Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=O.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=O.[OH-:29].[K+]>C(O)C.O>[C:8]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]([C:3]2[C:2]([CH3:1])=[C:21]([C:22]([OH:27])=[O:29])[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)[N:23]=2)=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CCC(=O)c1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Yield: 42.9 %

Procedure:
4-Phenylpropiophenone (18.9 g, 0.09 mole) and 5-fluoroisatin (20 g, 0.09 mole) were suspended in 360 ml of ethanol and stirred mechanically as a solution of 35.2 g KOH in 100 ml water was added dropwise over 15 minutes. The reaction mixture was heated at reflux for 12 hours, cooled, and the ethanol evaporated under reduced pressure. The resulting yellow solid was dissolved in water and washed with ethyl ether. The aqueous layer was cooled to 5° and acidified with glacial acetic acid. The resulting yellow precipitate was filtered and dried. Recrystallization from 200 ml of dimethylformamide and 25 ml water provided 13.8 g of 2-(4-biphenylyl)-6-fluoro-3-methylquinoline-4-carboxylic acid as a white solid, m.p. 303°-306°(d).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](Cl)=[O:11]>O.C(OCC)C>[S:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([N:1]=[N+:2]=[N-:3])=[O:11]
Reactant: O=C(Cl)C1CCCS1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=NC(=O)C1CCCS1
Yield: 86.2 %

Procedure:
A solution of sodium azide (4.14 g.) in water (16 ml.) was added dropwise to a solution of 2-tetrahydrothiophenecarboxylic acid chloride (9.60 g.) in diethyl ether (24 ml.) with stirring under ice-cooling and stirred for further 15 minutes at the same temperature. After the mixture was stirred for 1 hour at ambient temperature, nitrogen gas was introduced to remove off diethyl ether. The resultant mixture was extracted with diethyl ether (50 ml.). The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give oily 2-tetrahydrothiophenecarboxylic acid azide (8.63 g.).
Reaction SMILES: [I:1]I.N1C=CC=CC=1.[Si:9]([O:16][C@@H:17]1[CH2:21][C:20](=[O:22])[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].Cl>C(Cl)Cl>[Si:9]([O:16][C@@H:17]1[CH2:21][C:20](=[O:22])[C:19]([I:1])=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C(I)C(=O)C1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
The procedure described in Johnson, C. R., Braun, M. P. J. Am. Chem Soc. 1993, 115, 11014 was followed with modification. A solution of I2 (6.55 g, 25.8 mmol) and pyridine (12 mL) in CH2Cl2 (12 mL) was cannula transferred to a 0° C. solution of (R)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone (3.17 g, 14.9 mmol) and pyridine (5.4 mL) in CH2Cl2 (5.4 mL). The reaction was allowed to warm to room temperature and after 2 h, 100 mL 1 M HCl was added. The resulting mixture was extracted with CH2Cl2 (3×60 mL) and the combined organic solution was washed with 100 mL saturated NaHSO3 solution and 50 mL brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (4.997 g, 99%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:11]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16].O>ClC(Cl)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:9][C:10]1[C:11]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cnc(OCC(F)(F)F)c(CBr)c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A mixture of N-bromosuccinimide (464 mg, 2.61 mmol), 2,2′-azobis(2-methylpropionitrile) (16 mg, 0.10 mmol) and methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate (500 mg, 2.01 mmol, Step-1) in dichloroethane (10 mL) is stirred at 85° C. for 4 hours. After cooling to room temperature, the reaction mixture is poured into water extracted with dichloroethane and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-Hexane/ethyl acetate (10:1) to give 658 mg (>99% yield) of the title compound as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[N+:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1)([O-:11])=[O:10].[N+](C1C=CC(C(=O)C[Cl:31])=CC=1)([O-])=O>N1C=CC=CC=1>[Cl-:31].[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16](=[O:19])[CH2:17][N+:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:20][CH:21]=1)([O-:11])=[O:10]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccncc1
Reactant: O=C(CCl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: N#Cc1cc[n+](CC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Product: [Cl-]

Procedure:
Employing the procedure of Example III but replacing pyridine with a substantially equimolecular amount of 4-cyanopyridine and replacing 4-nitrophenacyl bromide with a substantially equimolecular amount of 4-nitrophenacyl chloride there is obtained N-(4-nitrophenacyl) 4-cyanopyridinium chloride, a white solid soluble in water.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1>>[O:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:2]#[C:1][C:3]3[CH:15]=[CH:14][C:6]4[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=4[CH:4]=3)=[CH:18][C:19]=2[O:23][CH2:22]1
Reactant: Ic1ccc2c(c1)OCO2
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CC1(C)COc2ccc(C#Cc3ccc4c(c3)OCO4)cc2OC1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 5-iodo-benzo[1,3]dioxole. MS (ESI) 322.2 (M•)+.
