Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[N:4][C:3]1=2.C(O)(=[O:20])C.N([O-])=O.[Na+]>O>[O:20]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c1N=CNC2N
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 0 °C
Yield: 30 %

Procedure:
3-(1.6-dihydro-6-amino-9H-purin-9-yl)propionic acid, ethyl ester (15.2 g., 64.6 mmol) (AIT-0026) was placed into a 500 ml round bottom flask with 350 ml glacial acetic acid and was stirred to complete dissolution. While stirring, 22.3 g (0.323 mol) NaNO2 dissolved in water (saturated) was added dropwise over a period of one hour using a dropping funnel (pressure equalizing). A brown gas formed during the addition. The flask was stoppered shortly after the addition was complete and the solution was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure (approximately 45°-50° C.). The residue was washed with cold (0° C.) absolute ethanol and filtered. The resulting white solid was dissolved in 175 ml ethanol/water (70/30) and was cooled to 0° C. overnight. The resulting precipitate was obtained by filtration. The solid was placed into a flask with a magnetic stirring bar and was washed with water by vigorous stirring. The solution was filtered by Buchner vacuum filtration and the resulting white solid was dried in vacuo at 50° C. to yield 4.6 g (19.5 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027). Yield: 30%.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:11].C(N(C(C)C)CC)(C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].P([O-])(O)(O)=O.[K+]>C1(C)C=CC=CC=1.C1COCC1>[CH3:12][C:3]1[C:2]([O:1][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:10][N:9]2[C:4]=1[C:5](=[O:11])[NH:6][CH:7]=[N:8]2
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(O)cn2nc[nH]c(=O)c12
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(OC(=O)C(C)(C)C)cn2nc[nH]c(=O)c12
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A mixture of 2.9 kg 6-hydroxy-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, 4.6 kg of diisopropylethylamine and 17.0 kg of THF was cooled to 0-10° C., then treated with 2.6 kg pivaloyl chloride at a rate to maintain the temperature <20° C. The mixture was stirred until the reaction was complete by HPLC, then 17.8 kg of toluene was added, followed by 20.6 kg of 15% aqueous potassium dihydrogen phosphate solution. The phases were separated and the organic was washed with 10.2 kg water. The organic phase was filtered, then distilled under vacuum with a maximum temperature of 65° C. Additional toluene can be added and distillation continued until the concentration of THF was <8%, and the total reactor volume was reduced to 31 L. The resulting slurry was cooled to 20-25° C. and treated with 20.3 kg heptane over 1.5 h. The slurry was cooled to 0-5° C. and held for 1 h, then the solid was collected by filtration and dried to yield 4.0 kg of 2,2-dimethyl-propionic acid 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-6-yl ester with a purity of 95-99%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.O>C(Cl)(Cl)Cl>[F:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.7 %

Procedure:
368 mg (corresponding to 1.1 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 15 mL of N,N-dimethylformamide, and 453 mg (corresponding to 3.3 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 280 μL (corresponding to 1.6 mmol) of 2-fluoroethyl-p-toluenesulfonate, and then the solution was stirred at room temperature for 22 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1), and further by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 222 mg (corresponding to 0.580 mmol) of 2-[4′-(2″-fluoroethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1-7, Step 3).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.CC1(C)COB([C:26]2[CH:27]=[C:28]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])OC1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)Cl>[CH3:17][CH:16]([S:13]([NH:12][C@@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:26]3[CH:27]=[C:28]([CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])[CH:4]=2)[CH2:8]1)(=[O:15])=[O:14])[CH3:18]
Reactant: COC(=O)c1cc(B2OCC(C)(C)CO2)cc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CCl)cc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
To (S)-N-(5-(chloromethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.160 mmol, 46 mg) in THF (1 mL) was added methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)benzoate (0.160 mmol, 50.5 mg), Bromo(N-succinimidyl)bis-(triphenylphosphine)palladium(II) (7.99 μmol, 6.46 mg) and sodium carbonate (1.000 mmol, 0.5 mL). The reaction was heated to 100° C. for 10 minutes by microwave irradiation before diluting with DCM and filtering through a hydrophobic frit. The solvent was removed in vacuo before redissolving in MeCN (500 μL) and purifying by reverse phase preparative chromatography to give (S)-methyl 3-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)benzoate (23.2 mg, 31.9%). MS (ESI): m/z [M+H]+ 456.0
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH2:5]Br.C[N+]1([O-])CC[O:16]CC1>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=[O:16]
Reactant: Cc1c(Cl)ccc(Cl)c1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: Cc1c(Cl)ccc(Cl)c1C=O
Temperature: 4 °C
Reaction time: 1 h

