Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)[CH:19]=2)[CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH:12]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)[CH:19]=2)[CH2:14]1)=[O:11]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CC(CO)C3)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(C=O)C3)nc1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
Combine DCM (3 mL) and oxalyl chloride (41 uL) under nitrogen atmosphere at −78° C., and then add DMSO (49 uL) in DCM (2 mL). After the solution stirs for 15 minutes, add 6-(2-Hydroxymethyl-indan-5-yloxy)nicotinamide (33.1 mg, 0.116 mmol) in DCM (2 mL). After 15 minutes, add Et3N (97 uL, 0.70 mmol). After the reaction gradually warms to room temperature over the next 5 hours, then quench with water. Add the mixture to a separatory funnel and extract the product with DCM. Wash the organic phase with brine and then dry over Na2SO4. After concentrating under reduced pressure, flash chromatograph using 10% THF/CH2Cl2 eluent affords 27.4 mg, 0.10 mmol (84% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 3.1-3.2 (2H, m), 3.2-3.4 (3H, m), 6.8-7.0 (4H, m), 7.1-7.3 (1H, m), 8.8-8.9 (1H, m), 8.4 (1H, s), 9.7 (1H, s); TLC 1:6 THF:CH2Cl2Rf:=0.7.
Reaction SMILES: C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH2:12]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[N:39]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:38]=[C:37]([OH:46])[CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:47](Cl)(=[O:57])[O:48][CH2:49][CH:50]([CH2:55][CH3:56])[CH2:51][CH2:52][CH2:53][CH3:54]>O>[CH2:55]([CH:50]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:49][O:48][C:47]([O:46][C:37]1[CH:36]=[C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:30]=2)[N:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:38]=1)=[O:57])[CH3:56]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOc1cccc(-c2cc(O)nn2-c2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1cccc(-c2cc(OC(=O)OCC(CC)CCCC)nn2-c2ccccc2)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
50 ml of chloroform and 1.9 ml (0.014 mol) of triethylamine were added to 5.3 g (0.011 mol) of 5-(3-hexadecyloxyphenyl)-3-hydroxy-1-phenylpyrazole to dissolve it, and the solution was stirred at 25° C. 2.3 g (0.012 mol) of 2-ethylhexyl chlorocarbonate was added to the solution dropwise. After stirring for 30 min, cold water was added thereto, and the separated chloroform layer was washed twice with 50 ml of cold water and then dried over Glauber's salt. The Glauber's salt was filtered out, and the chloroform was then removed by distillation. The product thus obtained was purified by column chromatography to produce 5.7 g of exemplified compound I-13 as an oil in a yield of 82%.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:48]([C:50]1[N:51]=[C:52]([C:63]([O-])=[O:64])[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=1)#[N:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][C:15]([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=2[NH:14][C:63]([C:52]2[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=[C:50]([C:48]#[N:49])[N:51]=2)=[O:64])=[CH:16][CH2:17]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CNS(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Yield: 83.1 %

Procedure:
A solution of 65.0 mg (0.202 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid methylamide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with 141 mg (0.303 mmol) of PyBroP, 67.7 mg (0.222 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 105 μL (0.605 mmol) of DIEA at RT for 2 h. The mixture was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 96.0 mg (83%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C28H41N5O4SSi, 572.3 (M+H). found 572.0.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6](=O)[CH2:5]1>C(OCC)C>[CH3:3][C:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]([CH3:1])[CH:5]=1
Reactant: [Li]C
Reactant: CC1CC(=O)C2=C1CCCC2
Solvent: CCOCC
Product: CC1=CC(C)C2=C1CCCC2
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Methyl lithium (96 mL, 1.5M, 0.144 mol) was added dropwise to a solution of 4,5,6,7-tetrahydro-1-methyl-indan-3-one (17.7 g, 0.118 mol) in 50 mL of diethyl ether under an argon atmosphere whereupon the reaction mixture was refluxed for 18 hours. The mixture was hydrolyzed, and extracted with diethyl ether. The ether extracts were dried over anhydrous MgSO4 and filtered. To the ether solution 0.5 mL of 6M HCl was added and the solution was stirred for one hour. After this time period the ether solution was washed with water, dried over anhydrous MgSO4, filtered, and concentrated. Distillation at reduced pressure afforded 8.0 g (45 percent) of product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]([Mg]Br)=[CH2:12].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:11]=[CH2:12])[C:5]([O:8][CH3:9])=[C:4]([Cl:10])[N:3]=1
