Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][N:3]=1.C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:8]([N:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCNc1nnc(C)s1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCN(C(=O)Cc1ccccc1)c1nnc(C)s1
Reaction time: 24 h

Procedure:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)-hexylamine (5.98 g, 0.03 mole) in toluene (60 ml) was stirred together with triethylamine (4.59 ml) and phenylacetyl chloride (4.64 g, 0.03 mole) and refluxed overnight. Further triethylamine (4.6 ml) and phenylacetyl chloride (4 ml) were added and refluxing was continued for a further 24 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform. The chloroform extract was washed with 2N sodium hydroxide solution and with water, and was dried (Na2SO4), filtered and evaporated to yield the title product as an oil, b.p. 190° C./0.1 mm (8.03 g). This was recrystallised from ethanol to give the title compound as a solid, m.p. 90° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH:7]([CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][CH:7]([CH:12]([CH3:13])[CH3:14])[C:6]=3[CH:15]=2)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)C1OC(=O)Nc2ccc(O)cc21
Product: CC(C)C1OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4-isopropyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25](=[O:27])[CH2:24][C:23]2=[O:28])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:30]1(C)[CH:35]=CC(S(O)(=O)=O)=C[CH:31]=1>C(O)CC>[CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][CH2:31][CH2:30][CH3:35])=[CH:24][C:23]2=[O:28])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(=O)CC2=O)n1
Solvent: O
Solvent: CCCO
Product: CCCOC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 105.5 %

Procedure:
(S)-3-cyclohexyl-2-(2,4-dioxo-pyrrolidin-1-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (100 mg, 0.26 mmol) was added to n-propyl alcohol (3 mL), and toluene-4-sulfonic acid hydrate (10 mg). The mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated and the crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(2-oxo-4-propoxy-2,5-dihydro-pyrrol-1-yl)-propionamide (24 mg, 22%) as an off-white solid: LR-ES-MS m/z calculated for C22H34N4O4 [M]+ 432, observed [M+H]+ 433; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.82-0.95 (m, 5H), 0.96-1.14 (m, 2H), 1.27 (d, J=6.0 Hz, 6H), 1.37-1.89 (m, 11H), 3.90 (d, J=17.6 Hz, 1H), 3.88 (s, 2H), 4.28 (d, J=17.6 Hz, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.67 (s, 1H), 4.76 (dd, J=10.3, 3.9 Hz, 1H), 5.12 (s, 1H), 6.42 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Br:24])C(=O)C1.[OH-].[Na+]>O1CCCC1>[Br:24][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 47.4 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol) [prepared in Example 116] and n-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13.6 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (4.54 ml, 27.2 mmol) which stirred at 70° C. in a sealed tube for 4 h. The solution was partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (369 mg, 1.29 mmol, 48% yield) as an orange oil: LCMS (ES) m/e 285, 287 (M, M+2)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[C:19]([CH3:28])[C:18]=1[CH3:29]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([O:16][CH3:15])=[C:18]([CH3:29])[C:19]=3[CH3:28])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(C)c1C
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3C)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.9 g (13.9 mmol) of 4-methoxy-2,3-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 0.80 g (yield of Compound 72 as white crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:28][C:29]1[N:34]=[C:33](Cl)[N:32]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1>C1COCC1>[Cl:28][C:29]1[N:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:32]=[C:33]([N:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:17]=3[C:18]3[C:10]2=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=3)[N:34]=1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc(-c2ccccc2)nc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
29.9 g (93.6 mmol) of 3,6-diphenyl-9H-carbazole are dissolved in 660 ml of THF under a protective-gas atmosphere, and 7.49 g of 60% NaH in mineral oil (187 mmol) are added. After 1 h at room temperature, a solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (63.1 g, 279.3 mmol) in 300 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene and recrystallised from dichloromethane/isopropanol. The yield is 28.4 g (56 mmol, 60%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@H:26]([CH2:45][C:46]3[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[C:49]([NH2:56])=[C:48]([Cl:57])[CH:47]=3)[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=[O:43])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:58]=[CH:59][CH:60]=[CH:61][C:12]=2[NH:11]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@H:26]([CH2:45][C:46]3[CH:51]=[C:50]([C:52]([F:53])([F:55])[F:54])[C:49]([NH2:56])=[C:48]([Cl:57])[CH:47]=3)[C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:41][C:42]([O:44][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:43])[CH2:37][CH2:36]4)[CH2:33][CH2:34]3)=[O:28])=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:58]=[CH:59][CH:60]=[CH:61][C:12]=2[NH:11]1
Reactant: COCCOCCO
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 μL (0.11 mmol) 2-(2-methoxy-ethoxy)-ethanol were added to a mixture of 75 mg (0.10 mmol) of (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 4.1), 35 mg (0.11 mmol) TBTU and 28 μL (0.20 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred for 1 h at RT. This was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:3]=1.[CH2:22]1COC[CH2:23]1.C([Mg]Br)C>C(OCC)(=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:22][CH3:23])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1F
Reactant: C1CCOC1
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc(F)cc1Nc1ccccc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
In a 500 mL round bottom flask, 4-fluoro-2-(2-fluoro-phenylamino)-N-methoxy-N-methyl-benzamide (6.0 g, 20.5 mmol) was added to THF (60 mL) to give a colorless solution. The reaction was cooled to 0° C. in an ice bath and ethyl magnesium bromide (3.0 M in THF, 27.4 mL, 82.2 mmol) was added slowly over a 15 min. period. The mixture was stirred at 0° C. for 4 hr. The reaction mixture was poured into ethyl acetate (250 mL) and washed with 1N HCl (1×150 mL), water (2×150 mL) and brine (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The crude material was purified by flash chromatography using 20% ethyl acetate-hexanes to give 1-[4-fluoro-2-(2-fluoro-phenylamino)-phenyl]-propan-1-one (3.0 g, 56%).
Reaction SMILES: [CH2:1]([C:3]1[O:8]C(C)(C)[O:6][C:5](=O)[CH:4]=1)[CH3:2].[CH3:12][NH2:13].Cl>C1(C)C(C)=CC=CC=1>[CH3:12][NH:13][C:5](=[O:6])[CH2:4][C:3](=[O:8])[CH2:1][CH3:2]
Reactant: CN
Reactant: CCC1=CC(=O)OC(C)(C)O1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCC(=O)CC(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-ethyl-2,2-dimethyl-4H-1,3-dioxin-4-one (10.0 g, 64.0 mmol) in 20 ml of xylene was bubbled with methylamine gas at 110° C. for 3 hrs. After cooling to room temperature, 5.3 ml of 1N HCl aqueous solution was added and the mixture was stirred at r.t. for 2 hrs. The organic layer was separated, the water layer was extracted by Et2O (3×30 ml). The organic layers were combined and dried (Na2SO4). After evaporation of solvent, N-methyl propionylacetamide was obtained as a colorless oil (4.25 g, 51%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:29])[CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccnc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccnc3)CC1)O2

