Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20]([F:19])([F:30])[F:31])=[O:24])[CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccc(-c2ccc(N3CCNCC3)nc2)nc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3ccccn3)cn2)CC1
Yield: 20 %

Procedure:
Following the procedure as described in Example 5, making variations only as required to use 6′-piperazin-1-yl-[2,3′]bipyridine in place of 3-piperazin-1-yl-6-pyridin-2-ylpyridazine to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as a white solid in 20% yield (0.102 g). 1H NMR (300 MHz, CDCl3) δ 8.75 (m, 1H), 8.62 (m, 1H), 8.19 (m, 1H), 7.73-7.67 (m, 2H), 7.63-7.58 (m, 2H), 7.53 (t, J=7.4 Hz, 7.39, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.16 (m, 1H), 6.73 (d, J=8.9 Hz, 1H), 4.01-3.85 (m, 2H), 3.73-3.69 (m, 2H), 3.59-3.56 (m, 2H), 3.31-3.28 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.5, 158.9, 155.1, 149.7, 146.6, 136.7, 136.3, 132.2, 129.3, 127.3, 126.8, 126.7, 125.3, 121.5, 119.2, 106.9, 134.6, 46.7, 45.0, 44.9, 41.4. MS (ES+) m/z 413.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=O)=[CH:12][N:11]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[N:9]=1.N1C(C)=CC=CC=1C.CS(Cl)(=O)=O.[NH2:40][C:41]1[C:49]([CH3:50])=[CH:48][C:47]([Cl:51])=[CH:46][C:42]=1[C:43]([OH:45])=[O:44]>C(#N)C>[Cl:51][C:47]1[CH:48]=[C:49]([CH3:50])[C:41]2[N:40]=[C:14]([C:13]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:9][C:10]([CH2:17][N:18]4[N:22]=[N:21][C:20]([C:23]([F:24])([F:26])[F:25])=[N:19]4)=[N:11][CH:12]=3)[O:44][C:43](=[O:45])[C:42]=2[CH:46]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cnc(Cn4nnc(C(F)(F)F)n4)nc3-c3ccccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At RT, 385 mg (1.30 mmol) of 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidine-5-carboxylic acid was initially charged in 5 ml of acetonitrile, and 0.27 ml (2.33 mmol) of lutidine was added. With stirring, the solution was then cooled to 0° C., 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was added dropwise and the mixture was stirred at 0° C. for another 15 min. A little at a time, an acetonitrile suspension (3 ml) of 0.53 ml (4.54 mmol) of lutidine and 289 mg (1.56 mmol) of 2-amino-5-chloro-3-methylbenzoic acid was then added to this reaction mixture, and stirring was continued for another 15 min. 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was then added dropwise. The reaction was stirred overnight, with the temperature increasing to RT. The solvent was removed under reduced pressure. The residue was then poured into ice-water and mixed in an ultrasonic bath. The residue was filtered off, again taken up in water and sonicated once more. The residue is filtered off, washed with water and dried under reduced pressure. 708 mg (88% of theory; content 86%) of the desired product were isolated. There was not further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:21][Zn+]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH3:21])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Agent: [Cl-]
Product: Cc1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Yield: 55 %

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester by a method analogous to that of Preparation 117 using methyl zinc chloride (2.0 M in THF, 9.75 mmol), to give the title compound (510 mg, 55%) as a colourless oil. MS: [M+H]+=263.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH:30][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CCOC(=O)CNc1ncccc1N
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1cc(Cl)ccn1
Reaction time: 8 h

Procedure:
The crude 4-chloro picolinoyl chloride and triethylamine (5.55 g, 0.055 mole) were added dropwise simulaneously to the above stirred filtrate of N-(3-amino-2-pyridinyl)glycine ethyl ester at room temperature and allowed to stir overnight.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=O)[O:19][C:17](=[O:18])[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].Cl>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:20](=[O:19])[C:15]3=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:23][CH:22]=[C:16]3[C:17]2=[O:18])[CH2:3]1)[CH3:9]
Reactant: CCN1CCCC(N)C1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CCN1CCCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C1
Temperature: 25 °C

