Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29]>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:15](=[O:24])[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:28]#[CH:27]
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccccc2)C(C)(C)C)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCN(C(=O)c1ccccc1)N(C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred suspension of N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine (1.5 g) in dimethylformamide (DMF) (20 ml) was added sodium hydride (200 mg of 60% oil dispersion) portionwise. After 15 min., propargyl bromide (0.6 g) was added to the reaction mixture dropwise and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (5×20 ml). The organic layer was then dried over magnesium sulfate and the solvent removed under vacuum to afford N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine as a yellow amorphous solid. The product, N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine, was purified by column chromatography on silica gel (solvent system:methylene chloride) to afford a 70% yield as a white solid.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH3:11])(=[O:9])[CH2:7][CH3:8].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:8]#[C:7][C:6]([O:10][CH3:11])=[O:9])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.57N hexane solution, 6.4 ml) was added dropwise to a solution of methyl propionate (893 μl) in tetrahydrofuran (50 ml) at −78° C. After stirring for 30 minutes, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran (10 ml) was added, and the mixture was gradually warmed to room temperature and stirred overnight. A saturated aqueous solution (50 ml) of ammonium chloride and ethyl acetate (50 ml) were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate 3:1) to obtain the title compound (1.78 g) as a pale yellow caramel-like substance.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>>[CH3:15][C:6]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=[C:2]1[O:1][Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCC1(C)SC(=O)C=C1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 32 (46 mg, 0.19 mmol) dissolved in hexanes was added triethylamine (43 μL, 0.31 mmol) and trimethylsilylchloride (36 μL, 0.29 mmol) and the solution was allowed to stir at room temperature for 4 h. The mixture was filtered over celite and evaporated to provide 5-methyl-5-octyl-4-trimethylsilanyloxy-5-H-thiopen-2-one which was redissolved in CH2Cl2 (0.4 mL). To this mixture was added isopropyl isocyanate (19.2 mL, 0.19 mmol) and the solution was allowed to stir at room temperature for 2 hours. NH4Cl(sat) (5 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The organics were combined, dried (MgSO4), filtered and evaporated to give crude 71. Flash chromatography (20% EtOAc/2% AcOH/Hexanes) gave pure 71 (35 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 0.85 (t, J=7.0 Hz, 3H), 1.14-1.24 (m, 17H), 1.45 (m, 1H), 1.63 (s, 3H), 1.76-1.79 (m, 2H), 3.81-3.88 (m, 1H), 5.16 (d, J=7 Hz, 1H), 6.33 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 13.9, 20.4, 22.5, 22.8, 25.1, 25.9, 29.1, 29.3, 29.5, 31.8, 38.7, 44.0, 60.2, 111.6, 149.7, 176.2, 194.5.
Reaction SMILES: [CH2:1]([N:4]([C:9]1[C:10]([CH3:19])=[N:11][C:12]([N:16]([CH3:18])[CH3:17])=[N:13][C:14]=1[CH3:15])[C:5](=[O:8])[CH2:6]O)[C:2]#[CH:3].S([Cl:24])(C)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH2:1]([N:4]([C:9]1[C:10]([CH3:19])=[N:11][C:12]([N:16]([CH3:18])[CH3:17])=[N:13][C:14]=1[CH3:15])[C:5](=[O:8])[CH2:6][Cl:24])[C:2]#[CH:3]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCN(C(=O)CO)c1c(C)nc(N(C)C)nc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C#CCN(C(=O)CCl)c1c(C)nc(N(C)C)nc1C

Procedure:
8.0 g of N-propargyl-N-(4,6-dimethyl-2-dimethylamino-pyrimidin-5-yl)-hydroxyacetamide, 3.7 g 4-dimethylaminopyridine and 100 ml dry CH2Cl2 are charged in a sulphonation flask. Thereto are added, dropwise, 3.43 g mesyl chloride in 30 ml of dry CH2Cl2. The reaction temperature rises from 22° up to 33°. The mixture is heated under reflux for 34 hours, cooled and diluted with water. The organic phase is partitioned off, dried over Na2SO4 and evaporated. The oily residue is chromatographed on silica gel with diethylether/hexane 1:1 to give the title compound, m.p. 108°-110°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13])=O.O1CCCC1>CO>[OH:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13]
Reactant: O=CO[C@H](CCc1ccccc1)[C@H](CCn1nnc2ccccc2c1=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CCn1nnc2ccccc2c1=O)[C@H](O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.11 g) was added to a solution of the compound obtained from step c above (0.3 g) in methanol (4 mL) and tetrahydrofuran (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated, and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 10% methanol in dichloromethane as eluant to afford the title compound (0.020 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N:12]([CH2:20][C:21]1[N:22]([CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][C:33]([O-:35])=[O:34])[C:23]([CH3:27])=[C:24]([CH3:26])[N:25]=1)[C:13]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14]>Cl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N:12]([CH2:20][C:21]1[N:22]([CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][C:33]([OH:35])=[O:34])[C:23]([CH3:27])=[C:24]([CH3:26])[N:25]=1)[C:13]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: COc1ccc(N(Cc2nc(C)c(C)n2Cc2ccccc2OCC(=O)[O-])C(=O)CCC(C)C)c(Cl)c1OC
Agent: Cl
Product: COc1ccc(N(Cc2nc(C)c(C)n2Cc2ccccc2OCC(=O)O)C(=O)CCC(C)C)c(Cl)c1OC
Yield: 101.5 %