Procedure:
Compound 59 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, nicotinoyl chloride and conditions outlined in procedure N. M.p.=218-220° C.; 300 MHz 1H NMR (CDCl3) δ 8.71 (brs, 2H), 8.08 (d, J=7.5 Hz, 1H), 7.77 (m, 3H), 7.53 (t, J=7.5 Hz, 1H), 7.40 (m, 1H), 4.62 (m, 1H), 3.78 (m, 1H), 3.42 (m 2H), 2.99 (s, 2H), 2.24 (s, 2H), 1.90 (m, 2H); LCMS: 407 [M+H].
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[C:22]([CH3:30])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:30][C:22]1[CH:21]=[C:20]([NH:19][CH:2]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:29]=[CH:28][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)cc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.1 g), methyl 4-amino-2-methylbenzoate (1.1 g), sodium carbonate (0.6 g) and sodium iodide (2.4 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.5 g, 33%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[CH:5]([O:6][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC1C(c2ccccc2)=C(c2ccc(S(C)(=O)=O)cc2)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Example 62 (100 mg) in CH2Cl2 (1.5 mL) at r.t., was added diisopropylethylamine (105 μL) and pivaloyl chloride (70 μL). The mixture was stirred at r.t. for 1.5 hr and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (80:20)) to give the title compound as a yellow solid, m.p. 66°-67° C.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].O.S([O-])([O-])=O.[Na+].[Na+].[Br:30]Br>C(O)(=O)C>[CH2:1]([CH:3]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([Br:30])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h

