Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)[C:21](OC)=[O:22])=[O:18].Cl>CN(C)C=O.ClCCl>[CH2:1]([N:8]1[CH2:16][C:17](=[O:18])[NH:19][C@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=2)[C:21]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(C)c1)NC(=O)CCl
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1C
Temperature: 35 °C
Reaction time: 3 h

Procedure:
Benzylamine (5.4 ml) and potassium carbonate (4.08 g) were added successively to a solution of methyl (2R)-2-(2-chloroacetylamino)-3-(3,4-dimethylphenyl)propionate (5.33 g) in N,N-dimethylformamide (25 ml) at 20° C. After 3 hours of stirring at 35° C., the mixture was poured into a mixture of ice-water (40 ml) and dichloromethane (40 ml). After the mixture was adjusted to pH 6 with concentrated hydrochloric acid (ca. 1.4 ml), the organic layer was separated, washed with brine (20 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with n-hexane and filtered to give colorless powders of (3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.51 g). The filtrate was evaporated under reduced pressure to give an oil of methyl (2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate (5.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[C:44]1([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid pyrrolidine-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15]N(C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[NH2:24][C@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][NH:24][C@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)c(OC)cc1OC
Reactant: CC(C)[C@H](N)CO
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN[C@H](CO)C(C)C)C(=O)c1cc(Br)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate obtained in Step 4 of Example 1 in toluene was added L-valinol (20.6 g). After stirring at room temperature for 1 hr, the completion of the reaction was confirmed by HPLC. 1 mol/L Hydrochloric acid (200 mL) was added to the reaction mixture, and after stirring, the toluene layer was separated. The toluene layer was further washed successively with 1 mol/L hydrochloric acid (200 mL), water (200 mL), 5% aqueous sodium hydrogencarbonate solution (200 mL) and water (200 mL). After washing, toluene was evaporated under reduced pressure, toluene (200 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. THF (200 mL) was further added to the concentrated residue, and the mixture was concentrated again under reduced pressure. THF (160 mL) was added to the obtained concentrated residue to give ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate as a tetrahydrofuran solution. The solution was directly used in the next step.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH:19]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][CH2:20]2)[CH2:13]1)C.O>C1COCC1>[O:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][CH2:20][CH:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][CH2:10][OH:9])[CH2:13]1
Reactant: CCOC(=O)CC1CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a suspension of LiAlH4 (0.12 g, 3.16 mmol) in dry THF (4 ml) was added [1-(2,3-dihydrobenzo-[1,4]dioxin-2-ylmethyl)piperidin-3-yl]acetic acid ethyl ester 2.0 g (0.62 mmol) in dry THF (2 ml). The reaction mixture was refluxed for 1.5 h. Water was slowly added and the reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the desired product which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Cl/[C:8](=[N:14]/[OH:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[C:1]([C:5]1[O:15][N:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
5.61 g of t-butylacetylene and 9.09 g of ethyl (2E)-chloro(hydroxyimino)acetate were dissolved in 70 ml of tetrahydrofuran, and 11.4 ml of triethylamine was then added dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight. After aqueous saturated sodium chloride was added, the reaction mixture was separated into layers. The aqueous layer was extracted with methyl-t-butyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.83 g of ethyl 5-t-butyl-isoxazole-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[N:3]=1.OS(O)(=O)=O.[CH3:16][CH2:17]O>C(Cl)Cl>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([O:10][CH2:16][CH3:17])=[O:9])[N:3]=1
Reactant: CCO
Reactant: Cc1ccn(CC(=O)O)n1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc(C)n1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A suspension of (3-methyl-1H-pyrazol-1-yl)acetic acid (200 mg) and H2SO4 (0.1 mL) in EtOH (2 mL) was stirred at 80° C. for 4 h. After cooling down, the reaction mixture was diluted with DCM and washed with sat. Na2CO3, water and brine. The aq. layers were extracted with DCM, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo to afford ethyl 2-(3-methyl-1H-pyrazol-1-yl)acetate (101 mg, colourless liquid). LC-MS (B): tR=0.57 min; [M+H]+: 169.01.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:34])[C@@H:23]4[C@H:27]([O:29][Si](C)(C)C)[CH3:28])[C:20]=3[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[S:16][CH:17]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].O.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:4][C:5]([N:7]1[C@@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:34])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[S:16][CH:17]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(5S)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (85 mg, 0.14 mmol) in THF (6 ml) was added at 0° C. water and then the solution was adjusted to pH about 3 with 1N hydrochloric acid and stirred for 10 minutes. To the reaction solution was added an aqueous sodium hydrogen carbonate solution and the reaction mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1/2) to give allyl (4R,5S,6S)-3-[(4-{(5S)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (60 mg, 80%) as a pale yellowish amorphous.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:28]=[CH:29][C:30]([C:33]([OH:35])=O)=[N:31][CH:32]=1.CCN(C(C)C)C(C)C.[F:45][C:46]([F:59])([F:58])[C:47]1[NH:48][C:49]2[C:54]([CH:55]=1)=[CH:53][C:52]([CH2:56][NH2:57])=[CH:51][CH:50]=2>CN(C=O)C>[CH3:25][O:26][C:27]1[N:28]=[CH:29][C:30]([C:33]([NH:57][CH2:56][C:52]2[CH:53]=[C:54]3[C:49](=[CH:50][CH:51]=2)[NH:48][C:47]([C:46]([F:59])([F:45])[F:58])=[CH:55]3)=[O:35])=[N:31][CH:32]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)NCc2ccc3[nH]c(C(F)(F)F)cc3c2)cn1
Reaction time: 24 h
Yield: 60.7 %

