Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[C:11]([CH3:17])[CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:11]([CH3:17])[CH:10]=1
Reactant: Cc1cc(Br)ccc1CBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1Cn1ccnc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was treated with NaH (20.0 mg, 0.86 mmol) and heated to 90° C. After lh a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 190.0 mg, 0.72 mmol) in 3 mL DMF was added and stirring at 90° C. continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 160.0 mg (88%) was isolated by column chromatography (5% MeOH-EtOAc) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>COCCOC>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12]#[N:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CN=C(c2ccccc2)C1
Solvent: COCCOC
Solvent: c1ccncc1
Product: N#Cc1c[nH]c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
Under a nitrogen purge 2,3-dichloro-5,6-dicyano-1,4-bonzoquinone (0.23 g; 0.001 mol) and 2-phenyl-1-pyrroline-4-carbonitrile (0.17 g; 0.001 mol) is dissolved in 1,2-dimethoxyethane (13 mL) to form a clear orange solution. Pyridine (0.08 mL; 0,001 mol) is added in a single portion, causing a slight exotherm (to ca. 28° C.) and an immediate formation of a green/grey precipitate. The suspension is stirred at room temperature for 18 hours during which time much of the solvent evaporates. The brownish semi-solid residue is partitioned between ether and a half-saturated solution of sodium carbonate. The red-brown aqueous layer is extracted twice with ether and the combined ether layer is washed with fresh water, then saturated sodium chloride. After drying with MgSO4, solvent is removed under reduced pressure to obtain a white semi-solid. This material was recrystallized from ethylene dichloride (DARCO treatment) to yield lavender crystals (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=1Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26].O1CCOCC1>O>[Cl:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:22]([O:21][CH3:20])[CH:23]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)CCCCCOc1n[nH]c(=O)c(Cl)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCCCCOc1n[nH]c(=O)c(Cl)c1NCc1ccc(OC)c(OC)c1
Reaction time: 8 h

Procedure:
A mixture comprising 4.13 g of 4,5-dichloro-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone, 6.70 g of 3,4-dimethoxybenzylamine, 130 ml of 1,4-dioxane and 130 ml of water, was refluxed with stirring overnight. The solvent was evaporated under reduced pressure, and water was poured to the residue, whereupon the product was extracted with chloroform. The extract was washed with dilute hydrochloric acid, water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-n-hexane-diethyl ether to obtain 5.28 g of the above identified compound as colorless crystals having a melting point of from 111° C. to 112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1C=CC=CC=1.BrCC#[N:21].C(=O)([O-])[O-].[K+].[K+]>CO.[Pd].C(C(C)=O)C>[C:2]([CH2:1][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)#[N:21]
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Reactant: N#CCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CO
Product: N#CCOc1cccc2cc[nH]c12

Procedure:
A solution of 7-benzyloxyindole (0.5 g, 2.24 mmol) in methanol (100 ml) is hydrogenated at 60 psi (4.38 Kg/cm2) over 10% palladium on charcoal (50 mg) for 4 hours. The catalyst is filtered off and the filtrate was evaporated. A stirred solution of the residue and bromoacetonitrile (0.16 ml, 2.3 mmol) in methyl ethyl ketone (5 ml) is heated under reflux with solid anhydrous potassium carbonate (0.62 g, 4.5 mmol) for 2 hours, cooled, poured onto ice-hydrochloric acid and extracted with dichloromethane. The extract is dried and evaporated and the residue is chromatographed on silica in ethyl acetate-hexane (1:2) to give a pale solid.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:20][CH2:21][C:22]([O:24]CC)=O)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1>O>[CH3:6][C:7]1[N:8]([CH2:20][CH2:21][C:22]([NH2:5])=[O:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1
Reactant: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: Cc1nc2cnc3ccccc3c2n1CCC(N)=O
Temperature: 130 °C

Procedure:
Ammonium acetate (4.0 g) and ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.5 g, 17 mmol, prepared as described in Parts A through C of Example 22) were heated for three days at 130° C. in a sealed vessel. The reaction was allowed to cool to ambient temperature, and water was added. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 90:10 to 85:15) to provide 2.20 g of 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide as a tan solid.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[N:6][C:7](Cl)=[N:8][CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[N:6][C:7]([NH:2][CH3:1])=[N:8][CH:9]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CN
Solvent: CO
Product: CNc1ncc(Br)cn1
Yield: 100 %

