Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:5]([Cl:16])=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1.Cl.[F:25][C:26]1[CH:27]=[N:28][C:29]([C@@H:32]([NH2:34])[CH3:33])=[N:30][CH:31]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:5]1[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:7][C:2]([NH:34][C@H:32]([C:29]2[N:30]=[CH:31][C:26]([F:25])=[CH:27][N:28]=2)[CH3:33])=[N:3][C:4]=1[NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1
Reactant: Cc1cc(Nc2nc(Cl)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 89.4 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 24, 83.9 mg, 0.221 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 78.4 mg, 0.443 mmol), and DIPEA (0.120 ml, 0.682 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (95.8 mg, 89.6%). LC-MS, 485 (M+1). 1H-NMR (DMSO-d6, 400 MHz, 80° C.) δ 11.48-12.40 (br, 1H), 8.77 (s, 1H), 7.85-8.66 (br, 1H), 6.98-7.61 (br, 1H), 6.23 (s, 1H), 5.14-5.11 (m, 1H), 2.93 (s, 3H), 2.83 (s, 6H), 2.21 (s, 3H), 1.53 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1.O.CO.Cl>[OH-].[Na+]>[C:23]([CH2:22][CH2:21][CH2:20][O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([NH:6][C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[F:30])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18])([OH:25])=[O:24]
Reactant: CCOC(=O)CCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Temperature: 40 °C
Yield: 83.8 %

Procedure:
A mixture of 4-(4-chloro2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)6-methoxyquinazoline (220 mg, 0.5 mmol) in aqueous sodium hydroxide solution (4 ml of a 2M solution, 8 mmol), water (2 ml) and methanol (0.5 ml) was stirred and heated at 40° C. for 3 hours. The mixture was allowed to cool and was then acidified with 2M hydrochloric acid. The resulting white precipitate was collected by filtration and washed with acetone and water to give 7-(3carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (170 mg, 83%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH:3]=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:15])=[O:10])([CH3:1])[CH:3]=[O:4]
Reactant: CC(C)(C=O)c1cccc(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C(C)(C)C=O)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(1,1-dimethyl-2-oxoethyl)benzoic acid in acetone (60 mL) were added potassium carbonate (3.78 g, 27.3 mmol) and methyl iodide (3.40 mL, 54.6 mmol), and the mixture was stirred at 60° C. for 5 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogencarbonate solution (50 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 3-(1,1-dimethyl-2-oxoethyl)benzoate as a yellow oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
tert-Butyl amine (14.6 g, 0.200 mole) was stirred in ethyl acetate (150 mL, purified by washing with 5% sodium carbonate solution, saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and filtering through fluted filter paper) and cooled to 5° C. with an ice bath. Benzoyl chloride (14.0 g, 0.100 mole) in purified ethyl acetate (75 mL) was added dropwise at such a rate to maintain the temperature below 10° C. The ice bath was removed upon complete addition of benzoyl chloride solution and the reaction stirred for 4 hours. The reaction mixture was then filtered on a Buchner funnel, the filtrate washed three times with 5% HCl, once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered through fluted filter paper, and the solvent stripped off leaving white crystalline product. The product was dried in a vacuum oven at 24 mm and 45° C. for 14 hours. This procedure produced 15.46 g of crystals of the desired product N-tert-butyl benzamide (CPI1010) (87% yield), mp 133°-135° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.75 ppm (m, 2H; 2,6-aryl H); 7.45 ppm (m, 3H; 3,4,5-aryl H); 5.97 ppm (bs, 1H; N-H); 1.471 ppm (s, 9H, tert-butyl H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]1.[H-].[Na+].[CH3:20]S(C)=O>CI>[CH3:20][N:9]1[C:10]2[C:15](=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[CH:8]1
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1cc(C2CCC(=O)C2)c2cc(C#N)ccc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