Procedure:
A solution of 58 mg of {2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetate in 2 mL of 5N HCl is heated under reflux for 15 min. The volatiles are evaporated under reduced pressure, and the residue is dried in a vacuum oven at 90° C. to give 59 mg of the title compound as the hydrochloride salt. Mass Spec m/z (M++1) 558.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[C:10]([N+:18]([O-:19])=[O:17])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]=O
Reactant: Cc1cc2cccc(Br)n2n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Cc1nn2c(Br)cccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 57.1 %

Procedure:
To a solution of 7-bromo-2-methylpyrazolo[1,5-a]pyridine (1.3 g) dissolved in acetonitrile (25 mL) was added nitronium tetrafluoroborate (900 mg) while stirring on ice, and the reaction mixture was stirred for 10 minutes. The obtained reaction mixture was added to ice water, and the precipitated crystals were collected by filtration, washed with water and then dried under reduced pressure to afford crude crystals. These were purified by silica gel column chromatography and the title compound (900 mg) was obtained as yellow crystals from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)[C:6]([O:9][CH2:10][CH3:11])=[N:7][CH:8]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=2)O1.CCO.C(=O)(O)[O-].[Na+]>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.C1C=CC=CC=1>[F:20][CH:19]([F:21])[O:18][C:14]1[CH:13]=[C:12]([C:5]2[N:4]=[C:3]([CH2:2][C:30]3[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=3)[CH:8]=[N:7][C:6]=2[O:9][CH2:10][CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Reactant: CCOc1ncc(CBr)nc1-c1cccc(OC(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOc1ncc(Cc2cnc(C#N)nc2)nc1-c1cccc(OC(F)F)c1
Temperature: 125 °C
Yield: 53.2 %

Procedure:
Into a 5 mL microwave vial was combined 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine (Intermediate 1, 176.00 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), tetrakis(triphenylphosphine)palladium(0) (56.63 mg, 0.05 mmol), and sodium bicarbonate (1.38 mL, 1.15 mol/L; 1.59 mmol). The vial was sealed, purged with nitrogen and heated to 125° C. under microwave conditions for 15 minutes. Water was removed from the reaction with a pipette, and the crude reaction mixture was filtered thru CELITE®, and washed with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-30%, EtOAc/hexanes) afforded the title compound as a white solid (100 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.19 (dd, J=2.3, 7.8 Hz, 1H), 7.04-6.61 (m, 1H), 4.49 (q, J=7.0 Hz, 2H), 4.30-4.25 (m, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=384.15.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[OH-].[NH4+:13]>>[NH2:13][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([F:11])[C:2]=1[Cl:1]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1c(F)c(F)nc(F)c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
This compound was prepared by a modification of the procedure of Chambers et al., J. Chem. Soc. 1964, 5634-5640. A mixture of 3-chloro-2,4,5,6-tetrafluoropyridine (1, 37.4 g, 201 mmol) and 150 mL of 28% ammonium hydroxide was stirred at room temperature for 5 h. The resulting white crystals were collected and carefully washed with ice water to give 2 as a white solid (35 g). The combined filtrate and washings were extracted with ether. The ether extract was dried (MgSO4), filtered and evaporated in vacuo to give additional 2 (1.3 g); total yield: 26.3 g (99%). The product was used directly for the next step in the reaction. A small sample was purified by silica gel column chromatography: mp 118-120° C. (Lit., Chambers et al., J. Chem. Soc. 1964, 5634-5640, mp 117-118° C.).
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.C[O:15][B:16](OC)[O:17]C>CCCCCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([B:16]([OH:17])[OH:15])=[CH:8][CH:9]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COB(OC)OC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In a flask replaced by nitrogen, tetrahydrofuran solution (80 g) containing 5-bromo-2-chloropyridine (9.6 g, 50.0 mmol) was charged, and cooled at −78° C., and then n-hexane solution of n-butyllthium (15% by weight, 24.6 g, 57.5 mmol) was added dropwise at −78° C. Next, at −78° C., trimethoxyborane (5.7 g, 55.0 mmol) was added dropwise. After 30 minutes from adding dropwise, cooling bath was removed off, and the reaction mixture was stirred at room temperature overnight. Then, 10% by weight of hydrochloric acid (50 g) was added under ice cooling condition, and the reaction mixture was stirred for 1.5 hours, and then neutralized by adding 40% by weight of sodium hydroxide aqueous solution (15 g). Ethyl acetate (50 g) was added to the reaction mixture, and the reaction mixture was stirred for 1.0 hour, and then left to stand to separate organic layer. Organic layer was dried with anhydrous magnesium sulfate, and then condensed under reduced pressure to obtain 6-chloro-3-pyridylboronic acid (6.9 g, 44.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.[C:12](#[N:15])[CH:13]=[CH2:14]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:14][CH2:13][C:12]#[N:15])[C:8]([CH3:11])=[CH:7]2
Reactant: C=CC#N
Reactant: Cc1cc2cccc(Cl)c2[nH]1
Solvent: C1COCCO1
Product: Cc1cc2cccc(Cl)c2n1CCC#N
Temperature: 60 °C

