Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:51]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:52]>C(#N)C.O>[CH3:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][O:53][C:51](/[N:33]=[C:31](\[NH2:32])/[C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH2:23][C:21]2[N:20]([CH3:34])[C:19]3[CH:35]=[CH:36][C:16]([C:14]([N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:15])=[CH:17][C:18]=3[N:22]=2)=[CH:30][CH:29]=1)=[O:52]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C

Procedure:
A solution of 1-methyl-2[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-6a (100 g) in a mixture of acetonitrile (1200 ml) and water (800 ml) was cooled to 12-18° C. Potassium carbonate (66.24 g) was added to the above reaction mixture and stirred for 15 minutes at 12-18° C. n-hexyl chloroformate (28.95 g) was added to the reaction mixture and stirred for 4½ hours at 12-18° C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the obtained solid, washed with acetonitrile and water. Dried the solid to get the title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Yield: 98 g; Purity by HPLC: 99.58%
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.ClC1N=C(N[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)C(F)=CN=1>>[F:1][C:2]1[C:3]([NH:9][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1ncc(F)c(N)n1
Product: Nc1ncc(F)c(Nc2cccc(O)c2)n1
Yield: 41 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl))-5-fluoro-2,4-pyrimidinediamine, 4-(aminocarbonylmethyleneoxy)aniline (198 mg, 1.2 mmol) and 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (95 mg, 0.4 mmol) gave N2-[4-aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (60 mg, 41%). 1H NMR (CD3OD): δ 4.55 (s, 2H), 6.75 (dm, J=7.5 Hz, 1H), 7.08 (d, J=9.3 Hz, 2H), 7.18 (m, 2H), 7.22 (d, J=8.7 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H), 8.09 (d, 1H); LCMS: ret. time: 14.38 min.; purity: 100%; MS (m/e): 370.00 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([CH2:14][N:8]2[C:7](=[O:12])[CH:6]=[C:5]3[C:10]([N:11]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[CH:9]2)=[CH:16][CH:17]=1
Reactant: Oc1cc2ccc(Br)nc2cn1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cc3nc(Br)ccc3cc2=O)cc1

Procedure:
The alkylation of 7-bromo-3-hydroxy-8-azaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-(bromomethyl)benzoate (1.53 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). The solid is crystallized from hexanes/ethyl acetate 2:1, the white crystals collected by filtration and dried to give the desired product.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([C:24](=[O:30])[CH2:25][C:26](OC)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CO>[C:1]1([NH:7][C:8]([NH:10][C:11]([CH2:12][O:13][C:26](=[O:27])[CH2:25][C:24]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:30])([CH2:16][O:17][C:26](=[O:27])[CH2:25][C:24](=[O:30])[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:14][O:15][C:26](=[O:27])[CH2:25][C:24]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:30])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CC(=O)C1CCCCC1
Reactant: O=C(Nc1ccccc1)NC(CO)(CO)CO
Solvent: CO
Product: O=C(Nc1ccccc1)NC(COC(=O)CC(=O)C1CCCCC1)(COC(=O)CC(=O)C1CCCCC1)COC(=O)CC(=O)C1CCCCC1

Procedure:
8.4 g (35 mmol) of the compound (11) and 22.0 g (119 mmol) of methyl 3-cyclohexyl-3-oxo-propionate are heated at 130° C. in a Claisen apparatus for 4 hours under application of a weak vacuum, the methyl alcohol formed being distilled off. The excess methyl 3-cyclohexyl-3-oxo-propionate (boiling point 75°-76° C./0.05 mm Hg) is then distilled off from the mixture. A brownish highly viscous oil of N-phenyl-N'-[1,1-bis-(5-cyclohexyl-3,5-dioxo-2-oxa-pentyl)-6-cyclohexyl-4,6-dioxo-3-oxa-hexyl]-urea (12) remains and can be further used without additional purification.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][CH2:61][C@H:60]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:58])([CH3:55])([CH3:54])[CH3:53]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:65](=[O:66])[C@H:64]([C@@H:60]3[CH2:61][CH2:62][CH2:63][N:59]3[C:57]([O:56][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:58])[C:68]3[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=3)[CH2:17][CH2:18]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Yield: 82.9 %