3-(3-oxocyclopentyl)-1H-indole-5-carbonitrile (11.21 g, 0.05 mMol) was dissolved in anhydrous DMSO (30 mL) and added dropwise to a suspension of sodium hydride (2.25 g, 0.055 mMol, 60% in mineral oil) in dry DMSO (50 mL) under nitrogen at 25–30° C. The reaction was heated to 40° C. for 15 min, then cooled to room temperature. Methyl iodide (3.42 mL, 0.055 mMol) was added dropwise, maintaining reaction temperature at 25–30° C. with an external ice water bath. After stirring for 2 h at room temperature, the reaction was poured into 1 L ice water. The tan solid was filtered, washed with H2O, dissolved in ethyl acetate (750 mL), extracted with H2O (500 mL) and brine (500 mL), and dried over sodium sulfate. The ethyl acetate extract was concentrated in vacuo and the product was purified by chromatography on silica gel with a 10% step gradient of 25–45% ethyl acetate in hexane. Pure product fractions were concentrated in vacuo and dried under high vacuum to give 1-methyl-3-(3-oxo-cyclopentyl)-1H-indole-5-carbonitrile (8.52 g, 72%). 1H NMR (500 MHz, CDCl3) δ 7.95 (1 H, s), 7.46 (1 H, dd, J=8.54, 1.22), 7.34 (1 H, d, J=8.54), 6.94 (1 H, s), 3.78 (3 H, s), 3.69 (1 H, m), 2.74 (1 H, dd, J=7.63, 18.01 Hz), 2.53 (1 H, m), 2.38 (3 H, m), 2.06 (1 H, m). MS m/e 239.3 (M+H)+. Anal. calcd. for C15H14N2O: C, 75.60; H, 5.92; N, 11.75. Found: C, 75.31; H, 5.86; N, 11.55. IR (KBr) 2219, 1728 cm−1.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][Si](CC=[N+]=[N-])(C)C>CO.ClCCl>[CH:1]1([C:5]2[C:14]([C:15]3[NH:19][CH:18]([CH2:20][CH3:21])[N:17]([CH3:23])[N:16]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Reactant: C[Si](C)(C)CC=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CCC1NC(c2cc(C(=O)OC)c(C)cc2C2CCC2)=NN1C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Methyl 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate (compound 164.1, 87 mg, 0.29 mmol) was dissolved in methanol and dichloromethane (1:1 v/v) (6 ml). ((Trimethylsilyl)methyl)diazomethane (2.0 M in ether) (220 ul, 0.44 mmol) was added. The mixture was stiffed for 16 hours and quenched with HOAc (300 ul). The volatiles were removed in vacuo to afford an oil (85 mg). The residue was carried as crude onto the next step without further purification. m/z (ES+) 314 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)=[O:7].Cl.Cl[CH2:40][C:41]#[C:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][C:41]#[C:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)[CH2:10][CH:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)=[O:7]
Reactant: ClCC#Cc1cccnc1
Reactant: COCCOCOc1cc(CC2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCCOCOc1cc(CC2CN(CC#Cc3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Yield: 90.5 %

Procedure:
A mixture of 1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (0.4 g), 1-chloro-3-(3-pyridyl)-2-propyne hydrochloride (0.17 g), potassium carbonate (0.52 g) and a trace of potassium iodide in N,N-dimethylformamide (7 ml) was stirred for 4 hours at 80° C. After cooling, the solvent was removed by evaporation, and ethyl acetate and aqueous sodium hydrogen carbonate solution were added thereto. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-4-[3-(3-pyridyl)-2-propynyl]piperazine (0.44 g) as an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].CO[CH:30](OC)[CH:31](Br)[CH3:32].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][C:31]([CH3:32])=[CH:30][N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: COC(OC)C(C)Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
A mixture of 1.50 g (3.90 mmol) of starting material I, 3.57 g (19.50 mmol) of 2-bromopropionaldehyde dimethyl acetal and 15 ml of dimethylformamide was stirred at 90° C. for 1.5 h. Then the reaction mixture was diluted with water and the crude product obtained was purified by column chromatography using silica gel (MN Kieselgel 60; Macherey-Nagel, Düren, Germany) as adsorbent and a mixture of toluene-ethyl acetate (16:1) as eluent to yield 1.08 g (66%) of the title compound; Mp.: 193-195° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11](O)=[O:12]>C(OC(=O)C)(=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:15](=[O:17])[O:16][C:11](=[O:12])[CH2:10]1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccccc2C(F)(F)F)CC(=O)O1
