Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14][OH:15])=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:11]1[S:10][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[N:13][CH:12]=1)(=[O:25])=[O:24]
Reactant: CC1(c2ncc(CO)s2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ncc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methanol (389 mg, 1.93 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.35 mL, 2.50 mmol) followed by DMAP (24 mg, 0.19 mmol) and Ms-Cl (0.19 mL, 2.40 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC (1:1->1:2 hept-EA+1% Et3N) gave pure (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methyl methanesulfonate as a pale yellow oil. Part of this material (140 mg, 0.50 mmol) was dissolved in dry DMF (1 mL) and treated with NaN3 (35 mg, 0.53 mmol) at 80° C. for 1 h30. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-(2-methyl-[1,3]dioxolan-2-yl)thiazole as a brown oil. LC-MS-conditions 01: tR=0.80 min; [M+H]+=226.96.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]3[CH2:13][CH2:14][CH:15]([CH:17]=O)[O:16][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:28][CH:29]=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH:30]=[CH:29][CH:28]=[CH:17][CH:15]1[CH2:14][CH2:13][C:12]2[CH:19]=[CH:20][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:10][C:11]=2[O:16]1)[CH3:35]
Reactant: O=CC1CCc2ccc(OCc3ccccc3)cc2O1
Reactant: CCOC(=O)C=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC=CC1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 30.2 %

Procedure:
Using the procedure of example 30, 2.7 g (10 mmoles) of the aldehyde product from example 83 was condensed with 4.4 g (12 mmoles) of ethyl 4-(triphenylphosphoranylidene)-2-butenoate in 30 ml of toluene (3.5 hr at 100° C.). Chromatography of the crude product on 100 g of silica gel gave 1.1 g (30%) of racemic-5-[3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-yl]-2,4-pentadienoic acid ethyl ester (mixture of E- and Z-isomers) as a yellow oil eluted with toluene and 19:1 toluene-ethyl acetate.
Reaction SMILES: C(Cl)Cl.[C:4]12([C:14](Cl)=[O:15])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2.[OH:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20]>N1C=CC=CC=1>[C:4]12([C:14]([O:17][CH2:18][CH:19]([CH2:21][O:22][C:14]([C:4]34[CH2:13][CH:8]5[CH2:7][CH:6]([CH2:12][CH:10]([CH2:9]5)[CH2:11]3)[CH2:5]4)=[O:15])[OH:20])=[O:15])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: OCC(O)CO
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCC(O)COC(=O)C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2

Procedure:
In a flask under nitrogen 1.053 gms of glycerol is dissolved in 4 ml of pyridine and 6 ml of methylene chloride and cooled to about -10° C. Then 5.00 gms of (1-adamantanoyl)-chloride (Aldrich Chemical Co.) is added in one portion and stirring is continued for about half an hour with cooling and then another two hours at ambient temperature. The resulting solid is filtered and washed with methylene chloride. The combined organic layers are washed twice with dilute aqueous HCl and then once with water and dried over magnesium sulfate. 1,3-di(1-adamantanoyl) glycerol is isolated as an oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)=[C:17]([F:28])[CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].Br[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1.[NH4+].[Cl-]>C1COCC1.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[Zn+2].[Br-].[Br-]>[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:26]([C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([F:28])[CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(Br)cc3)c(F)c2)CC1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccccc3-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Reaction time: 24 h

Procedure:
25 ml of butyllithium (15% in hexane) are added dropwise at -70 ° C. to a solution of 15 g of 4-(trans-4-n-propylcyclohexyl)-2-fluoro-4'-bromobiphenyl in 50 ml of THF and a cooled solution of 4.5 g of ZnBr2 in 25 ml of THF is added after 30 min. After addition of 8.5 g of 1-bromo-3,4,5-triflurobenzene in 75 ml of THF and 0.6 g of PdCl2 -dppf, the mixture is allowed to come to room temperature. After stirring for 24 h, the mixture is poured into 100 ml of saturated NH4Cl solution and worked up as usual. 4"-(trans-4-n-Propylcyclohexyl)-2",3,4,5-tetrafluoroterphenyl is obtained, C 148 N 233 I.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]#[N:20].O.[OH-].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[CH2:19][NH2:20]
