Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cc(C)ccn2)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cc(C)ccn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.1 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(4-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 71) (192.2 mg, 0.371 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo. Purification of the residue on SP4 using a 25 G silica cartridge (gradient:1 to 10% (2M NH3 in MeOH) in DCM) gave a first residue which was purified by MDAP (modifier: formic acid) to give another residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.22 mL, 0.220 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(4-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (79.7 mg, 0.171 mmol, 46.1% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CCOC(=O)c1cc(O)ccc1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(O)ccc1-c1cc(OC)ccc1F
Temperature: 100 °C
Reaction time: 21.5 h
Yield: 103.1 %

Procedure:
Under an argon atmosphere, to a solution of ethyl 2-bromo-5-hydroxybenzoate (1.13 g) in toluene (30 mL) were added 2-fluoro-5-methoxyphenylboronic acid (1.18 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (379 mg), 75% tris(dibenzylideneacetone)dipalladium (0) (281 mg) and 2.0 M aqueous sodium carbonate solution (6.9 mL), and the mixture was stirred at 100° C. for 21.5 hr. The reaction mixture was diluted with water and 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.38 g) as a pale-yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[Br:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[Br:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(Br)c(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Example 1, Step B, 0.053 g, 0.114 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.040 g, 76%) as a white solid. LC/MS (Table 1, Method 5) Rt=1.865 min.; MS m/z: 366 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:30])[N:17]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[N:18]=2)[C:5]([CH3:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1COCC1.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.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:6]=[C:5]([CH3:15])[N:4]3[C:16](=[O:30])[N:17]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[N:18]=[C:3]3[C:2]=2[C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)=[CH:9][CH:10]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccncc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 100 °C
Yield: 45.5 %

Procedure:
A suspension of 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (50 mg, 0.10 mmol), pyridine-4-boronic acid (62 mg, 0.30 mmol), K3PO4 (64 mg, 0.30 mmol), and Pd(dppf)Cl2.CH2Cl2 (16 mg, 0.02 mmol) in THF (1 mL) at room temperature was degassed by bubbling with argon for 2 min. This was then stirred and heated at 100° C. in a sealed vessel for 6 h. Analysis by HPLC/MS indicated that the starting material had been consumed. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (22.6 mg) as a yellow solid. HPLC/MS (methanol-water with 10 mM NH4OAc): retention time=3.61 min, [M+H]30 =497.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C([O:51][C:52](=[O:55])[CH2:53]Cl)(C)(C)C.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:53][C:52]([OH:55])=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOCOCC
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 9.62 g (100 mmol) of sodium-t-butoxide in 350 ml of diethoxymethane is cooled to 0° C. At 0° C., 30.12 g (200 mmol) of chloroacetic acid-tert-butyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for one hour at 10° C. 250 ml of methyl-tert-butyl ether is added, the organic phase is separated, and the aqueous phase is extracted twice with 250 ml of water. The solvent of the combined organic phases is dried on sodium sulfate, dessicant is filtered off, and it is distilled off in a vacuum. The residue is taken up in 500 ml of ethanol. 40 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for 0.5 hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[OH-].[Li+:24].O1CCCC1.CO>O>[C:1]([C:3]1[CH:4]=[C:5]([CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[Li+:24]
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C)c3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)cc2nc(-c3ccc(C(=O)[O-])cc3)oc12
Reaction time: 8 h