Procedure:
20 g of 7-chloro-2-methyl-1H-indole are mixed in 100 ml of dioxane with 3 g of triton B, 3 g of acrylonitrile are slowly added, 250 ml of dioxane are added again and then the mixture is heated at 60° C. for 2 hours. The medium is evaporated and then the residue is taken up in AcOEt. The precipitate formed being removed, the product obtained is used as is in the following stage.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]2)=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1CCCNC1
Agent: Cl
Product: CCOC(=O)C1CCCN(c2ccncc2)C1

Procedure:
Ethyl (+) nipecotate (7.0 g, 44.53 mmol) was reacted with 4-chlorpyridine hydrochloride (6.67 g, 44.53 mmol) as described for 21-1 to give the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](S(C)=O)=[N:6][N:7]=1.[CH3:13][O-:14].[Na+]>CO>[NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5]([O:14][CH3:13])=[N:6][N:7]=1
Reactant: Cn1c(S(C)=O)nnc(N)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nnc(N)c(=O)n1C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4.1 g of 6-amino-4-methyl-3-methylsulfinyl-1,2,4-triazin-5-one are suspended in 50 ml of absolute methanol, and 4.3 ml of 30% strength methanolic sodium methylate solution are added at room temperature. The reaction proceeds slightly exothermically and the temperature rises to 35° C. The solution is then stirred at 50° C. for 30 minutes, whereupon a colourless precipitate separates out of the clear yellow solution. The reaction miture is evaporated and the residue is taken up in ethyl acetate and ice-water. The organic phase is separated off, dried with magnesium sulfate and evaporated. The residue is washed with a little methanol and dried. 1.6 g of 6-amino-4-methyl-3-methoxy-1,2,4-triazin-5-one with a melting point of 198°-199° C. are obtained in this manner.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([C:17](OCC)=[O:18])[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].[BH4-].[Na+].Cl.[OH-].[Na+]>O.O1CCCC1.C(O)C>[OH:18][CH2:17][C:14]1[CH:13]=[C:12]([C:11]2[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:22])([CH3:1])[CH3:23])=[N:7][CH:8]=[CH:9][CH:10]=2)[O:16][N:15]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2NC(=O)C(C)(C)C)on1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1-c1cc(CO)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a mixture of ethyl 5-{2-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}isoxazol-3-carboxylate (111 g, 350 mmol), ethanol (110 mL) and tetrahydrofuran (350 mL) was added sodium borohydride (13.2 g, 350 mmol) at room temperature, which was stirred at room temperature for 6 hours. To the reaction mixture were added water (350 mL) and 5N hydrochloric acid (90 mL), which was stirred at room temperature for 30 minutes, 5N aqueous sodium hydroxide (110 mL) was added thereto, the solution was extracted with a mixture of ethyl acetate and tetrahydrofuran, and the organic layer was washed with water and saturated sodium chloride water. The solvent was evaporated under a reduced pressure, so as to obtain the title compound (83.8 g) as a yellow solid, partially contaminated with [5-(2-aminopyridin-3-yl)isoxazol-3-yl]methanol.
Reaction SMILES: Cl.[Na].[C:3]([C:11]1[N:12]([CH2:16][CH2:17][CH:18]2[C:23](=[O:24])[O:22][C:21](C)(C)[O:20][C:19]2=[O:27])[CH:13]=[CH:14][CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]O>>[C:3]([C:11]1[N:12]([CH2:16][CH2:17][CH:18]([C:23]([O:22][CH3:21])=[O:24])[C:19]([O:20][CH3:28])=[O:27])[CH:13]=[CH:14][CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OC(=O)C(CCn2cccc2C(=O)c2ccccc2)C(=O)O1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OC
Temperature: 25 °C
Yield: 42 %

