Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=1[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:18]
Reactant: O=C1CCc2sccc21
Reactant: COc1ccc(C(=O)Oc2ccccc2)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)C2Cc3sccc3C2=O)c(OC)c1
Temperature: 100 °C
Yield: 47 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60 percent, 1.45 g, 12.4 mmol). After the addition of 2,4-Dimethoxy-benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2,4-Dimethoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.0 g, 6.6 mmol) as brown solid in 47% yield.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)([Cl:8])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:18][CH:19]=[C:20](O)[N:21]=2)[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:8][C:20]1[N:21]=[C:17]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[S:18][C:19]=1[CH:4]=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: Oc1csc(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1sc(-c2cccnc2)nc1Cl
Temperature: 110 °C

Procedure:
Dry DMF (20 ml, 0.255 mol) was cooled to 0-5° C. with an ice/water bath. Phosphorus oxychloride (20 ml, 0.215 mol) was added dropwise over 0.5 h. 2-(3-pyridyl)thiazol-4-ol (hybromide salt, 13 g, 0.05 mol) was added in one portion and the reaction mixture was heated to 110° C. for 15 min. After cooling the reaction mixture was poured on ice water and neutralized with solid potassium carbonate. The precipitate was filtered, washed with water, once with ethanol, and dried to dryness to get 4-chloro-2-(3-pyridyl)thiazole-5-carbaldehyde as brown solid. 1H NMR (300 Mz, DMSO-d6): δ: 10.00 (s, 1H), 9.21 (d, 1H, J=1.2 Hz), 8.78 (dd, 1H, J=1.5 Hz), 8.42 (d, 1H, J=7.2 Hz), 7.60 (m, 1H). MS(ESI): 255, 257 (M+MeOH).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[N:5]=[CH:4][N:3]=1.Cl[N:11]([C:13]1[N:18]=CC=C[N:14]=1)Cl>>[BrH:1].[NH2:8][C:7]1[C:2]([NH:14][C:13]([NH2:18])=[NH:11])=[N:3][CH:4]=[N:5][C:6]=1[Br:9]
Reactant: Nc1c(Br)ncnc1Br
Reactant: ClN(Cl)c1ncccn1
Product: Br
Product: N=C(N)Nc1ncnc(Br)c1N

Procedure:
Repeating this reaction with 4,6-dibromo-5-aminopyrimidine prepared as is the dichloroaminopyrimidine gives 5-amino-6-bromo-4-guanidinopyrimidine hydrobromide. Other 6-halo congeners are made by variations of these reactions.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:13]3([OH:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[N:9]2[CH3:12])=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:4]=1.[CH:26](I)([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:13]3([OH:19])[CH2:18][CH2:17][CH2:16][N:15]([CH:26]([CH3:28])[CH3:27])[CH2:14]3)[N:9]2[CH3:12])=[C:5]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:4]=1
Reactant: Cn1c(C2(O)CCCNC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)N1CCCC(O)(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C1
Temperature: 50 °C

Procedure:
The HCl salt of 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)piperidin-3-ol (70 mg) was reacted with isopropyl iodide (1.5 eq), cesium carbonate (2 eq) and DIPEA (3 eq) in DMF (1 mL). The reaction was heated at 50° C. for several hours until complete. The reaction mixture was diluted with Ethyl acetate and extracted with a saturated ammonium chloride solution. The organic layer was dried, filtered and concentrated to give 70 mg of crude 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-1-isopropylpiperidin-3-ol which was reacted with 2-ethyl benzimidazole via General Procedure I for Buchwald coupling to give 515 [7.6 mg; MS (Q1) 505.3 (M)+] and 518 [7.7 mg; MS (Q1) 505.2 (M)+] following reverse phase purification and subsequent chiral separation.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22]([CH:24]=[O:25])=O>Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22]1[C:24](=[O:25])[N:3]2[C:4]3[C:9]([NH:10][CH:11]=[C:2]2[N:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: COc1ccc(F)c(C(=O)C=O)c1
Reactant: Nc1cnc2ccccc2n1
Agent: Cl
Solvent: O
Product: COc1ccc(F)c(-c2nc3c[nH]c4ccccc4n-3c2=O)c1
Temperature: 25 °C