Procedure:
6.40 Grams of 3-amino-1-ethylpiperidine in 150 milliliters of chloroform were added to a suspension of 9.65 grams of 4-nitrophthalic anhydride in 100 milliliters of chloroform. The solution formed was stirred at room temperature for twenty minutes and evaporated to dryness. The gummy residue was dissolved in 50 milliliters of acetic anhydride and the mixture was heated to 100° C. for thirty-five minutes. The excess acetic anhydride was distilled and the residue extracted into 100 milliliters of chloroform and the solution was washed with 50 milliliters of saturated sodium bicarbonate solution, 50 milliliters of water, dried over magnesium sulphate and evaporated to give a brown oil. The oil was dissolved in 20 milliliters of isopropanol and ethereal hydrogen chloride was added to give 9.33 grams of the title compound as the hydrochloride, quarterhydrate.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][Si:20]([CH3:22])([CH3:21])[C:23]#[C:24][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
Add copper (I) iodide (48.2 mg, 0.25 mmol), bis(triphenylphosphine)palladium (II) dichloride (155.8 m g, 0.22 mmol) and triethylamine (2.51 mL, 17.8 mmol), to a solution of 1-bromo-3-trifluoromethylbenzene (0.62 mL, 4.44 mmol) and trimethylsilylacetylene (0.81 mL, 5.78 mmol), in ethyl acetate (4 mL). Stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify the residue by silica gel chromatography, eluting with hexanes, to give the title compound (1.1 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH2:27][CH2:28][CH3:29])([O-:26])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:27]([N+:24]([O-:26])=[O:25])[CH2:28][CH3:29])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: CCC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCC(=Cc1ccc(OC)c(OCc2ccccc2)c1)[N+](=O)[O-]
Temperature: 160 °C
Yield: 44.9 %

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (24.23 g, 100 mmol) and ammonium acetate (7.73 g, 100 mmol) were covered with 1-nitropropane (90 mL, 1008 mmol) and heated to 160° C. for 22 h. The reaction mixture was then cooled to room temperature and the excess of 1-nitropropane was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL), washed with water (100 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was boiled up in ethanol (100 mL). After cooling to room temperature the yellow precipitate was collected on a sinter funnel and washed with ethanol (4×30 mL). The solid was dried in vacuo to give the title compound as yellow powder (14.07 g, 44%). 1H NMR (270 MHz, CDCl3) δ 1.14 (3H, t, J 7.3, CH2CH3), 2.71 (2H, q, J 7.4, CH2CH3), 3.93 (3H, s, OCH3), 5.19 (2H, s, OCH2Ph), 6.91 (1H, d, J 1.9, CH), 6.94 (1H, d, J 8.5, CH), 7.05 (1H, dd, J 8.4, CH), 7.25-7.48 (5H, m, OCH2C6H5), 7.91 (1H, s, HC═CNO2).
Reaction SMILES: C([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[N:6]([CH3:20])[CH:5]=1)(=O)C.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[OH:29][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[N:6]([CH3:20])[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc2c(c1)c(=O)c(C(C)=O)cn2C
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)c(=O)c(O)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of ethyl 3-acetyl-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (1.79 g, 6.55 mmol) in dichloromethane (40 ml) was added meta-chloroperbenzoic acid (2.2057 g, 9.84 mmol). The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to roughly one half of the reaction volume. The resulting precipitate (O-acetate) was collected, added to methanol (20.0 ml), and heated at 65° C. overnight. After cooling, the reaction was filtered, and the precipitate was washed with dichloromethane to give ethyl 3-hydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (0.9956 g, 4.03 mmol, 61.5% yield) as white solid. LCMS: (M+H)+: 248.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].Cl[C:19]1[S:20][C:21]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:19]3[S:20][C:21]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Temperature: 60 °C
Yield: 57.2 %

Procedure:
A mixture of the compound of step 2 (3.0 g; 12.9 mmol) and 2-chloro-6-fluoro benzothiazole (2.67 g; 14.2 mmol) in EtOH (60 ml) was heated at 60° C. to get a clear solution. To the hot solution 4N HCl in dioxane (1.6 ml; 6.45 mmol) was added and the resulting reaction mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature and the solid was filtered, and washed with EtOH (2×10 ml). The solid was dried under vacuum to yield 2.83 g (57.2%) of the title compound. Mass (ES−) 382 (M−1); IR (KBr): 3410 (br), 2710 (br), 1729, 1719, 1630, 1598; 1H NMR (DMSO-d6): δ 1.36 (t, 3H), 4.41 (q, 2H), 7.20 (m, 1H), 7.67 (m, 1H), 7.78 (m, 1H), 7.81 (s, 1H), 7.87-7.99 (m, 4H), 10.92 (br, 1H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Product: COc1ccc2c(Cl)ncc(N3CCNCC3)c2c1
Yield: 37.3 %