Reaction SMILES: C(OC(C)(C)C)(=O)C.[Li].C(O)(C(F)(F)F)=O.C([C:21](C(=O)C)([CH:25]([OH:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([OH:24])=[O:23])(C)(C)C>>[OH:33][CH:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCCCCC(O)C(C(C)=O)(C(=O)O)C(C)(C)C
Agent: [Li]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)(C)C
Product: CCCCCCCC(O)CC(=O)O

Procedure:
Synthesis of analogs (18), (20) and (21) proceeded by a shortened piperidine deblock of Fmoc-OBzl-D-Glu (Schiffler, R. J., et al., Amer. Med. Assoc. 251:2983 (1984)). The reduction of deblock from 20 to 5 minutes was necessary to prevent the cyclization (Hubert, A. J., et al., Helv. Chim. Acta 46:1429-1445 (1963)) of OBzl-D-Glu to pyroglutamic acid. The orthoganol Boc/Fmoc protection scheme allowed the selective removal of the base labile Fmoc group, while maintaining the base insensitive Boc protection on the L-Ile. The synthesis was continued by coupling of Fmoc-L-Leu (Keierszenbaum, F., Trop. Med. Parasit, Mansfield ed., Marcel Dekker, New York (1984)) in the usual manner (DCC/HOBT) which was followed by piperidine-catalyzed Fmoc deprotection (20 minutes) and final acylation with either (-)-D-3-hydroxydecanoic acid (-), structure (23) (for analogs (18) and (20)), or decanoic acid (for analog (21)). Coupling of D-3-hydroxydecanoic acid was as the Pfp ester (24), with the 3-hydroxyl group unprotected. The acid was obtained by (-)-cinchonidine resolution (Cartwright, N.J., Biochem. J. 67:663-669 (1957)) of synthetic (±)-3-hydroxydecanoic acid [(35)-(12)]. The (±)-3-hydroxydecanoic acid itself (mp 55°-56° C.; 57° C.) was synthesized by the aldol condensation of lithium tert butyl acetate (Rathke, M. W., et al., J. Amer. Chem. Soc. 95:3050-3051 (1973)) with n-octyl aldehyde, followed by TFA hydrolysis of the resulting (±)-tert butyl acetyl-3-hydroxydecanoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8](O)([CH3:10])[CH3:9].[NH2:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1.C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O.O>CN1CCCC1=O>[C:12]([C:5]1[N:6]=[C:7]([C:8]([CH3:10])=[CH2:9])[C:2]([NH:24][C@@H:25]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]2)=[N:3][C:4]=1[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=1)(=[O:13])[NH2:14]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=C(C)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
A mixture of 5-chloro-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (700 mg), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (1.05 mL), diisopropylethylamine (1.06 mL), and N-methylpyrrolidone (2.5 mL) was reacted in a microwave reaction device at 180° C. for 1 hour. To the reactant was added a mixed solution of saturated brine:water (1:1), followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=99:1-90:10, NH2 type: eluent; chloroform:methanol=99:1-95:5) to obtain tert-butyl (3R)-3-{[5-carbamoyl-6-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-3-(prop-1-en-2-yl)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (928 mg) as a yellow amorphous substance.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].C(O)(=O)CC>O.C(Cl)CCl>[C:19]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=2[CH3:13])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(O)cc(=O)[nH]c2c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: CCC(=O)O
Product: CC(=O)c1c(O)c2ccc(C)c(C)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
10 g of 4-hydroxy-7,8-dimethyl-2-quinolone was added to 60 cc of ethylene dichloride, and 14 g of aluminum chloride was added thereto under stirring at room temperature. The reaction solution was first slurried by the formation of a complex and then became a uniform solution. Then, a solution of a mixture of 5.3 cc of acetyl chloride and 16 cc of ethylene dichloride was dropwise added thereto at room temperature, and the acetylation reaction was conducted at 50° C. for 3 hours. The reaction solution was cooled to room temperature, and 50 cc of water was carefully added for hydrolysis. Then, 5 cc of propionic acid was added thereto, and ethylene dichloride was distilled off together with water under heating, and the mixture was aged at 100° C. for 3 hours under stirring. The slurry was cooled at room temperature and subjected to filtration. The obtained crystals were dried to obtain 11.5 g of 3-acetyl-4-hydroxy-7,8-dimethyl-2-quinolone. Yield was 94%, and the purity was 98% (as analyzed by liquid chromatography). ##STR7##
