Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>O1CCOCC1.O>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:6]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCOC(C(=O)NC1CCNCC1)(c1ccccc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(C(=O)NC1CCN(Cc2ccc(OC)cc2)CC1)(c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(4-Piperidinyl)-2-butoxy-3-methyl-2-phenylbutanamide (invention compound, Compound No. 27) (4.5 g) was dissolved in dioxane (25 ml) and water (25 ml). To the resulting solution, potassium carbonate (0.7 g) and 4-methoxybenzyl chloride (0.8 g) were added, followed by stirring at room temperature for 2 days. To the reaction mixture, was added water (40 ml). The resulting mixture was extracted with an ethyl acetate. The extract was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by a silica gel column to obtain the invention compound (Compound No. 29, 0.60 g, 26.4%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 377.18 g/mol.
Reaction SMILES: O[C:2]1[C:7]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:6](O)[N:5]=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:6]=2[N:5]=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CCNc2nc(O)c(NC(=O)c3ccco3)c(O)n2)cc1
Product: COc1ccc(CCNc2nc(Cl)c3nc(-c4ccco4)oc3n2)cc1
Temperature: 90 °C
Yield: 83.2 %

Procedure:
A mixture of 4,6-dihydroxy-5-(2-furanylcarbonyl)amino-2-[(4-methoxyphenyl)ethyl]aminopyrimidine (408 mg) and phosphorus oxychloride (5 ml) was heated at 90° C. for 3 hours. The excess phosphorus oxychloride was removed by evaporation, in vacuo, and then by azeotroping with toluene (2×50 ml). The residue was added to water and the resultant precipitate filtered off, washed with water and dried. There was thus produced 7-chloro-2-(2-furyl)-5-[2-(4-methoxyphenyl)ethyl]amino oxazolo[5,4-d]pyrimidine (340 mg, 83.2% yield); m.p.169.5°-171° C.: NMR:DMSO-d6 : 2.80(t,2H,ArCH2), 3.48(q,2H, CH2NH), 3.72(s, 3H, OMe), 6.80(m, 1H, furyl-H), 6.85(d,2H,ArH), 7.16(d,2H,ArH), 7.44(d,1H,furyl-H), 8.07(m, 1H, furyl-H), 8.13(brs,1H,NH).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:27][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccccn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccccn1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
2-Ethylpyridine (20.0 g, 186.65 mmol) was placed in carbon tetrachloride (830 mL) and benzoyl peroxide (4.5211 g, 18.665 mmol) and 1-bromopyrrolidine-2,5-dione (33.221 g, 186.65 mmol) were added. The reaction mixture was heated to reflux for 18 hours, then cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified over a plug of silica to give 2-(1-bromoethyl)pyridine (17.312 g, 49.9%). 1H NMR (CDCl3) δ 8.58 (d, 1H), 7.69 (td, 1H), 7.76 (d, 1H), 7.20 (dd, 1H), 5.24 (q, 1H), 2.08 (d, 3H)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]1.[H-].[Na+].[CH3:20]S(C)=O>CI>[CH3:20][N:9]1[C:10]2[C:15](=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[CH:8]1
Reactant: CS(C)=O
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1cc(C2CCC(=O)C2)c2cc(C#N)ccc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
3-(3-oxocyclopentyl)-1H-indole-5-carbonitrile (11.21 g, 0.05 mMol) was dissolved in anhydrous DMSO (30 mL) and added dropwise to a suspension of sodium hydride (2.25 g, 0.055 mMol, 60% in mineral oil) in dry DMSO (50 mL) under nitrogen at 25–30° C. The reaction was heated to 40° C. for 15 min, then cooled to room temperature. Methyl iodide (3.42 mL, 0.055 mMol) was added dropwise, maintaining reaction temperature at 25–30° C. with an external ice water bath. After stirring for 2 h at room temperature, the reaction was poured into 1 L ice water. The tan solid was filtered, washed with H2O, dissolved in ethyl acetate (750 mL), extracted with H2O (500 mL) and brine (500 mL), and dried over sodium sulfate. The ethyl acetate extract was concentrated in vacuo and the product was purified by chromatography on silica gel with a 10% step gradient of 25–45% ethyl acetate in hexane. Pure product fractions were concentrated in vacuo and dried under high vacuum to give 1-methyl-3-(3-oxo-cyclopentyl)-1H-indole-5-carbonitrile (8.52 g, 72%). 1H NMR (500 MHz, CDCl3) δ 7.95 (1 H, s), 7.46 (1 H, dd, J=8.54, 1.22), 7.34 (1 H, d, J=8.54), 6.94 (1 H, s), 3.78 (3 H, s), 3.69 (1 H, m), 2.74 (1 H, dd, J=7.63, 18.01 Hz), 2.53 (1 H, m), 2.38 (3 H, m), 2.06 (1 H, m). MS m/e 239.3 (M+H)+. Anal. calcd. for C15H14N2O: C, 75.60; H, 5.92; N, 11.75. Found: C, 75.31; H, 5.86; N, 11.55. IR (KBr) 2219, 1728 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[H-].[Na+].[C:23]([O:27][C:28]([N:30]1[C:38]2[N:33]([C:34](=[O:40])[N:35]=[C:36](Cl)[CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:36]3[CH:37]=[C:38]4[N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31][CH2:32][N:33]4[C:34](=[O:40])[N:35]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol, NaH and tert-butyl-7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[K].