Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].Br[C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([Cl:19])=[N:17][CH:18]=1>>[NH2:20][C:15]1[CH:14]=[C:13]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=2[CH3:11])[CH:18]=[N:17][C:16]=1[Cl:19]
Reactant: CC(=O)Nc1nc(C)c(I)s1
Reactant: Nc1cc(Br)cnc1Cl
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Yield: 25 %

Procedure:
Using an analogous method to that described in Example 7, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide was reacted with 5-bromo-2-chloropyridin-3-amine to give the title compound (Method A HPLC: retention time 5.5 minutes) in 25% yield; 1H NMR Spectrum: (acetone-d6) 12.17 (1H, br s); 7.68 (1H, d); 7.20 (1H, d); 5.70 (2H, br s); 2.34 (3H, s); 2.14 (3H, s); Mass Spectrum: M+H+ 283 and 285.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([OH:41])[CH2:34][N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:27][C:25]=2[N:26]=1>CCO>[CH:7]1([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:38]2[CH2:39][CH2:40][N:35]([CH2:34][C@@H:33]([OH:41])[CH2:32][O:31][C:28]3[CH:29]=[CH:30][C:24]4[S:23][C:22]([CH3:21])=[N:26][C:25]=4[CH:27]=3)[CH2:36][CH2:37]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Reactant: BrCCCCOC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOC4CCCC4)CC3)ccc2s1

Procedure:
A solution of (4-bromobutoxy)cyclopentane (400 mg, 1.81 mmol) in EtOH (5 mL) was treated with DIEA (0.64 mL, 3.62 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as prepared in Example 3A (557 mg, 1.81 mmol). The solution was stirred at reflux 15 hours. Upon cooling, the product was concentrated and purified by flash column chromatography (10% MeOH/EtOAc) to yield (2R)-3-[4-(4-cyclopentyloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[SH:19]>>[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[S:19][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Cn1ccnc1S
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2nccn2C)s1

Procedure:
Prepared according to the procedure described for example 14 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.1 g, 0.49 mmol) and N-methyl imidazole-2-thiol (0.056 g, 0.49 mmol). The title compound was obtained as a solid (50 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.48 (2H, s) 7.64 (2H, dd) 7.28 (2H, dd), 3.42 (3H, s), 2.52 (3H, s). MS m/z: 283.9 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH3:29])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:36]1(N)C[CH2:37]1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH:29]5[CH2:37][CH2:36]5)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NC1CC1
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(NC3CC3)nc2n(C)c1=O
Yield: 63.2 %

Procedure:
Using general method E, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and cyclopropanamine (0.027 g, 0.48 mmol) were combined in THF (1 mL) to provide 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea as a white solid (0.051 g, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.60 (brs, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.06-8.04 (m, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.36 (s, 1H), 7.10 (d, J=12.4 Hz, 1H), 3.61-3.54 (m, 3H), 2.78-2.83 (m, 1H), 2.05 (s, 3H), 1.45 (s, 9H), 0.725 (brs, 2H), 0.55-0.53 (m, 2H); (ESI) m/z: 505.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.Cl.Cl.[CH3:18][NH:19][CH2:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:23]=2[N:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:19]([CH3:18])[CH2:20][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:23]=4[N:22]=3)=[O:14])[C:6]=2[CH:15]=1
Reactant: O=C(O)Cn1c(=O)oc2ccc(Cl)cc21
Reactant: CNCc1nc2cc(C(F)(F)F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(Cc1nc2cc(C(F)(F)F)ccc2[nH]1)C(=O)Cn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (300 mg), N-methyl-1-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]methanamine dihydrochloride (420 mg), and dichloromethane (10 mL) were added TEA (552 μL), HOBt (214 mg), and WSC.HCl (303 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The resulting solid was collected by filtration and washed with EtOAc. To a mixture of the obtained solid (325 mg) and MeOH (5 mL) was added 4 M hydrogen chloride/EtOAc (330 μL), followed by stirring at room temperature for 1 hour. To the reaction mixture was added EtOAc. The resulting solid was collected by filtration and then washed with EtOAc to obtain 2-(5-chloro-2-oxo-1,3-benzoxazol-3 (2H)-yl)-N-methyl-N-{[5-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}acetamide hydrochloride (277 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11](O)[C:10]=1[CH3:18].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:11]1[C:10]([CH3:18])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:14]=[C:13]([S:15][CH3:16])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c(C)c(-c2ccc(F)cc2F)n1
Product: CSc1nc(Cl)c(C)c(-c2ccc(F)cc2F)n1
Reaction time: 5 h

