Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>C1C=CC=CC=1.CCOCC>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 77.2 %

Procedure:
D-Acetone glycerol (4 grams) for synthesis of L-ALLE or L-Acetone glycerol for synthesis of D-ALLE, powdered potassium hydroxide (approximately 10 grams) and hexadecyl bromide (9.3 grams) in benzene (100 ml) were stirred and refluxed for 5 hours, while removing the water formed by azeotropic distillation (compare W. J. Baumann and H. K. Mangold, J. Org. Chem. 29: 3055, 1964 and F. Paltauf, Monatsh. 99:1277, 1968). The volume of the solvent was gradually reduced to about 20 ml, and the resulting mixture was cooled to room temperature and dissolved in ether (100 ml). The resulting solution was washed with water (2×50 ml), and the solvent was removed under reduced pressure. A 100 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid was added to the residue and the mixture was refluxed for 10 minutes. The product was extracted with ether (200 ml) and was washed consecutively with water (50 ml), 10% sodium hydroxide (20 ml) and again with water (volumes of 20 ml) until neutral. The solvent was removed under reduced pressure and the product (8.8 grams) was crystallized from hexane to give 7.4 grams of pure 1-hexadecyl-glyceryl ether (compound I, FIG. 1) for synthesis of D-ALLE or 3-hexadecyl-glyceryl ether for synthesis of L-ALLE.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19](/[CH:20]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:1]/[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: COc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OC)cc3)C2=O)cc1

Procedure:
Calone is reacted with 4-methoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(4-methoxyphenyl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[N:21]([CH2:34][CH2:35][CH3:36])[N:22]=[C:23]2[C:32]=1[C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:25]=[C:24]2[NH2:33]>CN(C=O)C>[NH2:33][C:24]1[C:23]2=[N:22][N:21]([CH2:34][CH2:35][CH3:36])[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[C:32]2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A mixture of potassium phthalimide (6.61 g, 35.7 mmol), sodium iodide (0.669 g, 4.46 mmol) and 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 46, 5.65 g, 17.8 mmol) in DMF (30 mL) was heated at 90° C. for 3 hours. The reaction mixture was allowed to cool to room temperature overnight, then was diluted with ice water (300 mL) and stirred for 10 minutes. A solid formed that was collected by filtration and dried to yield 7.14 g of 2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3 (2H)-dione as a tan solid, mp 204-206° C. 1H-NMR (300 MHz, CDCl3) δ 7.86-7.70 (m, 5H), 7.69-7.64 (m, 1H), 7.43-7.36 (m, 1H), 7.29-7.22 (m, 1H), 5.37 (br s, 2H), 4.30 (t, J=7.3 Hz, 2H), 3.77 (t, J=6.8 Hz, 2H), 3.31-3.21 (m, 2H), 2.05-1.75 (m, 6H), 0.98 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36](O)=[O:37])[CH3:34].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][N:33]([CH3:34])[CH3:32])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
A solution of 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (45 mg, 0.11 mmol) in N,N-dimethylformamide (1.0 mL) at 25° C. was treated with dimethylamino-acetic acid (11 mg, 0.11 mmol), O-benzotriazol-1-yl-N,N.N′N′-tetramethyluronium hexafluorophosphate (45 mg, 0.12 mmol), and N,N-diisopropylethylamine (56 μL, 0.32 mmol). The resulting solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in chloroform and then was washed with a saturated aqueous sodium chloride solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water/0.075% trifluoroacetic acid over 30 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford N-{4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-2-dimethylamino-acetamide (24 mg, 44.3%) as an off-white solid: LR-MS for C27H29FN6O3 (M+H)+ at m/z=505.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[C:8]([F:16])[CH:7]=1.Cl[Sn]Cl>Cl>[NH:5]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[C:8]([F:16])[CH:7]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: CNC(=O)c1ccc(N)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CNC(=O)c1ccc(NN)cc1F
