Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=1[CH3:23])=[O:9]
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (2.0 g, 0.008 mol) in CH2Cl2 (20 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (1.28 g, 0.0072, see preparation 12) and N,N-diisopropylethylamine (4.12 g, 0.032 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 7.63 g, 0.024 mol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted twice with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 12% ethyl acetate in hexane to give the title compound as a white solid (2.9 g, 97%). Mass spectrum (m/z): 376.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH:41]2[CH2:42][CH2:43][CH:37]1[CH2:38][NH:39][CH2:40]2)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH:37]2[CH2:43][CH2:42][CH:41]1[CH2:40][N:39]([CH2:20][C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:28])[CH3:1])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)[CH2:38]2)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.153 g, 0.405 mmol) and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (95 mg, 0.445 mmol) gave 3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as an off white solid (0.186 g, 80%) [following purification by SiO2 chromatography, eluting with 0-5% MeOH/EtOAc]. MS (ESI) m/z 575.3 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:7](OC)=[O:8].CO.[OH-].[Li+]>O1CCCC1>[O:8]=[C:7]1[NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: COC(=O)CN(CCCN)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCNC(=O)C1
Reaction time: 6 h

Procedure:
To a solution of methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)glycinate (10.2 g) in tetrahydrofuran (THP)/methanol (2/1, 300 mL) was added 1M aqueous lithium hydroxide solution (60 mL). The resultant mixture was stirred at room temperature overnight. An additional 20 ML of 1M aqueous lithium hydroxide solution was added and the mixture was stirred for 6 h. Solvent was removed under reduced pressure, and the residue was dissolved in 50 mL of methanol and 200 mL of toluene and concentrated in vacuo. To the residue in dichloromethane (300 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 9.6 g) and 1-hydroxybenzotriazole (HOBT, 6.8 g). The mixture was stirred at room temperature for three days, then treated with saturated aqueous ammonium chloride solution and extracted with three portions of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluting with 4 to 5% [10:1 methanol/aqueous ammonium hydroxide] in dichloromethane) to yield the title compound. MS 215.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=1)=[O:5])C.Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=O>C(O)C>[CH3:1][O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[S:14][C:25]3[CH2:26][CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=4)[C:24]=3[N:15]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(N)=S)cc1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(Nc2nc3c(s2)CCCC3c2ccccc2)cc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A suspension of 1-(4-ethoxycarbonylphenyl)-2-thiourea (105 mg, 0.5 mmol) and of 2-bromo-6-phenyl-cyclohexanone (253.1 mg, 1.00 mmol) in ethanol (4 mL) was heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The product was precipitated with diethyl ether and heptane as an oil, which was purified on silica gel with dichloromethane as eluent to yield the title compound (120 mg, 63%) as a pale-yellow solid. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.42 (s, 1H), 7.77 (d, 2H), 7.50 (d, 2H), 7.28 (t, 2H), 7.27 (t, 1H), 7.12 (d, 2H), 4.23 (q, 2H), 4.06 (m, 1H), 2.73 (m, 2H), 2.12 (m, 1H), 1.70-1.90 (m, 3H), 1.27 (t, 3H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].C(N(C(C)C)CC)(C)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1(C)C=CC=CC=1>[C:21]1([O:20][C:18]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CO
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COC(=O)Oc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 25 g (240 mmol) of ethyl glycolate and of 55 ml (315 mmol) of diisopropylethylamine in 500 ml of toluene is admixed slowly at ambient temperature with 32 ml (256 mmol) of phenyl chloroformate. Stirring is continued at ambient temperature for 2 hours. The salt formed is separated off and the filtrate is concentrated under reduced pressure. This gives 53.7 g of oily product, used as it is in the following step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[C:9]=12)=[O:12].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(OCC)C>[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[C:9]=12)=[O:12]
Reactant: CN1CCNCC1
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Solvent: CCOCC
Product: CN1CCNCC1CCCCCCc1cccc2c1C(=O)NC2=O