Procedure:
A solution of 2-aminoquinoxaline (100 mg) and 2-fluoro-5-methoxyphenylglyoxal monohydrate (150 mg) in 5% HCl (6 mL) was heated to 60°-65° C. for 8 h. After cooling the mixture to room temperature the precipitate which had formed during the reaction was collected via suction filtration and washed with 5% HCl (1×) followed by H2O (3×). The product was then washed with methylene chloride and dried. The above procedure provided 2-(2-fluoro-5-methoxyphenyl)-imidazo-[1,2-a]quinoxalin-1(5H)-one (Compound 30) as a brick-red solid, mp 318°-320° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][C:18]=1[CH:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:33].CN(C1C=CC=CN=1)C.CCOCC>CN(C=O)C>[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][C:18]=1/[CH:23]=[C:24]1\[C:25](=[O:33])[N:26]([C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:27]2[C:32]\1=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)CNC(=O)OCc3ccccc3)c3ccccc32)[nH]1
Temperature: 55 °C

Procedure:
A mixture of N-(benzyloxycarbonyl)glycine (4.9 g, 23 mmol), 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (2.38 g, 10 mmol), dimethylaminopyridine (1.28 g, 10 mmol) in DMF (20 mL) was heated at 55° C. for 2 h. The solution was cooled, ether (10 mL) was added and the precipitate of the title compound was filtered off and dried to give 2.35 g, mp 193–196° C. HPLC Rt 7.04 min. 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.42 (s, 3H), 4.87 (d, 2H), 5.18 (s, 2H), 5.74 (t, 1H), 6.06 (d, 1H), 7.2 (m, 3H), 7.3–7.65 (m, 7H), 7.49 (m, 1H), and 8.23 (m, 1H). Anal Calcd for C25H23N3O: C, 69.92; H, 5.40; N, 9.78. Found: C, 69.91; H, 5.50; N, 9.86.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]2)=[C:5]2[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]2=[N:7][C:8]=1[CH2:9][CH3:10].C(N(CC)CC)C.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1.O>ClCCl>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:47]([NH:1][CH2:2][C:3]2[C:4]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]3)=[C:5]3[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]3=[N:7][C:8]=2[CH2:9][CH3:10])=[O:48])=[CH:50][CH:51]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CN
Reactant: O=C(Cl)c1ccc(CCCCOCCCCBr)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CNC(=O)c1ccc(CCCCOCCCCBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
A solution of 4-{[5-(aminomethyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxamide (0.21 g, 0.6 mmol, e.g. which can be as prepared in Intermediate 17) and triethylamine (0.21 ml, 1.52 mmol, 2.5 equivalents) in dichloromethane (20 ml) was stirred and cooled in an ice/water bath under an atmosphere of nitrogen. 4-{4-[(4-Bromobutyl)oxy]butyl}benzoyl chloride (0.32 g, 0.91 mmol, 1.5 equivalents, e.g. which can be as prepared in Intermediate 26) was added portion-wise over 2 minutes, and the mixture was stirred at 0° C. for 10 minutes and then at room temperature overnight. Iced water was added to the reaction mixture and the organic phase was separated and collected through a hydrophobic frit. The aqueous phase was extracted with dichloromethane (50 ml), and the combined organic extracts were evaporated to dryness to give a whitish foam. The residue was purified by passing through a 20 g silica column, eluting with a gradient of cyclohexane/ethyl acetate followed by a gradient of ethyl acetate/methanol. The fractions containing the product (obtained from 9:1 ethyl acetate/methanol) were pooled and evaporated to dryness to give the title compound as a pale yellow foam (0.27 g). LCMS showed MH+=656/658 (Bromine isotope pattern); TRET=2.88 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:20][CH2:21][CH2:22][N:23]1[CH:28]=[C:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]1=[O:42])(=O)=O.O>CN(C=O)C>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:27]2[CH:26]=[CH:25][C:24](=[O:42])[N:23]([CH2:22][CH2:21][CH2:20][S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH:28]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)OCCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Reactant: Oc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCSc1cccc(O)c1
Reaction time: 7 h
Yield: 81.1 %

