Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[C:7]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[N:11]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:8]2=[N:9][CH:10]=1.Cl.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[CH:25]1([CH2:24][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([NH:4][CH3:3])[CH:6]=[C:7]3[N:13]=[C:12]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:27][CH2:26]1
Reactant: CCOc1ccc(Cc2nc3cc(NC(=O)OC)cnc3n2CC2CC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1ccc(Cc2nc3cc(NC)cnc3n2CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To a solution of [3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-yl]-carbamic acid methyl ester (550 mg, 1.46 mmol) in dichloromethane (20 mL) at room temperature was added 1 M HCl in diethyl ether solution (3 mL). The mixture was stirred for 10 minutes and concentrated in vacuo. The residue was taken up into THE (5 mL) and diethyl ether (30 mL) and cooled to 0° C. LAH (137 mg, 3.61 mmol) was added to the solution. The mixture was stirred overnight. The reaction was then cooled to −78° C. and quenched with MeOH (3.20 mL) and water (3.20 mL). Na2SO4 was added to the mixture which was allowed to slowly warm up to room temperature. The mixture was filtered over Celite and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3.5% MeOH+0.5% NH4OH aq] in CH2Cl2) to provide 445 mg of the title compound 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine (90.6% yield from [3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-yl]-carbamic acid methyl ester). 1H-NMR (400 MHz, CDCl3): δ 0.35 (m, 2H), 0.46 (m, 2H), 1.11 (m, 1H), 1.39 (t, J=7.0 Hz, 3H), 2.90 (s, 3H), 3.98 (m, 4H), 4.25 (s, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.23 (d, J=2.5 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H). MS (ESI) (M+H)+: 337.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1.[C:34](O)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][O:28][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)(C)C(=O)O
Product: CCOC(=O)C1=C(CN2CCO[C@@H](COC(=O)C(C)(C)C)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 42.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)morpholino)methyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with pivalic acid (0.51 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.99 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1([CH:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:30]5[CH2:29][CH2:28][CH:27]([N:21]6[CH2:26][CH2:25][O:24][CH2:23][CH2:22]6)[CH2:33][CH2:32][C:31]=5[CH:34]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc5c(c4)CCC(N4CCOCC4)CC5)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (88.0 mg, 0.357 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (36.0 mg, 0.0658 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.107 g, 63%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.6 Hz, 1H), 8.23 (d, J=8.5 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.65 (d, J=7.4 Hz, 1H), 7.36 (dd, J=8.1, 2.2 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.01 (t, J=7.1 Hz, 1H), 6.81 (s, 1H), 3.73-3.67 (m, 4H), 3.10 (s, 3H), 2.85 (ddd, J=13.7, 13.7, 7.5 Hz, 2H), 2.76-2.51 (m, 7H), 2.10 (ddd, J=11.2, 11.2, 11.2 Hz, 2H), 1.44 (dddd, J=23.3, 11.5, 11.5, 11.5 Hz, 2H). MS=518 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)OC(C)(C)C
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: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)s1)NC(=O)OC(C)(C)C

Procedure:
Suzuki Coupling. To a solution of (S)-3-(5-bromo-thiophen-2-yl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in toluene (10 mL) was added 4-cyanobenzeneboronic acid, Pd(PPh3)4, and 1N Na2CO3 solution (4 mL). The mixture was heated at reflux for 7 h. After completion of the reaction, the aqueous layer was drained. The organic was washed with 10% Na2CO3 and 1 N HCl. The organic was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was then purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-butoxycarbonylamino-3-[5-(4-cyano-phenyl)-thiophen-2-yl]-propionic acid methyl ester.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:6]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C>ClCCl>[CH2:44]([O:51][NH:52][C:11]([C:10]1[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:8]([F:14])[CH:9]=1)=[O:13])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN1CCN(c2nc(NC3CC3)c(C(=O)O)cc2F)CC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2nc(NC3CC3)c(C(=O)NOCc3ccccc3)cc2F)CC1
Yield: 59.8 %