Procedure:
6-Bromohexylphthalimide (460 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]Br>CC(C)=O>[Cl:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: ClCCCBr
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C#N)ccc1OCCCCl
Temperature: 27.5 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
To 74.5 gms (0.5 mole) of 4-Hydroxy-3-methoxybenzonitrile in 450 ml. of acetone was added 138 gms (1 mole) of potassium carbonate and the resultant reaction mixture was stirred at about 25-30° C. for about 5 min. To the reaction suspension 110 gms (0.7 mole) of 3-Chloro-1-bromo propane was added drop-wise at about 25-35° C. for about 30 mins. The resultant reaction mixture was refluxed for about 12 hrs. The undissolved inorganic salts was filtered off and washed with acetone. The solvent was distilled completely under vacuum and the residue was re-crystallized from 300 ml of isopropyl alcohol to afford the title compound as white crystalline solid. Yield: 92.5 gms (% Yield: 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(NC(C)C)(C)C.[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[CH:37].CN(C=O)C>O.[Cu](I)I.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.C(OCC)(=O)C>[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[C:37][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 90 °C
Yield: 64.6 %

Procedure:
(5S)-3-Bromo-7-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (170 mg, 0.415 mmol), diisopropyl amine (2911 μL, 20.77 mmol), copper iodide (15.82 mg, 0.083 mmol), tetrakis(triphenylphosphine)palladium (48.0 mg, 0.042 mmol), 3,3-dimethylbut-1-yne (171 mg, 2.082 mmol) and DMF (2769 μL, 0.415 mmol) were combined in a sealable tube, which was then flushed with argon and heated at 90° C. for 5 hours. After cooling to room temperature the reaction in the tube was diluted with water (25 mL) and poured into a separatory funnel containing ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (5S)-3-(3,3-dimethyl-1-butyn-1-yl)-7-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (110 mg, 0.268 mmol, 64.5% yield) as a brown foam. MS m/z=411.2 [M+H]+. Calc'd for C25H23N4O3: 411.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[S:10][C:11]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[O:16])=[C:12]([CH3:14])[N:13]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC>C(O)C>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[S:10][C:11]=1[C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccccc1C(=O)c1sc(NCCCCCN)nc1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1C(=O)c1sc(NCCCCCNS(=O)(=O)c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
A solution of 18 mg (0.05 mmol) [2-(5-Amino-pentylamino)-4-methyl-thiazol-5-yl]-o-tolyl-methanone hydrochloride in 1 ml ethanol was treated with 10.6 mg (0.06 mmol) benzenesulfonylchloride and 21 ml NEt3. The mixture was allowed to stir for 15 h at room temperature and afterwards subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 12.6 mg (55%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:30](=[O:31])[NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:22])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)OC1CCCCO
Reactant: Cc1ccccc1N=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)OCCCCC1ON(C(=O)OCc2ccccc2)CC1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of N-benzyloxycarbonyl-5-(4-hydroxybutyl)-4-oxo-isoxazole (170 mg, 0.58 mmol) in dry toluene was added 2-methylphenyl isocyanate (76 μL, 0.61 mmol). The reaction mixture was heated at approximately 80° C. under nitrogen for 0.5 hour. One drop of pyridine was added and heating was continued for an additional 1.5 hours. A second portion (25 μL) of 2-methylphenyl isocyanate was added and the reaction mixture was heated for another 2 hours. The reaction mixture was then allowed to cool to ambient temperature and diluted with ethyl acetate and extracted with water. The aqueous layer was acidified with potassium hydrogen sulfate and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 240 mg of the title compound. MS (FAB+) m/e 427 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:23][C@@H:24]1[O:28][CH2:27][C@@H:26]([S:29][C:30](=[O:32])[CH3:31])[CH2:25]1)(=O)=O>C(Cl)Cl>[O:7]([CH2:23][C@@H:24]1[O:28][CH2:27][C@@H:26]([S:29][C:30](=[O:32])[CH3:31])[CH2:25]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@@H](COc2ccccc2)C1
Reaction time: 0.83 h
Yield: 60.9 %