Procedure:
To a solution of 3-hydroxythiophenol (222 mg) in DMF (15 mL) were added K2CO3 (243 mg) and 3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl methanesulfonate (700 mg) at ambient temperature and the mixture was stirred for 7 hours. Water was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford 5-(diphenylmethyl)-1-{3-[(3-hydroxyphenyl)sulfanyl]propyl}pyridin-2(1H)-one (610 mg) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7]N)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][C:14]([O:16]C(C)=O)=O.CC[N:22](CC)CC>CN(C=O)C.O>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:13][C:14]([NH2:22])=[O:16])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1csc2ccccc12
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
2-(Benzo[b]thien-3-yl)ethylamine (0.75 g, 4.23 mmol) was dissolved in DMF (5 mL) and 5 equivalents of Ac2O and 3 equivalents of Et3N were added. The mixture was stirred for 18 h at room temperature, diluted with H2O (25 mL) and extracted with CH2Cl2 (2×25 mL). The organic extracts were dried over Na2SO4 and concentrated to a residue to provide 0.88 g (94%) of 4 as a viscous liquid. 1H NMR (CDCl3) δ1.88 (s, 3, --CH3), 3.00(m, 2, --CH2 --), 3.54 (m, 2, CH2 --NH), 6.29 (br s, 1, NH), 7.10 (s, 1, CH--S), 7.25-7.37 (m, 2, phenyl), 7.72-7.86 (m, 2, phenyl).
Reaction SMILES: C([Li])CCC.[C:6]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2OC)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>O1CCCC1>[NH:12]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([B:24]([OH:29])[OH:25])=[CH:16][CH:15]=1)=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
n-Butyl lithium(1.6 M in hexane solution, 5.7 ml, 9.05 mmol) was added slowly to a solution of N1-phenyl-4-bromo-2-methoxybenzamide (1.0 g, 3.62 mmol) in tetrahydrofuran (27 mL) at −78° C. After 30 minutes, triisopropyl borate (1.25 mL, 5.43 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 6 hours. Hydrochloric acid (2.5N, 27 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized from ethyl acetate/heptane to give 4-(anilinocarbonyl)phenylboronic acid (0.354 g, 40%). 1H NMR (DMSO-d6) δ 7.10 (m, 1H), 7.35 (m, 2H), 7.80 (m, 4H), 7.92 (m, 2H), 8.23 (s, 2H), 10.23 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:24]1[O:26][C@H:25]1[CH2:27][OH:28]>C(#N)C>[Si:10]([O:28][CH2:27][C@H:25]([OH:26])[CH2:24][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1CO1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(C)[Si](OC[C@H](O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Add 1H-imidazole (14.70 g; 4 equiv; 215.99 mmoles) followed by tert-butylchlorodiphenylsilane (14.00 mL; 1.0 equiv; 54.00 mmoles) to a 0° C. solution of freshly distilled (S)-glycidol (3.66 mL; 1.0 equiv; 54.00 mmoles) in acetonitrile (40 mL). Stir the solution at ambient temperature for 30 minutes, then heat to reflux for 4 hours. Allow the mixture to cool to ambient temperature and concentrate the reaction mixture, then pour the residue into dichloromethane and 2M sodium bicarbonate solution (1:1, 400 mL). Separate the layers and further extract the aqueous layer with dichloromethane (2×). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to afford crude product. Purification by column chromatography affords the desired (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (9.25 g; 45%). MS (m/z): 381(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([NH2:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][CH:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])[CH3:35]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1ccccc1F
Solvent: Cc1ccccc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1F
Yield: 34.6 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.6 mmol) with (±)-1-(2-fluorophenyl)-ethylamine (206 mg, 1.5 mmol) in toluene (5 mL). Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain (±)-7-chloro-6-[1-(2-fluorophenyl)ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (86 mg, 35%). GC-MS m/z: 414 (M+).
Reaction SMILES: CN(C)[C:3](=[O:32])[NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=3)[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)[CH2:6]1.[C:34]1([C@@H:40]([NH2:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O.[ClH:50]>CN1C(=O)CCC1.CC#N>[CH3:31][O:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:13]2[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=[C:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@@H:5]([NH:4][C:3]([NH:42][C@H:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:41])=[O:32])[CH2:6]3)[N:12]=2)=[CH:22][CH:23]=1.[ClH:50]
Reactant: COCCOc1ccc(Nc2nc(N3CCC[C@@H](NC(=O)N(C)C)C3)cnc2C(N)=O)cc1
Reactant: C[C@H](N)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccc(Nc2nc(N3CCC[C@@H](NC(=O)N[C@@H](C)c4ccccc4)C3)cnc2C(N)=O)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(2-methoxyethoxyl)phenylamino)pyrazine-2-carboxamide (235) (14 mg, 0.03 mmol) in 1 mL NMP in a sealed tube added (S)-(−)-1-phenylethylamine (50 μL). The mixture was stirred in 100° C. bath for overnight. It was acidified with 0.5 mL TFA, and subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and neat MeCN to isolate the title compound, 3-(4-(2-methoxyethoxyl)phenylamino)-5-((R)-3-(3-((S)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide (506) as HCl salt (9.5 mg). LC-MS (ESI): m/z (M+1) 534.2. UV: λ=268, 276, 304, 339, 375 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][OH:25])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][O:25][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(COC(=O)C(C)(C)C)n4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg (0.48 mmol) of compound 3-(4-fluorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from Example 63 are dissolved in 3 ml of pyridine. 294 μl (2.38 mmol) of pivaloyl chloride are added and the mixture is then stirred at ambient temperature for 2 hours. H2O is added, the mixture is extracted with EtOAc, the organic phase is washed with a saturated NH4Cl solution and then dried over MgSO4, and the product is filtered and concentrated. Purification is carried out by chromatography on a silica gel column, elution being carried out with EtOAc.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+:23]>CCO.O>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[O:12][N:11]=2)=[CH:8][CH:9]=1.[Na+:23]
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (1.7 g, 5.6 mmol) in EtOH/H2O (30 mL), 1 M NaOH (8.4 mL, 8.4 mmol) was added at RT. The mixture was stirred at RT for 1 h, and concentrated under reduced pressure to afford sodium 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (1.6 g, 96%) as a white solid, which was directly used for next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([NH2:21])=[N:18][C:19]=2[NH2:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.O>N1C=CC=CC=1>[C:22]1(=[O:27])[N:21]([C:17]2[N:18]=[C:19]([NH2:20])[C:14]([CH2:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:15][N:16]=2)[C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(Cc2cnc(N3C(=O)c4ccccc4C3=O)nc2N)cc(OC)c1OC
Reaction time: 2 h
Yield: 55.6 %

