Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH2:14])=O)(C)(C)C.[N+:15]([C:18]1[CH:25]=[CH:24][C:21](CBr)=[CH:20][CH:19]=1)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH:13]=[CH2:14])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C=CC1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C=CC1CCCN1Cc1ccc([N+](=O)[O-])cc1
Yield: 85 %

Procedure:
2-Vinyl-pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.52 mmol) is dissolved in CH2Cl2 (4 mL) to which TFA (0.55 mL) is added dropwisely. The resulting mixture is stirred until TLC showed no starting material. All the volatiles were removed under vacuum. CH3CN (5 mL) is added followed by 4-nitrobenzylbromide (400 mg, 1.85 mmol) and K2CO3 (1 g, 7.2 mmol). The mixture is stirred until TLC suggested no starting material left. EtOAc and H2O were added and the EtOAc layer is washed with brine and dried. After evaporating the EtOAc, the residue is purified with flash chromatography to provide the desired product (300 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19])[CH2:5][CH2:6][CH3:7].C[C:22]1[C:23]([CH3:38])=[C:24](C)[C:25]([CH3:36])=[C:26]2[C:30]=1[N:29]([CH3:31])[C:28](C)=[C:27]2[CH2:33]NI.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:33][C:27]2[C:26]3[C:30](=[CH:22][C:23]([CH3:38])=[CH:24][C:25]=3[CH3:36])[N:29]([CH3:31])[CH:28]=2)[C:9]1=[O:19])[CH2:5][CH2:6][CH3:7]
Reactant: Cc1c(C)c(C)c2c(c1C)c(CNI)c(C)n2C
Reactant: CCC[C@H](C(=O)OC)n1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[C@H](C(=O)OC)n1c(=O)c2ccccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Temperature: 100 °C
Yield: 80.7 %

Procedure:
To a solution of (R)-2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)-pentanoic acid methyl ester (50 mg, 0.18 mmol) (prepared according to example 1, steps 1-3) in DMF (10 mL) are added trimethyl-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-amino iodide (97 mg, 0.27 mmol) and K2CO3 (50 mg, 0.36 mmol) at room temperature. The solution is heated to 100° C. for 4 hours. The solution is cooled and is extracted with water and EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 20% EtOAc in Hexane as the eluent to afford (R)-2-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (65 mg, 80%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Br:16][C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[Br:16][C:17]1[N:22]=[CH:21][C:20]([O:23][CH2:14][C:12]([CH3:15])([OH:13])[CH2:11][CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(Br)nc1
Yield: 70 %

Procedure:
Reaction of epoxide 140 (see Example 2JJ) with 6-bromo-3-pyridinol as in Example 2AA at 84° C. for 18.5 h, followed by chromatography of the product on silica gel, eluting with 25-40% EtOAc/petroleum ether (foreruns) and then with 40-50% EtOAc/petroleum ether, gave 1-[(6-bromo-3-pyridinyl)oxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-2-butanol (151) (70%) as a pale yellow-brown foam; 1H NMR (CDCl3) δ 8.09 (dd, J=3.0, 0.3 Hz, 1H), 7.80 (s, 1H), 7.41 (dd, J=8.7, 0.4 Hz, 1H), 7.13 (dd, J=8.7, 3.2 Hz, 1H), 4.29 (ddd, J=14.2, 9.4, 6.4 Hz, 1H), 4.25 (ddd, J=14.1, 9.4, 6.7 Hz, 1H), 3.89 (d, J=8.9 Hz, 1H), 3.86 (d, J=9.0 Hz, 1H), 2.22 (ddd, J=13.9, 9.3, 6.5 Hz, 1H), 2.18 (s, 1H), 2.04 (ddd, J=13.8, 9.4, 6.7 Hz, 1H), 1.42 (s, 3H); HRESIMS calcd for C13H15BrClN4O4 m/z [M+H]+ 408.9910, 406.9939, 404.9960. found 408.9920, 406.9945, 404.9966.
Reaction SMILES: [C:1]([OH:7])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[C:19]=1[C:20](Cl)=[O:21]>ClCCl>[CH3:3]/[C:2](=[CH:4]/[CH3:5])/[C:1]([O:7][C:20](=[O:21])[C:19]1[C:23]([Cl:28])=[CH:24][C:25]([Cl:27])=[CH:26][C:18]=1[Cl:17])=[O:6]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: C/C=C(/C)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C/C=C(/C)C(=O)OC(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: 2 °C
Reaction time: 0.75 h
Yield: 32.8 %