Reactant: COc1cccc2c(C#N)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c(CN)cccc12
Temperature: 90 °C

Procedure:
To a solution of LiAlH4 (244 mg, 6.44 mmol) in THF (30 mL) at rt under nitrogen was added 5-methoxynaphthalene-1-carbonitrile (Preparation 11) (513 mg, 2.80 mmol). The reaction mixture was heated to 90° C. for 3 h, then cooled to rt. Water (0.25 mL) was added followed by 1M NaOH (0.25 mL) and water (0.5 mL). The mixture was filtered through Celite and the solvent removed in vacuo to give the title compound: RT=1.99 min; m/z (ES+)=188.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:18][C:19]4[CH:29]=[CH:28][C:27]5[C:22](=[C:23]([OH:33])[CH:24]=[C:25]([C:30](O)=[O:31])[CH:26]=5)[C:20]=4[N:21]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH2:42])(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:18][C:19]4[CH:29]=[CH:28][C:27]5[C:22](=[C:23]([OH:33])[CH:24]=[C:25]([C:30]([NH:42][C@@H:41]([CH2:43][C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)[C:40]([OH:50])=[O:39])=[O:31])[CH:26]=5)[C:20]=4[N:21]=3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)c2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)N[C@@H](Cc6ccccc6)C(=O)O)cc(O)c54)[nH]3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the 2-(4′-tert-butylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazole-7-carboxylic acid (0.047 g, 0.1 mmol) in dimethylformamide (0.5 mL)at room temperature was added phenylalanine tert butyl ester hydrochloride (0.11 mmol). A cocktail solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.021 g, 0.11 mmol), triethylamine (0.3 mmol) in DMF (0.5 mL) was added and the reaction was agitated at room temperature for 18 hours. 1 ml water was added to the reaction mixture resulting in the formation of a tan precipitate. the mixture was filtered and allowed to dry. The solid mass was transferred into vial and dissolved in 1 ml of 90% trifluoroacetic acid. The solutions were agitated for 6 hrs then concentrated under reduced pressure. The residures were taked up in DMSO and subjected to Gilson HPLC purification. The title compound was abtained as solid.(0.016 g, 28%). MS(ES) m/z 584 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:3]=1[NH2:4].[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:3]=1[N:4]=[C:15]=[O:14]
Reactant: COC(=O)c1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(N=C=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 2-fluoro-4-chloro-5-methoxycarbonylaniline (1.0 g, 5 mmol) in THF (10 mL) was added dropwist to a solution of diphosgene (2.0 g, 10 mmol) in toluene (20 mL) with stirring at room temperature. The reaction mixture was stirred at room temperature for one hour and then heated to reflux for 4 hours. The mixture was then cooled to room temperature and the solvents were evaporated under reduced pressure to give 1.1 g of 2-fluoro-4-chloro-5-methoxycarbonylphenyl isocyanate as a solid. This was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[C:26](=[O:34])[CH:25]=2)=[CH:18][N:17]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[C:26](=[O:34])[CH:25]=2)=[CH:18][N:17]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: c1ccncc1
Product: CCCCn1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cc1=O

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.39 g) were refluxed in pyridine (12 ml) for 17 hours. The reaction mixture was evaporated under reduced pressure and the residue washed with hot water. The mixture was allowed to cool and the water was decanted to give the title compound as a residue. Ethanolic HCl was added with warming and on subsequent cooling the trihydrochloride salt of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one was obtained as a solid (2.50 g); recrystallisation from ethanolic HCl afforded material, m.p. 170°-173.5° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:38]([OH:40])=O)[CH2:13][C:14]2[N:18]=[CH:17][N:16]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.[NH2:52][C@@H:53]([CH2:62][CH:63]([CH3:65])[CH3:64])[CH:54]([OH:61])[C:55]([O:57]C(C)C)=[O:56].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:61][CH:54]([CH:53]([NH:52][C:38](=[O:40])[CH:12]([NH:11][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])[CH2:13][C:14]1[N:18]=[CH:17][N:16]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=1)[CH2:62][CH:63]([CH3:64])[CH3:65])[C:55]([OH:57])=[O:56]
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
