F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-c2nn3c(-c4ccc(F)cc4)c(-c4ccc(F)cc4)[nH]c3c2-c2ccncc2)cc1

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (100 mg), 1,2-bis-(4-fluorophenyl)-2-hydroxyethan-1-one (167 mg) and concentrated hydrochloric acid (1 ml) in ethanol was refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the obtained crystalline was washed with hot ethanol to give 2,3,6-tris-(4-fluorophenyl)-7-(pyridin-4-yl)-1H-imidazo[1,2-b]pyrazole hydrochloride (50 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N+:4]([O-])[C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:15].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:11][OH:15])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(Cl)[n+]([O-])c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)nc(CO)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-6-chloro-2,4-dimethylpyridine 1-oxide (28.7 g, 121 mmol) in CH2Cl2 (240 mL) was added trifluoracetic anhydride (240 mL, 1699 mmol). The reaction was stirred for 3 hours at room temperature and then concentrated. The residue was dissolved in MeOH (1.7 L) and cooled to 0° C. 1M K2CO3 (360 mL, 360 mmol) was added dropwise, and the reaction was stirred for 10 minutes at 0° C. and then warmed to r.t. for 1 hour. The reaction was then concentrated to a volume of 300 mL and diluted with EtOAc (1 L). Water (1 L) was added and the layers were separated. The aqueous layer was extracted with additional EtOAc (2×1 L). The organic layers were combined, washed with brine (1 L), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 75% EtOAc/heptanes afforded (3-bromo-6-chloro-4-methylpyridin-2-yl)methanol. LCMS=236.1 and 238.1 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.17 (s, 1H), 4.73 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[OH:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1c(Cl)cccc1Cl

Procedure:
In a similar manner as described for example B11, 103.5 mg of 2,6-dichlorobenzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: C[CH:2]([OH:4])[CH3:3].[CH:5]1([C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=C(C#N)[CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1.[OH-:20].[K+].Cl>O>[CH:5]1([C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([OH:4])=[O:20])[CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1ccc2nc(C3CC3)ncc2c1
Reactant: CC(C)O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc2nc(C3CC3)ncc2c1

Procedure:
Into 8 ml of 2-propanol and 1 ml of water were dissolved 210 mg of 2-cyclopropylquinazoline-6-carbonitrile and 450 mg of potassium hydroxide, followed by heating under refluxing overnight. Hydrochloric acid was added thereto and the solvent was removed by evaporation to obtain the title compound as a crude carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:38]I>C1(C)C=CC=CC=1.CCOCC.C(#N)C>[I:38][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCOCCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: ICCCOCCc1ccccc1
Temperature: 50 °C

Procedure:
To 3-(2-phenylethoxy)-1-propanol (2 g; 11 mmol) dissolved in toluene (50 ml), acetonitrile (50 ml), imidazole (2.2 g; 33 mmol) and triphenylphosphine (2.8 g; 11 mmol) is added iodine (2.8 g; 11 mmol). The reaction mixture is heated for 1 hour at 50° C., then it is cooled, diluted with Et2O, washed with 1N HCl, NaS2O3 solution, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to dryness. The residue is purified by column chromatography using 10% ether/90% petroleum ether to obtain 1-iodo-3-(2-phenylethoxy)propane which is used directly in Step D.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[F:35])=O)(C)(C)C>Cl>[ClH:17].[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)[CH:21]=[CH:20][C:19]=3[F:35])=[N:10][C:11]=2[CH:16]=1
Reactant: CCOC(=O)C1CCN(c2ccc(F)c(-c3nc4cc(Cl)ccc4n3C(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Product: O=C(O)C1CCN(c2ccc(F)c(-c3nc4cc(Cl)ccc4[nH]3)c2)CC1
Temperature: 120 °C
Yield: 138.1 %

Procedure:
Method 10—Step b A mixture of 5-Chloro-2-[5-(4-ethoxycarbonyl-piperidin-1-yl)-2-fluoro-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.30 g, 0.60 mmol) in 6N HCl (10 mL) was heated in microwave at 120° C. for 15 minutes, two cycles were needed. Solvent was removed under vacuum, then the solid was filtered and washed with diethyl ether and dried to obtain 0.17 g of the title compound (70%).
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[CH:10](=O)[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1.C(O)C.[OH-].[K+]>O>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:10][C:11]1[O:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccco1
Reactant: CC1N(C)C=C[NH+]1C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1C=C[NH+](C)C1C=Cc1ccco1