Reaction time: 0.5 h

Procedure:
2.5M Solution of NaNO2 (2.38 ml) was added dropwise to a solution of 4-amino-N-methyl-2-fluorobenzamide (1 g, 5.95 mmol) in B 5N HCl (3.1 ml), so that the temperature of the reaction mixture did not exceed 5° C. The mixture was stirred for additional 30 min at the same temperature, after that the prepared solution was added drop by drop to a suspension of SnCl2*2H2O (4.03 g, 17.9 mmol) in HCl (4.2 ml) at 0° C., and stirring was continued for 2 h at the same temperature. Precipitated solid was filtered off, dissolved in water (40 ml) and NaOH was added to strongly basic reaction. The mixture was extracted with ether (3*100 ml), dried over MgSO4 and evaporated in vacuo. It gave 4-hydrazino-N-methyl-2-fluorobenzamide 7 (R1=CH3). LCMS (M+H)+ 184. 1H NMR (CDCl3, 400 MHz): 7.96 (t, J=8.4 Hz, 1H), 6.64 (br. m, 1H), 6.60 (t, J=1.6 Hz, 1H), 6.57 (dd, J1=7.2 Hz, J2=2.0 Hz, 1H), 5.60 (br. s, 1H), 3.66 (br. s, 2H), 3.00 (dd, J1=4.8 Hz, J2=1.2 Hz, 1H). The solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (59 mg, 0.27 mmol) 3.1 in dioxane (2 ml) was added to a solution of 4-hydrazino-N-methyl-2-fluorobenzamide (54 mg, 0.29 mmol) 7 in dioxane (3 ml), and the resultant mixture was stirred for 2 h. Then dioxane was distilled in vacuo, the residue was crumbled with ether, filtered off and dried in vacuo. It gave 2-[(4-methylcarbamoyl)-3-fluorophenyl]-N-[3-(trifluoromethyl)-4-cyanophenyl]-hydrazine carboxamide 8(1) (R1=CH3). LCMS (M+H)+ 405. 1H NMR (DMSO-d6, 400 MHz): 9.65 (br. s, 1H), 8.72 (br. s, 1H), 8.37 (s, 1H), 8.25 (br. s, 1H), 8.03 (br. m, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.58 (m, 2H), 6.63 (d, J=8.4 Hz, 1H), 6.48 (d, J=14.0 Hz, 1H), 2.77 (d, J=4.4 Hz, 3H). Triethylamine (56 mkl, 0.4 mmol) and diphosgene (27 mkl, 0.22 mmol) were added one after another to 2-[(4-methylcarbamoyl)-3-fluorophenyl]-N-[3-(trifluoromethyl)-4-cyanophenyl]-hydrazine carboxamide (80 mg, 0.2 mmol) 8(1) in dichloroethane (2 ml). The reaction mixture was stirred in a closed vial at 80° C. for 15 h. The solvent was evaporated in vacuo and the residue was subjected to chromatography on SiO2 (eluent—CH2Cl2:MeOH, gradient from 100:1 till 20:1). It gave N-methyl-2-fluoro-4-[4-[3-(trifluoromethyl)-4-cyanophenyl]-3,5-dioxo-1,2,4-triazolidin-1-yl]benzamide 1.4 (R1=CH3). Ki1.4=55.2 nM, LCMS (M+H)+ 422. 1H NMR (DMSO-d6, 400 MHz): 11.53 (s, 1H), 8.22 (br. m, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.99 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.81 (t, J=8.4 Hz, 1H), 7.69 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.62 (dd, J1=12.0 Hz, J2=2.0 Hz, 1H), 2.79 (d, J=4.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[O:9][C:10](=O)[C:5]=2[CH:4]=1)[CH3:2].[NH2:29][CH2:30]C(O)=O>C(O)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[CH2:30][NH:29][C:10](=[O:9])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)oc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CNC2=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-2H-thieno[2,3-d][1,3]oxazine-1(4H)-yl)methyl]biphenyl-2-carbonitrile (2 g), glycine (0.46 g) and acetic acid (20 mL) was stirred at 100° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1 g, 48%).