Procedure:
Methyl 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate (134 mg, INTERMEDIATE 22) and lithium hydroxide (22 mg) were combined in 10 ml of a 1:1:1 mixture of tetrahydrofuran, methanol, and water. The solution was stirred overnight. The solvents were removed in vacuo to provide the desired intermediate, lithium 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate, as an off-white solid (140 mg). Mass spectrum (ESI) 279.0 (M+1). To a solution of lithium 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate (28 mg) in 2 ml of dichloromethane was added 2.5 ml of a 2M solution of oxalyl chloride in dichloromethane followed by 10 μl of dimethylformamide. The mixture was warmed and stirred until the solids dissolved (about 0.5 h). The mixture was concentrated in vacuo with minimal or no heating (<30° C.) and then dried under high vacuum to remove traces of water. To the residue was added 2 ml of dichloromethane, 28 mg of ({1-[4-(trifluoromethyl)phenyl]piperidin-4-yl}methyl)amine, and 87 μl of diisopropylethylamine. The mixture was stirred at room temperature for 15 min and then was added directly to a 40M samplet. The product was purified via flash chromatography on a Biotage Horizon, 40M column, eluting with 1 column volume of 10% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 10 to 100% over 10 column volumes to provide the title compound (38 mg, 73%). Mass spectrum (ESI) 519.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.5 Hz, 2H), 7.95 (m, 4H), 7.49 (m, 4H), 6.37 (bs, 2H), 3.83 (d, J=12.6 Hz, 2H), 3.49 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 2.87 (m, 2H), 2.65 (s, 3H), 1.92 (m, 3H).
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH2:47]([S:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(O)C>[CH2:47]([S:54][C:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:33][CH:32]=[C:31]([N:30]([CH3:42])[CH3:29])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCOC(=O)CSCc1ccccc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccccc1
Yield: 96.3 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (15.7 g), a 2M ethanolic solution of sodium ethylate (27.5 cc) and ethyl (benzylthio)acetate (11.6 g) in ethanol (110 cc). Diethyl 5-benzylthio-2-dimethylamino-2,4-hexadienedioate (19.2 g) is thereby obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C=NN2[CH2:27][CH2:26][N:25]([CH2:28]CCCI)[C:24]2=O)C=CC=CC=1.[H-].[Na+].CN(CCCl)C>CN(C)C=O.O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][N:25]([CH3:28])[CH3:24])[C:10]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Reactant: O=C1NCCN1N=Cc1ccccc1
Agent: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(N=Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A solution of 1-phenylmethyleneamino-2-imidazolidinone (prepared as described in Part II of Example A (14.4 g, 0.076 mole) in dry dimethylformamide (338 ml) is stirred and treated portionwise over a 3 minute period with sodium hydride (60% dispersion in mineral oil) (3.0 g, 0.023 mole). During the addition, a nitrogen sweep is maintained. After the addition is complete, the reaction is heated on a steam bath for 15 minutes and then chilled to ambient temperature. The nitrogen sweep is discontinued and the reaction mixture is treated all at once with dimethylaminoethyl chloride (17.66 g, 0.16 mole), prepared as described in Part I herein. The reaction is stirred at ambient temperature for 15 minutes and then heated at 80° to 90° C. for 3 hours. The reaction is filtered hot, and the filtrate is chilled and concentrated under reduced pressure to leave an oily residue. The residue is treated with 300 ml of water and extracted with 3×300 ml portions of chloroform. The extracts are combined and dried over anhydrous MgSO4. The extract is filtered and the filtrate is concentrated under reduced pressure to leave a tan-colored semi-solid. The semi-solid is triturated with anhydrous ether to give the 1-phenylmethyleneamino-3-[2-(dimethylamino)ethyl]-2-imidazolidinone, weighing 6.17 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([OH:13])=O)[CH:7]=1)#[N:2].CN1CCOCC1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].O>CC1CCCO1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:33][O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[O:13])[CH:7]=1)#[N:2]
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(C#N)cn1)(C(=O)O)S(C)(=O)=O
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(C#N)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of the crude (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid in 2-methyltetrahydrofuran (20 mL) was added N-methyl morpholine (0.494 g, 4.83 mmol, 3 eq) and CDMT (0.424 g, 2.42 mmol, 1.5 eq). The solution was allowed to stir at room temperature for one hour. O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.283 g, 2.42 mmol, 1.5 eq) was added to the solution, and the reaction mixture was allowed to stir for an additional hour at room temperature. Water (20 mL) was added, and the solution was extracted with 2-methyltetrahydrofuran (100 mL). The aqueous layer was re-extracted with 2-methyltetrahydrofuran (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product mixture was purified by flash chromatography on a 40 g silica column eluting with 70-100% EtOAc/Heptane to give (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (165 mg, 28% yield over two steps) as a white solid. LC-MS M−H 369.4.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1>C(O)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2cnc3nc(N)nc(N)c3c2)cc1
Solvent: O=CO
Product: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Yield: 79.1 %