Procedure:
40% Aqueous methylamine solution (35 ml) and methanol (20 ml) were added to 5-bromo-2-chloropyrimidine (3 g, 15.5 mmol) and the resulting mixture was heated to reflux for 3 days. The mixture was cooled, then the solvent was evaporated under reduced pressure, the residue was partitioned with methylene chloride and 1 M sodium hydroxide, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.0 g, 100%) as a white solid.
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[CH:4].C[Si](C)(C)[O:8][C:9]([O:14][CH2:15][CH3:16])=[CH:10][CH:11]([CH3:13])[CH3:12].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH:11]([CH:10]([CH:3]([CH3:4])[C:2]#[CH:5])[C:9]([O:14][CH2:15][CH3:16])=[O:8])([CH3:13])[CH3:12]
Reactant: CCOC(=CC(C)C)O[Si](C)(C)C
Reactant: C#CC(C)Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C#CC(C)C(C(=O)OCC)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.3 %

Procedure:
A 250 milliliter flask was equipped with a magnetic stirrer, reflux condenser and nitrogen inlet. The flask was dried with external heat and then charged with 19.92 grams (0.22 mol) of 3-chloro-1-butyne, 30.49 grams (0.15 mol) of 1-trimethylsilyloxy-1-ethoxy-3-methylbutene prepared in Part A, 100 milliliters of dry methylene chloride, and 0.5 grams of anhydrous zinc chloride. The reaction mixture was stirred at room temperature and monitored by infrared for 48 hours. The disappearance of the ketene acetal C=C peak at 1675 cm-1 and the appearance of an ester C=O peak at 1720 cm-1 was observed. The reaction mixture was then worked up by diluting with 150 milliliters of methylene chloride and washing five times with 100 milliliters of 5% sodium bicarbonate and twice with water. The methylene chloride was dried (MgSO4) and removed under vacuum to give a residue. The residue was vacuum distilled through a vigreux column to give 8.44 grams (0.05 mol) of ethyl 2-isopropyl-3-methyl-4-pentynoate having the appearance of a colorless oil and a boiling point of 66°-76° C. at 7 millimeters pressure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(NC3CCCC3)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(O)cc2)c2c(NC3CCCC3)nc(Cl)nc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
2-Chloro-N-cyclopentyl-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1 equiv), 4-hydroxyphenylboronic acid (1 equiv), potassium carbonate (2.5 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.2 equiv), suspended in 1,4-dioxane/water, and flushed with nitrogen, were stirred at 100° C. for 16 h. The reaction mixture was loaded directly onto a silica gel column and purified using 5-100% ethyl acetate in hexanes. Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give 4-(2-chloro-4-(cyclopentylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol (32.2% yield) as a yellow solid. MS (ESI) m/z 459.3 [M+1]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:20].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:33]([C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[Cl:25])(=[O:35])=[O:34])=[CH:15][C:14]=1[Cl:20]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine (obtained as per procedure described in preparation 4) and 2,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([O:15][CH3:16])[C:8]=1[F:17])[CH3:2].[CH:20]([O-])([O-])[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[CH3:16][O:15][C:9]1[C:8]([F:17])=[C:7]([CH:12]=[C:11]([F:13])[C:10]=1[F:14])[C:6]([C:5](=[CH:20][O:21][CH2:22][CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:19])=[O:18]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC)c1F
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC)c1F
Temperature: 110 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of ethyl-3-methoxy-2,4,5-trifluorobenzoylacetate (500 mg, 1.8 mmol), ethyl orthoformate (0.45 mL, 2.72 mmol) and acetic anhydride (460 mg, 4.5 mmol, 2.5 eq) was stirred at 110° C. for 12 hours and the excess reagents were removed by distillation under high vacuum (0.1 mmHg) to give 590 mg of a yellow-orange oil. This material was used directly in the next step without further purification or characterization.
Reaction SMILES: [CH2:1]([N:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5](=[O:7])[O-:6])[CH:2]=[CH2:3].Br[C:13]1[CH:14]=[C:15]2[C@@H:22]([NH2:23])[CH2:21][C:20]3([CH2:26][CH2:25][CH2:24]3)[O:19][C:16]2=[N:17][CH:18]=1.C([Li])(C)(C)C.[CH:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CCOCC>[CH2:1]([N:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5](=[O:6])[O-:7])[CH:2]=[CH2:3].[OH:37][CH:32]([C:13]1[CH:14]=[C:15]2[C@@H:22]([NH2:23])[CH2:21][C:20]3([CH2:26][CH2:25][CH2:24]3)[O:19][C:16]2=[N:17][CH:18]=1)[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C=O
Reactant: N[C@H]1CC2(CCC2)Oc2ncc(Br)cc21
Agent: C=CCN(C(=O)[O-])C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)C(O)c1cnc2c(c1)[C@@H](N)CC1(CCC1)O2
Reaction time: 0.08 h