Procedure:
Angelic acid (601 mg, 6.0 mmol) was dissolved in dichloromethane (3.0 mL) under argon. Diisopropylethylamine (1.23 mL, 7.20 mmol) was added at 5-10° C. in a period of 1 min. To this solution was added 2,4,6-trichlorobenzoyl chloride (1.12 mL, 7.20 mmol) at 3-6° C. in a period of 4 min. After the reaction solution had been stirred at 2° C. for 45 min, petroleum ether (9.0 mL) was added. The obtained suspension was purified by flash chromatography (petroleum ether/dichloromethane 3:1), giving the title compound as a white solid (605 mg, 33%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1/[CH:34]=[CH:35]/[O:36][CH2:37][CH3:38].[F:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[C:43](B1OC(C)(C)C(C)(C)O1)[NH:44]2>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:37]([O:36]/[CH:35]=[CH:34]/[C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)=[N:7][C:2]=1[C:43]1[NH:44][C:45]2[C:41]([CH:42]=1)=[C:40]([F:39])[CH:48]=[CH:47][CH:46]=2)[CH3:38]
Reactant: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
To a degassed solution of (E)-5-(6-chloro-5-(2-ethoxyvinyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.36 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (140 mg, 0.54 mmol) in 1,4-dioxane (3 mL) and water (200 μl) was added CS2CO3 (234 mg, 0.72 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (24 mg, 0.04 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature for 3 hours. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with 0-30% acetone/hexane) provided (E)-5-(5-(2-ethoxyvinyl)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (65 mg, yield: 28%) MS (M+H)+: 657.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:36][C:37]1[CH:46]=[C:45]2[CH:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[CH2:44]2)[CH2:39][CH:38]=1.Cl>O1CCOCC1.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:37]4[CH:46]=[C:45]5[C:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:49])[F:50])[CH2:44]5)=[CH:39][CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35])=[O:33]
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Reactant: NC1=CCC2CCN(C(=O)C(F)(F)F)CC2=C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 80 °C
Yield: 44.7 %

Procedure:
To a solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzamide (158 mg, 0.32 mmol) in 1,4-dioxane (6 mL) and 2-propanol (2 mL) was added 7-amino-N-trifluoroacetyl tetrahydroisoquinoline (158 mg, 0.64 mmol) followed by catalytic 12M HCl. After heating overnight at 80° C., reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (25 mL), the organic layer was concentrated and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (100 mg, 44%) as an off-white solid. ESIMS (M+H)+=700.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:12]1([C:11]#[C:10][CH2:9][CH2:8][NH2:7])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC#Cc1ccccc1

Procedure:
A solution of (4-phenyl-but-3-ynyl)-carbamic acid tert-butyl ester (98 mg) was stirred for 0.5 h in 1:1 trifluoroacetic acid/dichloromethane (10 ml). The volatile materials were evaporated to give the crude 4-phenyl-but-3-ynylamine, which was used in subsequent transformations without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][Mg]Br.Cl>C(OCC)C>[CH:1]1([CH2:6][CH2:7][C:8](=[O:10])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCC1CCCC1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC(=O)CCC1CCCC1
Temperature: -20 °C

Procedure:
10 Parts of 3-cyclopentyl propionic acid are dissolved in 150 parts by volume of ethyl ether and chilled to -20° C. under argon. 50 Parts by volume of 2.8 molar methyl magnesium bromide are added dropwise. After the addition of the methyl magnesium bromide is completed, the mixture is allowed to warm to room temperature. The cloudy reaction mixture is treated with 1N hydrochloric acid and the clearified reaction mixture is extracted with ether followed by ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residual oil is chromatographed on silica gel using 10% ethyl acetate/hexane as the eluent, to provide 4-cyclopentyl-2-butanone.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[N:32]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH2:37][CH2:38][N:32]([CH2:39][CH2:40][OH:41])[CH2:33][CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCCN1CCCNCC1
Product: O=C1N=C(N2CCCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-[1,4]diazepan-1-yl-ethanol following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:22][CH:21]=3)\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)(=[O:35])[CH3:34]
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and acetylchloride
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: FC(F)(F)c1ccccc1CBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3C(F)(F)F)C2=O)cn1
Yield: 37 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-(trifluoromethyl)benzene. Yield: 37%. MS M+H calculated 434.1. found 434.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.2 uM.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[N:9][OH:10])[S:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.[I-].[K+].N12CCCC1=NCCC2>C(#N)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](=[N:9][O:10][CH2:18][C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[S:4][N:3]=1
Reactant: Nc1nc(CCl)cs1
Reactant: ON=C(c1ccsc1)c1snc(Cl)c1Cl
Agent: C1CN=C2CCCN2C1
Agent: Cl
Agent: [I-]
Solvent: CC#N
Product: Nc1nc(CON=C(c2ccsc2)c2snc(Cl)c2Cl)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.7 %