Procedure:
Following the procedure of Example 1-2, the reaction of 2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxylic acid (Example H-2, 200 mg, 0.67 mmol) and HOBT (99.5 mg, 0.74 mmol) with EDCI (154.6 mg, 0.81 mmol) in dichloromethane (10 mL) followed by adding O-benzylhydroxylamine hydrochloride (0.81 mmol) and triethylamine (0.113 mL. 0.81 mmol) gave a crude oil. Purification of the oil by flash chromatography on a silica gel column with 5% of MeOH in dichloromethane provided 160 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=3)[C:14]([N+:27]([O-])=O)=[CH:13][N:12]=2)[CH3:9])=[N:6][CH:7]=1.[CH2:30](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]3[C:14]([N:27]=[CH:30][N:17]3[C:18]3[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=3)=[CH:13][N:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-n2cnc3cnc(N[C@@H](C)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidine-2,4-diamine (Intermediate 31, 1.0 g) was dissolved into ethanol (20 mL) with Pd—C (150 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (1.0 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.7 g desired product. MS (electrospray): 383 (M+1) for C18H19FN8O. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 1H) 8.40 (m, 2H) 7.50 (dd, 2H) 6.00 (s, 1H) 5.20 (m, 1H) 4.20 (m, 1H) 1.50 (d, 3H) 1.40 (d, 6H).
Reaction SMILES: [CH:1]1[C:17]2[C:16]3[C:8](=[C:9]4[C:13](=[CH:14][CH:15]=3)[CH2:12][CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:27])C=1Cl>C(O)(=O)C.CCOCC>[CH:1]1[C:17]2[C:16]3[C:8](=[C:9]4[C:13](=[CH:14][CH:15]=3)[C:12](=[O:27])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: c1ccc2c(c1)CCc1c-2ccc2c1CCC2
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CCc2c1ccc1c2CCc2ccccc2-1
Yield: 76.4 %

Procedure:
The hydrocarbon (5) 48 mg; 0.22 mmol) was dissolved in hot acetic acid (15 ml) and water (5 ml) was added slowly with stirring to maintain homogeneity of the solution. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (198 mg, 0.88 mmol) was added, changing the color of the solution to dark green. Stirring was continued at reflux for 30 min. during which time the color of the solution changed to dark red. The reaction mixture was cooled and diluted with ether, and the ether layer was washed with water and aqueous NaOH. The solution was dried over MgSO4 and evaporated to provide a white solid which was chromatographed on a column of Florisil™. Elution with ether yielded 6 (39 mg, 76%):m.p. 127°-128° C.; NMR δ272 (t,l,H15 or16), 2.85-2.91 (m,4,H6,7), 3.07 (t,l,H15 or16), 7.24-7.31 (m,3,H2,3,4), 7.67-7.77 (m,3,H1,11,12) Anal. Calc'd. for C17H14O: C,87.25; H,6.02. Found: C,87.13; H,6.03.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]([O:48][CH2:49][CH3:50])(=[O:47])[CH:45]=[CH2:46].[O-]CC.[Na+]>C(O)C>[CH2:26]([O:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:46][CH2:45][C:44]([O:48][CH2:49][CH3:50])=[O:47])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: C=CC(=O)OCC
Reactant: CCCCCCCC/C=C\CCCCCCCCOCCNCCOCCCCCCCC/C=C\CCCCCCCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCC/C=C\CCCCCCCCOCCN(CCOCCCCCCCC/C=C\CCCCCCCC)CCC(=O)OCC
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Compound 67 (400 mg, 0.660 mmol) obtained in Example 67 was dissolved in ethanol (8 mL), and stirred overnight under heat and reflux after adding ethyl acrylate (3.59 mL, 33.0 mmol) and sodium ethoxide (22.5 mg, 0.330 mmol). After cooling the reaction solution, the solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 98/2) to give ethyl 3-(bis(2-((Z)-octadec-9-enyloxy)ethyl)amino)propanoate (399 mg, 85.6%).
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:30][O:31][CH3:32])[CH2:20][CH2:21][O:22]CC2C=CC=CC=2)[CH2:13][C@H:12]1[CH3:33])=O)C1C=CC=CC=1.[ClH:34]>>[ClH:34].[OH:22][CH2:21][CH2:20][C@H:19]([N:14]1[C:15](=[O:18])[CH2:16][CH2:17][NH:11][C@H:12]([CH3:33])[CH2:13]1)[CH2:30][O:31][CH3:32]
Reactant: COC[C@H](CCOCc1ccccc1)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O
Agent: Cl
Product: COC[C@H](CCO)N1C[C@@H](C)NCCC1=O
Reaction time: 6 h
Yield: 98 %

