Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:16])=[O:15].Cl>CCOCC>[C:1]1([CH2:7][C:8](=[O:10])[CH2:13][C:14](=[O:15])[CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)CC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of NaNH2 (19.02 g, 480 mmol) in anhydrous ether (400 mL) under N2 at −5° C. was added dropwise ethyl phenylacetate (19.2 g, 150 mmol) and then acetone (21.23 g, 370 mmol) with vigorous stirring. After addition, the reaction mixture was stirred at room temperature overnight. The mixture was then acidified to pH 4.0-5.0 with 1N HCl. The organic layer was separated and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1-phenyl-2,4-pentanedione (18.32 g, 44%). 1H NMR (400 MHz, CDCl3-d3) δ 15.49 (br s, 1H), 7.33-7.45 (m, 5H), 5.53 (s, 1H), 3.66 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5](C)[NH:4]1)[CH3:2].C(N1C(=O)C(=O)C(C2C=CC=CC=2)N1)C.C(N1C(=O)C(=O)C(C2C=CC(Cl)=CC=2)N1)C.C(N1C(=O)C(=O)C(C2C=CC=C(OC)C=2)N1)C.C(N1C(=O)C(=O)C(C2C=CC(OC)=CC=2)N1)C.C(N1C(=O)C(=O)C(C2C=CC=C([N+]([O-])=O)C=2)N1)C.C(N1C(=O)C(=O)C(C2C=CC(C)=CC=2)N1)C.C(N1C(=O)C(=O)C(OC)N1)C.C(N1C(=O)C(=O)C(OCC)N1)C.C(N1C(=O)C(=O)C(N(C)C)N1)C.C(N1C(=O)C(=O)C(N(CC)CC)N1)C.C(N1C(=O)C(=O)C(NC(=O)C)N1)C.C(N1C(=O)C(=O)C(C(O)=O)N1)C.C(N1C(=O)C(=O)C(C(OC)=O)N1)C.C(N1C(=O)C(=O)C(C(OCC)=O)N1)C>>[CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH2:5][NH:4]1)[CH3:2]
Reactant: CCN1NC(C)C(=O)C1=O
Agent: CCN1NC(C(=O)O)C(=O)C1=O
Agent: CCN1NC(C(=O)OC)C(=O)C1=O
Agent: CCN1NC(N(C)C)C(=O)C1=O
Product: CCN1NCC(=O)C1=O

Procedure:
1-ethyl-3-methyl-4,5-pyrazolinedione; 1-ethyl-3-phenyl-4,5-pyrazolinedione; 1-ethyl-3-(4′-chlorophenyl)-4,5-pyrazolinedione; 1-ethyl-3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-ethyl-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-ethyl-3-(3′-nitrophenyl)-4,5-pyrazolinedione; 1-ethyl-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-ethyl-3-(2′-furyl)-4,5-pyrazolinedione; 1-ethyl-3-(2′-thienyl)-4,5-pyrazolinedione; 1-ethyl-3-(5′-pyrazolyl)-4,5-pyrazolinedione; 1-ethyl-3-methoxy-4,5-pyrazolinedione; 1-ethyl-3-ethoxy-4,5-pyrazolinedione; 1-ethyl-3-dimethylamino-4,5-pyrazolinedione; 1-ethyl-3-diethylamino-4,5-pyrazolinedione; 1-ethyl-3-acetamido-4,5-pyrazolinedione; 1-ethyl-3-carboxy-4,5-pyrazolinedione; 1-ethyl-3-methoxycarbonyl-4,5-pyrazolinedione; 1-ethyl-3-ethoxycarbonyl-4,5-pyrazolinedione;
Reaction SMILES: [OH-].[OH:2][P:3]([O:12][CH2:13][CH:14]1[CH2:18][CH:17]([S:19][C:20]2[CH:26]([CH3:27])[CH:25]3[N:22]([C:23](=[O:31])[CH:24]3[CH:28]([OH:30])[CH3:29])[C:21]=2[C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])[CH2:16][O:15]1)([O:5][CH:6]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH3:7])=[O:4].C(=O)(O)[O-].[Na+].O>[Pd].O1CCOCC1>[OH-:2].[C:32]([C:21]1[N:22]2[CH:25]([CH:26]([CH3:27])[C:20]=1[S:19][CH:17]1[CH2:16][O:15][CH:14]([CH2:13][O:12][P:3]([OH:4])([O:5][CH:6]([N+:8]([CH3:9])([CH3:10])[CH3:11])[CH3:7])=[O:2])[CH2:18]1)[CH:24]([CH:28]([OH:30])[CH3:29])[C:23]2=[O:31])([OH:34])=[O:33]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COP(=O)(O)OC(C)[N+](C)(C)C)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(COP(=O)(O)OC(C)[N+](C)(C)C)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.387 gof product from Example 91, 0.046 g of sodium bicarbonate, 4 ml of water, 19 ml of dioxane, and 0.050 g of 10% palladium/carbon to give 0.031 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[NH:8][CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:17])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cc2cc[nH]c(=O)c2cc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2ccnc(Cl)c2cc1C
Temperature: 100 °C