Procedure:
To a 0° C. solution of 0.326 g of phenol, 1.8 ml of Hunig's base, and 2.5 ml of methylene chloride is added, via syringe, 1.07 g of product from Example 22 in 0.50 ml of methylene chloride. The reaction is stirred in an ice bath for 50 minutes; during which time the progress of reaction is checked by thin layer chromatography. The mixture is concentrated in vacuo, dissolved in ethyl acetate and washed with sodium bicarbonate. The organic layer is dried, concentrated in vacuo, and purified by chromatography (Silica Gel: 30% ethyl acetate/hexane) to give 0.532 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].P.[OH-].[Na+]>Cl[Pd]Cl.O.C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:10]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: P
Solvent: Cc1ccccc1C
Solvent: O
Product: N#Cc1ccc(Cl)c(N)c1

Procedure:
A degassed solution of 40 mmol of 4-chloro-3-nitrobenzonitrile (starting material) and 40 ml of xylene are placed in an autoclave (volume: 200 ml).5.0 mmol of TPPTS (in the form of 9.2 g of an aqueous solution containing 0.546 mol of TPPTS/kg of solution) as phosphine and 2.4 g (60 mmol) of NaOH, 23.8 ml of H2O and 1.0 mmol of PdCl2 are added. The pH isfrom 10.5 to 11.0.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C[Si](N[Si](C)(C)C)(C)C.CC(O[CH:23]1[O:27][C@H:26]([CH2:28][O:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[C@@H:25]([O:38][C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:40])[C@H:24]1[O:47][C:48]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:49])=O.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]([C@@H:23]2[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:31])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:25]([O:38][C:39](=[O:40])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:24]2[O:47][C:48](=[O:49])[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:6](=[O:8])[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1cc(N)[nH]c(=O)n1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: Nc1cc(N)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Reaction time: 12 h
Yield: 54.3 %