Procedure:
A solution of N-allyl-N-t-butylcarbamate-(4′S)-6′-(bromo)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine (4.12 g, 10.1 mmol) in ether (80 mL) was cooled to −78° C. and then t-butyllithium (12.5 ml, 21.3 mmol) was added and stirred for 15 minutes before the pivalaldehyde (3.80 ml, 35.0 mmol) (Note: freshly distilled) was added. After 5 minutes, LC-MS shows the starting material has been consumed. The reaction was quenched with sat'd NH4Cl and the organic layer separated. The organic layer was combined with previous trial reactions and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with 0% to 30% EtOAc in hexane, to provide N-allyl-N-t-butylcarbamate-(4′S)-6′-(1-hydroxy-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine as a yellow oil. MS m/z: 417 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N[C@@H](CO)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N[C@@H](CO)C(=O)O)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
L-Serine (100 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), potassium carbonate (131.5 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), and water 1 L were placed into a recovery flask (egg plant flask), followed by stirring vigorously. p-Methylbenzoyl chloride prepared in Step 1 was dissolved in tetrahydrofuran (Wako Pure Chemical Industries, Ltd.), which was added dropwise to this solution for 30 minutes. During this process, pH was maintained in the vicinity of 8 while additionally adding potassium carbonate. After the completion of the dropwise addition, the agitation was performed for 1 hour. The reaction solution was added to water 1 L which was prepared in a distinct vessel, and then pH was adjusted to not more than 3 with hydrochloric acid, followed by being cooled to 4° C. Precipitated crystals were filtrated, followed by being recrystallized with a mixed solvent of ethanol (Wako Pure Chemical Industries, Ltd.)/water=6/4. An objective substance was obtained in an amount of 106.0 g (yield: 64.7%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C>CO>[N+:20]([C:17]1[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:19][C:18]=1[NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](Cc1ccccc1)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a mixture of L-phenylalanine (8.88 g, 53.7 mmol) and 1-fluoro-2,4-dinitrobenzene (3.24 ml, 26.9 mmol) was added triethylamine (7.86 ml, 56.4 mmol). The resulting mixture was warmed using a Biotage Initiator microwave to 100° C. for 4 min. The solid was diluted with MeOH and the slurry was dropped into distilled water. Dichloromethane was added to the slurry and the organic phase was separated. The organic phase was further extracted with 1.2 M hydrogen chloride solution and brine. The organic phase was dried over Na2SO4, filtered and the solvents were evaporated. The residue was diluted with dichlormethane and the slurry was filtered. The precipitate was then washed with a small amount of dichlormethane. The combined filtrates were evaporated and the residue was purified by flash chromatography using a dichloromethane/methanol gradient (0% to 5%) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[F:37]>CC#N>[F:37][C:29]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:28]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.3 %

Procedure:
A solution of 6,7-dimethoxyquinolin-4-ol (50 g, 0.244 mol) and Cs2CO3 (159 g, 0.488 mol) in CH3CN (300 mL)/DMF (300 mL) was stirred at room temperature for 30 min. 1,2-Difluoro-4-nitrobenzene (42.7 g, 0.268 mol) was then added dropwise. After stirring at rt for 3.5 h, the reaction solution was concentrated in vacuo. Ice (500 mL) was added to the residual suspension and the mixture was stirred overnight for precipitation. The solid was collected by filtration and further purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow powder (43.1 g, 51.2%).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:27]=[C:26]([N:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1)[CH2:28][C:29]#[N:30]
Reactant: c1nc(N2CCCC3(CCCN3)C2)c2cc[nH]c2n1
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CCC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 110 °C
Reaction time: 1.25 h
Yield: 84.6 %