Procedure:
A solution of 1.27 g of 2,4 -diamino-6-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyrido[2,3-d]pyrimidine and 10 mL 88% formic acid was stirred at room temperature. A yellow solid started to form after about 12 hours and after 4 days of stirring, the reaction mixture was filtered. The collected solid was washed well successively with water, methanol, and acetone and was then dried under reduced pressure to give 0.85 g (79%) of the title compound, which can be alternatively named as 2,4-diamino-6-(4-carboxystyryl)-5-deazapteridine, mp >300° C.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH2:6]([O:13][C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26]O>>[CH3:26][O:24][C:23](=[O:25])[C@H:17]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[NH:16][C:14]([O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sulphuryl chloride (1 g) was added to a stirred mixture of N-benzyloxycarbonyl-L-glutamine (100 g) and methanol (1200 ml) and the mixture was stirred at ambient temperature for 24 hours. The mixture was evaporated to give N-benzyloxycarbonyl-L-glutamine methyl ester (105 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1>C(OCC)C.[Ag]=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C@H:17]([O:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Agent: O=[Ag]
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)OCc1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
1.9 ml (16 mmol) of benzyl bromide are added to a mixture of 4.4 g (19 mmol) of silver oxide and 3.5 g (13 mmol) of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate in 20 ml of diethyl ether. The reaction mixture is stirred at 50° C. for 12 hours. The mixture is filtered and then the solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 4 g of methyl (S)-3-(4-bromophenyl)-2-benzyloxypropanoate are obtained in the form of an oil. Yield=85%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[N:12]([C@H:13]2[O:25][C@@H:24]([CH2:26][O:27]C(=O)C)[C@H:19]([O:20]C(=O)C)[C@@H:14]2[O:15]C(=O)C)[C:11]2[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:10]=2[N:9]=1.O.C(O)(=O)C>C(Cl)Cl.C(O)C.CO>[Br:7][C:8]1[N:12]([C@H:13]2[O:25][C@@H:24]([CH2:26][OH:27])[C@H:19]([OH:20])[C@@H:14]2[OH:15])[C:11]2[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:10]=2[N:9]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium carbonate (0.28 g, 2.65 mmol) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole (1.39 g, 2.65 mmol) were combined with water (4 mL), methanol (20 mL) and ethanol (20 mL) and stirred at rt for 1.5 h. Acetic acid (0.3 mL, 5.3 mmol) was added and the suspension was concentrated to a solid. Purification of the residue on a silica gel column (2.5×20 cm, 230-400 mesh) with 1:9 ethanol:CH2Cl2 gave the title compound as a white amorphous solid (0.79 g, 2.0 mmol, 75%); m.p. 169° C.; [a]20D=(+)105 (c=0.5 DMF); UVλmax (E) pH=7.0: 298 nm (6,700), 289 (6,500), 255 (6,900); 0.1 nNaOH: 298 nm (6,700), 295 (5,400), 256 (6,700); MS (Cl): m/z 399 (M+); 1H NMR (DMSO-d6) d 8.57 (s, 1H, Ar—H), 7.96 (s, 1H, Ar—H), 5.89 (d, J=7.9 Hz, H-1′), 5.48 (d, 1H, OH, J=6.3 Hz), 5.42 (t, 1H, OH, J=4.5 Hz), 5.29 (d, 1H, OH, J=4.2 Hz), 4.43 (apparent dd, 1H, H-2′, J=13.3 Hz, J=6.1 Hz), 4.14 (apparent t, 1H, H-3′, J=4.3 Hz), 4.01 (apparent d, 1H, H-4′, J=1.7 Hz), 3.77-3.63 (m, 2H, H-5′).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[C:10](=O)([O:13]C)[O:11][CH3:12]>C[O-].[Na+].CO>[C:10](=[O:13])([O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])[O:11][CH3:12]
Reactant: COC(=O)OC
Reactant: OCC(F)(F)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OCC(F)(F)C(F)(F)F
Temperature: 120 °C
Yield: 50.9 %

Procedure:
In a flask (500-ml volume) equipped with 10 distillation columns, 2,2,3,3,3-pentafluoropropanol (100 g, 0.67 mol), dimethyl carbonate (180 g, 2.0 mol) and a 28% sodium methoxide/methanol solution (1.3 g) were charged. The flask was heated to 120° C. to allow the starting materials to react for 10 hours while removing the methanol from the distillation columns by evaporation. After allowing the mixture to cool to room temperature, an aqueous solution of ammonium chloride was added to the mixture and the mixture was shaken to remove the sodium methoxide. The organic layer was washed with water, dried and distilled to give methyl 2,2,3,3,3-pentafluoropropyl carbonate as a colorless liquid (71 g, yield 51%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 7 and FIG. 8 respectively and the mass spectrometry spectrum (M/e=208).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[H-].[Na+].[CH3:27]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12]
Reactant: COc1ccc(CC(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (5.9 g, 17 mmol) in tetrahydrofuran (380 ml) was added sodium hydride (60% dispersion in mineral oil, 0.72 g, 17.9 mmol). The mixture was stirred at room temperature for 1.5 h and then placed in an ice bath. A solution of methyl iodide (2.54 g, 17.9 mmol) in tetrahydrofuran (15 ml) was added dropwise (5 min). The ice bath was removed and the mixture was stirred at 35° C. for 3.5 h. The reaction mixture was poured on ice-water and extracted twice with AcOEt. The organic phases were washed with water and brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, heptane/EtOAc 2:1) to give the title compound (3.3 g) as a light yellow foam. MS (m/e)=360.2 [M+H+].