Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[CH3:14][S-:15].[Na+]>C(O)C.C(Cl)Cl.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>[CH3:14][S:15][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)ncc2c1
Reactant: C[S-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCS
Solvent: CCO
Product: CSc1ncc2cc(O)ccc2n1

Procedure:
In the alternate reaction Scheme B, above, the 2-chloro-6-methoxyquinazoline 8 is reacted with sodium thiomethoxide in ethanol, dry methylene chloride, ethane thiol and aluminum chloride to obtain the 2-methylthioquinazolin-6-ol 13. The desired substituent, in this case 4-chloro(2-pyridyl)-N-methylcarboxamide, is added to the alcohol group to obtain the corresponding substituted methylthioquinazoline 14. Treatment with 3-chloroperoxybenzoic acid in acetic acid results in the corresponding sulfonyl 15, which is replaced by a desired substituent, in this case 2-naphthylaniline, to obtain the desired compound of the invention, in this case N-methyl-4-{[2-(naphthalen-2-ylamino)-quinazolin-6-yl]oxy}pyridine-2-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH3:12][C:13]([CH3:15])=O.C([BH3-])#N.[Na+].CC(O)=O>CCO>[CH:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11])([CH3:15])[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1ccc([N+](=O)[O-])cc1O

Procedure:
A solution of 2-amino-5-nitrophenol (2.00 g, 13.0 mmol) in absolute EtOH (52 mL) and acetone (14.3 mL, 195 mmol, 15 equiv.) is treated with sodium cyanoborohydride (408 mg, 6.49 mmol), the pH is adjusted to 4.5–5.0 with glacial AcOH, and the mixture is stirred at ambient temperature for 4 days, during which time additional acetone (2×14.3 mL), sodium cyanoborohydride (3×408 mg) and glacial AcOH is added. The reaction mixture is then readjusted to pH 6, concentrated under reduced pressure, diluted with water (50 mL) and CH2Cl2 (75 mL), and the layers are separated. The organic phase is washed with saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M 90 g silica gel cartridge with EtOAc/heptane (20/80). Pooling and concentration of those fractions with an Rf=0.59 by TLC (EtOAc/hexanes, 50/50) gives the title compound, mp 108–110° C.; MS (ESI+) for C9H12N2O3 m/z 197 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:29]([O:31][CH3:32])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:29]([O:31][CH3:32])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (3 mL). Add trifluoracetic acid (1 mL) and stir for 2 hours. Dilute into ethyl acetate and rinse with saturated sodium bicarbonate. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].N12CCCN=C1CCCCC2.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1.0 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, 0.28 ml of 1,8-diazabicyclo[5.4.0]-undec-7-ene, 0.34 ml of methyl acrylate and 10 ml of N,N-dimethylformamide was stirred at room temperature for 12 hours. Then, the solvent was distilled off under reduced pressure, after which the resulting residue was added to a mixed solvent of 30 ml of ethyl acetate and 30 ml of water, and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with three 30-ml portions of ethyl acetate. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=20:1) to obtain 0.68 g of methyl 3-[4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]propionate as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]N=C2CCCCCC2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH:20](O)([CH3:22])[CH3:21]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:20]3[CH2:22][CH2:6][CH2:5][CH2:4][CH2:9][C:21]=3[C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc(ON=C2CCCCCC2)cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCCC3