Procedure:
67.4 g (0.19 mol) of 72.2% pure 3,6-dichloro-2-methylbenzyl bromide is initially charged in 280 ml of acetonitrile. At 0-5° C., a solution of 54.0 g (0.46 mol) of N-methylmorpholine N-oxide and 280 ml of acetonitrile is added over a period of 25 min, and the mixture is stirred at 0-8° C. for 1 h. The precipitate is filtered off with suction and taken up in 280 ml of acetonitrile, and 250 g (0.42 mol) of 20% strength NMO in acetonitrile are then added at 40° C. The reaction mixture is stirred at 40° C. for 1 h and concentrated under reduced pressure, the residue is taken up in 250 ml of methylene chloride and the mixture is washed three times with 250 ml of water, dried over Na2SO4 and concentrated under reduced pressure. This gives 32.9 g of a product which is 92.6% pure.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH2:21]([P:24]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([O:36][CH3:37])[CH:30]=1)([CH2:26][CH2:27]C)=[O:25])[CH2:22]C.Cl>COCCO.C(O)C>[CH2:21]([P:24]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=2)=[C:31]([O:36][CH3:37])[CH:30]=1)([CH2:26][CH3:27])=[O:25])[CH3:22]
Reactant: CCCP(=O)(CCC)c1ccc(N)c(OC)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: CCP(=O)(CC)c1ccc(Nc2cc(Nc3ccccc3S(=O)(=O)C(C)C)cnn2)c(OC)c1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 4-(Dipropylphosphoryl)-2-methoxyaniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)=[O:9])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Reaction time: 17 h
Yield: 99.3 %

Procedure:
tert-Butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (12.9 g, 38.5 mmol) was dissolved in methanol (150 ml) and transferred into a 500-ml PARR flask. The flask was flushed with nitrogen, 10% Pd/C (0.38 g, 0.357 mmol) was added, flushed again with nitrogen, then hydrogen, then hydrogenate for 17 hours while shaking. (H2 pressure 50 psi). The reaction mixture was filtered through CELITE®, the CELITE® washed with MeOH and the collected liquids concentrated in vacuum. 11.67 g of tert-butyl 4-(4-amino-benzoyl)piperazine-1-carboxylate were isolated as a beige solid. MS (ESI) m/z 306 (M+H). 1H NMR (CDCl3) δ ppm 7.25 (d, 2H, J=7.7), 6.64 (d, 2H, J=7.7), 3.89 (bs, 2H), 3.58 (bs, 4H), 4.43 (bs, 4H), 1.46 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[C:18](O)=[CH:17][C:16](=[O:20])[N:15]([CH3:21])[CH:14]=1)=[O:12])[CH3:9].O=P(Cl)(Cl)[Cl:24]>>[CH2:8]([O:10][C:11]([C:13]1[C:18]([Cl:24])=[CH:17][C:16](=[O:20])[N:15]([CH3:21])[CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn(C)c(=O)cc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C)c(=O)cc1Cl
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Triethyl amine (7.07 mL, 50.7 mmol) was added to a suspension of 4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (10.0 g, 50.7 mmol) and POCl3 (27.85 mL, 304.3 mmol). After stirring 16 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was poured onto ice, carefully neutralized with saturated K2CO3 solution, and diluted with EtOAc. The layers were separated and the aqueous phase further extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield 7.3 g (67%) clean desired product.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([S:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CCOC(C)=O>CS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][CH2:7][CH2:8][C:9](=[O:11])[C:12]=2[CH:13]=1
Reactant: O=C(O)CCSc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCSc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A solution of 3.63 g (13.9 mmol) of 3-(4-bromothiophenoxy)propionic acid in 60 ml methanesulfonic acid was heated to 75° C. for 1.5 hours. After cooling to room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with 2N aqueous NaOH, H2O, and saturated aqueous NaCl and then dried over MgSO4. Removal of the solvent under reduced pressure afforded a yellow solid from which the product was isolated by column chromatography (3% EtOAc--hexanes) as a pale-yellow solid. 1H NMR (CDCl3): δ 8.22 (1H, d, J=2.1 Hz), 7.48 1H, dd, J=2.1,8.3 Hz), 7.17 (1H, d, J=8.5 Hz), 3.24 (2H, t, J=6.4 Hz), 2.98 (2H, t, J=6.7 Hz).
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[CH3:17][O:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:17][O:18][C:19]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)/C=C/C(C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)OC(=O)OC
Temperature: 1 °C

