Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][C:28]3([CH2:31][OH:32])[CH2:30][CH:29]3[C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([N:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>N1C=CC=CC=1>[C:33]1([N:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40](=[O:41])[O:32][CH2:31][C:28]23[CH2:30][CH:29]2[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:24]=2[CH2:25][CH2:26][CH2:27]3)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC1(CO)CC21)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC1(COC(=O)N(c3ccccc3)c3ccccc3)CC21)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 22 h
Yield: 84.9 %

Procedure:
A mixture of [5-(tert-butyldiphenylsilyloxy)-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropa[c]cyclohepten-1a-yl]methanol (639 mg) and diphenylcarbamoyl chloride (1.0 g) in pyridine (6 ml) was stirred at 100° C. for 22 hours. After cooling, the reaction mixture was poured into 6N-hydrochloric acid (16 ml) under ice-cooling. The resultant was extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 12:1 to 10:1) to give [5-(tert-butyldiphenylsilyloxy)-1,1a,2,3,4,8b -hexahydrobenzo[a]cyclopropa[c]cyclohepten-1a-yl]methyl N,N-diphenylcarbamate (782.2 mg) as an amorphous solid.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[N:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:10]=1.CC(O)C.C1COCC1>Cl>[OH:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[N:7][C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(CC(C)(C)C)nc1C(C)=O
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(=O)c1nc(CC(C)(C)C)ccc1O
Yield: 63.7 %

Procedure:
A solution of 1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone (3.75 g, 15 mmol) in (2:1:1) 5 M HCl: i-PrOH:THF (100 mL) was stirred 16 h at rt. The mixture was concentrated to remove the THF and i-PrOH. The resulting solution consisting of the product in aqueous HCl was quenched by slow addition to a solution of saturated aqueous NaHCO3 (500 mL) containing excess solid NaHCO3 (28 g). The aqueous layer was extracted with CH2Cl2 (3×100 mL), the organic layers combined and washed with saturated aqueous NaCl (100 mL), dried (MgSO4), and concentrated to give the crude product as a brown oil. The product was purified by ISCO (0-10% EtOAc/Hexanes) to give 1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone (1.98 g, 64% yield) as a clear, colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: NC1CCCC1
Reactant: O=C(CBr)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(S(=O)(=O)NC2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(2-Bromo-acetyl)-benzenesulfonyl chloride (150 mg, 0.17 mmol) was dissolved in 4 mL of dry dichloromethane. To this solution at 0° C., was added triethylamine (0.03 mL, 0.2 mmol), followed by cyclopentylamine (0.2 mmol, 0.011 g). Reaction mixture was stirred at 0° C. for 15 minutes and then quenched with H2O. The reaction mixture was extracted with H2O. The organic phase was isolated, dried over MgSO4 and evaporated. It was used in the next step without any further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([NH2:16])[C@H:13]([N:17]2[C:21]3[N:22]=[C:23]([NH2:27])[NH:24][C:25](=[O:26])[C:20]=3[S:19][C:18]2=[O:28])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.C1COCC1>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([NH:16][S:30]([CH3:29])(=[O:32])=[O:31])[C@H:13]([N:17]2[C:21]3[N:22]=[C:23]([NH2:27])[NH:24][C:25](=[O:26])[C:20]=3[S:19][C:18]2=[O:28])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)C[C@H]2N)c(=O)[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of compound [(2S,4R,5R)-4-amino-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]methyl benzoate (compound 33c, crude, 80 mg, 0.198 mmoL) in DCM (10 mL) and THF (2 mL) were added TEA (44 mg, 0.436 mmoL) and methanesulfonyl chloride (27 mg, 0.237 mmol) at 0° C. After being stirred at room temperature for 2 hours, the reaction mixture was diluted by DCM, washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford 80 mg crude product of [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-(methanesulfonamido)tetrahydrofuran-2-yl]methyl benzoate (compound 33d), which was used in next step directly. MS obsd. (ESI−) [(M−H)+]: 480.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([NH:12][NH2:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>CCO>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([S:8][CH3:9])=[N:4][C:3]=1[C:10]([NH:12][NH:13][C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)=[S:23])=[O:11]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CSc1ncc(Cl)c(C(=O)NN)n1
Solvent: CCO
Product: CSc1ncc(Cl)c(C(=O)NNC(=S)Nc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carbohydrazide (8.28 g, 38.0 mmol) and 4-fluoro-phenyl isothiocyanate (5.811 g, 38.0) were added to a 1 liter flask. A minimal amount of EtOH was added, just to ensure proper mixing. This suspension was stirred at room temperature overnight. The EtOH was removed under vacuum to give 13.5 g (95% yield) of product as a light yellow solid. MS (M+H)+ 372.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C@@H:6]([NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=1)[CH2:7][CH2:8][CH3:9])[CH3:2].C1C[O:23][CH2:22]C1>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C@@H:6]([N:10]1[C:11]2=[N:12][C:13]([CH3:18])=[CH:14][CH:15]=[C:16]2[NH:17][C:22]1=[O:23])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: C1CCOC1
Reactant: CCC[C@@H](CC(=O)OCC)Nc1nc(C)ccc1N
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
To a solution of (S)-3-(3-amino-6-methyl-pyridin-2-ylamino)-hexanoic acid ethyl ester (350 mg, 1.32 mmol) in THF (10 mL) was added N,N′-carbonyldiimidazole (CDI) (321 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 247 mg (64%) of the title compound as a light brown oily residue. LCMS, M++1, m/z: 292.59.
Reaction SMILES: [CH3:1][N:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][NH:5][CH3:6].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[CH3:6][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CNCCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Yield: 100 %