Procedure:
Potassium t-butoxide (19 g, 1600 mmol) was added in portions to a cooled (2° C.) solution of cycloheptanone oxime (19 g, 150 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 40 minutes and then 1-chloro-4-nitrobenzene (25 g, 160 mmol) in DMF (50 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 2 hours, and then stood at ambient temperature for 16 hours. The reaction mixture poured into water (1600 mL) with stirring. The mixture was stirred for an additional 20 minutes and then allowed to stand at room temperature for 5 hours. The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from hexane provided cycloheptanone O-(4-nitro-phenyl)-oxime (30 g). Cycloheptanone O-(4-nitro-phenyl)-oxime (12 g, 50 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (17 mL) was added. The reaction mixture was heated to reflux for 4 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (7.8 g, 34 mmol). A mixture of 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (5.8 g, 25 mmol) and Raney nickel (-5.6 g wet weight) in ethanol (270 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (gradient elution with 15-25% ethyl acetate-hexanes) to give 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (4.6 g). Mp 98-99° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:29][CH3:30])=[CH:22][C:21]=2F)=[CH:14][C:13]=1[Cl:33].[F:34][CH2:35][CH2:36][OH:37]>C1COCC1>[Cl:33][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:29][CH3:30])=[CH:22][C:21]=2[O:37][CH2:36][CH2:35][F:34])[CH:16]=[CH:17][C:12]=1[F:11]
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reactant: OCCF
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CNc1cc(OCCF)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
KHMDS (0.320 g, 1.60 mmol) is added to an ice-cooled mixture of N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (500 mg, 1.46 mmol), 2-fluoroethanol (0.129 ml, 2.19 mmol) and 30 ml THF. After 30 min the temperature is raised to 60° C. for 4.5 h, then it is stirred at rt overnight. Additional 2-fluoroethanol (0.129 ml, 2.19 mmol) and KHMDS (0.160 g, 0.80 mmol) are added and it is stirred for 4.5 h at 60° C. Then the mixture is diluted with satd. aq. NaHCO3-solution and the precipitate is filtered off, washed with water and dried.
Reaction SMILES: Br[C:2]1[C:3]([CH2:12][CH2:13][CH:14]=[CH2:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:15]=[C:14]1[C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[CH2:12][CH2:13]1
Reactant: C=CCCc1c(Br)cccc1C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: C=C1CCc2c1cccc2C(=O)OC
Temperature: 120 °C

Procedure:
To a microwave tube charged with methyl 3-bromo-2-but-3-en-1-ylbenzoate (800 mg, 3.0 mmol) and a stir bar was added palladium (II) acetate (67 mg, 0.30 mmol), triphenylphoshpine (310 mg, 1.19 mmol), potassium carbonate (2.46 g, 18.0 mmol), and acetonitrile (20 mL). The reaction tube was sealed, and the solution was purged three times with nitrogen, and heated in a microwave apparatus to 120° C. for 10 minutes. TLC showed a big blue spot right below the SM. The product was isolated by silica gel chromatography. LC-MS M+1 (calc. 189, found 189).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6]([NH:8][C@@H:9]([C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C@@H:5]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:6]([NH:8][C@@H:9]([C:25]1[NH:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]2)=[CH:15][CH:16]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)c1nc2ccccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)c1nc2ccccc2[nH]1
Yield: 37.7 %