Procedure:
A solution of tert-butyl 4-(1-hydroxy-6-methoxyisoquinolin-4-yl)piperazine-1-carboxylate (0.3 g, 1.157 mmol) in POCl3 (5 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.2 g, 37.3%) as a gummy compound. MS: MS m/z 278.56 (M++1).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].[C:8](OC)(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].Cl>CS(C)=O>[NH2:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8](=[O:16])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3]
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1ccccc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)CC(=O)c1ccccc1N
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
Dimethylsulfone (120 g, 1.28 mol) was stirred in DMSO (350 mL). Sodium hydride (48 g of 60 wt % in mineral oil) was added in portions and the mixture heated to 60° C. Methyl anthranilate (48.3 g, 0.32 mol) was added dropwise over 3 hours while the temperature rose to 100° C. The mixture was poured into ice (500 mL) and concentrated HCl (100 mL) and the mixture stored at 4° C. overnight. The mixture was extracted with dichloromethane (3×400 mL), and the combined extracts were washed with saturated bicarbonate (3×30 mL), dried (MgSO4), and reduced to 800 mL volume. The solid that formed was removed by filtration. The filtrate was reduced to 80 mL volume. The resulting solid was collected and washed with a small volume of dichloromethane. The solid was recrystallized from chloroform to give 1-(2-aminophenyl)-2-(methylsulfonyl)ethanone (24 g).
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].P(Br)(Br)[Br:20]>N1C=CC=CC=1.CCOCC>[Br:20][CH2:1][C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: BrP(Br)Br
Reactant: CCCCCC#CCC#CCC#CCC#CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC#CCC#CCC#CCC#CCBr
Temperature: 0 °C

Procedure:
A mixture of 5 g of 2,5,8,11-heptadecatetrayn-1-ol, 1.25 c3 of phosphorus tribromide and one drop of pyridine in 15 cm3 of anhydrous ether, stirred in the absence of light, is heated under reflux for 2 hours. The solution is then poured into 100 cm3 of ice water and extracted twice with ethyl ether. The ether phases are washed initially with a solution of sodium bicarbonate and then with water, and finally dried over sodium sulphate.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=O)=O)=CC=1.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(OCCOCc1ccccc1)c1ccc(Br)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of (benzyloxy)ethyl 4-bromobenzenesulfonate (Preparation 89, 6.92 g, 19.5 mmol) in acetone (60 ml) was added sodium iodide (5.84 g, 39.0 mmol) and the reaction mixture was left to stir at room temperature for 16 h. The resulting precipitate was filtered and the filtrate was concentrated in vacuo. The crude residue was dissolved in dichloromethane and washed with aqueous sodium thiosulphate solution and then with water (2×60 ml). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale brown oil (4.5 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=O)[NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C([O:16][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]CBr)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:13]=[C:6]([C:7]([NH:8][CH2:9][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([OH:26])=[O:16])=[O:12])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Reactant: CCOC(=O)CCCCCCCBr
Solvent: CC(=O)N(C)C
Product: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 45 °C
Reaction time: 7 h