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[CH3:9][C:10]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[N:25][O:26][CH3:27])[C:21]([NH:23][CH3:24])=[O:22]>O>[CH3:9][C:10]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)C(=NOC)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Toluene (3 ml) and conc. hydrochloric acid (0.61 g, 6 mmol) were added to 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.98 g, E/Z=75/25), and the mixture was stirred at 80° C. for 2 hours. After completion of the reaction, water (150 ml) was added. The mixture was extracted with methylene chloride (50 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystals (1.01 g, E/Z=95/5). The crystals were recrystallized from toluene to give (E)-2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-methoxyimino-N-methylacetamide (0.72 .g, Yield 71.5%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([NH2:21])=[C:18]([NH2:20])[N:19]=2)=[N:6]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[NH2:20][C:18]1[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:15]=[N:16][C:17]=1[NH:21][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 72 h

Procedure:
200 mg (0.595 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5,6-diamine were admixed with 8 ml of dichloromethane and cooled to 0° C. 545 mg (4.757 mmol) of methanesulphonyl chloride and 481 mg (4.757 mmol) of triethylamine were added and the mixture was stirred at RT for 72 h. The mixture was diluted with dichloromethane and the precipitate was filtered off with suction. The filtrate was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 57 mg (18% of theory) of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:21]3[CH:25]=[C:24]([CH3:26])[O:23][C:22]=3[CH3:27])/[CH:18]([CH3:20])[CH3:19])/[C:9]2=[O:28])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>ClCCl.C(N(CC)CC)C>[C:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:21]3[CH:25]=[C:24]([CH3:26])[O:23][C:22]=3[CH3:27])/[CH:18]([CH3:20])[CH3:19])/[C:9]2=[O:28])=[CH:4][CH:3]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)Cl
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(/c1cc(C)oc1C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(\c3cc(C)oc3C)C(C)C)C2=O)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution obtained by dissolving 1.13 g of n-(4-hydroxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)isobutylidene]-3-isopropylidenesuccinimide obtained in Example 18 in 30 ml of dichloromethane, 0.62 ml of triethylamine, followed by dropwise addition of 0.36 ml of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl) isobutylidene]-3-isopropylidenesuccinimide in yield of 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:19]([O-])=[O:20].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([N:19]=[O:20])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Fc1ccc(C2CNc3ccccc3C2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=NN1CC(c2ccc(F)cc2)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline (0.25 g, 0.0011 mol) in ethanol (1.2 mL) was added 1N hydrochloric acid (1.2 mL). The reaction mixture was cooled to 0° C., and to this a cold solution of sodium nitrite (0.151 g, 0.0022 mol) in water (3.0 mL) was added at the same temperature. The reaction mixture was warmed to RT and stirred for 1 h. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure to obtain product as a brown colored oil (0.27 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[O:20]([CH2:19][CH2:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H]1CCCCN1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCCCN1CCOc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Dissolve methyl (R)-piperidine-2-carboxylate (5.00 g, 34.9 mmol) in DMF (87 mL) and treat with K2CO3 (14.48 g, 104.8 mmol) and β-bromophenetole (7.16 g, 34.9 mmol). Stir the mixture overnight at 100° C. Cool the mixture to room temperature and add EtOAc (250 mL). Wash the organic phase with water (4×100 mL) and saturated aqueous NaCl (100 mL). Dry the organic phase over K2CO3, filter to remove the solids, and concentrate the filtrate under reduced pressure to furnish a yellow oil. Subject this crude material to flash chromatography on silica gel eluting with a gradient of 20% to 100% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a colorless oil in ca. 90% purity by 1H NMR analysis (6.50 g, 64% yield). Mass spectrum (m/z) 264 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.27 (dd, J=8.5, 7.3 Hz, 2H), 6.93 (t, J=7.3 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (app t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.29 (dd, J=8.4, 4.0 Hz, 1H), 3.14 (app dt, J=11.3, 6.4 Hz, 1H), 2.95 (app dt, J=13.7, 6.1 Hz, 1H), 2.89 (app dt, J=13.7, 6.1 Hz, 1H), 2.42 (ddd, J=11.6, 7.9, 3.7 Hz, 1H), 1.90-1.82 (m, 1H), 1.79 (app td, J=8.9, 3.8 Hz, 1H), 1.67-1.59 (m, 3H), 1.39 (app td, J=8.8, 4.0 Hz, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2)([OH:16])=[O:15].N1CCCCC1>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[C:17]([C:14]([OH:16])=[O:15])[CH:18]=3)[NH:22][C:21]2=[O:26])[NH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(C(=O)O)cc21