Procedure:
To a solution of (2S)-2-(acetylamino)-N-{(1R)-1-(1H-benzimidazol-2-yl)-2-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl}-3-phenylpropanamide (5.0 mg, 0.009 mmol) in methanol (1.5 mL) was added 5% palladium on carbon (3 mg, 0.03 mmol), and mixed for 1.5 h under hydrogen gas (50 psi). Product was filtered and purified by preparative LCMS to afford the final product (1.9 mg, 38%). 1H NMR (500 MHz, CD3OD): δ 7.73–7.76 (m, 2H), 7.58–7.60 (m, 2H), 7.43 (d, J=7.0 Hz, 2H), 7.23–7.26 (m, 5H), 7.14–7.16 (m, 2H), 5.42–5.47 (m, 1H), 5.11–5.16 (m, 1H), 4.52–4.56 (m, 1H), 3.40–3.46 (m, 2H), 2.76–2.92 (m, 4H), 1.90 (s, 3H); LCMS found for C29H30N5O5S (M+H)+: m/z=560.1
Reaction SMILES: CO.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18](=[O:36])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:50](=S)=[S:51]>O>[N:3]([CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18](=[O:36])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=1)=[C:50]=[S:51]
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCN)c2ccccc2c1O
Reactant: S=C=S
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCN=C=S)c2ccccc2c1O
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Into 300 ml of methanol were dissolved 64 g of 4-(2-aminoethyloxy)-2-hexadecylcarbamoyl-1-naphthol and 35 g of triethylamine. To this mixture was added dropwise 19 g of carbon disulfide at a temperature not exceeding 10° C., and the resulting mixture was stirred for 1 hour. Thereafter, 11.9 g of ethyl chloroformate was added dropwise and stirred for additional 30 minutes. The resulting reaction mixture was poured into 1.5 l of water, and precipitated crystals were collected by filtration and recrystallization from acetonitrile to give 47 g of 4-(2-isothiocyanatoethyloxy)-2-hexadecylcarbamoyl-1-naphthol. Yield: 92%. M.P.: 90°-91° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].[BH3-]C#N.[Na+]>C(O)C>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)NCc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.68 g (8.43 mmol) of 6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde, 3.07 g (42.1 mmol) of tert-butylamine and 800 mg (12.7 mmol) of NaBH3CN and 100 ml of dry ethanol was stirred overnight at room temperature. The resulting mixture was evaporated to dryness, and the product was isolated by flash chromatography on silica gel 60 (40-63 um; ethyl acetate-triethylamine=20:1, vol.). Yield 1.61 g (51%) of white solid. Anal. calc. for C25H33N3: C, 79.95; H, 8.86; N, 11.19. Found: C, 80.11; H, 8.95; N, 10.95. 1H NMR (CDCl3): 8.87 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.83 (m, 1H, 8-H in naphthyl), 7.77 (m, 1H, 4-H in Py), 7.63 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.46 (m, 1H, 3-H in Py), 7.41 (m, 1H, 7-H in naphthyl), 7.31-7.34 (m, 2H, 5,6-H in naphthyl), 7.27 (m, 1H, 5-H in Py), 3.97 (m, 2H, NaphCH2N), 3.53 (s, 21-1, PyCH2N), 1.17 (s, 9H, PyCH2NHtBu), 0.96 (s, 9H, NaphCH2NH′Bu).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][OH:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 34.8 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (34 mg, 0.072 mmol) and 2-bromo ethanol (9 mg, 0.216 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (12 mg, 32%). MS (ESI) m/z 479.3 (M+H)+
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.[BH4-].[Na+]>CO>[F:13][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) solution of commercially available 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde (1.500 g; 8.06 mmol) in anh. MeOH (60 ml) was treated portionwise with NaBH4 (1.524 g; 40.29 mmol), and the resulting mixture was stirred at 0° C., under nitrogen, for 1 h. After concentration to dryness under reduced pressure, the resulting residue was treated with water (30 ml), and extracted with DCM (2×100 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, concentrated to dryness under reduced pressure, and the residue was further dried under HV affording (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol as a colorless oil. LC-MS (conditions D): tR=0.85 min.; no ionisation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:28])[CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:27][C:24]1[CH:23]=[N:22][C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:28])[CH3:16])=[CH:26][CH:25]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)CCNc1ccc(N)cn1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(NCCN(C)C)nc1
Yield: 74.7 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (284 mg, 1 mmol) was reacted with N2-(2-(dimethylamino)ethyl)pyridine-2,5-diamine (270 mg, 1.5 mmol) to afford the desired product (320 mg, 74%) as a yellow solid: ESI MS m/z 428 [C20H22BrN5O+H]+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(C#Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 1.43 g (0.005 mole) of 1-(trimethylsilylethynyl)-4-(4-methylphenylethynyl)benzene, 1.37 g (0.01 mole) potassium carbonate, 20 ml of methanol and 20 ml of methylene chloride. The mixture was stirred at room temperature under nitrogen overnight. The dark brown suspension was filtered and the filtrate was washed twice with water (20 ml each). The aqueous layers were combined and extracted twice with methylene chloride (10 ml each). The methylene chloride layers were combined and dried over anhydrous MgSO4, filtered and concentrated. 0.7 g (73.1% yield) of brownish yellow solid was obtained. 1HNMR: 2.40 ppm (2, 3H); 3.19 ppm (s, 1H); 7.15-7.18 ppm (d, 2H); 7.43-7.46 ppm (d, 2H); 7.49 (s, 4H). The NMR indicated that there were some by-products present. It was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:6](B(O)O)[CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:15]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:11]([O:13][CH3:14])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(F)cc1B(O)O
Reactant: BrCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1Cc1ccccc1