Procedure:
To a stirred suspension of 1-(3,4-dichloro-1,2-thiazol-5-yl)-N-hydroxy-1-(3-thienyl)methanimine (1.60 g, 5.73 mmol), 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (937 mg, 6.30 mmol) and potassium iodide (951 mg, 5.73 mmol) in acetonitrile (15 mL) at 0° C. was added 1,5-diazabicyclo(4.3.0)non-5-ene (1.44 mL, 12.0 mmol). The mixture was stirred 10 min at 0° C., then overnight at room temperature. After dilution of the reaction mixture with water and extraction with ethyl acetate, the combined organic layers were dried over MgSO4, concentrated in vacuo, and the residue purified by reverse phase HPLC to afford 4-[({[(3,4-dichloro-1,2-thiazol-5-yl)(3-thienyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine [16 mg, yield 0.7%].
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(C(F)(F)F)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([CH2:26][N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(C(F)(F)F)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: FC(F)(F)c1ccc(NCC2CCCC2)cc1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(C(F)(F)F)cc2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH2:13]O)=[CH:11][N:12]=1.[CH:15]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>O=S(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH2:13][N:21]2[CH2:22][CH2:23][CH2:24][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]2)=[CH:11][N:12]=1
Reactant: CC(C)N1CCCNCC1
Reactant: OCc1cnc(-c2ccccc2F)[nH]1
Solvent: O=S(Cl)Cl
Product: CC(C)N1CCCN(Cc2cnc(-c3ccccc3F)[nH]2)CC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
[2-(2-Fluorophenyl)-1H-imidazol-5-yl]methyl alcohol (69 mg, 0.36 mmol, prepared essentially as described in PCT International Publication No. WO 96/16040) is dissolved in SOCl2 (4 mL) and stirred at 65° C. for 1 hr. The reaction mixture is cooled to rt then concentrated in vacuo. The residue is dissolved in toluene, and then re-concentrated. The residue is suspended in CHCl3 (3 mL) at it Et3N (1 mL) is added, followed by 4-isopropyl-1,4-diazepane (0.8 mL, 0.4 mmol). The reaction mixture is stirred for 90 min at rt, and then the solvent is removed in vacuo. The residue is dissolved in CH2Cl2 and applied to a PTLC plate then eluted with EtOAc/MeOH/Et3N (10/2/1). The product is removed from the plate and the silica stirred in EtOAc/MeOH (10/1) then filtered. The filtrate is concentrated to give the title compound. 1H NMR 8.24 (br t, 1H), 7.30-7.21 (m, 2H), 7.13 (dd, 1H), 7.01 (s, 1H), 3.70 (s, 2H), 2.90 (m, 1H), 2.74-2.71 (m, 8H), 1.80 (br s, 2H), 1.06 (d, 3H), 1.02 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]2[N:9]=[N:10][N:11]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cccc2nnnn12
Yield: 25.4 %

Procedure:
2,5-Dibromopyridine (1.0 g, 4.2 mmol), sodium azide (412 mg, 6.3 mmol) and NH4Cl (339 mg, 6.3 mmol) were heated in 20 mL DMF to 100° C. for 16 h. The mixture was diluted with 150 mL EtOAc, washed with H2O (2×) and sat'd NaCl then dried over Na2SO4 and concentrated. Flash chromatography (30 g silica, 2/1 hexane/EtOAc eluant) afforded 212 mg (25%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[N:11]=[CH:12][N:13](C)C)#[N:2].Cl.[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22]N.C(O)C>C(O)(=O)C>[F:9][C:8]1[CH:7]=[CH:6][C:5]([F:10])=[C:4]2[C:3]=1[C:1]([NH:2][CH2:22][CH2:21][C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([CH3:17])[CH:19]=1)=[N:13][CH:12]=[N:11]2
Reactant: COc1ccc(CCN)cc1C
Reactant: CN(C)C=Nc1c(F)ccc(F)c1C#N
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CCNc2ncnc3c(F)ccc(F)c23)cc1C
Yield: 58 %