Procedure:
A mixture of 5.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2.5 ml of furfural, 20 ml of ethanol and 1 g of potassium hydroxide is refluxed for 10 minutes. The mixture is cooled, water is added, and the resulting solid is filtered off and crystallized from ethanol to yield 5.0 g of the title compound, melting point 299°-300° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[Br:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH2:16][CH2:15][Br:14]
Reactant: BrCCBr
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(Br)cc(Br)c1OCCBr

Procedure:
To a solution of 2,4-dibromo-6-tert-butylphenol (5.00 g, 16.2 mmol) in acetone (70 mL) is added 1,2-dibromoethane (2.80 mL, 32.5 mmol) and K2CO3 (6.70 g, 48.7 mmol). The mixture is heated at reflux for 14 h, and then is filtered and evaporated. The residue is purified by chromatography over SiO2 eluting 15 with hexanes. The resulting oil is distilled to give 1,5-dibromo-(2-bromoethoxy)-3-tert-butylbenzene as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:21]=[CH:22][C:23]2[NH:27][CH:26]=[N:25][C:24]=2[CH:28]=1.[K+].[Br-]>C(Cl)Cl.CO>[NH:25]1[C:24]2[CH:28]=[C:20]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)[CH:21]=[CH:22][C:23]=2[N:27]=[CH:26]1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc2[nH]cnc2c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5nc[nH]c5c4)c3c2s1
Yield: 98 %

Procedure:
Prepared from VII and 6-aminobenzimidazole. Flash chromatography eluent (DCM-MeOH 8:2). Yield: 98%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3084, 2226, 1615, 1557, 1464, 1376, 1347, 1248, 1147, 967, 939, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.48 (d, 1H, J=8.7 Hz), 8.15-8.10 (m, 2H), 8.02 (m, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.56 (m, 1H), 7.04 (m, 1H); HRMS calcd for C17H10N7S (M+H+): 344.0718, found 344.0705.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[O:16]1[CH2:40][CH:17]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]3[O:39][CH2:38]3)=[CH:31][CH:30]=2)([CH3:28])[CH3:27])=[CH:22][CH:21]=1>CO>[CH2:1]([N:5]([CH2:40][CH:17]([OH:16])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH:37]([OH:39])[CH2:38][N:5]([CH:6]3[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][C:10]([CH3:12])([CH3:13])[CH2:11]3)[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:33][CH:34]=2)([CH3:27])[CH3:28])=[CH:24][CH:25]=1)[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CCCCN(CC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CN(CCCC)C3CC(C)(C)NC(C)(C)C3)cc2)cc1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 5 h

Procedure:
To 150 ml of methanol were added 21.2 g of 4-butylamino-2,2,6,6-tetramethylpiperidine and 17.0 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then refluxed, with stirring, for 5 hours. After completion of the reaction, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel eluted with a 5:1 by volume mixture of ethyl acetate and triethylamine. The desired compound was obtained in the form of a white powder having an Rf value of 0.63 on thin layer chromatography on silica gel developed with a 5:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]=[C:12]([CH3:27])[CH:11]=1>CS(C)=O.C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[CH:11]=[C:12]([CH3:27])[N:13]=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:15]=1[CH3:16])[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 130 °C
Yield: 6 %

Procedure:
To a solution of 3-pentanol (0.2 ml, 0.5205 mol) in DMSO (1 ml) was added 60% sodium hydride in oil (30 mg) in a portionwise. After stirring at room temperature for 5 min. a solution of 4-chloro-2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)pyridine (98 mg) in 0.5 ml of dry THF was added and the resulting mixture was heated at 130° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 20% chloroform in hexane to chloroform as eluent to give 7 mg of the title compound as white crystals, mp 72.5-74° C. 1H NMR (CDCl3) δ 6.84 (s, 2H), 6.26 (s, 1H), 4.16 (m, 1H), 2.27 (s, 3H), 2.17 (s, 6H). 2.04 (s, 6H), 1.69 (m, 4H), 0.95 (t, 6H) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)=[CH:6][CH:5]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.C(N(CC)CC)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCN)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 2-{4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1-H-pyrazol-1-yl]phenoxy}ethanamine hydrochloride obtained by Example 96 (100 mg) in dichloromethane (5 ml) and triethylamine (0.1 ml) was added dropwise methanesulfonyl chloride (38 μl) at room temperature.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:6][C:7]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=1[CH:9]=[CH2:2]
Reactant: [Li]CCCC
Reactant: O=Cc1cc(F)ccc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (26.4 g, 73.9 mmol) in tetrahydrofuran (350 mL) at 0° C. was added nBuLi (2.5M in hexane, 29.6 mL, 73.9 mmol). After addition was complete, the reaction was stirred at 0° C. for 10 min. To this was added 2,5-difluorobenzaldehyde (5.35 mL, 49.3 mmol). The ice bath was removed, and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride. The reaction was poured into ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (2.5% EtOAc/Hex) gave 2.1 g (30%) as a colorless oil. 1H NMR (CDCl3) Shift: 7.20 (ddd, J=9.2, 5.9, 3.2 Hz, 1H), 7.02 (td, J=9.3, 4.6 Hz, 1H), 6.90-6.97 (m, 1H), 6.86 (dd, J=17.7, 11.3 Hz, 1H), 5.84 (d, J=17.7 Hz, 1H), 5.45 (d, J=11.0 Hz, 1H). 13C NMR (CDCl3) Shift: 158.6, 156.3, 128.6, 126.8, 117.6, 116.8, 115.6, 113.0. 19F NMR (CDCl3) Shift: −120.17-119.46 (m, 1F), −125.20 (d, J=17.3 Hz, 1F).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])=[C:13](C(OCC)=O)[C:12]2=[O:32])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:32])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OC)cc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: COc1ccc(NC2=CC(=O)C(=Cc3c[nH]c4ncccc34)O2)c(OC)c1
Temperature: 25 °C
Yield: 17.9 %