A mixture of 12.4 g (23.4 mmol) of N-[(phenylmethoxy)carbonyl]-1-(triphenylmethyl)-L-histidine, (Jones, J. H., et al, Synthesis, page 1110 (1987)) 3.3 g (24.6 mmol) of 1-hydroxybenzotriazole and 50 ml of dimethylformamide is cooled to <0° C. and treated with a mixture of 5.6 g (23.4 mmol) of (3S)-3-amino-2-hydroxy-5methylhexanoic acid, 1-methylethyl ester, monohydrochloride (mixture of isomers at hydroxy center) (Example B), and 2.5 g (25 mmol) of triethylamine in 30 ml of dimethylformamide at -5° C. The solution is stirred for five minutes, treated with 5.1 g (24.6 mmol) of dicyclohexylcarbodiimide in 30 ml of dimethylformamide and stirred for eight hours at -5 to 0° C., kept at -5° C. overnight, allowed to warm to room temperature under a nitrogen atmosphere and stirred for 24 hours. The mixture is treated with 1 g (10 mmol) of triethylamine, stirred at room temperature for 72 hours, filtered and the dimethylformamide evaporated in vacuo. The residue is dissolved in 200 ml of ethyl acetate, extracted with 200 ml of 1N citric acid solution, filtered, extracted with 200 ml of saturated sodium chloride solution, 200 ml of saturated solution of sodium bicarbonate and 200 ml of saturated solution of sodium chloride. The organic layer is separated, dried (magnesium sulfate) and the solvent evaporated in vacuo to give 14.1 g of the title compound as a tan foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:20](C)[CH2:21][CH2:22][CH2:23]N=C=NCC.C(N)C#C.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:20][CH2:21][C:22]#[CH:23])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: C#CCN
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C#CCNC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(benzyloxy)phenylacetic acid (20.7 mmol), 1-hydroxybenzotrizole hydrate (37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37 mmol), propargylamine (20.7 mmol) and N-methylmorpholine (62 mmol) in DMF (60 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (400 mL), washed with 1N HCl, water, saturated Na2CO3 solution, brine and dried over Na2SO4. After removing solvent under reduced pressure, the residue was triturated with dichloromethane. Compound 60.1 was obtained as a white solid after filtration and drying. LC-MS ESI (pos.) m/e: 280 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[O:4][C:5]([CH3:10])([CH3:9])[O:6][C:7]=1[CH3:8].[N+:12]([C:15]1[CH:20]=CC(O)=C[CH:16]=1)([O-:14])=[O:13]>C1(C)C(C)=CC=CC=1>[Cl:1][CH:2]([C:7]([CH3:8])=[O:6])[C:3]([O:4][C:5]1[CH:10]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:9]=1)=[O:11]
Reactant: CC1=C(Cl)C(=O)OC(C)(C)O1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: CC(=O)C(Cl)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 135 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
A solution of 5-chloro-2,2,6-trimethyl-4H-1,3-dioxin-4-one (8.8 g, 50 mmol) and 4-nitrophenol (7.65 g, 55 mmol) in 5 ml of xylene under continuous nitrogen purge was immersed in an oil bath preheated to 110° C. The reaction was then heated to 135° C. and then stirred an additional 15 minutes. The pale brown reaction was cooled to 20° C. and the precipitated product washed with ether/hexanes to afford 10.9 g (84%) of the title compound as flaky, white crystals.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[OH:16][C@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([OH:31])=O)[CH2:18]1.[NH2:32][C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2.C(N(C(C)C)CC)(C)C>ClCCl>[N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:42]=[C:33]([NH:32][C:29](=[O:31])[C@@H:19]2[CH2:18][C@@H:17]([OH:16])[CH2:21][N:20]2[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH:34]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 109.1 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (5.72 g) was added to a solution of trans-4-hydroxy-N-tert-butoxycarbonyl-L-proline (3.47 g), 3-aminoquinoline (2.17 g), and diisopropylethylamine (5 mL) in dichloromethane (100 mL) at 0° C. After stirring at room temperature for 45 hr, the solvent was removed in vacuo. Ethyl acetate (500 mL) and 2 N sodium carbonate (500 mL) were added to the residue. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 30:1, 20:1, and 10:1, v/v) to afford the title compound (5.85 g) as a colorless sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.5 (m, 9H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 3.5-3.7 (m, 2H), 4.4-4.6 (m, 2), 7.61 (m, 1H), 7.69 (m, 1H), 7.88 (m, 1H), 7.97 (m, 1H), 8.71-8.76 (m, 1H), and 8.93-8.94 (m, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([OH:30])=O)=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:35][CH2:36][C@@H:37]([OH:46])[CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([NH:35][CH2:36][C@@H:37]([OH:46])[CH2:38][N:39]5[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]5)=[O:30])=[C:21]5[C:25]=4[O:24][C:23]([CH3:26])([CH3:27])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(C[C@H](O)CN)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H](O)CN4CCN(C)CC4)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 77.3 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylic acid 4f (116 mg, 0.25 mmol) was dissolved in 15 mL of dichloromethane followed by the addition of (2R)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 20e (48 mg, 0.28 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (80 mg, 0.25 mmol) and diisopropylethylamine (97 mg, 0.75 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (50 mL), saturated sodium chloride solution (50 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2R)-3-(4-methylpiperazin-1-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-benzofuran-4-carboxamide 20 (120 mg, yield: 77.4%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17](O)=[O:18])=[C:14]([I:16])[N:15]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH3:29]>C1COCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([NH2:29])=[O:18])=[C:14]([I:16])[N:15]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2nc(I)c(C(=O)O)o2)c(C)cn1
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(I)c(C(N)=O)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-1,3-oxazole-5-carboxylic acid (10.0 g, 26 mmol) in THF (200 mL) was added TEA (11.0 mL, 78.0 mmol). The reaction mixture was allowed to stir at rt for 1 h and then isobutyl carbonochloridate (10.0 mL, 74.0 mmol) was added. The reaction mixture was allowed to stir at rt for 5 hr and then saturated ammonia in THF (100 mL) was added. The reaction mixture was allowed to stir at rt for 30 min and was then diluted with water. The organic solvent was removed by evaporation and the slurry was filtered. The solid was collected, washed with water and dried to give 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-1,3-oxazole-5-carboxamide (8.7 g, 87%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([CH2:39][C:40](Cl)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:40](=[O:41])[CH2:39][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)CC1CCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CC5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 47.5 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and cyclohexyl acetyl chloride (39 mL, 0.690 mmol) gave 2-{5-[4-(2-cyclohexyl acetyl)-piperazin-1-yl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (61 mg, 47%). MS (ESI) m/z 559.4 (M+H)+
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2O[C:16]([CH3:29])=[C:17]([CH2:27][CH3:28])[C:18]3[C:19]=2[CH:20]=[C:21]([O:25][CH3:26])[C:22](=[O:24])[CH:23]=3)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C1C2C=CC=CC=2CC=[N:32][N:31]=1>C(O)(=O)C.[OH-].[Na+]>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:19]3[CH:20]=[C:21]([O:25][CH3:26])[C:22]([OH:24])=[CH:23][C:18]=3[CH:17]([CH2:27][CH3:28])[C:16]([CH3:29])=[N:32][N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: C1=NN=Cc2ccccc2C1
Reactant: CCc1c2cc(=O)c(OC)cc-2c(-c2ccc(OC)c(OC)c2)oc1C
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(O)cc21
Reaction time: 1 h
Yield: 94 %

Procedure:
34.5 ml of 98% hydrazine hydrate are added dropwise, within 5 minutes, to a stirred solution of 115 g (0.325 mole) of 1-(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran-6-one in 115 ml of glacial acetic acid. During this operation the solution is maintained at 80° to 100° C. The solution is immersed into a water bath (95° to 100° C.) for one hour, then it is diluted with 140 ml of 2% aqueous sodium hydroxide solution and cooled. The 5H-2,3-benzodiazepine derivative separates as a beige crystalline substance. The solids are filtered off, washed four times with 50 ml of water each and dried. 111.7 g of the crude product are obtained; m.p.: 210°-212° C. To purify the crude product it is dissolved in 223 ml of dimethyl formamide at 100° to 130° C., and the solution is decolorized with 2 g of activated carbon. The carbon is filtered off and washed thrice with 50 ml of dimethyl formamide each. The solution is filtered with 1300 ml of distilled water, whereupon the pure product separates in crystalline form. 110.35 g (94%) of the title compound are obtained; m.p.: 210°-212° C. According to gas chromatographical examination the purity grade of the product is above 99%. C21H24N2O4 =368.4.