Procedure:
A solution of 5.9 g of 6-(2,4-difluorophenyl)-5-methyl-2-(methylthio)pyrimidin-4-ol in 25 mL of POCl3 was heated to reflux and stirred at this temperature for 5 h. All but ca. 5 mL of POCl3 was removed by vacuum distillation, and the residue was quenched by pouring into 200 mL of ice-water, neutralizing with Na2CO3 and extracting with 3×100 mL of EtOAc. The combined organics were washed with 100 mL of brine, dried, and concentrated. The residue was purified by flash chromatography on a Biotage 40M column, eluting with 95:5 hexanes-acetone to yield the title compound as a light yellow solid. Mass spectrum (ESI) 287 (M+1).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([C:36](=[O:38])[CH3:37])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CNCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(Cc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: {3-[2-(benzylamino-methyl)-quinolin-3-yl]-4-methoxy-phenyl}-acetic acid ethyl ester, dihydrochloride and acetic anhydride.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C(Cl)(Cl)Cl>[CH3:2][N:3]([OH:4])[C:21]([NH:20][C:15]1[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=1)=[O:22]
Reactant: CNO
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(O)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A mixture of 10 g of N-methyl-hydroxylamine hydrochloride in 100 ml of chloroform was stirred while 18 ml of triethylamine were added at 0° C. Then, 20 g of 3,5-dichlorophenyl isocyanate in 30 ml of chloroform were added to the mixture at 10° to 15° C and the mixture was stirred for 5 hours at 20° C and was then distilled to dryness under reduced pressure. The residue was taken up in water and dried to obtain 22 g of N-methyl-N-hydroxy-N'-(3,5-dichlorophenyl)-urea melting at 131°-132° C.
Reaction SMILES: [N:1]1[N:2]([CH2:10][CH2:11]O)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:13]1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(OCC)C>[N:1]1[N:2]([CH2:10][CH2:11][NH2:13])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCCn1nc2ccccc2n1
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: NCCn1nc2ccccc2n1
Temperature: -50 °C
Yield: 44791.7 %

Procedure:
4.70 g Of the 2-(2-benzotriazolyl)ethanol (28.8 mmol) was dissolved in 200 ml diethyl ether and 2.28 g pyridine (28.8 mmol) was added. The mixture was cooled to -50° C., and 8.18 g triflic anhydride (29 mmol) was added. The mixture was removed from the cooling bath, and was allowed to reach room temperature. The mixture was filtered under dry conditions and added to a cold -40° C. solution of ca 150 ml ammonia in 50 ml diethyl ether. This mixture was allowed to reach room temperature, and ether was removed. 50 ml 2M HCl was added, and this mixture was washed with methylene chloride. The aqueous phase was made basic by addition of 50 ml 25% sodium hydroxide and extracted with 3×25 ml methylene chloride. Evaporation of the solvent gave 2.10 g 2-(2-benzotriazolyl)ethylamine (12.9 mol). This amine was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[N:1]1[CH2:6][CH2:5][N:4]([C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:32])([F:16])[F:33])[O:22][N:21]=3)[CH:24]=2)=[O:27])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ccc2[nH]c(N3CCNCC3)nc2c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2nc3ccccc3[nH]2)CC1
Yield: 23 %