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[N:26]=1>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[N:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (106 mg, 0.840 mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (91 μL, 1.01 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL) and added to a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol) in N,N-dimethylacetamide (5.0 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→95/5) and precipitated from ethyl acetate/hexane to give the title compound (241 mg, 89%) as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=O)[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5].C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][N:2]([CH3:3])[CH3:1])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5]
Reactant: CNC
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethylamine (5.6 M solution in EtOH, 4.2 ml, 23.20 mmol) is added under an atmosphere of argon to a solution of (2-Chloro-7-formyl-naphthalen-1-yl)-acetic acid ethyl ester (4.28 g, 15.46 mmol) in THF (80 ml). The mixture is stirred at RT for 18 h, before a solution of sodium cyanoborohydride (1.16 g, 18.56 mmol) in MeOH (20 ml) and glacial acetic acid (4.4 ml, 77.33 mmol) are added. After stirring at RT for 2 h, TLC analysis indicates complete consumption of starting material. The reaction mixture is diluted with water and adjusted to pH 8-9 by the addition of conc. aq. NaHCO3 solution. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent yields the crude reaction product. Purification by FCC (EtOAc, then EtOAc/MeOH 4:1) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=8.8 Hz, 3H), 2.28 (s, 6H), 3.62 (s, 3H), 4.18 (q, J=8.8 Hz, 2H), 4.32 (s, 3H), 7.48 (d, J=9.9 Hz, 1H), 7.52 (d, J=9.9 Hz, 1H), 7.73 (d, J=9.9 Hz, 1H), 7.80-7.84 (m, 2H). ES+−MS: 306.3, 308.2. [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41]3)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCc3ccccc32)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (100 mg), 2,3-dihydro-1H-indole (62 μl) and diisopropylethylamine (96 μl) were dissolved in 1,2-dichloroethane (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (155 mg) was added, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:1) was concentrated under reduced pressure to give the object compound (100 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ncccn1
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2c1ncccn1)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
A solution of amine 84 (325 mg, 0.59 mmol) in DMF (8 mL) was treated with 2-chloropyrimidine (88 mg, 0.76 mmol) and DIPEA (0.15 mL, 0.88 mmol) and heated to 80° C. in an oil bath. After 18 h, the reaction mixture was cooled to ambient temperature, diluted with water, and extracted with Et2O (3×). The combined organic extracts were washed successively with water (3×), and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 89 (341 mg, 92%) as an orange-colored solid that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ8.67 (d, J=4.8 Hz, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.30 (t, J=4.8 Hz, 1H), 7.08-6.87 (m, 1H), 6.86 (br s, 1H), 6.79-6.72 (m, 1H), 6.67-6.49 (m, 2H), 4.74-4.53 (m, 3H), 4.40-4.36 (m, 0.5H), 4.19-4.17 (m, 0.5H), 4.08-3.93 (m, 3H), 3.86-3.80 (m, 1H), 3.68-3.54 (m, 1H), 3.49-3.99 (m, 1H), 3.27-2.89 (m, 2H), 2.79 (s, 3H), 2.48-2.44 (m, 1.5H), 2.21-2.11 (m, 0.5H), 2.01-1.84 (m, 2H), 1.50-1.48 (m, 9H), 1.34-1.30 (m, 3H), 1.03-0.95 (m, 9H) ppm.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][C:6](=[O:7])[CH2:5][CH2:4]1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CN=C1>[Si:9]([O:1][CH2:2][C@@H:3]1[O:8][C:6](=[O:7])[CH2:5][CH2:4]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C1CC[C@H](CO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)O1