[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29]Br)=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C.O>[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29][NH2:5])=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1ccc2c(c1)C=C(CBr)CO2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.25 g (6.75 mmol) of potassium phthalimide are added to a solution of 1.4 g (4.5 mmol) of the brominated compound obtained in Step D in 15 ml of DMF; the medium is then stirred overnight at ambient temperature and under argon. After evaporation of the solvent in vacuo, the residue obtained is taken up in water; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on a silica column (eluant: ethyl acetate/petroleum ether 10/90) allows access to the title phthalimide in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[O:11][C:7]=2[C:6]([C:17]2[CH2:21]C[CH:19]([CH2:22][NH:23][C:24](=O)OC(C)(C)C)[CH:18]=2)=[C:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4]=1[CH3:37])#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:13]([CH3:15])[CH3:14])=[O:16])[O:11][C:7]=2[C:6]([CH:17]2[CH2:18][CH2:19][C:22]([NH:23][CH3:24])=[CH:21]2)=[C:5]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:4]=1[CH3:37])#[N:2]
Reactant: Cc1c(-c2ccccc2)c(C2=CC(CNC(=O)OC(C)(C)C)CC2)c2oc(C(=O)N(C)C)nc2c1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CNC1=CC(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
tert-Butyl {3-[4-cyano-2-dimethylcarbamoyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl]cyclopent-2-enyl}methylcarbamate (I-340-1) (134 mg, 0.27 mmol) was dissolved in 4 N hydrochloric acid/1,4-dioxane solution (3 ml), and stirred at room temperature for 2 hours. The solvent was evaporated away under reduced pressure, then ethanol was added to the resulting residue, followed by concentration under reduced pressure. This operation was repeated once again. The residue was dissolved in chloroform (15 ml) and an aqueous saturated sodium hydrogencarbonate solution (15 ml), and vigorously stirred for 10 minutes. The aqueous layer was separated, extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:7 N ammonia-containing methanol solution=93:7, v/v) to obtain a roughly-purified product (60 mg). This was further purified by preparative TLC (eluent, chloroform:methanol=9:1, v/v) to obtain a brown solid (50 mg). The solid was washed in slurry with diisopropyl ether, and a pale brown solid was collected by filtration. The solid was dried at 60° C. under reduced pressure for 48 hours to obtain the entitled compound (42 mg, 39%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](S(C2C=CC(C)=CC=2)(=O)=O)(SC)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][C:6]=1[N+:32]([O-:34])=[O:33])([CH3:4])([CH3:3])[CH3:2].Cl.C[OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:37])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][C:6]=1[N+:32]([O-:34])=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(Cc1ccc(C(C)(C)C)c([N+](=O)[O-])c1)(CC1CCCCC1)S(=O)(=O)c1ccc(C)cc1
Reactant: CO
Agent: Cl
Product: CC(C)(C)c1ccc(CC(=O)CC2CCCCC2)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
The whole of the 2-t-butyl-5-[3-cyclohexyl-2-(4-methylphenyl)sulfonyl-2-methylthiopropyl]-1-nitrobenzene prepared as described in step (i) above was dissolved in 50 ml of methanol. 5 ml of concentrated aqueous hydrochloric acid were added, and the resulting solution was heated for 2 hours under reflux. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in diethyl ether, and the solution was washed with water, with a saturated aqueous solution of sodium hydrogen carbonate, with water and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 150 g of silica gel. Elution with a 1:5 by volume mixture of ethyl acetate and hexane afforded 1.20 g (yield 73%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2[nH]cc(CCC(=O)O)c2c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Acrylic acid (16.5 mL, 240.6 mmol) was added to a solution of 5-methyl-1H-indole (10.5 g, 80.2 mmol) in acetic acid (20 mL) and acetic anhydride (20 mL) and the mixture was stirred at room temperature for 1 week. Aqueous sodium hydroxide (4N, 100 mL) was added and the mixture was washed with ethyl acetate. The aqueous fraction was acidified to pH 1 with hydrochloric acid (5M) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (7 g, 43%). 1H NMR (360MHz, CDCl3) δ7.85 (1H, br s), 7.38 (1H, s), 7.24 (1H, d, J 8.3 Hz), 7.02 (1H, dd, J 8.3, 2.3 Hz), 6.97 (1H, d, J 2.3 Hz), 3.09 (2H, t, J 7.6 Hz), 2.76 (2H, t, J 7.6 Hz), and 2.46 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH:12]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccc(Cl)cc2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCn1cnc(-c2ccc(Cl)cc2)c1