Procedure:
This compound was synthesized from 2-(piperazin-1-yl)-1H-benzo[d]imidazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 23%). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br s, 1H), 8.19-8.17 (d, J=8.5 Hz, 1H), 8.11 (s, 1H), 7.76-7.72 (m, 2H), 7.21 (m, 2H), 6.94 (m, 2H), 3.80 (m, 2H), 3.63-3.52 (m, 6H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 441.4 (M−H)−
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:20](I)[CH:21]=[CH2:22]>C(O)C.CCOCC>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH:21]=[CH2:20]
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Reactant: C=CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 34.4 %

Procedure:
To a rapidly stirred solution of (trans)-N-[[2-(3-hydroxyphenyl)cyclopropyl]methyl] butanamide (0.8 g, 3.4 mmol) and KOH (210 mg, 3.74 mmol) in ethanol (15 mL) was added allyl iodide (622 mg, 3.7 mmol). After stirring for 18 h, the suspension was diluted with Et2O (100 mL), and washed with H2O, 2N NaOH, brine, dried (K2CO3), and concentrated to a give a crude residue. The resulting material was purified by chromatography (silica gel, 40 % EtOAc/hexane) to afford 320 mg (34%) of the title compound: 1H NMR (300 MHz, CDCl3) δ0.70-0.94 (m, 5H), 1.12-1.32 (m, 1H), 1.58-1.84 (m, 3H), 2.20 (t, J=6.0 Hz, 2H), 3.15-3.36 (m, 2H), 4.48 (d, J=5.6 Hz, 2H), 5.24 (d, J=10.0 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.56 (br s, 1H), 5.96-6.07 (m, 1H), 6.57-6.70 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3296, 2962, 1644, 1607, 1548, 1494 cm-1 ; MS m/e 273; Analysis calc'd for C17H23NO2 0.20(H2O): C, 73.72; H, 8.52; N, 5.06; found: C, 73.77; H, 8.63; N, 5.00.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:33]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:25][CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:33][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)[C:14]([N:16]([CH2:25][CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[C@@H:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18])=[O:15]
Reactant: CCOC(CN(C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C)c1ccccc1)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)[C@H](C)c1ccccc1)OCC
Yield: 96.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)((R)-1-phenylethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-14) (3.08 g, 4.5 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (1.99 g, 97%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4N=[CH:24][N:23]=[C:22](N)[C:21]=4[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:16][CH2:15]3)[N:11](C)[CH:12]=2)=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].Br[C:40]1C=NC=CC=1N1CCC(C2NC=C(C3C=CC=C(C(F)(F)F)C=3)N=2)CC1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[CH:22]=[N:23][CH:24]=[CH:40][C:20]=2[N:17]2[CH2:16][CH2:15][CH:14]([C:10]3[NH:11][CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][CH:2]=[C:3]([C:35]([F:38])([F:36])[F:37])[CH:4]=4)[N:9]=3)[CH2:19][CH2:18]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cc1
Reactant: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ccncc4Br)CC3)n2)c1
Product: COc1ccc(-c2cnccc2N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamine using 3-bromo-4-(4-{4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidin-1-yl)pyridine instead of 5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine. LC-MS: (M+1=479, obsd.=479).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:35].[OH-].[Na+:37]>O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:32])[C:29]([O-:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:35].[Na+:37]
Reactant: Cc1ccc(OC(C)C(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(OC(C)C(=O)[O-])cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-{{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}propionic acid (0.500 g) and sodium hydroxide (0.0360 g) in water is stirred at room temperature overnight, concentrated in vacuo to one-half volume, and filtered to give the title product as a solid which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.Cl>CS(C)=O>[C:22]([C:19]1[O:18][C:17]([S:14]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:4]2)(=[O:15])=[O:16])=[CH:21][CH:20]=1)(=[O:24])[CH3:23]