Procedure:
rac-Ethyl (2E)-4-hydroxypent-2-enoate (21) (10.09 g, 70 mmol), DMAP (1.71 g, 14 mmol) and pyridine (17 mL, 210 mmol) are dissolved in THF (400 mL). The solution is cooled to 1° C. Methylchloroformate (16.1 mL, 210 mmol) in THF (50 ml) is then added dropwise over 3 hours under stirring at 1° C. After 2 hours methylchloroformate (199 ml, 2.50 mol) in THF (150 ml) is added dropwise in four portions. After every portion, the reaction mixture is stirred for 5 hours at 1° C. The reaction mixture is quenched with 10% HCl (0.5 l) and extracted with tBuOMe (1.5 and 0.5 l). The organic phases are washed with 10% HCl (0.6 l), saturated NaHCO3 (0.3 l) and brine (2×0.2 l) successively. The combined organic phases are dried with N2SO4 and evaporated under reduced pressure. The residue is purified by flash chromatography (tBuOMe:heptane fraction 15:85 to 25:75) and yields 1 (rac-Ethyl (2E)-4-(methoxycarbonyloxy)pent-2-enoate) (8.64 g, 61%) as a yellowish oil.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].CO[C:8]1[C:17]2[CH:16]=[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]3=[CH:13][N+:12]=2[CH:11]=[CH:10][CH:9]=1.O.Cl([O-])(=O)(=O)=O.[Na+]>Br>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:17]([C:13]1[N+:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:17]=2[CH:16]=[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=12)[CH2:8][CH2:9][CH3:10]
Reactant: COc1ccc[n+]2cc3ccccc3cc12
Agent: Br
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: CCCCc1c2ccccc2cc2cccc[n+]12
Temperature: 100 °C
Yield: 156.2 %

Procedure:
A mixture of 1-methoxybenzo[b]quinolizinium perchlorate (1.4 g; 6.1 mmol) in 30 ml of 48% HBr was heated at 100° C. for 16 hour. The reaction mixture was poured into 100 ml of water and 50 ml of sodium perchlorate was added with stirring. The resulting solid was filtered and dried to afford 1.6 g (88.8%) of 1-hydroxybenzo[b]quinolizinium perchlorate (Formula II: R1 =1--OH; R2 =R3 =H; X- =ClO4-) as a solid.
Reaction SMILES: [C:1]1([S:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:28]I.[Cl-].[NH4+]>CN(C)C=O>[C:1]1([S:7][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)([CH3:28])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Sc1ccccc1)c1cccc(Oc2ccccc2)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Sc1ccccc1)c1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Methyl α-phenylthio(m-phenoxyphenyl)acetate (521 mg) was dissolved in 2 ml of anhydrous dimethylformamide. After cooling with ice, 65 mg (65% content) of sodium hydride was added, and the mixture was stirred for 30 minutes. Then, 0.15 ml of methyl iodide was added, and the mixture was stirred for 5 minutes with ice cooling and then for 2 hours at room temperature. After an aqueous solution of ammonium chloride (1 g/40 ml) was added, the mixture was extracted three times with 40 ml of diethyl ether. The organic layer was washed twice with 20 ml of water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using benzene as an eluent to afford 522 mg of methyl α-phenylthio-α-(m-phenoxyphenyl)propionate as an oil in a yield of 96%.
Reaction SMILES: CON(C)[C:4](=[O:26])[CH:5]([OH:25])[CH:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>O1CCCC1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][C:4](=[O:26])[CH:5]([OH:25])[CH:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:34]
Reactant: [Li]CC(=O)OCC
Reactant: CON(C)C(=O)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-4-phenyl-3-[((phenylmethoxy)carbonyl)amino]butanoic acid, N-methoxy-N-methylamide (372 mg, 1.0 mmol) in tetrahydrofuran is cooled to -78° C. and ethyl lithioacetate (72 mg, 3.0 mmol) is added. The solution is stirred at -78° C. for 1 hour, allowed to warm to room temperature, stirred for 1 hour and poured into dilute HCl. The product is extracted by ethyl acetate (3×150 ml) and the combined organic extracts are washed with NaHCO3, dried over Na2SO4 and the solvent removed in vacuo. The crude product is purified by flash chromatography on silica gel.
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O.C1(OC)C=CC=CC=1.C1(O)C=CC=CC=1>>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: Oc1ccccc1
Solvent: COc1ccccc1
Product: O=C(O)CCCCC(=O)O
Yield: 59.2 %

Procedure:
A solution is formed by mixing 60.0 grams of trimellitic acid anhydride and 135.0 grams of p,p'diphenyl methane diisocyanate and 110.0 grams of Anisole and 4.8 grams of phenol by heating the mixture. At approximately 170°C. a clear, homogeneous solution is obtained. Once clarity is obtained 27.0 grams of adipic acid are added slowly. The temperature of the mixture is raised to approximately 170°C. and slow reflux is maintained. After approximately 120 minutes, a yellow viscous resin is obtained and 55.5 grams of cumene and 346.5 grams of phenol are added to quench and stop the reaction. The solution is maintained at 130°C. until all the resin is dissolved. The resultant solution is cooled to room temperature and filtered. The viscosity of the product at 25°C. was measured at about 1200 cps, utilizing a Brookfield viscometer, and a resin solution of approximately 30% weight resin.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[Br:6][C:7]1[CH:12]=[N:11][CH:10]([Cl:13])[N:9](Cl)[CH:8]=1.[H-].[Na+].[Cl-].[Na+].O.O>CN(C)C=O>[Br:6][C:7]1[C:8]([O:5][CH2:4][CH:2]2[CH2:1][O:3]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: OCC1CO1
Reactant: ClC1N=CC(Br)=CN1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(Br)c(OCC2CO2)n1
Yield: 96.2 %