Procedure:
A solution of 5-chloro-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (75 mg, 0.205 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (“HATU”; 78.0 mg, 0.205 mmol), N-ethyl-N-isopropylpropan-2-amine (143 μL, 0.821 mmol), and (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (83.7 mg, 0.246 mmol, see Example C) in CH2Cl2 (5 mL) was stirred at room temperature for 1 hour. The solvent was removed, and the resulting residue was redissolved in EtOAc (20 mL) and washed with water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude obtained was purified by C-18 reverse phase column chromatography (Biotage C-18 12M+) using 10-90% CHsCN/water gradient on Biotage SP4 unit. The fractions containing the product were pooled, and the solvents were removed and evaporated from CH3CN (3×10 mL). The residue was transferred to a 25 mL round bottom flask using EtOAc (about 5 to about 10 mL). The residue was concentrated in vacuo and dried under high vacuum for 2 hours to provide (S)-tert-butyl 2-((S)-2-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-(4-chlorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylate (95 mg, 0.170 mmol, 82.7% yield) as a solid. LCMS (APCI+) m/z 459.1 [(M-Boc)+H]+.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C([Li])CCC.[CH3:12][O:13][CH2:14][C:15](=[O:17])[CH3:16]>O1CCCC1>[CH3:12][O:13][CH2:14][C:15]([CH3:16])([OH:17])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1]
Reactant: C#CC(C)(C)O
Reactant: COCC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC(C)(O)C#CC(C)(C)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of 2-methyl-3-butyne-2-ol (25 g, 0.3 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and to this solution, n-butyl lithium (1.6 molar solution in hexanes, 372 ml, 0.59 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of methoxyacetone (38 g, 0.43 mol) in tetrahydrofuran (50 ml) is added. The reaction mixture is stirred at −78° C. for one hour, allowed to come to ambient temperature, and stirred for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with ethyl acetate (3×250 ml), and the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 1-methoxy-2,5-dimethylhex-3-yne-2,5-diol (15 g) as a colourless oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:14]([NH:16][C:17]3[S:18][C:19]([CH:22]=O)=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:31]O.Cl.CC(OC(C)=O)=O>N1C=CC=CC=1>[C:22]([C:19]1[S:18][C:17]([NH:16][C:14](=[O:15])[CH:13]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:5])=[O:6])=[CH:8][CH:9]=2)[CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:21][CH:20]=1)#[N:31]
Reactant: NO
Reactant: O=Cc1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A stirred solution of 2-(4-cyclopropanesulfonylphenyl)-N-(5-formylthiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (EXAMPLE 86, 369 mg, 0.82 mmol) in pyridine (1.53 mL) was treated with H2NOH.HCl (63 mg, 0.91 mmol) at 0° C. The mixture was stirred at 20° C. for 3 h, before being warmed up to 60° C. and treated with Ac2O (155 μL, 1.65 mmol). After 3 h, the mixture was cooled to 20° C., before being concentrated in vacuo and treated with CH2Cl2 (6 mL) and H2O (6 mL). The aqueous phase was acidified to pH 3 with 10% aqueous citric acid. The organic layer was separated, then the aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by column chromatography (IH-EtOAc, 1:3) to furnish the title compound: RTA=3.40 min; m/z (ES+)=487.4 [M+MeCN+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.CC1(C)[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.C(N(CC)CC)C.Cl>O1CCCC1>[OH:37][C@H:36]([CH2:35][OH:34])[CH2:38][CH2:39][NH:40][C:20]([N:12]1[CH2:13][CH:14]([CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:31])[CH:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:21]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride (0.14 g, 0.28 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 7 (49 mg, 0.34 mmol) and triethylamine (0.078 mL, 0.56 mmol). The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (Yield 75 mg, 50%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M217) (299 mg, 0.57 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (194 mg, 83%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:21]/[N:22]([CH3:24])[CH3:23])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/c1ccc(S(=O)(=O)NC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 76.6 %