Procedure:
The methodology of Taniguchi et al. (Tetrahedron, 30, 3532, 1974) and Farina et al. (Tetrahedron Lett., 29, 1239, 1988) for the syntheses of D-ribose derivatives provided a model for our synthetic approach to the syntheses of the corresponding L-ribose derivatives. Nitrous acid deamination of D-glutamic acid (1) gave lactone 2, which was then converted to the corresponding ester 3 by treatment of compound 2, with ethanol and catalytic amount of p-toluenesulfonic acid (See Scheme 1). Reduction of compound 3 with NaBH4 in ethanol gave (R)-4-(hydroxymethyl)-4-butyrolactone (4). Protection of the hydroxy group of compound 4 with tert-butyldimethylsilyl chloride in methylene chloride using imidazole as catalyst produced (R)-4-{[(tert-butyldimethylsilyl)oxy]methyl}-4-butyrolactone (5), which was then converted to the corresponding lactol 6 by reduction with diisobutyaluminum hydride (DIBAL) in toluene at -78° C. Acetylation of 6 with acetic anhydride and triethylamine afforded the key sugar intermediate, 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (7) as a mixture of alpha and beta anomers: MS, m/e 231 (M+ -CH3CO), 215 (M+ -CH3COO); NMR(CDCl3)) delta 0.10 (s, 6H, SiMe2), 0.95 (s, 9H, tert-butyl), 1.85-2.15 (m, 7H, CH2CH2 and COCH3), 3.50-3.65 (M, 2H, 5-H), 4.10-4.30 (m, 1H, 4-H), 6.20-6.30 (m, 1H, 1-H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O-:9])=[O:8])[CH2:2]1.B(O[O-])=O.[Na+].O.[OH-].[Na+].[C:18](O)(=O)C>>[S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:18])=[O:8])[CH2:2]1
Reactant: O=C([O-])C1=CCCSC1
Reactant: CC(=O)O
Agent: O=BO[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C1=CCCSC1
Temperature: 55 °C
Reaction time: 19 h
Yield: 76 %

Procedure:
To a solution of 0.934 gm (5.75 mmol) of 5,6-dihydro-2H-thiopyran-3-carboxylate from part C in glacial acetic acid (40 mL) was added 1.98 gm (12.88 mmole) sodium perborate. The reaction mixture was stirred at 55° C. under N2 for 19 hrs. whereupon the solution was poured into H2O (50 mL) and neutralized with 50% NaOH to pH==7. The solution was extracted three times with methylene chloride. The combined organic layers were washed once with saturated sodium bicarbonate and once with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.832 gm (76%) of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide as a white solid; mass spectrum m/e=190 (EI, M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1.CN(C=O)C>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(C#N)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
A solution of 5-cyanooxindole (285 mg, 1.8 mmol), (Tet. Lett., 1987, 28, 4027), in THF (12 ml) was added dropwise under nitrogen, to a suspension of sodium hydride (96 mg, 2.4 mmol, prewashed with hexane) in THF (5 ml). The mixture was stirred for 20 minutes at ambient temperature, and a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (162 mg, 0.6 mmol), (prepared as described for the starting material in Example 2), in DMF (0.5 ml) in THF (3 ml) was added dropwise. The mixture was stirred for 20 minutes at ambient temperature and then 1 hour at 65° C. The solvent was removed by evaporation and the residue was purified by column flash chromatography eluting with methylene chloride/methanol (97/3 followed by 96/4 and 90/10). The solid was collected by filtration, resuspended in methylene chloride and 2M ethereal hydrogen chloride was added. The solid was collected by filtration, washed with ether and dried under vacuum at 60° C. to give 4-(5-cyanooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (92 mg, 40%).