Reactant: C=C[Mg]Br
Reactant: COc1cnc(Cl)nc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of commercially available 2,6-dichloro-5-methoxy pyrimidine (100 grams (g), 0.55 moles (mol)) in dry tetrahydrofuran was added, dropwise, 1 molar (M) vinyl magnesium bromide in tetrahydrofuran solvent (124 g, 0.94 mol) over one hour (h) at room temperature. The mixture was then stirred for 4 h at room temperature. Excess Grignard reagent was quenched by addition of acetone (200 milliliters (mL)) while the temperature of the mixture was maintained at a temperature below 20° C. Thereafter, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ; 151 g, 0.67 mol) was added at once and stirred overnight. A yellow solid precipitated out. The solid was filtered and washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure and the resulting crude compound was diluted with ethyl acetate (2 liters (L)). The resulting undissolved, dark, semi-solid was separated by filtration using ethyl acetate. It was further concentrated under reduced pressure to provide a crude compound, which was purified by column chromatography. The compound was eluted with 5% to 10% ethyl acetate in hexane mixture to provide the title compound (70 g, 60%): mp 60-61° C.; 1H NMR (CDCl3) δ 3.99 (s, 3H), 5.85 (d, 1H), 6.75 (d, 1H), 6.95 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[N:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH:23]1([C:2]2[CH:22]=[N:21][C:5]3[N:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:8][C:9](=[O:10])[C:4]=3[CH:3]=2)[CH2:25][CH2:24]1
Reactant: O=c1[nH]c(CCCCc2ccccc2)nc2ncc(Br)cc12
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c(CCCCc2ccccc2)nc2ncc(C3CC3)cc12
Temperature: 0 °C
Yield: 5.6 %

Procedure:
Palladium(II) acetate (1 mg, 4.5 μmol) was added to a degassed suspension of 6-bromo-2-(4-phenyl-butyl)-3H-pyrido[2,3-d]pyrimidin-4-one (20 mg, 55 μmol; example 26), cyclopropyl boronic acid (10 mg, 110 μmol), potassium phosphate (59 mg, 275 μmol) and tricyclohexylphosphine (3 mg, 9 μmol) in toluene (360 μl) and water (24 μl) under an argon atmosphere. The reaction mixture was heated for 14 h to 100° C. and poured onto ice cold isopropyl acetate/brine 1/1. The layers were separated, the aqueous layer was extracted two times with isopropyl acetate, the combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure left a yellow solid which was purified by preparative thin layer chromatography (silica gel, isopropyl acetate/heptane) to give 6-cyclopropyl-2-(4-phenyl-butyl)-3H-pyrido[2,3-d]pyrimidin-4-one (1 mg, 3.1 μmol; 6%) as yellow crystals. MS: m/e=320.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:14]([N:35]1[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]1)=[O:16])([CH3:17])[CH2:6][CH2:5]2
Reactant: OC1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCC(O)CC1)O2
Yield: 33.3 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 370 mg CDI (2.28 mmol) and 222 mg 4-hydroxypiperidine (2.20 mmol) produced 222 mg of a (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-hydroxypiperidin-1-yl)methanone as a white foam.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[OH:21].[C:22]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([OH:39])[C:33]([CH3:41])([CH3:40])[CH2:32]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCCC>ClC1C=CC=CC=1.CCCCCCC.C(OCC)(=O)C>[C:22]([O:30][CH:31]1[CH2:32][C:33]([CH3:40])([CH3:41])[N:34]([O:39][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[OH:21])[C:35]([CH3:38])([CH3:37])[CH2:36]1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: OC1CCCCC1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCCC
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1O

Procedure:
Tributyltin hydride is added dropwise to a solution of 2-bromocyclohexanol and excess 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine in chlorobenzene. The mixture is heated to facilitate reaction. The crude reaction mixture is passed through silica gel with heptane and then heptane/ethyl acetate to afford the title compound as a mixture os cis/trans isomers.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([O:9][C:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N[C@H]1[C@@H](OC(C2C=CC(OC)=CC=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)CN(C(OC(C)(C)C)=O)C1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:103]([O:105][CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)=[O:104]>C1COCC1.O1CCOCC1.O>[CH2:106]([O:105][C:103]([NH:1][C@H:4]1[C@@H:8]([O:9][C:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5]1)=[O:104])[C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2NC(=O)OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of (3R,4S)-tert-butyl 3-azido-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (3.0 g, 5.65 mmol) in anhydrous THF (70 mL) was added triphenylphosphine (2.97 g, 11.3 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and to the residue were added methanol (35 mL) and a 0.5 N sodium hydroxide solution (35 mL). The mixture was stirred at ambient temperature 18 hours, and then partitioned between water (35 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous layer was back extracted with ethyl acetate. The combined organic extracts washed with water and brine, dried (MgSO4), filtered and concentrated under reduce pressure. The residue was purified by column chromatography (Biotage 40M; 2.5% MeOH:dichloromethane). To a solution of (3R,4S)-tert-butyl 3-amino-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (2.85 g, 5.65 mmol) in a 50% mixture of 1,4-dioxane/water (20 mL) was added sodium carbonate (0.72 g, 6.78 mmol) and the mixture cooled to 0° C. in an ice bath. Benzyl chloroformate (1 mL, 6.78 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 18 hours. The mixture was partitioned between water (20 mL) and diethyl ether (100 mL), and the layers were separated. The organic layer was washed sequentially with water, saturated sodium bicarbonate and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M 25% ethyl acetate/hexanes) to afford (3R,4S)-tert-butyl 3-(benzyloxycarbonylamino)-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (2.18 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14](Cl)(=[O:17])[CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:7]2
Reactant: CCC(=O)Cl
Reactant: COc1ccc2ccccc2c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(Cl)c(OC)ccc2c1

Procedure:
reacting under Friedel-Crafts conditions 1-chloro-2-methoxy-naphthalene with propionyl chloride in methylene chloride at a temperature of from about 0° C. to ambient temperature in the presence of aluminum chloride to form 1-(5-chloro-6-methoxy-2-naphthyl)-1-propanone,
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccccc1O
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccccc1O

Procedure:
The stirred solution of 2-(2-Hydroxyphenyl)acetic acid (10 g, 65.7 mmol) and p-Toluenesulfonic acid monohydrate (1.40 g, 7.3 mmol) in abs ethanol (100 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1M HCl and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[C:13]([F:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:25]([O:24][C:20](=[O:23])[CH:21]=[CH:22][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:19])=[CH:12][C:13]=1[F:18])[CH3:26]
Reactant: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A suspension of 9.72 g (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (30 mmol), 6 g ethyl acrylate (60 mmol), 10.2 ml DIPEA (60 mmol), 112 mg palladium acetate (3 mmol), and 1.57 g triphenylphosphine (6 mmol) in 10 ml DMF were stirred at 130° C. for 48 h. The reaction was monitored by TLC. The DMF was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography, using a 7/3 N-hexane/ethyl acetate mixture as eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:17])[CH2:3]1.CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:1])([CH3:18])[CH2:3][C:4](=[O:17])[NH:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1N)NC(=O)CC2(C)C
Yield: 92 %

Procedure:
4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (250 mg, 1.00 mmol) was dissolved in ethyl acetate (10 mL) and transferred to a Fischer Porter apparatus. 10% Palladium on carbon (250 mg, Aldrich) was added followed by methanol (20 mL) and the mixture stirred under 60 psi hydrogen pressure for 16 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 7-amino-4,4-dimethyl-6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (213 mg, 0.92 mmol, 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 6 H), 2.22 (s, 2 H), 3.72 (s, 3 H), 4.66 (s, 2 H), 6.20 (s, 1 H), 6.67 (s, 1 H), 9.76 (s, 1 H).