Procedure:
Using the procedure of Stage B of Example 1, 14.2 g of product of Stage B and 3.6 ml of hydrazine hydrate in 200 ml of ethanol were reacted to obtain 12 g of crude product which was chromatographed on silica (eluant CH2Cl2 --MeOH--NH4OH 8-2-0.04) to obtain the expected product, which is used as is for the synthesis.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](NC2C3C(=CC=CC=3)N=C(C)C=2)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.C[O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32].CCN(C(C)C)C(C)C>CO>[CH3:34][CH:33]([CH3:35])[C@H:31]([NH:32][C:13]([NH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)=[O:14])[C:30]([OH:29])=[O:36]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1cc(NC(=O)Nc2cc(C)nc3ccccc23)c2ccccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(NC(=O)N[C@H](C(=O)O)C(C)C)c2ccccc2n1
Temperature: 80 °C

Procedure:
A suspension of 1,3-bis-(2-methyl-quinolin-4-yl)-urea (342.4 mg, 1 mmol), valin methyl ester hydrochloride (167.6 mg, 1 mmol) and DIPEA (0.34 mL, 2 mmol) in MeOH (10 mL) is heated at 80° C. for 15 h. The solvent is evaporated and the residue is dissolved in 6N aqueous HCl (6 mL). The reaction mixture is heated at 90° C. for 12 h. Evaporation and purification by preparative HPLC provides the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[NH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=2[OH:23])[CH:14]1[OH:25]>C(O)C>[C:1]1([CH2:7][CH2:8][CH:9]=[N:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=3[OH:23])[CH:14]2[OH:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Reactant: NC1CCc2c(ccc(O)c2O)C1O
Agent: Br
Solvent: CCO
Product: Oc1ccc2c(c1O)CCC(N=CCCc1ccccc1)C2O

Procedure:
In 200 volume parts of ethanol is dissolved 2 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, followed by the addition of 20 parts of β-phenylpropionaldehyde to produce 2-(3-phenylpropylideneamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene. Using palladium-on-carbon as a catalyst, the reaction mixture is subjected to catalytic reduction at ordinary temperature and pressure. After a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered to remove the catalyst and, then, 5000 volume parts of ethyl ether is added to the filtrate. The procedure yields 2 parts of 2-(3-phenylpropylamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as white crystals melting at 136°-139° C (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Br)=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[S:6](=[O:21])(=[O:20])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:24][Si](C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:24])=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[S:6](=[O:21])(=[O:20])[N:5]=1)[CH3:2]
Reactant: CCOC1=NS(=O)(=O)C(C(=O)OCc2ccccc2)=C1Br
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)C(C(=O)OCc2ccccc2)=C1N
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a suspension of 3-ethoxy-4-bromo-5-benzyloxycarbonylisothiazole-1,1-dioxide (1.50 g, 0.0040 mol) in acetonitrile (6 ml) there was added hexamethyldisilazane (0.91 ml, 0.0043 mol). The mixture was heated at 70° for 3.5 hours. Additional hexamethyldisilazane (0.21 ml, 0.0010 mol) was added and the solution stirred at 70° for 1.5 hours. The mixture was then concentrated to dryness in vacuo and the residue dissolved in ethanol (50 ml) and stirred for 15 minutes. The solution was concentrated to dryness in vacuo and the residue recrystallized from ethanol to give the title product (0.95 g, 77%, mp 149°-151°).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH:24]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH:24]=[N:35][O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(C=O)cc2c(Cl)nc(-c3ccccc3)nc21
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1c(C=NOCc2ccccc2)cc2c(Cl)nc(-c3ccccc3)nc21
Yield: 47.9 %