Procedure:
A mixture of 6-aminocytosine (1.00 g, 5.71 mmol) and HMDS (10 mL) was refluxed for 3 h and concentrated to give a solid, which was dissolved in anhydrous CH2Cl2 (15 mL). To the solution were added 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribose (1.92 g, 3.81 mmol) and TMSOTf (1.66 mL, 8.59 mmol) at 0° C., and the mixture was stirred at room temp. for 12 h and poured into saturated sodium bicarbonate solution with vigorous stirring. The mixture was extracted with CHCl3 (150 mL×2), the combined extracts dried (Na2SO4) and concentrated in vacuo, and the residue purified by silica gel column chromatography (CHCl3:MeOH=30:1) to give compound 21 (1.18 g, 54%) as a white foam. 1H NMR (DMSO-d6) δ 7.97-7.40 (m, 15H), 6.18 (s, 1H), 6.18 (m, 3H), 5.10 (s, 1H), 4.65 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26](B(O)O)=[CH:25][CH:24]=[N:23]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[C:26]1[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(OCc2ccccc2)c(Br)c1
Reactant: Cn1nccc1B(O)O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(OC(F)(F)F)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 1-(benzyloxy)-2-bromo-4-(trifluoromethoxy)benzene (Preparation 535, 3.3 g, 9.5 mmol) and (1-methyl-1H-pyrazol-5-yl)boronic acid (Preparation 403, 1.2 g, 9.5 mmol) 1,4-in dioxane (25 mL) was degassed under argon for 30 minutes. Under argon, (1E,4E)-1,5-Diphenylpenta-1,4-dien-3-one-palladium (3:2) (348 mg, 0.38 mmol) and tricyclohexylphosphine (213 mg, 0.76 mmol) were added followed by the dropwise addition of a degassed solution of tripotassium phosphate (4 g, 19 mmol) in water (12.6 mL). Reaction mixture was refluxed for 16 hours before cooling to room temperature and filtering through Celite™. The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate (100 mL). The organic extract was washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel column chromatography eluting with ethyl acetate:hexane (1:9, by volume) afforded the title compound, 2.3 g, 70% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[CH3:21][C:22]1[C:23]([CH3:31])=[N:24][C:25]([SH:30])=[C:26]([CH:29]=1)[C:27]#[N:28]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:29]=[C:26]2[C:27]([NH2:28])=[C:13]([C:12](=[O:15])[C:11]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=3[O:9][CH2:7][CH3:8])[S:30][C:25]2=[N:24][C:23]=1[CH3:31]
Reactant: Cc1cc(C#N)c(S)nc1C
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2nc(C)c(C)cc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.189 g, 1.37 mmol), 2-ethoxy-5-fluorophenacyl bromide (1.02 g, 3.95 mmol) and 5,6-dimethyl-2-mercaptonicotine nitrile (0.50 g, 3.04 mmol) in dry DMF (10 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]([CH3:17])([CH2:15]O)[CH2:13][OH:14]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:8][CH2:15][C:12]([CH2:13][OH:14])([CH3:17])[N:11]=2)=[CH:9][CH:10]=1
Reactant: CC(N)(CO)CO
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CC1(CO)COC(c2ccc(Cl)nc2)=N1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A suspension of 6-chloronicotinic acid (3.2 g, 20.4 mmol) and 2-amino-2-methyl-1,3-propanediol (2.1 g, 20 mmol) in xylenes (mixture of isomers, 80 ml) is heated at reflux under Dean-Stark conditions for 24 h, during which the mixture clarifies. Upon cooling to room temperature, a solid settles down. The mixture is filtered through a silicagel column, eluting first with hexane to remove the xylenes and then with ethyl acetate to afford 1.8 g of [2-(6-chloropyridin-3-yl)-4-methyl-4,5-dihydro-1,3-oxazol-4-yl]methanol ax55.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:21])[CH2:16][O:15][CH:14]([CH2:17][CH2:18][CH:19]=[O:20])[O:13][CH2:12]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]([OH:20])[CH2:18][CH2:17][CH:14]2[O:15][CH2:16][C:11]([CH3:10])([CH3:21])[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: CC1(C)COC(CCC=O)OC1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC1(C)COC(CCC(O)c2ccc(F)cc2)OC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
4-Fluorophenyl magnesium bromide (8.7 ml, 2M solution in ether, 17.44 mmol) was added to a solution of 5,5-dimethyl-1,3-dioxane-2-propanal (2 g, 11.62 mmol) (Step 2) in THF (50 ml) at −70° C. After stirring at −70° C. for 2 hr, the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic fractions were combined and washed successively with water and brine. After drying (MgSO4), filtration and concentration, the crude compound (3.5 g) was chromatographed to give α-(4-fluorophenyl)-5,5-dimethyl-1,3-dioxane-2-propanol (2.73 g) as a white solid: mp (DSC) 84° C. Anal Calc'd. for C15H21FO3: C, 67.14; H, 7.89. Found: C, 67.18; H, 7.98.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1>>[Br:24][C:22]1[CH:23]=[C:18]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[N:12]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: Cn1cc(Br)cc(Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)c1=O
Yield: 73.4 %

Procedure:
Using the same general procedure as described for the preparation of 103l, reaction of 119b (400 mg, 1.66 mmol) with 3,5-dibromo-1-methylpyridin-2(1H)-one (441 mg, 1.66 mmol) gave a 76% yield (521 mg) of 119c as a yellow solid: mp 96-97° C.; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, 1H, J=2.5 Hz), 7.42 (s, 1H), 5.31 (d, 1H, J=2.5 Hz), 6.87 (d, 1H, J=2.5 Hz), 5.84 (d, 1H, J=2.5 Hz), 4.16 (t, 2H, J=5.0 Hz), 3.96 (t, 2H, J=5.5 Hz), 3.58 (s, 3H), 0.85 (s, 9H), −0.04 (s, 6H). MS (APCI+) m/z 427.4 (M+H).