Procedure:
In analogy to the procedure described in intermediate SE, (R)-4-((S)-3-benzyloxy-1-methoxymethyl-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and 0.95 eq. of 1 M aq. hydrochloric acid solution was hydrogenated for 6 h to give the title compound in 98% yield as white foam. MS: 231.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:33]Br)=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=1>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:33][C:26]3[C:25]([Br:24])=[CH:30][N:29]=[C:28]([S:31][CH3:32])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CSc1ncc(Br)c(CBr)n1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reaction time: 1 h

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 1, 326 mg, 1.041 mmol) was dissolved in THF (7 mL) and cooled in an ice bath. To this solution was added NaH (27.3 mg, 1.136 mmol) all at once. The resulting bubbling/foaming mixture was stirred in an ice bath for 1 h followed by addition of 5-bromo-4-(bromomethyl)-2-(methylthio)pyrimidine (Step C, 282 mg, 0.946 mmol) in THF (3 mL). The resulting yellow mixture was stirred in an ice bath and allowed to warm to ambient overnight. The reaction crude was then quenched by adding NH4Cl (aq., sat.). The resulting mixture was worked up with brine, dried (Na2SO4), filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a EtOAc/hexanes gradient mixture (0% to 20%). Related fractions were pooled and evaporated into a colorless glass/gum as the titled compound. LCMS calc.=530.99; found=532.00.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6](=[S:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[NH2:17][C:3]1[C:4](=[O:16])[NH:5][C:6](=[S:15])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:2]=1[NH2:1]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1ccccn1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N)n(Cc2ccccn2)c(=S)[nH]c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
6-Amino-1-(pyridin-2-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.60 g, 2.56 mmol, obtained from Example 1(b)) was dissolved in acetic acid (90% aq., 10 mL) and was heated at 75° C. for 5 minutes. Sodium nitrite (0.20 g, 2.95 mmol) was added and heating was continued for another 30 minutes. The solvent was removed in vacuo and the residue was suspended in water (6 mL), and ammonia (32% aq., 6 mL) was added. The reaction mixture was heated at 75° C. and sodium dithionite (1.1 g, 6.4 mmol) was added and the resulting mixture was continued stirring at 75° C. for 5 minutes, and then stirred at r.t. for 30 minutes. After adjusting the solution to neutral pH with 2M sulfuric acid the precipitated solid was collected by filtration, washed with a small amount of water and dried, giving the title compound (0.331 g, 52%) as a solid. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10](CCCCO)[O:9]N=2)C=CC=C[CH:2]=1.[OH:17][N:18]=[C:19](Cl)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)CCC#C>>[C:21]1([CH2:20][C:19]2[CH:2]=[C:1]([CH2:7][CH2:11][CH2:10][OH:9])[O:17][N:18]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCCc1cc(-c2ccccc2)no1
Reactant: ON=C(Cl)Cc1ccccc1
Agent: C#CCCCO
Product: OCCCc1cc(Cc2ccccc2)no1

Procedure:
Synthesised as with 4-(3-phenyl-5-isoxazolyl)-1-butanol, using N-hydroxy-2-phenylethanimidoyl chloride (253 mg, 1.5 mmol) and 4-pentyn-1-ol (139 mg, 1.65 mmol). Yield 61 mg of pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19].Cl[C:21]([O:23][CH3:24])=[O:22].C([O:27]CC)C>C(OCC)(=O)C>[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19].[CH3:24][O:23][C:21](=[O:27])[O-:22]
Reactant: CCOCC
Reactant: COC(=O)Cl
Agent: Cc1ccc2ccccc2c1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[O-]
Reaction time: 1 h

Procedure:
2.64 g (26 mmole) of triethylamine were added to a stirred solution of 3.16 g (20 mmole) of 2-methyl-1-naphthol in 25 mL of ethyl acetate, while the solution was maintained in an ice bath. Then 2.36 g (25 mmole) methyl chloroformate were added portionwise to the solution. The reaction mixture was stirred for one hour and then 100 mL diethylether was added. The reaction mixture was filtered over a Celite pad and the filtrate concentrated to give 3.65 g (85% yield) of an oil which was crystallized in hexane. The resulting crystals had a melting point of 54-55° C. The following 1HNMR was obtained: (300 MHz, DMSO-d6) δ2.30 (s, 3H), 3.89 (s, 3H), 7.44 (d, 1H, J=8 Hz), 7.48-7.58 (m, 2H), 7.78 (t, 2H, J=9 Hz), 7.95 (d, 1H, J=8 Hz). The mass spectrum showed a molecular ion at m/z 216.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:30]=1[NH2:31].Cl.ClC1C=C(NC2C3C(=CC(OC4CCNCC4)=C(OC)C=3)N=CN=2)C=CC=1F>>[ClH:1].[Cl:36][C:33]1[CH:34]=[CH:35][C:29]([F:28])=[C:30]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCNCC1
Agent: Cl
Product: COc1cc2c(Nc3cc(Cl)ccc3F)ncnc2cc1OC1CCNCC1