Procedure:
A solution of the aldehyde 20 (50 mg, 0.14 mmol), O-benzylhydroxylamine hydrochloride (26 mg, 0.16 mmol), and pyridine (12 mg, 0.15 mmol) in CH2Cl2 (2 mL) is stirred at ambient temp. for 5 h, then sat. NH4Cl solution is added, and the mixture is extracted with EtOAc (3×5 mL). The combined extracts are washed with brine and dried over MgSO4. Crystallization of the crude solid from hexanes gives 31 mg (0.067 mmol, 48%) of the title compound as colorless solid, single oxime isomer. MS (ES): m/z 463.0/465.0 (90/48) [MH+], 363.1/365.2 (100/32) [MH+-Boc].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:20]1([O:26][CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([C:7]([C:23]2[CH:24]=[CH:25][C:20]([O:26][CH2:27][CH3:28])=[CH:21][CH:22]=2)=[O:9])[CH:10]=1
Reactant: CCOc1ccccc1
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2cc(Br)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acid 56 (4.9 g, 18.57 mmol) in CH2Cl2 (62 mL) were added oxalyl chloride (2.1 mL, 24.14 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (93 mL) and cooled to 0° C. To the mixture was added phenetole (2.4 mL, 18.57 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (2.7 g, 20.43 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 73 was dried under high vacuum and used without further purification (7.0 g).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([O:13]C(C)(C)C)=O)[C:5]2=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22]>FC(F)(F)C(O)=O>[F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([NH2:22])=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2nc(F)ccc12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1n[nH]c2nc(F)ccc12
Reaction time: 2 h
Yield: 89.1 %

Procedure:
t-Butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (8.90 g, 37.5 mmole) was dissolved in 30 mL of trifluoroacetic acid and allowed to stand undisturbed for 2 hours. The solvent was then evaporated and the residue was dissolved in 30 mL of DMF. N,N'-Carbonyldiimidazole (7.0 g, 43.2 mmol) was added and the reaction mixture was stirred overnight. Ammonium acetate (8.7 g, 113 mmol) was then added to the resulting suspendion and stirring was continued for 4 hours. The solvent was evaporated under high vacuum and the residue was triturated well with H2O to give 6.02 g (89%) of product after drying. An analytical sample was obtained by recrystallization from HOAc, mp 295° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br>>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Yield: 77.6 %

Procedure:
Following General Procedure A: 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (1.6 g, 6.0 mmol) was reacted with 2-bromomethyl-5-cyano-benzoic acid methyl ester (1.5 g, 6.0 mmol) to give 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (2.05 g, 78%), as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]1.CO.[Li+].[OH-]>O>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1
Reactant: COC(=O)C1CCN(c2ccncc2N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cnccc1N1CCC(C(=O)O)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A microwave vial was charged with methyl 1-(3-amino-4-pyridyl)piperidine-4-carboxylate (prepared according to methods similar to the one depicted in Preparation N-1) (176 mg, 0.7106 mmol), MeOH (3 mL) and H2O (0.1 mL). LiOH (51.06 mg, 2.132 mmol) was added and the mixture was stirred overnight at 50° C. The reaction was quenched by addition of an aqueous solution of HCl until pH=3-4 is reached. The reaction mixture was then concentrated under reduced pressure to yield 1-(3-amino-4-pyridyl)piperidine-4-carboxylic acid that was used without further purification. MS (ES+) 222.1.