Procedure:
To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 5-(methyloxy)-2-pyrazinecarboxylic acid (AniChem LLC; 49.2 mg, 0.319 mmol) in DMF (0.5 ml), followed by DIPEA (0.084 ml, 0.479 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 40 mg, 0.160 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge. The organic layer was evaporated to dryness and purified using MDAP to give the title compound as a white solid (34 mg);
Reaction SMILES: N1C=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[N:18]1C=CC(B(O)O)=C[CH:19]=1>>[N:18]1[CH:19]=[CH:2][C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[CH:4][CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Product: O=Cc1ccc2c(-c3ccncc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting pyridin-4-ylboronic acid (27 mg, 0.22 mmol), the title compound was obtained as a beige solid (3.7 mg, 9%). 1H NMR (400 MHz, CD3OD) δ ppm 10.15 (s, 1H), 8.69 (d, J=6.3 Hz, 2H), 8.32 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 8.10 (d, J=6.3 Hz, 2H), 7.84 (d, J=6.3 Hz, 1H); MS ESI 224.0 (100) [M+H]+, calcd for [C13H9N3O+H]+ 224.07.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:23][C:24]2[CH:25]=[N:26][N:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH:28]=2)[N:3]=1.B(O)(O)O.F[C:43]([K])=[C:44](F)F.C(N(CC)CC)C.CO>C1COCC1.CC(O)C.[OH-].[OH-].[Pd+2]>[CH2:43]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:23][C:24]2[CH:25]=[N:26][N:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH:28]=2)[N:3]=1)[CH3:44]
Reactant: COc1ccc(Cn2cc(Cn3nc(I)c4c(NC(=O)c5cnc6ccccn56)cccc43)cn2)cc1
Reactant: FC(F)=C(F)[K]
Agent: [Pd+2]
Agent: OB(O)O
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCc1nn(Cc2cnn(Cc3ccc(OC)cc3)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 86 °C
Reaction time: 5 h
Yield: 64.6 %

Procedure:
To N-(3-iodo-1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.59 g, 0.98 mmol) in THF/IPA (1 mL/3 mL) was added trifluorovinylpotassium borate (0.20 g, 1.5 mmol), triethylamine (0.20 g, 2.0 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.080 g, 0.098 mmol). The reaction mixture was heated at 86° C. and stirred for 5 hours. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure, and triturated with Et2O (30 mL) to give crude vinyl product, to which palladium hydroxide on carbon (20% wt, 0.27 mmol) and MeOH (20 mL) was added. The system was purged with N2 three times and a H2 balloon was applied to the system for 2 hours. The reaction mixture was filtered through Celite, washed with MeOH (20 mL), and concentrated to give the product (0.32 g). MS (ES+APCI) m/z=506 (M+H).
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[F:20][C:18]1[C:17]([F:21])=[CH:16][N:15]([C:8]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([OH:5])[CH:7]=2)[CH:19]=1
Reactant: CC(C)(C)Oc1cc(-n2cc(F)c(F)c2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1O
Yield: 95.6 %