Procedure:
A solution of glycidol (13.0 g, 0.175 mole) and 5-bromo-2,3-dichloropyrimidine (40.0 g, 0.175 mole) in dimethylformamide (350 mL) was added dropwise to a stirring nitrogen-flushed, chilled suspension of sodium hydride (from 10.1 g, 0.21 mole, of NaH washed free of mineral oil) in dimethylformamide (350 mL). Following the addition, the reaction mixture was poured into 1:1 brine-water (4.5 l) and extracted with ethyl acetate (5×750 mL). Combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo to give 44.7 g of an oil which solidified. Trituration of the crude product in isopropyl alcohol-isopropyl ether gave 21.9 g (47%) of product, m.p. 63°-73°.
Reaction SMILES: [OH-].[Na+].[C:3]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:16](Cl)[CH:17]=[CH2:18].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:3]1=[O:15])[CH:17]=[CH2:16]
Reactant: O=C1CCCCCCCCCCC1
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCC1CCCCCCCCCCC1=O
Reaction time: 1 h

Procedure:
40 g (1 mole) of sodium hydroxide platelets, 182 g (1 mole) of cyclododecanone dissolved in 200 ml of toluene, and 10 g of tetrabutylammonium bromide are placed in a 500 ml three-necked flask provided with a stirrer, reflux cooler and dropping funnel. Over a period of one hour, 1 mole of allyl chloride is added dropwise, with stirring, at a reaction-mixture temperature of from 70° to 80° C. The reaction mixture is subsequently stirred for a further 5 hours at 80° C. and finally 200 ml of water are added and the phases are separated. The organic phase is then washed until neutral with a further 100 ml of water and subsequently distilled. After the low-boiling components have been drawn off, unreacted cyclododecanone is first distilled off. Finally, at 0.01 torr and from 82° to 84° C., the desired 2-(2-propenyl)-cyclododecanone is obtained as a colorless liquid in a yield of 149.8 g, corresponding to 67.5% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].N1C=CC=CC=1.[Br:17][CH2:18][CH2:19][OH:20]>ClCCl>[Br:17][CH2:18][CH2:19][O:20][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: OCCBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCBr)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of 3-chlorobenzoyl chloride (2) (0.21 g, 2.8 mmol) and pyridine (0.46 mL, 5.7 mmol) in anhydrous dichloromethane (10 mL) at room temperature was (dropwise) added 2-bromoethanol (1) (0.23 mL, 3.1 mmol). The reaction mixture was stirred for 2 h at room temperature and quenched with 1N HCl. The organic phase was washed with saturated aqueous solution of NaHCO3, brine and then dried over anhydrous MgSO4. The crude product was purified by silica gel chromatography to give 2-bromoethyl 3-chlorobenzoate (3) as colorless oil (0.64 g). 1H NMR (CDCl3): δ 8.04 (t, J=1.8 Hz, 1H), 7.98-7.93 (m, 1H), 7.58-7.52 (m, 1H), 7.40 (t, J=8.4 Hz, 1H), 4.63 (t, J=6.0 Hz, 2H), 3.64 (t, J=6.0 Hz, 2H)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][N:5]=1)[CH3:2].N1C=CC=CC=1.C1([Se][Br:29])C=CC=CC=1>C(Cl)Cl>[Br:29][C:9]1[C:10](=[O:15])[N:11]([CH3:14])[C:12]2[C:7]([CH:8]=1)=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[CH:13]=2
Reactant: Br[Se]c1ccccc1
Reactant: CCNc1cc2c(ccc(=O)n2C)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1cc2c(cn1)cc(Br)c(=O)n2C
Temperature: 39 °C

Procedure:
To a solution of 7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (20 mg, 0.1 mmol) and pyridine (27 μL, 0.3 mmol) in DCM (2 mL) was added phenylselenium bromide (72 mg, 0.3 mmol). The mixture was heated at 39° C. for 6 h, and then the solvent was removed under vacuum. The residue was chromatographed on silica gel (30% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z) 282.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(Cl)c4Cl)c3)cnc2c1F
Yield: 2 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2,3-dichlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2′,3′-dichloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (3 mg, 2%): m/z (ES+) 434 [MH+].