Procedure:
To a 0° C. solution of methanol (10 mL) which had been saturated with gaseous hydrogen chloride was added a solution of the sodium salt of 2-benzoyl-1-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethyl]pyrrole (1.41 g, 3.9 mmol) in methanol (10 mL). The mixture was stirred for sixteen hours at room temperature and was then concentrated under reduced pressure. The residue was purified by chromato-graphy on silica eluting with hexane/ethyl acetate (70:30) to yield 530 mg (42%) of 2-benzoyl-1-[3,3-di(methoxycarbonyl)propyl]pyrrole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(CCCC#N)=NCCCC#N.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccc(Br)cc21
Agent: N#CCCCN=NCCCC#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccc(Br)cc21

Procedure:
6-Bromophthalide (5.85 gms; 0.0275 mole), N-bromosuccinimide (4.89 gm; 0.0275 mole) and azobisbutyronitrile (0.1 gm) were gently refluxed in dry carbon tetrachloride (200 ml.) for 2 hours. On cooling, the succinimide was filered off and the solvent removed in vacuo to give an oil, which was used immediately.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O:22][C:23](OC(C)C)(OC(C)C)[C:24]1([O:40][CH3:41])[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:32])=[CH:26][CH2:25]1)(C)C>C1COCC1.C(OCC)(=O)C>[OH:22][CH2:23][C:24]1([O:40][CH3:41])[CH:25]=[CH:26][C:27]([CH2:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:32])=[CH:28][CH2:29]1
Reactant: COC1(C(OC(C)C)(OC(C)C)OC(C)C)C=CC(CC(=O)Nc2ccccc2)=CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1(CO)C=CC(CC(=O)Nc2ccccc2)=CC1
Reaction time: 2 h
Yield: 149.2 %

Procedure:
Tetra-butylammonium fluoride (4.48 mL of a 1M solution in THF) was added to a solution of 4-tri-isopropoxymethyl-2-(4′-methoxyphenyl)acetanilide (1.87 g, 4.07 mmol) in THF (12 mL) and stirred for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride then water and finally dried over sodium sulphate. The solvent was evaporated to afford 1.66 g of a yellow oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.[OH-].[Na+]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc(-c2cccc(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(-c2cccc(Cl)c2)cc1

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g), 3'-chlorobiphenyl-4-ol (1.4 g), ethanol (30 ml) and aqueous sodium hydroxide (1.5 M, 5 ml) to give the title compound after purification as a white solid (0.34 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].Cl.[OH-].[Na+].[CH2:12]1COC[CH2:13]1>CO.C(Cl)Cl>[O:3]=[C:1]1[CH2:2][CH2:13][CH2:12][N:4]1[CH2:5][C:6]([OH:8])=[O:7]
Reactant: C1CCOC1
Reactant: CC(=O)NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CN1CCCC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N-Acetylglycine (0.031 ml, 0.22 mmol) was dissolved in 1:1 10N NaOH/THF (2 ml) and was stirred at 50° C. for 1 h. The mixture was neutralized to pH 4 with 6N HCl, then concentrated. The yellowish solid was diluted with 1:1 MeOH/CH2Cl2 (25 ml), filtered to remove inorganic salts, and concentrated. The solid obtained was diluted again with 1:1 MeOH/CH2Cl2 and concentrated to give (2-oxo-pyrrolidin-1-yl)-acetic acid as a white solid. The crude product was used in the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:3]1[CH2:4][CH2:5]2)=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1.C1(C)C(C)=CC=CC=1>O>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:7](=[O:9])[CH:6]3[C:2]([CH3:1])([CH3:12])[CH:3]([CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:19][CH2:20]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: CC1(C)C2CCC1C(=O)OC2=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1(C)C2CCC1C(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O

Procedure:
2,2-Dimethylcyclopentane-1,3-dicarboxylic anhydride (1.68 g., 10 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (2.55 g., 11 mmole) were combined in 500 ml. of xylene and refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was removed in vacuo and the residue column chromatographed on 100 g. of silica gel using a gradient elution from straight chloroform to 5% ethanol/chloroform. Concentration of the product in vacuum and recrystallization from isopropanol with addition of 4N isopropanolic HCl and acetone gave 600 mg. of the title compound as the dihydrochloride, monohydrate; m.p. 227°-229° C. (d).