Procedure:
8.7 g of trimethoprim are dissolved in 50 ml of pyridine at about 50° C., and then 4.5 g of phthalic anhydride are added. The mixture is stirred for another two hours at from 80° to 90° C.; after cooling, 100 ml of water are added. The precipitate is washed with water and recrystallized from ethanol. 7 g of 2-phthalimido-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 221° C. are obtained as intermediate product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([CH2:38][CH3:39])[CH2:36][NH2:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:37][CH2:36][CH:35]([CH3:34])[CH2:38][CH3:39])=[O:23])(=[O:16])=[O:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCC(C)CN
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CCC(C)CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 0.023 cm3 of 2-methylbutylamine. 49 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-methylbutyl)benzamide are thus obtained [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 0.80 to 0.95 (mt, 6H), from 1.05 to 120 (mt, 1H), 1.41 (mt, 1H), 1.64 (mt, 1H), 2.98 (s, 3H), 3.06 (mt, 1H), 3.19 (mt, 1H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.35 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.49 (t, J=5.5 Hz, 1H)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]([OH:41])([CH:39]=[CH2:40])[CH3:38]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:40][CH2:39][C:37]([OH:41])([CH3:38])[CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: C=CC(C)(C)O
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(O)CCc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 247 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.278 mmol) and 2-Methyl-3-buten-2-ol (0.087 ml, 0.835 mmol), the title compound was obtained as a solid (86 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) ppm 10.88 (s, 1H), 8.47 (dd, J=5.31, 1.46 Hz, 1H), 7.67 (m, 1H), 7.43 (m, 2H), 7.31 (t, J=8.15 Hz, 1H), 7.23 (t, J=9.61 Hz, 2H), 6.63 (d, J=4.94 Hz, 1H), 4.29 (s, 1H), 2.87 (m, 2H), 1.78 (d, J=8.42 Hz, 2H), 1.43 (d, J=1.46 Hz, 9H), 1.13 (d, J=1.28 Hz, 6H); MS (ESI): 591 [M+H]+.