Temperature: 110 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
3-(2-Trifluoromethylphenyl)pentanedioic acid (1.2 g) was dissolved in acetic anhydride (12 mL), and the mixture was stirred at 110° C. for two hours. The oil after concentration under reduced pressure was dissolved in ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. After drying over magnesium sulfate, concentration under reduced pressure gave an orange solid. The solid was recrystallized from ethyl acetate (10 mL) and heptane (70 mL) to obtain the title compound (636 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:24]=2[CH:23]=[CH:22]1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]5[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1cc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)c2cc[nH]c2c1
Temperature: 90 °C
Yield: 87.1 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and Indole-4-boronic acid pinacol ester (MW 243) (267 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 15 h 30 min, cooled and diluted with EtOAc (20 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from 100% hexane in EtOAc to 50% hexane) gave a yellowish solid (89.0 mg, 87%).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20](O)=[O:21])[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH2:20][OH:21])[C:3](=[O:11])[C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)c1ccccc1CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccc(Cl)cc1)c1ccccc1CCCO
Reaction time: 4 h
Yield: 78.8 %

Procedure:
15.8 g of 3-[2-(N-methyl-4-chlorobenzamido)-phenyl]-propionic acid and 15 g of oxalyl chloride are stirred in toluene for 2 hours. After following evaporation in vacuo, the residue is taken up in 60 ml of dioxane and added dropwise to 1.6 g of sodium borohydride in 40 ml of dioxane. Heating to 100° is effected for 4 hours, followed by addition of 2 N hydrochloric acid in an ice bath to the end of the gas development. Extraction with diethyl ether yields 11.9 g of 3-[2-(N-methyl-4-chlorobenzamido)-phenyl]-propanol as oil, which is reacted without further purification in 80 ml of toluene with 3 g of pyridine and 6 g of tosyl chloride to the 3-[2-(N-methyl-4-chlorobenzamido)-phenyl]-propyl-tosylate (33 hours of stirring at room temperature). The chromatographic purification (silica gel, eluent methylene chloride) yields 6.1 g (31% of theory). This tosylate in 70 ml of ethanol is added dropwise to a solution of 0.35 g of sodium and 3.2 g of diethyl malonate in 60 ml of ethanol. Following heating under reflux for 24 hours, working up by extraction with methylene chloride and chromatographic purification with silica gel/chloroform yield 5.4 g (89% of theory) of diethyl-3-[2-N-methyl-4-chlorobenzamido)-phenyl]-propyl malonate as oil, which is used under (a).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([S:13][CH3:14])=[N:6][CH:7]=[N:8]2.C(O)(C(F)(F)F)=O.[CH2:22]([O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH:23]=[CH2:24]>ClC(Cl)C>[CH2:22]([O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[C:5]([S:13][CH3:14])=[N:6][CH:7]=[N:8]3)[CH2:30][C@@H:29]1[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)[C@@H]1CCNC[C@@H]1C(=O)OC
Reactant: CSc1ncnc2cccc(CBr)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(SC)c23)C[C@@H]1C(=O)OC
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 15A (2.02 g, 7.5 mmol), TFA salt of (3R,4R)-methyl 4-(allyloxycarbonyl)piperidine-3-carboxylate (2.8 g, 7.87 mmol), (prepared as described in U.S. patent application Ser. No. 11/019,901) and TEA (3.14 ml, 22.5 mmol) in dichloroethane (50 ml) was heated at 70° C. for 1 h. After cooling to room temperature, the reaction mixture was washed with water, dried and concentrated in vacuo. Purification using silica gel flash column (DCM/MeOH=98/2) gave 15B (2.91 g, 90%) as a solid. The compound has an analytical HPLC retention time=1.547 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=431+.