Reactant: CC(O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Temperature: 60 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(1-hydroxyethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (234 mg) in dimethyl sulfoxide (3 mL) were added triethylamine (3 mL) and sulfur trioxide pyridine complex (449 mg), and the mixture was stirred at 60° C. for 3 days. 1 mol/L Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a pale-yellow oil (yield 180 mg, 77%).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[OH-].[Na+].[CH3:14][CH:15]=[O:16]>O>[F:11][CH:2]([F:1])[C:3]1[O:4][C:5]([CH:15]([OH:16])[CH3:14])=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1
Reactant: CC=O
Reactant: O=c1cc(C(F)F)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)c1oc(C(F)F)cc(=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice bath cooled suspension of 2-difluoromethyl-5-hydroxy-pyran-4-one (1.00 g, 6.17 mmol), obtained as described in Example 4, in deionized water was added a 6.0M NaOH solution (1.23 mL, 7.40 mmol). A clear dark brown red solution was obtained, and CH3CHO (6.0 mL, 107 mmol) was added dropwise. After 2 hrs, the reaction mixture was cooled in ice and another 3 mL of CH3CHO (54 mmol) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The progress of the reaction was monitored by HPLC Method 1 as described above. Thus, after 24 hrs, the composition (% as peak percent area) of the reaction mixture was as follows: desired product (72%), starting material (7%), side products (15%, 2 major less polar components). The reaction mixture was cooled in ice and the pH was adjusted to 6 with the addition of a 6.0M HCl solution (1 mL). The mixture was concentrated in vacuo, and the residue was taken up in EtOAc. The organic layer was washed with brine (2×15 mL). The combined brine layers were back-extracted with EtOAc (2×). The organic fractions were combined, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of CH2Cl2 and MeOH (25/1, v/v) as eluant. Fractions rich in product were combined together, and concentrated to give 6-difluoromethyl-3-hydroxy-2-(1-hydroxy-ethyl)-pyran-4-one as an oil. HPLC purity (peak area percent) of this material is 88.0% at λ=280 nm using HPLC Method 1 as described above.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH3:22]>O1CCCC1.CN(C)C=O>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:22])=[O:13])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccc(OC(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(OC(F)F)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 8.70 g (40.6 mmol) 3-(4-difluoromethoxy-phenyl)-acrylic acid in 60.0 ml tetrahydrofuran and 0.6 ml N,N-dimethylformamide a solution of 5.14 ml (60.9 mmol) oxalyl chloride in 10 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 150 ml of a 25% aqueous ammonia solution. The separating oil was collected and stirred for 30 min. with water. The precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 4.7 g (54%) 3-(4-Difluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:6][C:7]1[CH:31]=[CH:30][C:10]([N:11]([C:21](=[O:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[C:9]([CH2:32][CH3:33])[CH:8]=1)(=[O:3])[CH3:2].[C:40]1([C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N+]=[N-])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CC(C)=O>[C:1]([NH:4][CH:5]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:6][C:7]1[CH:31]=[CH:30][C:10]([N:11]([C:21](=[O:29])[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([O:16][CH:46]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:15])=[C:9]([CH2:32][CH3:33])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)C(Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)O)c(CC)c1)NC(C)=O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: C=CCOC(=O)C(Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)c(CC)c1)NC(C)=O

Procedure:
To 2-{4-[2-(acetylamino)-3-(allyloxy)-3-oxopropyl][tert-butoxy(oxo)acetyl]-2-ethylanilino}benzoic acid in acetone was added diphenyldiazomethane (until all starting material was consumed as evident by monitoring via TLC). The reaction mixture was concentrated under reduced pressure, purified on silica gel using ethyl acetate as eluent to provide the titled compound. MS (ESI(+)) m/e 705 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.51-8.01 (m, 2H), 7.73-6.86 (m, 16H), 5.93-5.78 (m, 1H), 5.34-5.10 (m, 2H), 4.57-4.40 (m, 3H), 3.10-2.84 (m, 2H), 2.58-2.42 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.07, 1.05, 1.00 (s, s, s, 9H).