Procedure:
N′-(2-Cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (1.65 g, 7.9 mmol) and 3-methyl-4-methoxyphenethylamine hydrochloride (2.4 g, 11.8 mmol) were combined in acetic acid (2.55 mL) and absolute ethanol (15 mL) and heated to reflux for 16 h. Upon cooling, the solvent was removed under reduced pressure and the remaining solid was slurried with water, suction filtered and washed with water, dried in vacuum at 45° C. to give 1.51 g (58%) of (5,8-difluoroquinazolin-4-yl)-[2-(4-methoxy-3-methylphenyl)-ethyl]-amine as an off-white solid. LC/MS: 330.18 (M++1). 1H NMR (CDCl3): δ 8.67 (s, 1H), 7.35 (m, 1H), 6.94-7.09 (m, 3H), 6.79 (d, J=9.0 Hz, 1H), 6.65-6.80 (br, 1H), 3.87 (q, J=6.9 Hz, 2H), 3.83 (s, 3H), 2.93 (t, J=6.9 Hz, 2H), 2.22 (s, 3H). M.P. 162-169° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=[N:16][O:17][CH:18]=2)=[CH:10][CH:11]=1)=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:15]2[C:14]([CH2:13][O:12][C:9]3[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=3)=[CH:18][O:17][N:16]=2)=[N:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(OCc2conc2-c2ccc(F)cn2)nn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: O=C(O)c1ccc(OCc2conc2-c2ccc(F)cn2)nn1
Yield: 93.5 %

Procedure:
As described for example 112a, 6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (405 mg, 1.18 mmol) was converted, instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, to the title compound (349 mg, 94%) which was obtained as an off white solid. MS: m/e=315.1 [M−H]−.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([C:18]2[CH:19]=[CH:20][C:21](=[O:27])[N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=2)=[N:15][C:16]=1Br.CCOC(C)=O>CN1C(=O)CCC1.O>[NH2:10][C:11]1[N:12]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]([C:18]2[CH:19]=[CH:20][C:21](=[O:27])[N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=2)=[N:15][C:16]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2nc(Oc3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 85.1 %

Procedure:
To a solution of phenol (147 mg) in NMP (1.0 ml), was added 60% NaH (52 mg) under ice-bath cooling. After 5 minutes stirring, 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) was added to the mixture at the same temperature. And then the mixture was heated at 100° C. with stirring for 5.5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE to give 5-(5-amino-6-phenoxy-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (88 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[CH:21]=O)([O-:3])=[O:2].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].[S]>CN(C)C=O>[NH:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:30]=[C:21]1[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=1
Reactant: Nc1ccccc1N
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2cc([N+](=O)[O-])ccc21
Agent: [S]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc([N+](=O)[O-])ccc21

Procedure:
3-(1H-Benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: a suspension of 720 mg of 5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole-3-carboxaldehyde, of 216 mg of 1,2-phenylenediamine and of 77 mg of sulfur (0) in 70 ml of anhydrous dimethylformamide is heated at 95° C. for 16 hours. After returning to a temperature in the region of 20° C., the reaction medium is concentrated to dryness under reduced pressure and the evaporation residue is taken up with 20 ml of distilled water and 20 ml of ethyl acetate. The insoluble material floating at the surface is isolated by filtration, washed and dried and makes it possible to obtain a first crop of 160 mg of of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in the form of a yellow solid (Rf=0.22, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (75/25 by volume)). The filtrate is concentrated to dryness under reduced pressure and the solid residue is resuspended in a cyclohexane/ethyl acetate (80/20 by volume) mixture, isolated by filtration, washed and dried. A second crop of 200 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of an orangey solid with the same Rf as the first crop (mass analysis: CI: m/z 410 (M+H)+)+ (base peak)).