Procedure:
222 L of dry dimethylacetamide is charged to a dry 200 gallon glass-lined reactor. The reactor agitator is set to 100–125 rpm. Cooling is applied to the condenser and valve reactor overheads are set for distillation. 41.6 kg of dry anhydrous sodium carbonate is charged to the reactor and the reactor charging port is closed. Caution is used due to some off-gassing and a slight exothermic reaction. 77.5 kg of dry 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione is charged to the reactor. Quickly, 88 kg of dry ethyl-8-bromooctanoate is charged to the reactor. The reaction is evacuated to 22–24 inches of vacuum and the reactor temperature is raised to 65–75° C. The reactor temperature is maintained and the contents are watched for foaming. The reactor mixture is sampled and monitored for conversion by monitoring for the disappearance of the bromo ester in the reaction mixture by gas chromatography. The reaction is complete after 7 hours. The vacuum is broken and the reactor contents are cooled to 45–50° C. The contents are centrifuged and the filtrate sent into a second 200 gallon glass-lined reactor. 119 L of ethanol (200 proof denatured with 0.5% toluene) is charged to the first 200 gallon reactor, warmed to about 45° C. and the filter cake washed with warm ethanol and this wash is charged to the reaction mixture in the second 200 gallon reactor.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(OCC)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(Diethoxymethyl)benzaldehyde (10 g, 48 mmol) was dissolved in methanol (200 ml) and cooled to 0° C. NaBH4 (4.54 g, 120 mmol, 2.5 eq) was then added slowly and the reaction mixture was stirred for 1 hour, after which the solvent was evaporated. The residue obtained was dissolved in ethyl acetate (100 ml) and water (100 ml), the phases were separated and the organic phase was washed with water (100 ml), dried over magnesium sulphate, and evaporated to yield 1 as a clear oil (10.09 g, 48 mmol, 100%). 1H NMR (300 MHz, CDCl3) δ=7.48 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CH2OH), 7.37 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CH(OEt)2), 5.51 (s, 1H, CH(OEt)2), 4.70 (d, 3J(H,H)=5.9 Hz, 2H, CH2OH), 3.61 (dq, 3J(H,H)=7.1 Hz, 2J(H,H)=9.5 Hz, 2H, CH2CH3), 3.56 (dq, 3J(H,H)=7.1 Hz, 2J(H,H)=9.5 Hz, 2H, CH2CH3), 1.75 (t, 3J(H,H)=5.9 Hz, 1H, CH2OH), 1.24 (t, 3J(H,H)=7.1 Hz, 6H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ=140.9 (ArCCH2OH), 138.6 (ArCCH(OEt)2), 126.9 (ArCH α to ArCCH2OH), 126.8 (ArCH α to ArCCH(OEt)2), 101.3 (CH(OEt)2), 65.1 (CH2OH), 61.0 (OCH2CH3), 15.2 (OCH2CH3).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:14])=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1nc(-c2ccco2)c2ncn(CC(=O)O)c2n1
Reactant: NCc1ccccc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(CC(=O)NCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A suspension of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DMF (2 mL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with benzylamine (55 μL, 0.5 mmol), stirred at room temperature for 2 h, diluted with water, filtered and dried to give the title compound (115 mg, 66%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (3.000 g; 24.60 mmol), 2-iodopropane (12.528 g; 73.70 mmol), K2CO3 (6.790 g; 49.10 mmol), and Cs2CO3 (1.601 g; 4.91 mmol) in anh. DMF (60 ml) was stirred at rt, under nitrogen, for 17 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-isopropoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 165.24 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13].OC1C=CC=CN=1>CO.C1(C)C=CC=CC=1>[CH3:21][O:20][C:11]([CH:12]1[CH2:14][C:15](=[O:16])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13]1)=[O:19]
Reactant: COc1ccc(CN)cc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: Oc1ccccn1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 20 °C
Yield: 85.7 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer and reflux condenser, under inert atmosphere, 10 g (73 mmol, 1 eq) of 4-methoxy-benzylamine and 12.7 g (81 mmol, 1.1 eq) of dimethyl itaconate are dissolved in 100 ml of MeOH. The mixture is brought to reflux for 10 h, and cooled down slowly to 20° C. over 4 h and concentrated to dryness. In a 250 ml three necked flask fitted with a magnetic stirrer and Rashig column and distillation arm, under inert atmosphere, the crude intermediate and 0.69 g (7.30 mmol, 0.1 eq) of 2-hydroxypyridine are dissolved in 200 ml of toluene. The mixture is brought to reflux and the methanol formed distilled off for 8 h, until no more methanol is collected. Temperature in the pot reached 112° C. The mixture is cooled down and concentrated to dryness to give the crude ester. It is purified by column chromatography on silicagel (AcOEt/n-Hexane: 1/1 (v/v)) to afford the pure ester a1 (16.48 g, 85.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][C:8]([O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol) in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The reaction mixture was then diluted with toluene (500 ml), washed with water (×3), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96% yield) of the title material as a clear oil: Bp 80–90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).