Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Li+]>O1CCCC1>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][N:6]=2)=[O:29])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(C(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 53(B)(a), 100 mg, 0.23 mmol) in tetrahydrofuran (500 μL) was treated with a 0.8M aqueous lithium hydroxide solution (300 μL, 0.23 mmol). The solution was stirred at 25° C. for 4 h. The reaction mixture was then directly purified by column chromatography. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 methanol/ethyl acetate) afforded 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic acid (65 mg, 70%) as a white solid: mp 191-193° C.; FAB-HRMS m/e calcd for C21H24N2O5S (M+H)+ 417.1484, found 417.1484.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[C:19]=1[O:20][CH3:21])[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.P(Cl)(Cl)(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(C(=O)NCCc2ccccc2)cc([N+](=O)[O-])c1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C2=NCCc3ccccc32)cc([N+](=O)[O-])c1OC

Procedure:
3.6 g of 3,4-dimethoxy-5-nitro-N-phenethylbenzamide are heated under reflux with 36 ml of phosphorus oxychloride under a nitrogen atmosphere for 96 hours. After distilling the excess phosphorus oxychloride in a water-jet vacuum at 60°, the residue is treated three times with 100 ml of toluene each time, with the solvent being distilled each time. The residue is taken up in methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated in a water-jet vacuum. The red resin obtained is chromatographed on 120 g of silica gel with methylene chloride/ethyl acetate (1:1). There is obtained 1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisoquinoline in the form of a yellow resin.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[N:14]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:15]=[C:16]([CH3:27])[C:17]=2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[N:10][CH:11]=1)=[CH2:5])C>CO.Cl.[Cl-].[Na+].O>[C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[N:14]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:15]=[C:16]([CH3:27])[C:17]=2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[N:10][CH:11]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cncc(-c2c(CCCCC(=O)OCC)c(C)nn3c(CC)ccc23)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C(C)=O)c1
Yield: 90 %

Procedure:
A solution of ethyl 5-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate (190 mg) in methanol (5 mL) and 1N hydrochloric acid (5 mL) was stirred at ambient temperature for 2 hours. The solution was diluted with brine and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1–2:1) to give ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow oil (160 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1.C([Sn](CCCC)(CCCC)[C:34]1[S:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[S:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: COc1ccc(Br)c(NC(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2nc3ccccc3s2)c(NC(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 72.3 %

Procedure:
A mixture of N-(2-bromo-5-methoxyphenyl)-3-fluoro-4-(2-piperidin-1-ylethoxy)benzamide (1.0 g), dichlorobis(triphenylphosphine)palladium(II) (150 mg), xylene (30 ml) and 2-tributylstannylbenzothiazole (1.9 g) was refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (810 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.OB(O)[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.CN(C=O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-bromoindole (480 mg, 2.45 mmol), 4-(dihydroxyboryl)benzoic acid (406 mg, 2.45 mmol), Pd(dppf)Cl2CH2Cl2 (10 mg, 0.01 mmol), and 2M Na2CO3 (5.6 mL, 11.2 mmol) in a mixture of ethanol (4 mL) and DMF (7 mL) was heated to 100° C., stirred for 16 hours, filtered, and concentrated The concentrate was dissolved in ethyl acetate, washed sequentially with 1M H3PO4, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 236 (M−H)−.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:22])[CH:18]([CH2:20][OH:21])[NH2:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][O:16][C:17](=[O:22])[CH:18]([NH:19][C:11](=[O:13])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:10])[CH2:20][OH:21]
Reactant: COC(=O)C(N)CO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A round-bottomed flask was charged with Boc-D-alanine (600 mg, 3.17 mmol) and DL-serine methyl ester hydrochloride (691 mg, 4.44 mmol). DMF (12 ml) was added followed by N,N-diisopropylethylamine (1.5 ml, 8.6 mmol) and HATU (1.33 g, 3.49 mmol). The yellow reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 422 mg (41%) of 2-((R)-2-tert-butoxycarbonylamino-propionylamino)-3-hydroxy-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29].C(Cl)Cl>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cccc(CC2CNCCN2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100-mL round-bottomed flask were added 2-((6-methoxy-2-pyridinyl)methyl)piperazine (373 mg, 1.80 mmol), triethylamine (0.375 mL, 2.70 mmol), 2-thiophenesulfonyl chloride (0.328 mL, 1.80 mmol, Aldrich, St. Louis, Mo., and DCM (5 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((6-methoxy-2-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (135 mg) as viscous oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:4][CH2:3]1.Cl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([CH:11]3[CH2:13][CH2:12]3)=[O:10])[CH2:4][C:3]2=1)#[N:16]
Reactant: O=C1CCC(NC(=O)C2CC2)CC1
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(4-oxocyclohexyl)amide (51.3 g, 283 mmol) and 4-cyanophenylhydrazine hydrochloride (48.0 g, 283 mmol) by essentially following procedures as described in Preparation 3 to obtain 57.0 g (72%) of a pale yellow solid. mp: 231-233° C.; MS (ES): m/z 280 (M+1).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
Under a nitrogen atmosphere, heptyl 4-iodobenzoate (2a) (10.1 g, 29.3 mmol) was dissolved in anhydrous triethylamine (50 mL), Pd(PPh3)2Cl2 (0.0820 g, 0.117 mmol), triphenylphosphine (0.126 g, 0.480 mmol), copper (I) iodide (0.135 g, 0.192 mmol), and trimethylsilylacetylene (TMSA) (4.30 mL, 31.7 mmol) were added, and the mixture was stirred at room temperature for 20 hr. The reaction solution was filtered through celite, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:30) to give heptyl 4-[(trimethylsilyl)ethynyl]benzoate (3a) (9.23 g, yield 98%) as an oily liquid.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]3[CH3:29])=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][C:19]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH:8]3[CH2:9][CH2:10][CH:6]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:7]3)=[CH:13][CH:14]=2)[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(OS(C)(=O)=O)C2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(N3CCCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
3-[4-({3-[(methylsulfonyl)oxy]cyclopentyl}oxy)phenyl]-2-methyl -4(3H)-quinazolinone (550 mg, 1.33 mmol), pyrrolidine (474 mg, 6.7 mmol) and potassium carbonate (277 mg, 2.0 mmol) were mixed in dimethylformamide (10 mL) and stirred at 80° C. overnight. Distilled water was added, and the mixture extracted with ethyl acetate. The organic phase was dried by anhydrous magnesium sulfate, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain the title compound (143 mg) as a colorless solid. 2-methyl-3-[4-{[3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone (trans isomer)
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].[CH:7](=O)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:8]([CH:7]=[N+:5]([CH:2]([CH3:4])[CH3:3])[O-:6])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)NO
Reactant: O=C/C=C/c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)[N+]([O-])=CC=Cc1ccccc1
Reaction time: 1 h