Procedure:
A mixture of 1-(3-tert-butoxy-4-nitrophenyl)-3,4-difluoro-1H-pyrrole (8.30 g), TFA (30 mL) and THF (60 mL) was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane/ethyl acetate (10/1) to give the title compound (6.43 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:28][CH:29]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:28][CH:29]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (655 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (569 mg, yield: 92%). This was recrystallized from ethanol-hexane. Melting point: 121–122° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:16](#[N:18])[CH3:17]>Cl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[O:3][C:2]([NH:18][C:16]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:17]=3[CH2:5][CH:4]([OH:3])[CH2:8][CH2:9]4)=[N:6][C:5]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2oc(Cl)nc2C)cc1
Reactant: CC#N
Agent: Cl
Product: COc1ccc(-c2oc(Nc3cccc4c3CC(O)CC4)nc2C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
A mixture of Example 14D (0.840 g, 3.76 mmol) and Example 1A (1.04 g, 3.76 mmol) in acetonitrile (19 mL) was heated in a microwave reactor at 150° C. for 20 minutes. Two drops of aqueous concentrated HCl were added and the reaction was reheated in the microwave to 150° C. for 20 min. The volatiles were evaporated and the crude material was dissolved in tetrahydrofuran (20 mL), followed by addition of 10 mL 6N HCl. The mixture was stirred overnight at ambient temperature, then diluted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel using methanol/CH2Cl2 as eluent (2% to 20%), followed by triturating with diethyl ether to afford 122 mg (9% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.60 (d, J=7.93 Hz, 1H), 7.42 (d, J=9.12 Hz, 2H), 7.04 (m, 3H), 6.81 (d, J=7.54 Hz, 1H), 4.80 (d, J=3.97 Hz, 1H), 3.92 (bs, 1H), 3.78 (s, 3H), 2.90 (m, 2H), 2.75 (m, 1H), 2.22 (s, 3H), 1.87 (bs, 1H), 1.62 (bs, 1H). MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:17][C:14]([CH3:15])([CH2:13][CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:16])(=[O:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of the alcohol 2 (0.500 g, 1.937 mmol), ZrOCl28.H2O (0.0031 g, 0.5 mol %) in methylene chloride (5 mL), acetyl chloride (0.304 g, 3.87 mmol) is added and the reaction is stirred for overnight at 20° C. The reaction on completion, is diluted with methylene chloride (5 mL) and washed with saturated sodium bicarbonate (2×10 mL), brine (1×10 mL) and dried. The solvent is evaporated to get the crude product. 1H NMR (400 MHz, CDCl3): δ 1.54 (s, 6H), 1.59 (s, 3H), 2.14-2.07 (m, 2H), 2.43 (s, 3H), 4.26 (dt, J=6.9, 13.5, 3H), 7.33 (d, J=7.9, 2H), 7.77 (d, J=8.2, 2H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([NH2:16])[CH2:14][CH3:15]>C(O)(C)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH2:13][CH2:14][CH3:15])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCN
Solvent: CC(C)O
Product: CCCNC(=O)c1ccccc1N

Procedure:
To 32.6 g of isatoic anhydride in 150 ml of isopropyl alcohol was added 25 ml of n-propylamine portionwise as the reaction was exothermic. Evaporation of the solution gave 30 g of 2-amino-N-propylbenzamide as colorless crystals, mp 100°-102° C. To a stirred solution of 25.0 g of 2-amino-N-propylbenzamide in 300 ml of tetrahydrofuran was added 22.9 g of benzoylisothiocyanate over 10 minutes. After 2 hours the mixture was diluted with 100 ml of ether and was filtered to give 30.7 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide, mp 172°-174° C. Then, to a solution of 10.2 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide in 100 ml of dichloromethane was added 30 ml of 1N sodium hydroxide to form a two-phase mixture, and to this was added 20 ml of iodomethane and then 4 drops of benzyltrimethylammonium hydroxide solution. After stirring for 3 hours, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate gave 9.4 g of N-benzoyl-N'-(2-propylaminocarbonylphenyl)carbamimidothioic acid, methyl ester, mp 86°-89° C. To a solution of 7.10 g of this compound in 300 ml of anhydrous dioxane was added 1.45 g of 60% sodium hydride in mineral oil suspension and the mixture was refluxed for 5 hours. The reaction mixture was then poured into 1.5 liter of water and made acidic with hydrochloric acid. The crystals that formed were collected and recrystallized from ethyl acetate-hexane to give N-(3,4-dihydro-3-propyl-4oxo-2-quinazolinyl)benzamide as colorless crystals, mp 133°-135° C.
Reaction SMILES: S(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>C(O)C>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 71.3 %

Procedure:
Sodium bisulfite (14.4 g) is added to 4-bromobenzaldehye (17.1 g) in ethanol (100 mL) and the mixture stirred at reflux for 15 minutes. 1,2-Diaminobenzene (10 g) is added and the mixture stirred at reflux for 16 hours. The solvent is evaporated and the residue is washed with water and ethanol to afford 18.0 g of the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41]OS(C)(=O)=O)[CH:35]=2)[C:10]1=[O:47].[CH3:48][NH:49][CH3:50]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][N:49]([CH3:50])[CH3:48])[CH:35]=2)[C:10]1=[O:47]
Reactant: CNC
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCOS(C)(=O)=O)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Solvent: CCO
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCN(C)C)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 50 °C
Yield: 22 %

Procedure:
50 mg (0.07 mmol) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one of Example 81(a) was treated with 3 ml of a 33% solution of dimethylamine in ethanol and the mixture heated at 50° C. for 3 hours. The mixture was cooled and evaporated. The product was purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to afford 10 mg (22%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-(dimethylamino)ethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 92° C.