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][O:17][CH3:18])([CH3:8])[CH3:7].CN(C)CCN(C)C.[Cl-].[NH4+].CN(C)[CH:31]=[O:32]>C1COCC1.CCCCCC>[CH:6]([C:9]1[C:10]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH:31]=[O:32])([CH3:8])[CH3:7]
Reactant: COCOc1ccccc1C(C)C
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1c(C=O)cccc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
At −78° C., a hexane solution of n-butyl lithium (100 mmol/64 ml) was added dropwise to a THF (200 ml) solution including 15.0 g (83 mmol) of the above-mentioned compound A2 and 15 ml (100 mmol) of tetramethylethylenediamine (TMEDA). After 30 min, the solution was heated to 0° C., stirred for 1 hour, and again cooled to −78° C. Dimethylformamide (DMF) (15.9 ml) was then added dropwise. After the reaction solution was slowly heated to room temperature, the reaction solution was poured into a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ether. The organic phases were combined and washed with water and a saturated sodium chloride solution in that order and then dried using anhydrous sodium sulfate. After removing the drying agent by filtering, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 3-isopropyl-2-methoxy methoxybenzaldehyde (12.9 g, 74% yield, reference symbol A3 in FIG. 1).
Reaction SMILES: [N:1]1([C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[NH:8][CH:9]=[N:10]3)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[C@@H:19]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:20]1[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C.C([O-])(O)=O.[Na+].O>CC#N>[C:22]([O:21][C@@H:20]1[C@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[O:41][C@H:19]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][CH:13]=[N:14][C:6]=2[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1cn(-c2ncnc3nc[nH]c23)cn1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(-n4ccnc4)ncnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
6-(Imidazol-1-yl)purine (52 mg, 0.28 mmol) was suspended in a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (160 mg, 0.32 mmol) in dried CH3CN (10 mL). Stannic chloride (0.10 mL, 0.22 g, 0.85 mmol) was added, and the mixture very rapidly became a clear solution. The solution was stirred at ambient temperature for 4 h. NaHCO3 (0.8 g) and H2O (0.1 mL) were added sequentially, and the suspension was stirred for 1 h. The clear solution layer was separated, and the residue was extracted with CH3CN. The extracts and the solution layer were combined, and volatiles were evaporated in vacuo. The residue was chromatographed (CH2Cl2/MeOH, 1:90→1:15) to give 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-6-(imidazol-1-yl)purine (179 mg, quantitative): 1H NMR (500 MHz, CDCl3) δ 4.72 (dd, J=4.3, 12.2 Hz, 1H), 4.88 (br s, 1H), 4.95 (dd, J=3.0, 12.3 Hz, 1H), 6.29 (“t”, J=5.2 Hz, 1H), 6.47-6.50 (m, 2H), 7.24 (s, 1H), 7.35-7.60 (m, 9H), 7.93 (d, J=7.6 Hz, 2H), 8.03 (d, J=7.6 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H), 8.28 (s, 1H), 8.35 (s, 1H), 8.65 (s, 1H), 9.13 (s, 1H); 13C NMR (125 MHz, CDCCl3) δ 165.0, 164.3, 164.1, 152.1, 151.5, 144.9, 142.2, 136.6, 132.9, 132.8, 132.4, 129.7, 128.8, 128.7, 128.2, 127.5, 127.2, 122.0, 116.3, 86.4, 79.9, 72.9, 70.3, 62.3; HRMS m/z 653.1749 (MNa+[C34H26N6O7Na]=653.1761).