Procedure:
Dissolve N,N′-dimethyl-N-(6-nitro-benzothiazol-2-yl)-ethane-1,2-diamine (0.255 g, 0.957 mmol) in CH2Cl2 (10 mL) and add pyridine (0.1 mL, 1.2 mmol). Add acetyl chloride (0.102 mL, 1.43 mmol) and shake the mixture overnight at room temperature. Concentrate the reaction mixture in vacuo (adsorbing onto silica gel) and subject the mixture to silica gel flash column chromatography (40 g column, eluting with 1-10% MeOH/CH2Cl2) to yield the desired product (0.295 g, 100%). mass spectrum (m/e): 309.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH2:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][CH:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:27][C:7]([CH3:8])([CH3:2])[CH3:6])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ncn2c1C1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.1 g (3 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole in 10 ml of dry dimethylformamide is treated while stirring with 0.34 g (3 mmol) of potassium t-butylate, the mixture is stirred at room temperature for a further 30 minutes, then poured into 200 ml of water and extracted three times with chloroform. The chloroform solution is washed three times with water, dried over magnesium sulphate and evaporated. After crystallization from ethyl acetate, there is obtained t-butyl 8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 223°-225°.
Reaction SMILES: [CH3:1][CH:2]([NH:16][CH2:17][CH3:18])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH2:7][CH:6]=[CH:5]1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(=O)(O)[O-].[K+]>N1C=CC=CC=1>[CH2:17]([N:16]([CH:2]([CH3:1])[CH2:3][C:4]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH2:7][CH:8]=[CH:9]1)[C:19](=[O:21])[CH3:20])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCNC(C)CC1(c2ccccc2)C=CCC=C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Product: CCN(C(C)=O)C(C)CC1(c2ccccc2)C=CCC=C1
Reaction time: 8 h

Procedure:
1.5 g. of α-methyl-N-ethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine are dissolved in a mixture of 10 ml. of acetic acid anhydride and 8 ml. of pyridine and left to stand at room temperature overnight. Then, the mixture is stirred for 2 hours with 2 N aqueous potassium bicarbonate solution and subsequently extracted with ether. The ether phase is washed with dilute aqueous hydrochloride acid and then with water, dried with sodium sulfate, filtered and concentrated to dryness. The crude product obtained is chromatographed on silica gel with ether. There is obtained N-ethyl-N-[1-methyl-2-(1-phenyl-2,5-cyclohexadien-1-yl)ethyl]-acetamide in the form of an oily product.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([N:6]1[C:10](C=O)=[CH:9][N:8]=[C:7]1[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])(=[O:5])=[O:4].Cl.[OH-].[Na+]>>[CH3:1][N:2]([CH3:20])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:15])[CH3:14])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C