Procedure:
4-(1,7-Diazaspiro[4.5]dec-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (30 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (38 mg), N,N-diisopropylethylamine (42 μl) and 1,4-dioxane (1 ml), and the mixture was stirred at 110° C. for 75 minutes. The mixture was cooled to room temperature, and then thereto was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/2, followed by chloroform/methanol=25/1 to 20/1) to give the titled compound (32 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:4].I[C@@:21]1([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24](O)[C@H:22]1O>>[F:1][C:2]([F:18])([F:19])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:36]1[C:34](=[O:35])[NH:33][C:31](=[O:32])[N:30]([CH:37]=1)[C@@H:21]1[O:29][C@H:26]([CH2:27][OH:28])[CH2:24][CH2:22]1)=[O:4]
Reactant: C#CCCCCCCCCCCNC(=O)C(F)(F)F
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: O=C(NCCCCCCCCCCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Protected alkynylamine 63 was coupled for 24 h to 5-iodo-2',3'-dideoxyuridine (47, 676.2 mg, 2.00 mmol, prepared as described in Example 2A) following the general procedure described in EXAMPLE 1C. Chromatography on silica gel (100 g) eluting with a 0-5% methanol in dichloromethane gradient afforded a dark red foam. The red impurity was removed by chromatography on a reverse phase column (100 g, octadecylsilane on 40 micrometer silica gel, Baker) with 40% water in methanol. The appropriate fractions were combined, concentrated, and co-evaporated twice with absolute ethanol to afford 731 mg of alkynylamino nucleoside 60 as a clear oil. This material was homogeneous by TLC and NMR except for the presence of residual ethanol (25 mole %, corrected yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[H-].[Na+].[Cl:12][C:13]1[C:18]([C:19]#[N:20])=[C:17](Cl)[N:16]=[C:15]([S:22][CH3:23])[N:14]=1>CS(C)=O.CCOC(C)=O>[Cl:12][C:13]1[C:18]([C:19]#[N:20])=[C:17]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])[N:16]=[C:15]([S:22][CH3:23])[N:14]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: Nc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1nc(Cl)c(C#N)c(Nc2c(F)cccc2F)n1
Reaction time: 3 h
Yield: 87 %

Procedure:
2,6-di-Fluoroaniline (2.66 mL, 24 mmol), DMSO (12 mL) and NaH (0.912 g, 22.8 mmol) were combined at 23°. When the foaming ceased 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-453] (5.0 g, 22.82 mmol) was added in DMSO (12 mL). The reaction exothermed and the temperature was moderated with cold H2O bath, then stirred at 23° for 3 h. The reaction was diluted with EtOAc (300 mL) and washed with H2O (4×) and satd aq NaCl (1×). Dried (Na2SO4) and concentrated to afford 6.21 g (82%) of a tan foam. LC MS m/z=313 (MH+), Rt=2.37 min.
Reaction SMILES: Br.[C:2]([C:5]1[CH:6]=[CH:7][C:8](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:14]/[C@@H:15]2[N:19](CC3C=CC(OC)=CC=3OC)[C:18](=[O:31])[CH2:17][CH2:16]2)=[N:9][C:10]=1[O:11]C)(=[O:4])[CH3:3].O>O1CCOCC1>[C:2]([C:5]1[C:10](=[O:11])[NH:9][C:8](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:14]/[C@H:15]2[CH2:16][CH2:17][C:18](=[O:31])[NH:19]2)=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)=O)c(OC)n2)c(OC)c1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
48% hydrobromic acid (3.0 mL) was added to a solution of (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (300 mg) in 1,4-dioxane (3.0 mL), and the mixture was stirred at 65° C. for 0.5 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Anisole (2 mL) was added to a solution of the residue (278 mg) in trifluoroacetic acid (1 mL), and the mixture was stirred at 80° C. for 4.5 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give the title compound as a yellow powder (103 mg).