Procedure:
N-Isopropylhydroxylamine hydrochloride (5.04 grams, 45.2 millimoles, 1 molar equivalent; available from Acros Organics) was combined with trans-cinnamaldehyde (5.66 grams, 42.9 millimoles, 0.95 molar equivalent; available from Aldrich Chemical Company) in 16 milliliters of water. Initially, the mixture was an emulsion due to the low solubility of the trans-cinnamaldehyde. After being stirred rapidly for about one hour, the emulsion disappeared, and a homogeneous light yellow solution resulted. After being stirred for four hours, the reaction mixture was poured into methylene chloride and treated with 26 milliliters of saturated aqueous sodium carbonate solution until the pH was about 10.5. The phases were separated and the aqueous phase was extracted with additional methylene chloride. The combined organic phases were separated, dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue dried under vacuum overnight to produce 7.4 grams (91 percent of theory) of the desired product nitrone that was determined to be pure by liquid chromatography and further characterized by NMR spectroscopy. UV-visible spectrum of the product in absolute ethanol revealed an absorption maximum (λmax) at 330 nanometers. Exposure of this dilute solution to a 390 nanometer light source converted the nitrone to the corresponding oxaziridine with a shift of the absorption maximum to 256 nanometers. All sample manipulations were done in a dark room containing only red light to insure the stability of the nitrone product.
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]([C:21]#[N:22])=[CH:11][C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[NH4+].[OH-].[Pd].[Ni]>[NH2:22][CH2:21][CH:10]([CH2:11][C:12]([CH3:19])([CH3:20])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:9]([OH:23])=[O:8]
Reactant: [H][H]
Reactant: CC(C)CCCC(C)(C)C=C(C#N)C(=O)OCc1ccccc1
Agent: [Ni]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCCC(C)(C)CC(CN)C(=O)O
Yield: 16.9 %