Procedure:
5-Fluoro-2-(methoxycarbonyl)phenylboronic acid (1.00 g), benzyl bromide (0.50 mL), K2CO3 (1.75 g), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)) (0.17 g) were stirred in tetrahydrofuran (20 mL) at 60° C. for 24 hours. The reaction mixture was chromatographed on silica gel with 2% ethyl acetate/hexanes.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[N:15]([CH3:22])[C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)=[N:12][CH:13]=1)(=O)C.[ClH:23]>C(O)C>[ClH:23].[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[N:15]([CH3:22])[C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)=[N:10][CH:9]=1
Reactant: CC(=O)OCCOc1cnc(-c2ncc([N+](=O)[O-])n2C)nc1
Agent: Cl
Solvent: CCO
Product: Cn1c([N+](=O)[O-])cnc1-c1ncc(OCCO)cn1

Procedure:
0.2 g. of 5-(2-acetoxyethoxy)-2-(5-nitro-1-methyl-2-imidazolyl)-pyrimidine is refluxed in 5 ml. of ethanol with 2.5 ml. of concentrated hydrochloric acid. After concentration under vacuum, the residue is recrystallized from ethyl acetate; m.p. 158°-160° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:52])[C@@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=1)/[CH:26]=[CH:27]/[CH2:28][C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:53](Br)[CH:54]=[CH2:55]>C1COCC1>[CH2:55]([C@@H:28](/[CH:27]=[CH:26]/[C@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=1)[C:24]([N:19]1[C@@H:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][O:21][C:20]1=[O:23])=[O:52])[C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[CH:54]=[CH2:53]
Reactant: C=CCBr
Reactant: O=C(C/C=C/[C@H](Cc1cccc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](/C=C/[C@H](Cc1cccc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 25.2 %

Procedure:
A solution of NaHMDS (1.0 M in THF, 0.313 mL, 0.313 mmol) was slowly added dropwise over 5 min to a −78° C. solution of (S,E)-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(3-fluorobenzyl)hex-3-ene-1,6-dione (170 mg, 0.298 mmol) in THF (1.6 mL). After addition the reaction mixture was allowed to stir for another 25 min at −78° C. and then allyl bromide (108 mg, 0.894 mmol) was added dropwise. The reaction temperature was then slowly raised to 0° C. over 20 min and then stirred at 0° C. for an additional 1 hr. The reaction was quenched by addition of saturated NH4Cl. The mixture was then partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2S,5S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-(3-fluorobenzyl)hex-3-ene-1,6-dione (46 mg, 0.075 mmol, 25% yield) as a foam. Anal. Calcd. for C36H35FN2O6 m/z 610.2. found: 611.0 (M+H)+.
Reaction SMILES: N1CCCCC1.O=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.[CH3:18][O:19][C:20](=[O:24])[CH2:21][C:22]#[N:23]>C(O)C>[CH3:18][O:19][C:20](=[O:24])/[C:21](/[C:22]#[N:23])=[CH:8]/[C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=O)ccc1O
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)/C(C#N)=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
0.2 ml of piperidine were added carefully to a solution of 4.6 g (30 mmol) of vanillin, 3.4 ml (30.3 mmol) of cyanoacetic acid methyl ester and 0.5 ml of ethanol held at 45° C. The product started to precipitate on cooling to room temperature. The cold reaction mixture was diluted with 8 ml of ethanol, filtered and washed with cold ethanol to give 6.5 g (93%) of 2-cyano-(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid methyl ester in form of yellow crystals.