Procedure:
1-(N,N-dimethylsulfamoyl)imidazole (1.5 g, 8.6 mmol) was taken up in 28 mL of THF. The solution was cooled to −78° C. and n-BuLi (5.4 mL, 8.6 mmol) added dropwise via syringe. After stirring at −78° C. for 1 h TBSCl (1.3 g, 8.56 mmol) in 10 mL of THF was added. The bath was removed and the reaction allowed to warm-up to rt. The reaction mixture was stirred overnight. The reaction mixture was cooled to −20° C. and n-BuLi (5.4 mL, 8.6 mmol) added. After 45 min phenyldisulfide (1.9 g, 8.6 mmol) in 8 mL of THF was added. The reaction mixture was stirred at rt for 48 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was collected and washed with water and then brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (2.5% EtOAc/hexane) afforded 2.8 g (7.0 mmol) of 2-(t-butyldimethylsilyl)-5-phenylsulfanylimidazole-1-sulfonic acid dimethylamide (1) as a yellow color oil. The compound (1) (2.8 g, 7.0 mmol) was dissolved in THF and the solution cooled to 0° C. TBAF (7.0 mL, 7.0 mmol) was added dropwise to the solution. The reaction mixture was stirred overnight at rt. The next day the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (50% EtOAc/hexane) afforded 474 mg of 5-phenylsulfanylimidazole-1-sulfonic acid dimethylamide (2) and 290 mg of 5-phenylsulfanyl-1H-imidazole (3) (H). The 478 mg of (2) was added to 2N HCl and the solution heated at reflux for 2 h. The reaction mixture was made basic with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (EtOAc) afforded (3) as a white crystalline solid. A combined total of 360 mg (2.0 mmol) of (3) is recovered.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.N1C(C)=CC=CC=1C.[CH3:38][S:39]([NH:42][C:43]1[S:44][C:45]([CH2:48][C:49](O)=[O:50])=[CH:46][N:47]=1)(=[O:41])=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O>[CH3:38][S:39]([NH:42][C:43]1[S:44][C:45]([CH2:48][C:49]([NH:2][CH:3]2[C:28](=[O:29])[N:5]3[C:6]([C:12]([O:14][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]23)=[O:50])=[CH:46][N:47]=1)(=[O:40])=[O:41]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CS(=O)(=O)Nc1ncc(CC(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cnc(NS(C)(=O)=O)s3)[C@H]2SC1
Reaction time: 3.5 h

Procedure:
To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.3 g) in methylene chloride (100 ml) was added 2,6-lutidine (1.08 g) at 8° C., and the mixture was stirred for a while. To the resultant solution were added 2-(2-methanesulfonamidothiazol-5-yl)acetic acid (2.6 ml) and dicyclohexylcarbodiimide (2.06 g) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour and then at ambient temperature for additional 3.5 hours. After addition of water, the precipitated substance was removed by filtration. The filtrate was washed with 10% hydrochloric acid, and the organic layer was separated out, and washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain benzhydryl 7-[2-(2-methanesulfonamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.8 g). The same product (1.8 g) was recovered from the removed substance obtained above. Total yield: 3.6 g.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[Br:10].[CH3:11][C:12]([O:15][C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:17])([CH3:14])[CH3:13].[H-].[Na+]>O1CCCC1>[C:22]([O:21][C:19]([N:18]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([Br:10])[CH:4]=1)[C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(CBr)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-methyl-3-bromobenzylbromide (1.63 g, 6.2 mmol, prepared according to the procedure described in International Patent Application No. WO 0009475) and di-tert-butyliminodicarboxylate (1.48 g, 6.8 mmol) in anhydrous tetrahydrofuran (15 ml) was treated portionwise with sodium hydride (0.27 g of 60% dispersion in mineral oil, 6.8 mmol). The mixture was stirred at ambient temperature for 18 hours then partitioned between saturated aqueous ammonium chloride solution (20 ml) and ethyl acetate (3 lots of 80 ml). The combined organic layers were washed with brine (80 ml), then dried over magnesium sulfate and concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of cyclohexane and diethyl ether (9:1, v/v) to give 4-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-2-bromo-toluene as a pale yellow oil (2.4 g). 1H NMR (CDCl3, 500 MHz): δ 7.45 (s, 1H), 7.18 (m, 2H), 4.71 (s, 2H), 2.38 (s, 3H), 1.43 (s, 18H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[O:6]([CH2:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:1]([NH:5][C:14](=[O:15])[CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Product: CCCCNC(=O)COc1ccccc1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 104.2 %