Procedure:
tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with 2-fluoro-5-chloroaniline using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(5-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6) 1.8-2.1 (m, 2H), 2.1-2.35 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.8-5.0 (m, 1H), 7.4-7.55 (m, 2H), 7.55-7.75 (m, 2H), 8.45 (s, 1H), 8.82 (s, 1H), 9.22 (bs, 2H), 11.94 (s, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.C(Cl)(Cl)Cl.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CC1(C)CCCN(C)C1(C)C>CCOCC>[CH3:20][S:21]([N:10]1[CH2:9][CH2:8][N:7]=[C:6]1[CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=1[CH3:1])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Agent: CN1CCCC(C)(C)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1cccc(OCC2=NCCN2S(C)(=O)=O)c1C

Procedure:
2-(2,3-Dimethylphenoxymethyl)-2-imidazoline (8.0 g; 0.0392 moles) was dissolved in dry ether (75 ml) and sufficient dry chloroform (50 ml) and the solution cooled in ice (sufficient chloroform was used to prevent precipitation of the imidazoline on cooling). Methanesulphonyl chloride (4.50 g; 0.0393 moles) was added dropwise to the cold, stirred solution. When the addition was complete pentamethylpiperidine (6.08 g; 0.0392 moles) was added and the reaction mixture heated under reflux until tlc showed that reaction was complete (~3 hrs). The reaction mixture was then concentrated under reduced pressure and the residue extracted with a water/chloroform mixture (1:1; ~100 ml). The chloroform layer was washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a residue which was recrystallised from isopropanol to give 1-methanesulphonyl-2-(2,3-dimethylphenoxymethyl)-2-imidazoline, m.p. 142°-143° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[C:9]=2[F:18])=[CH:4][N:3]=1.Cl[CH:20]([C:30]1([C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][CH:37]=[CH:36]3)[CH2:32][CH2:31]1)[CH:21](N1C(=O)CCC1=O)O>C(O)C>[F:17][C:10]1[C:9]([F:18])=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:20]([C:30]4([C:33]5[CH:34]=[C:35]6[C:40](=[CH:41][CH:42]=5)[N:39]=[CH:38][CH:37]=[CH:36]6)[CH2:32][CH2:31]4)=[CH:21][N:1]=3)[CH:4]=2)[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Nc1ncc(-c2ccc(C(=O)O)c(F)c2F)cn1
Reactant: O=C1CCC(=O)N1C(O)C(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A mixture of 4-(2-aminopyrimidin-5-yl)-2,3-difluorobenzoic acid (15 mg, 0.060 mmol) and 1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione (20 mg, 0.058 mmol) in ethanol (1.0 mL) was stirred at 100° C. overnight. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product (9 mg, 40%). LCMS: (M+H)=443.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1.[C:25](Cl)(=[O:27])[CH3:26].[OH-].[Na+]>C1COCC1>[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH:1][C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]1)(=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 33.2 %

Procedure:
A solution of 5-nitro-2-(piperazin-1-yl)benzenamine (2.4 g, 10.7 mmol), benzoyl chloride (1.2 ml, 12.8 mmol) and triethylamine (6.0 ml, 42.7 mmol) in 40 ml DCM was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. (4-(2-Amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (3.0 g, 86%) was obtained by flash column chromatograph (40% ethyl acetate in hexanes). A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.3 g, 0.9 mmol), acetyl chloride (0.065 ml, 0.9 mmol) and sodium hydroxide (0.037 g, 0.9 mmol) in 20 ml THF was stirred at 0° C. for 2 hours. The mixture was concentrated. N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)acetamide (0.11 g, 32%) was obtained by flash column chromatograph (65% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.29 (s, 3H), 3.00 (s, br, 4H), 3.84 (s, br, 4H), 7.23 (d, J=8.8 Hz, 1H), 7.47-7.51 (m, 5H), 8.00 (dd, J=8.6, 2.6 Hz, 1H), 8.16 (s, br, 1H), 9.24 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 25.3, 52.3, 116.0, 119.9, 120.8, 127.6, 129.2, 130.7, 135.6, 171.2.