Procedure:
2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester (1.3 g, 4.14 mmol) in THF (50 mL) was treated with hydrogen in the presence of 20% Pd/C to give a mixture of the cyano acid and the cyano methyl ester. The mixture was purified by silica gel chromatography to give 278 mg of cyano acid. The acid was then treated with hydrogen in the presence of Raney Ni in MeOH/NH4OH to give 0.16 g of 2-aminomethyl-4,4,8-trimethyl-nonanoic acid. m/z 230.3 (M+).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12](C(O)=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:22](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[NH2:22][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]2[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: CCc1nn(C2CCCC2)c2cc(N)ccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (258 mg) and triethylamine (0.56 mL) in t-butanol (1 ml) was added diphenylphosphoryl azide (0.33 μL). The mixture was stirred at 100° C. for 4 h, then partitioned between water (25 mL) and ether (25 mL). The ether layer was collected, dried (MgSO4), and passed through a plug of silica. The silica was washed with an additional 25 mL of ether and the mixture was concentrated in vacuo. The residue was dissolved in THF (5 mL) and 6N aq. HCL (1 mL) was added and the mixture was stirred for 18 h. Ether (25 mL) and water (25 mL) were added and the ether layer was collected, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel to yield 0.14 g of 6-amino-1-cyclopentyl-3-ethyl-1H-indazole (59% yield). 1H NMR (300 MHz) δ 7.45 (d,J=8.4 Hz, 1H), 6.52 (m,2H), 4.74 (p,J=7.8 Hz, 1H), 3.86 (br,2H), 2.95 (q,J=7.7 Hz,2H), 2.3–1.8 (m,6H), 1.8–1.6 (m,2H), 1.37 (t,J=7.7 Hz,3H).
Reaction SMILES: C([NH2:5])CCC.[I:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[CH:9][CH:8]=1>CCOCC>[I:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH2:5])=[O:15])=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cc1ccc(I)cc1
Reactant: CCCCN
Solvent: CCOCC
Product: NC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-Butylamine (1.83 g) was added to a solution of 4-iodophenylacetyl chloride (2.80 g) in ether (25 ml), and the reaction mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was then partitioned between water (30 ml) and ethyl acetate (50 ml). The organic layer was washed with 2M aqueous hydrochloric acid (25 ml), water (30 ml), brine (25 ml), dried (MgSO4), and evaporated to give N-1-butyl, (4-iodophenyl)acetamide, as a colourless crystalline solid, (2.9 g), mp.: 100-102° C., NMR: 0.82-0.88(3H,t), 1.18-1.43(4H,m), 3.00-3.06(2H,q), 3.35(2H,s), 7.03-7.67(4H,AB), 7.97(H,bt); m/z 318 (M+H).
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[C:5]=1[Cl:1]
Reactant: ClCl
Reactant: Cc1cc(N)cc(C)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)c(Cl)c(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(EXAMPLE 6B): Chlorine gas (from 6 ml of pre-condensed chlorine) was passed into a solution of 4-amino-2,6-dimethylpyridine (2 g) in a mixture of concentrated sulphuric acid (20 ml) and water (20 ml) and the mixture was stirred for 1 hour. The mixture was then cooled to 0° C., basified with 4M sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, saturated sodium chloride solution and dried. Solvent was removed by evaporation and the residue was purified by flash chromatography eluting with dichloromethane/methanol (9:1 v/v) to give 4-amino-3-chloro-2,6-dimethylpyridine (1.45 g) as an off white solid, m.p. 86° C.; NMR (CDCl3): 2.37(s,3H), 2.52(s,3H), 4.47(s,2H), 6.37(s,1H); mass spectrum (chemical ionisation, ammonia): 157(M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: NCCC(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)CCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 80.1 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and β-alanine (0.23 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.55 g (80%) 121 as a pale yellow powder: mp=146–148° C.; Rf 0.73 (A): Rf 0.87 (C): Rf 0.57 (D): 1H NMR (DMSO-d6) δ 2.60 (t, J=7.4 Hz, 2H), 3.78 (t, J=7.4 Hz, 2H), 8.07 (dd, J=7.5, 8.0 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.27 (d, J=8.0, 1H); IR (cm−1): 2800–3200 (OH), 3097 (C═CH), 2620 (C—H), 1781 (C═O), 1725 (bs, C═O), 1617 (C═C), 1545 (N═O), 1468 (C═C), 1450 (C═C), 1395 (C—O), 1360 (N═O), 1235 (C—O), 723 (C═CH); MS m/z (rel intensity) 264 (76), 263 (100), 191 (90).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:6][C:5]=1[CH3:16])([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:12][OH:13])[CH2:14][OH:15])=[CH:6][C:5]=1[CH3:16]
Reactant: Cc1cc(NC(CO)CO)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(NC(CO)CO)ccc1N

Procedure:
The 2-(4-nitro-3-methylphenylamino)propane-1,3-diol (11) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH2:1]([N:8]1[C:12](CC#N)=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:27]([OH:30])(=[O:29])[CH3:28]>Cl>[CH2:1]([N:8]1[C:12]([CH2:28][C:27]([OH:30])=[O:29])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(-c2nc(Cl)c(CC#N)n2Cc2ccccc2)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CN(C)c1ccc(-c2nc(Cl)c(CC(=O)O)n2Cc2ccccc2)cc1

Procedure:
5 g of 1-benzyl-2-(p-dimethylaminophenyl)-4-chloro-5-cyanomethylimidazole was refluxed in a mixture of 25 ml concentrated hydrochloric acid, 25 ml water and 25 ml glacial acetic acid for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue dissolved in 50 ml of water and the solution adjusted to pH 3 with sodium hydrogen carbonate. The resulting precipitate was recovered by filtration and recrystallized from aqueous ethanol. By the above procedure was obtained 4 g of 1-benzyl-2-(p-dimethylaminophenyl)-4-chloroimidazole-5-acetic acid as pale yellow needles, m.p. 170°-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 63 %

Procedure:
To (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (880 mg, 3.09 mmol) in CH2Cl2 (15 mL) at room temperature was added Hunig's base (1.62 mL, 9.27 mmol, 3 equiv) and aniline (0.56 mL, 6.18 mmol, 2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (1.29 g, 3.40 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred in the ice bath for 45 minutes. LCMS showed conversion complete. The mixture was filtered, and the filtrate was concentrated in vacuo. Silica gel column chromatography with gradient elution of 1% EtOAc in CHCl3 to 35% EtOAc in CHCl3 gave 700 mg of the title compound. LC-MS (ES) m/z=360 [M+H]+.