Procedure:
A solution of the compound (0.10 g, 0.23 mmol) of Example 24 in N,N-dimethylformamide (3.0 mL) was refluxed for 7 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.015 g, y. 18%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1cc(-c2cncn2C)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cncn2C)ccc1-c1ccc(C(=O)O)cc1
Yield: 33.6 %

Procedure:
5-(4-Bromo-3-methylphenyl)-1-methylimidazole (D92, 1.52 g, 6.1 mmol) was dissolved in DME (50 ml) and water (50 ml), then treated with 4-boronobenzoic acid (1.0 g, 6.1 mmol), sodium carbonate (2.57 g, 24.2 mmol) and tetrakis(triphenylphosphine)palladium (O) (100 mg). The mixture was heated at reflux (48 hours), cooled and the DME removed in vacuo. The aqueous residue was treated with 10% Na2CO3 (approx 30 ml), then washed with ethyl acetate. The aqueous phase was acidified with 5N HCl and the solid that precipitated was collected by filtration. This solid was dried in vacuo to yield the title compound as a white solid (600 mg, 34%).
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:5]=2[O:4]1)[CH3:2]>Cl>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@@H]1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Agent: Cl
Product: CC[C@@H]1Oc2cc(C(=O)O)ccc2N(C(C)C)C1=O
Yield: 86.7 %

Procedure:
A mixture of (S)-2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.85 g) in concentrated hydrochloric acid (20 ml) was stirred under reflux for a day. The concentrated hydrochloric acid was distilled off under reduced pressure. Water was added to the residue and extraction with ethyl acetate was conducted. The extract was washed with water and then the solvent was distilled off under reduced pressure to give (S)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (0.70 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH3:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)c(C)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3,4-dimethylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.26 (1H, d, J=7.4 Hz), 8.14 (1H, d, J=2.6 Hz), 8.00 (2H, dd, J=6.6, 1.8 Hz), 7.42 (2H, d, J=8.4 Hz), 7.22 (1H, d, J=8.1 Hz), 6.97–6.87 (2H, m), 5.42–5.32 (1H, m), 3.90 (3H, s), 2.29 (6H, s), 1.58 (3H, d, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[Cl:14])[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:5]=[C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[N:7]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc(-c2sccc2Cl)nc(Cl)n1
Solvent: CCO
Product: CN1CCN(c2cc(-c3sccc3Cl)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a vial was added 2,4-dichloro-6-(3-chloro-thiophen-2-yl)-pyrimidine (50 mg, 0.19 mmol), 1-methylpiperazine (50 mg, 0.5 mmol), and ethanol (2 mL). The resulting mixture was stirred at room temperature for 3 hrs. Ethanol was removed and the resulting residue was dissolved with EtOAc. The organic layer was washed with 1N hydrochloric acid and concentrated to yield the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
1.75 g (0.01 mole) of 3-chloro-4-fluoronitrobenzene and 0.013 mole of phenylboric acid were dissolved in 70 mL of 1,2-dimethoxyethane under argon. Then, 0.5 g (0.0005 mole) of tetrakis(triphenylphosphine)palladium and 13 mL of 2N potassium carbonate solution were added, and the reaction mixture was heated to 80° C. At the end of the reaction, the reaction mixture was poured into 100 mL of ethyl acetate. The organic phase was extracted with dilute sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off from a rotary evaporator, and the residue was purified [by column chromatography] on silica gel using hexane/toluene (10:1) [as the eluent].