Procedure:
A 100 mL 3-neck, round-bottom flask was charged with N-butylamine (8 mL, 80 mmol) and CH2Cl2 (20 mL) under N2 purge. The reaction was cooled to −10° C. Phenoxylacetylchloride (2.8 mL, 20 mmol) was slowly added via syringe, and the reaction was stirred at −10° C. for 5 minutes and warmed to room temperature. After 2 hours, the solvent was removed under vacuum. The reaction was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The pale yellow oil crystallized upon standing to provide 4.32 g of the title compound as a pale yellow crystalline solid. MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1)=O.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]2[O:17][C:18]([CH3:23])([CH3:22])[O:19][C:20](=[O:21])[C:15]=2[CH:14]=1.O>C1(C)C=CC=CC=1>[CH3:23][C:18]1([CH3:22])[O:17][C:16]2[CH:24]=[CH:25][C:13]([NH:12][CH2:1][C:3]3[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:1][C:3]4[CH:11]=[CH:10][CH:6]=[CH:5][CH:4]=4)=[O:8])=[CH:5][CH:4]=3)=[CH:14][C:15]=2[C:20](=[O:21])[O:19]1
Reactant: O=Cc1ccc(C(=O)[O-])cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)c2cc(NCc3ccc(C(=O)OCc4ccccc4)cc3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
A solution of 4-formylbenzoate (481 mg) and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (386 mg) in toluene (20 mL) was heated at reflux for 12 h with azeotropic removal of water. The toluene was evaporated off under reduce pressure, the residue was taken up in methanol (10 mL) and cooled to 0° C. NaBH4 (114 mg) was added portionwise and the reaction mixture was stirred at 0° C. for 1 h then at rt for 2 h. The reaction mixture was poured into water and resulting mixture extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduce pressure to give the crude product as an oil. The product was purified by flash chromatography (SiO2, EtOAc/c-Hex 20/80) to give the title compound as a colorless oil (713 mg, 85%). 1H NMR (CDCl3) δ 8.07 (d, J=8.1 Hz, 2H), 7.54-7.32 (m, 7H), 7.17 (d, J=2.6 Hz, 1H), 6.89-6.78 (m, 2H), 5.37 (s, 2H), 4.41 (s, 2H), 1.70 (s, 6H). M+(ESI): 418.3; M−(ESI): 416.1. HPLC, Rt: 4.6 min (purity: 95.8%).
Reaction SMILES: Br[C:2]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:5]2[N:6]=[C:7]([NH:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[OH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]1([N:17]2[C:5]3[N:6]=[C:7]([NH:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:25])[CH:31]=3)[C:18]2=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1nc(NCC(C)(C)O)nc2c1cc(Br)c(=O)n2C1CCCC1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(NCC(C)(C)O)nc2c1cc(-c1cccc(O)c1)c(=O)n2C1CCCC1
Temperature: 110 °C
Yield: 22.1 %

Procedure:
To a solution of 6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (52.5 mg, 0.133 mmol), 3-hydroxyphenylboronic acid (20.5 mg, 0.149 mmol), potassium carbonate (3 M, 0.06 mL) in DMF (1.2 mL) was added dichlorobis(triphenylphosphine)palladium(II) (5 mg, 0.007 mmol). The mixture was degassed with N2, sealed and heated for 30 min at 110° C. The mixture was poured into brine and extracted with EtOAc. The EtOAc layer was dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to give the title compound (12 mg, 22%).
Reaction SMILES: CN(C1CCCCC1)[CH:3]1CCCC[CH2:4]1.Br[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]([CH2:28][C:29]([C:31]([F:34])([F:33])[F:32])=[O:30])=[O:27])=[CH:18][CH:17]=1.C=C.Cl>O.CCOCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH:3]([C:19]1([C:26]([CH2:28][C:29]([C:31]([F:34])([F:33])[F:32])=[O:30])=[O:27])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH2:18]1)=[CH2:4]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)c2ccccc12
Reactant: CN(C1CCCCC1)C1CCCCC1
Agent: C=C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: C=CC1(C(=O)CC(=O)C(F)(F)F)CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.9 %

Procedure:
1,4-Dioxane (40 mL), tri-t-butylphosphine (0.182 g, 0.9 mmol), and methyldicyclohexylamine (19.5 g, 100 mmol) were placed into a Schlenk flask and transferred by syringe to a PPI LC series 300 mL reactor containing dipalladium tris(dibenzylidenelacetone) (0.420 g, 0.45 mmol) and 4-bromonapthoyltrifluoroacetone (10.4 g, 30 mmol) under an argon atmosphere. The reactor was charged to 300 psi with ethylene and the reaction was allowed to stir for 48 hours at room temperature. Upon completion of the reaction the contents taken up in water (50 mL) and ether (50 mL), the aqueous phase acidified by addition of concentrated hydrochloric acid, and extracted with ether (2×50 mL). The combined organic phase was rinsed with saturated sodium chloride solution, and the organic phase was dried over magnesium sulfate overnight. The solution was filtered, the solvent was removed by vacuum, and the residue dissolved in chloroform (3 mL). The product was isolated by column chromatography from silica gel (Selecto, mesh size 63-200) with 10% ether in chloroform as eluent. The solvent was removed to give a light brown oil (9.08 g, 99% yield). 1H-NMR (90 MHz, 25° C., CDCl3): δ 14.49 (s, 1H), 8.48 (m, 1H), 8.06 (m, 1H), 7.58 (m, 4H), 7.45 (dd, 1H), 6.45 (s, 1H), 5.91 (dd, 1H), 5.62 (dd, 1H). Anal.: (found/calc for C17H14O2) 65.75 (81.58), H 3.79 (5.59).