Procedure:
A solution of N-tert-butyl-4-methyl-3-nitrobenzenesulfonamide (5.89 g, 21.6 mmol) in N,N-dimethylformamide dimethyl acetal (10 ml) was stirred with heating at 110° C. for 10 hr. The reaction solvent was evaporated under reduced pressure and diethyl ether was added. The precipitated solid was collected by filtration, washed with diethyl ether and dried in vacuo to give N-tert-butyl-4-((E)-2-dimethylaminovinyl)-3-nitrobenzenesulfonamide (5.41 g, yield 76.6%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15]>>[C:45]([O:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][C@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[O:15])=[CH:39][CH:40]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCNC(=O)NOCC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 48 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]=[CH2:11])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(OCC)C>[Cl:15][CH2:11]/[CH:10]=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: C=CC(O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(/C=C/CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the allylic alcohol obtained in step 1 (200 mg) in diethyl ether (3 ml) was added thionyl chloride (0.087 ml) and the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give 221 mg of the desired product (100%) as a colorless solid. Mp=70° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](I)[CH:25]=[CH2:26].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:26][CH:25]=[CH2:24])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To the solution was added 0.6 g of approximately 50 % sodium hydride and stirring was performed for 30 minutes. To this was added 3.4 g of allyl iodide and the mixture was reacted for 3 hours at room temperature. Then the solvent was evaporated from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.3 g of 1-(m-nitrophenyl)-3-allylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 188-189°C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[O:5]1[CH2:26][CH:6]1[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:25])[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16]2)=[CH:11][CH:10]=1>C(O)C>[OH:5][CH:6]([CH2:26][NH:4][CH2:1][CH2:2][CH3:3])[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:25])[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16]2)=[CH:11][CH:10]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Reactant: CCCN
Solvent: CCO
Product: CCCNCC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Yield: 56.9 %

Procedure:
To 10.35 liters (125.9 mol) of n-propylamine were added 530 g (1.8 mol) of 7-(2,3-epoxypropoxy)flavone and 5.4 liters of abs ethanol. The mixture was heated at 50° to 55° for 1.5 hr, with stirring. The reaction mixture was cooled and clarified by filtration, and the filtrate concentrated in a rotary evaporator to a volume of 4.0 liters. The resulting solid product was filtered and washed with 1 liter abs ethanol; yield 383 g (60%) of a bright yellow solid, m.p. 144°-146°. The bright yellow solid was suspended in a mixture of 3.41 liters of water and 1.14 liters of 95% ethanol and then treated with 537 ml of 2.5N hydrochloric acid to obtain a solution of pH 1 to 2. The resulting aqueous solution was extracted twice with 537 ml of methylene chloride and then four times with 268 ml of CH2Cl2. The aqueous solution was clarified by filtration. Water (1.14 liters) was added to the filtrate, followed by the slow addition of 537 ml of 2.5N NaOH until the mixture tested for a pH of 10 to 11 to give a solid precipitate. The mixture was stirred for 1/2 hr. The product was filtered, washed with 2.68 liters water and air dried; yield, 362 g (57%) of the title compound as a pale yellow powder, m.p. 145°-147°.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:21])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[N:41]1([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=3)[C:6]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:21])=[CH:5][N:4]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)OCc2ccccn2)cc1Cl
Reactant: C1CNCCN1
Agent: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc(CNc2nc(N3CCNCC3)ncc2C(=O)OCc2ccccn2)cc1Cl

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxycarbonyl]pyrimidine (prepared in Example 81) 0.1500 g is treated with m-chloroperbenzoic acid (80%) 78.9 mg at 0° C. for 15 minutes. Piperazine 0.2398 g is added thereto. The reaction mixture is treated in the same manner as Example 82-(1). The resulting residue is purified with silica gel chromatography (solvent; ethyl acetate sole—ethyl acetate:methanol=1:1) and recrystallized from ethyl acetate: isopropyl ether (1:1) to give 2-(1-pyperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxycarbonyl)pyrimidine as a colorless powder, 75.1 mg. mp 101–103° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:6]=1)C.[CH2:32]([NH2:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:32]([NH:44][C:4](=[O:3])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:6]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)c1cc(-c2cccc(OC)c2)c(OCCO)c(-c2cccc(OC)c2)c1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(OC)c2)c(OCCO)c(-c2cccc(OC)c2)c1
Yield: 66.1 %

Procedure:
In a manner similar to Example 1, Step 2, the title compound (0.386 g, 65%) was prepared from 3.5-bis-(3-methoxyphenyl)-4-(2-hydroxyethoxy) benzoic acid ethyl ester (0.44 g, 1.04 mmol) and dodecylamine (0.676 g, 3.65 mmol), 1H NMR (CDCl3) δ 7.75 (s, 2H), 7.38 (m, 2H), 7.19 (m, 4H), 6.94 (m, 2H), 6.21 (t, 1H), 3.85 (s, 6H), 3.41 (m, 4H), 3.28 (m, 2H), 1.60 (m, 2H), 1.23 (m, 18H), 0.85 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:32][C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (579.6 mg, 1.55 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (213.0 mg, 1.34 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (668.2 mg, 5.17 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/80) to give the title compound as a beige solid (672.6 mg, 100%).