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:12](=[O:26])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C@@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.CN1CCOCC1.Cl>C(OCC)(=O)C>[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C@@H:34]([NH:36][C:12](=[O:26])[C@H:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:35])=[CH:30][CH:29]=1
Reactant: O=C(CC[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1)OCc1ccccc1
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H](C)NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
(S)-3-Benzoyl-4-benzyloxycarbonylethyl-2,5-oxazolidinedione (L-N-benzoyl-O-benzylglutamic acid-NCA)(100 mg, 0.27 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (37 mg, 0.27 mmol) and N-methylmorpholine (28 mg, 0.27 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (106 mg, 85%) as white crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[N+:18]=[N-:19])([CH3:6])([CH3:5])[CH3:4].Br[CH2:22][C:23]#[C:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>CCCCCC.CN(C=O)C>[C:3]([O:7][C:8]([N:9]1[CH2:22][C:23]2[N:17]([N:18]=[N:19][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10]1)=[O:20])([CH3:6])([CH3:4])[CH3:5]
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
Sodium hydride (80.0 mg, 2.0 mmol; 60% suspension in mineral oil) was washed with hexane (2 mL) in a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of (2-azido-benzyl)-carbamic acid tert-butyl ester (250 mg, 1.0 mmol) in dry DMF (3 mL) dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 30 min followed by dropwise addition of a solution of 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (318.0 mg, 1.50 mmol) in dry DMF (1.5 mL). The reaction mixture was stirred at r.t. for 2 h. After the completion of the reaction as confirmed by TLC, the crude compound was extracted with ethylacetate (2×10 mL). The combined organic layer was washed with water (2×10 mL). Organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (silica gel, 1:9 EtOAc:Pet.Ether) to afford 3-(4-fluoro-phenyl)-4H,6H-1,2,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (70 mg, 12.2%) as a viscous oil.
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11](COCC[Si](C)(C)C)[C:12]([O:16][C@@H:17]4[CH2:21][O:20][C@@H:19]5[C@H:22]([O:25][Si](C(C)(C)C)(C)C)[CH2:23][O:24][C@H:18]45)=[N:13]3)=[CH:9][N:8]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].CCOC(C)=O>C(Cl)Cl>[C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:14]3[C:10]([NH:11][C:12]([O:16][C@H:17]4[C@H:18]5[O:24][CH2:23][C@@H:22]([OH:25])[C@H:19]5[O:20][CH2:21]4)=[N:13]3)=[CH:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)ncc2n1COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To 2-([1,1′-biphenyl]-4-yl)-8-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine (38.0 mg, 0.057 mmol) in anhydrous DCM (1.8 mL) was added TFA (1.33 mL, 17.25 mmol). The solution stirred at RT for 22 h. The reaction solution cooled to 0° C. and 1N NaOH (18.2 mL, 18.2 mmol) and EtOAc (60 mL) added. The organic layer washed with brine (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. Flash chromatography utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-15% MeOH/DCM gradient afforded the title compound. LC-MS: calculated for C23H20N4O4 416.15 observed m/e: 417.36 (M+H)+ (Rt 0.93/2.0 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.[C:19]1([C:25]2[CH:38]=[CH:37][C:28]([CH:29]=NC3C=CC=CC=3)=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH:16]=[CH:29][C:28]4[CH:37]=[CH:38][C:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Reactant: C(=Nc1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Clc1cc(Cl)c2oc(-c3ccc(C=Cc4ccc(-c5ccccc5)cc4)cc3)cc2c1

Procedure:
Following the procedure given in Example 1b equimolar quantities of the above named 5,7-dichloro-2-(p-tolyl)-benzofuran and 4-phenylbenzalaniline were interacted in the presence of potassium tert.-butoxide to give 5,7-dichloro2-{4-[2-(4-biphenylyl)vinyl]phenyl} benzofuran which, following recrystallization from chlorobenzene, melted at 258°-260° C. The wavelength of maximum excitation of this compound was 375 nm., and the wavelength of maximum emission was 431 nm.