Procedure:
EPAQ (20.02 g) was dissolved in hot acetic acid. In a separate flask, bromine (12.03 g) was dissolved in acetic acid (ca. 10 mL). The bromine solution was slowly added to the dye solution. The reaction was allowed to proceed for 1/2 hour, with occasional shaking. The reaction mixture was poured into water (600 mL), and aqueous sodium sulfite was added to discharge the bromine. The aqueous solution was decanted off. The solid was dissolved in methylene chloride and then concentrated and slowly added to cold methanol whereupon a solid precipitated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19]CC3C=CC(OC)=CC=3OC)=[N:15][CH:16]=2)[N:11]([CH3:31])[C:10]1=[O:32].FC(F)(F)C(O)=O>ClCCl>[NH2:19][C:14]1[N:13]=[C:12]2[N:11]([CH3:31])[C:10](=[O:32])[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1
Reactant: COc1ccc(CNc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
A solution of 200 mg (0.42 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(2,4-dimethoxybenzylamino)-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one in 2 ml of dichloromethane was treated with 2 ml of trifluoroacetic acid and the mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The solvent was evaporated, the residue was triturated with saturated aqueous sodium bicarbonate solution and the product was collected by filtration and sucked dry. The dried product was purified further by suspension in dichloromethane and filtration through a polytetrafluoroethylene membrane. The filtrate was evaporated and the residue was dried to give 115 mg (84%) of 7-amino-3-(2,6-dichlorophenyl)-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 176-184° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:14](=[O:15])[N:13]2[C:9](=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:20]([N:8]1[C:9]2=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[N:13]2[C:14](=[O:15])[C:6]([C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:5])=[CH:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2nc3ccccc3n2c1=O
Reactant: C1COCCN1
Product: O=C(c1cn(Cc2ccccc2)c2nc3ccccc3n2c1=O)N1CCOCC1

Procedure:
By substituting 1-benzyl-1,4-dihydro-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxylic acid ethyl ester in part a and morpholine in part b of Example 33, 1-benzyl-3-(4-morpholinylcarbonyl)pyrimido[1,2-a]benzimidazol-4(1H)one is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])=[CH:8][C:7]([Cl:20])=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:28][CH2:18][C:13]1[C:12]([F:19])=[C:11]([O:10][C:9]2[C:2]([Cl:1])=[C:3]([CH:6]=[C:7]([Cl:20])[CH:8]=2)[C:4]#[N:5])[C:16]([Cl:17])=[CH:15][CH:14]=1
Reactant: Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Yield: 51.6 %

Procedure:
2,5-dichloro-3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (1.01 g, 3.06 mmol) and NBS (0.544 g, 3.06 mmol) were combined in carbon tetrachloride (30 mL) with a catalytic amount of AIBN (0.025 g, 0.153 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography on 80 g silica gel eluted with 0 to 10% Et2O in hexanes to give the 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.647 g, 1.580 mmol, 51.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d, J=2.20 Hz, 1H), 7.53-7.64 (m, 2H), 7.29 (d, J=1.92 Hz, 1H), 4.75 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:13][CH2:35][CH2:36][NH:37][C:38]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:44]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OCCNC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 115 %

Procedure:
To a solution of 2-hydroxy-4-nitro benzoic acid methyl ester (7.0 g, 0.035 mol), triphenylphosphine (9.31 g, 0.035 mol) and t-butyl N-(2-hydroxyethyl)carbamate (3.82 g, 0.023 mol) in anhydrous THF (400 mL) (stirring for 1 hr.) was added diisopropyl azodicarboxylate (7.03 mL, 0.035 mol) and stirred for 2 days. The reaction was evaporated and the residue purified by ISCO chromatography to give 2-(tert-butoxycarbonylamino-ethoxy)-4-nitro-benzoic acid methyl ester (9.0 g,) as a white solid. 1H-NMR (DMSO-d6) δ 7.90 (s, 1H), 7.86 (s, 2H), 6.86-92 (br, 1H), 4.18-9 d, 2H), 3.85 (s, 2H), 3.31 (d, 2H), 1.37 (s, 9H); LC/MS (ESI+): 363 (M+Na).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[Cl:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH:32][C:6](=[O:8])[C@@H:5]1[CH2:9][CH2:10][C:11](=[O:12])[N:4]1[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)N1C(=O)CC[C@H]1C(=O)O
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
1-(1-Methylethyl)-5-oxo-proline (0.060 g, 0.35 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and dimethylformamide (1 ml) and to this was added 1-hydroxybenzotriazole (0.052 g, 0.39 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.061 g, 0.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.074 g, 0.39 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-(1-methylethyl)-5-oxo-prolinamide (0.032 g) as a white solid. LC/MS [M+H]+=313.1, retention time=2.26 minutes.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.O>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccs1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccs1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
The product of Example 240a (1.50 g, 5.63 mmol) was dissolved in DMF to which K2CO3 (1.55 g, 11.27 mmol), and 4-mercapto-phenol (711 mg, 5.634 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.66 g, 79%).