Yield: 30 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 88.6 mg 5-carboxy-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven. The crude product was purified by chromatography on a silica gel column using ethyl acetate-hexane-acetic acid as the eluant to give 51 mg(30%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12]2)[N:4]=1.CO.[O-][Cl:24].[Na+]>ClCCl>[Cl:24][C:11]1([C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[O:12]1
Reactant: [O-]Cl
Reactant: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3ncccc32)n1

Procedure:
A mixture of 490 mg of 5-(4,6-dimethoxy-2-pyrimidinyl)furo[3,4,b]-pyridine-7(5H)one and 50 ml of methanol is heated at 55° for 1/2 hour or until a homogenous solution is formed. 2.6 g of NaOCl (common house bleach) is added dropwise. The mixture is taken up in dichloromethane an the organic phase separated and evaporated to dryness to yield the title compound, mp 146°-148° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:6]=2[CH:17]=1.N1CCCCC1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:16][C:12]1[N:11]=[C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:32]#[C:31][C:29]([C:25]4[S:24][CH:28]=[CH:27][N:26]=4)([OH:33])[CH3:30])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][N:13]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Nc1nccc(-n2cnc3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2ncn(-c3ccnc(N)n3)c2c1)c1nccs1
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
To a pressure tube was added 4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (70% purity, 790 mg, 1.91 mmol), followed by piperidine (4 mL), tetrakis(triphenylphosphine)palladium (220 mg, 0.19 mmol), copper(I) iodide (36.3 mg, 0.19 mmol)) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (584.04 mg, 3.81 mmol). The reaction was capped and stirred at 75° C. for 3.5 hr. The reaction mixture was concentrated in vacuo and purified by flash chromatography (Isolute column, 2% MeOH in DCM to 3% MeOH in DCM) followed by reverse phase preparative HPLC to give the title compound as a pale yellow solid: 1H NMR (500 MHz, DMSO) δ 1.92 (3H, s), 7.03 (1H, br. s.), 7.08-7.20 (3H, m), 7.38 (1H, dd, J=8.35, 1.58 Hz), 7.69 (1H, d, J=3.15 Hz), 7.74 (1H, d, J=8.35 Hz), 7.78 (1H, d, J=3.31 Hz), 8.38 (1H, d, J=5.52 Hz), 8.56 (1H, d, J=0.95 Hz), 9.08 (1H, s); LC-MS: m/z=+363.4 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].C([NH+](CC)CC)C.CC[O:24]CC>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:4]([CH:1]([CH3:3])[CH3:2])[C:5]([OH:24])=[O:6])=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Agent: CC[NH+](CC)CC
Product: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution was prepared by admixing 3.0 grams (0.014 mole) of 6-(phenoxy)picolinalcohol, 3.5 grams (0.015 mole) of 2-isopropyl-2-(4-chlorophenyl)acetic acid chloride 10 milliliters of triethylammonium and 100 milliliters of dry ether. The reaction mixture was agitated at room temperature for 1 hour. The resulting reaction product mixture was successively washed with dilute hydrochloric acid, dilute sodium hydroxide, dried over anhydrous magnesium sulfate, filtered through silica gel and concentrated to give 5.3 grams of the desired 4-chloro-α-(1-methylethyl)benzeneacetic acid:(6-phenoxy-2-pyridinyl)methyl ester. The product, a viscous yellow oil, had a refractive index of 1.5664 and the structure of the product was confirmed by NMR. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 68.83, 5.19 and 3.10 percent, respectively, as compared with the theoretical contents of 69.78, 5.60 and 3.54 percent, respectively, as calculated for the above named compounds (Compound No. 2).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 54.9 %

Procedure:
A mixture of 0.15 g (0.48 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.078 g (0.57 mmole) of 4-amino-benzoic acid in 15 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-20)