Procedure:
A suspension of 6-methoxy-7-methyl-2H-isoquinolin-1-one (5 g, 26.45 mmol) was treated at room temperature with phosphorus oxychloride (22 ml). The mixture was heated at 100° C. for 1 h with stirring then concentrated in vacuo to give a residue. Toluene was added to the residue which was further concentrated in-vacuo to give a residue which was taken up in toluene and slowly added to saturated aqueous sodium carbonate. The toluene layer was then separated. The aqueous layer was further mixed and extracted with toluene. The combined toluene layers were dried (MgSO4) and concentrated in vacuo to give a residue. The residue was triturated with diethyl ether then filtered and dried in vacuo to give 1-chloro-6-methoxy-7-methyl-isoquinoline (4 g, 19.32 mmol).
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OC=C)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:11]([O:10][CH2:9][C@H:8]1[O:1][CH:2]=[CH:3][C@@H:4]([OH:5])[C@@H:6]1[OH:7])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: C=COC(=O)c1ccccc1
Solvent: C1CCOC1
Product: O=C(OC[C@H]1OC=C[C@@H](O)[C@@H]1O)c1ccccc1

Procedure:
1.0 g (6.85 mmol) of glucal is taken up in 1.5-2.0 ml of tetrahydrofuran and 3-5 ml of vinyl benzoate and stirred with 1 g of lipase from Candida cylindracea (Amano AY-20) at room temperature for 6 h. Filtering off the enzyme, concentration of the solution in vacuo, taking up the residue in ethyl acetate and extracting it with aqueous NaHCO3 solution, and subsequent chromatography on silica gel (ethyl acetate/hexane 1:1) result in 1.20 g (70%) of the desired 6-O-benzoylglucal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]([CH3:16])[C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH2:23])=[O:22].CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:23][C:2]1[CH:3]=[C:4]([N:9]([CH3:16])[C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1)=[O:22]
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: CN(c1cncnc1)c1cc(Cl)cc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(c1cncnc1)c1cc(Cl)cc(NC(=O)c2cccc(Cl)c2)c1
Temperature: 110 °C
Yield: 56.3 %

Procedure:
Compound 35 (59 mg, 0.20 mmol, 1.0 eq), 3-chlorobenzamide (46 mg, 0.30 mmol, 1.5 eq), NaOt-Bu (27 mg, 0.28 mmol, 1.4 eq), Pd(OAc)2 (2.2 mg, 0.0098 mmol, 0.050 eq) and Xantphos (11.4 mg, 0.0197 mmol, 0.100 eq) were dissolved in toluene (1 mL) in a microwave vial. The vial was purged with argon, capped, and heated at 110° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 42 mg (57%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.4 (s, 1H), 8.8 (s, 1H), 8.6 (s, 2H), 7.96 (t, J=1.8 Hz, 1H), 7.97-7.85 (m, 1H), 7.67-7.65 (m, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.41 (t, J=1.9 Hz, 1H), 6.95 (t, J=2.0 Hz, 1H), 3.34 (s, 3H); [M+1]+: 373.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:22][CH:21]=2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[CH2:33]([N:30]([CH2:31][CH3:32])[CH2:29][CH2:28][O:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:12]1[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=3)[NH:14][N:13]=1)=[CH:26]2)[CH3:34]
Reactant: CCN(CC)CCOc1ccc2[nH]c(-c3n[nH]c4ccc(OCc5ccccc5)cc34)cc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc2[nH]c(-c3n[nH]c4ccc(O)cc34)cc2c1
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
A suspension of 320 mg of {2-[2-(5-benzyloxy-1H-indazol-3-yl)-1H-indol-5-yloxy]ethyl}diethylamine, 32 mg of palladium-on-charcoal at 10%, and 180 mg of ammonium formate is irradiated in a Synthwave 402 microwave oven at atmospheric pressure for 35 minutes at 75° C. at 5% power, and then for 10 minutes at 20% power. The catalyst is filtered through a bed of celite, and the filtrate is evaporated under reduced pressure. The compound obtained is taken up in ethyl acetate (20 ml) and a saturated sodium bicarbonate solution (20 ml), separated by settling out, dried over magnesium sulfate and then evaporated under reduced pressure to obtain 115 mg of 3-[5-(2-diethylaminoethoxy)-1H-indol-2-yl]-1H-indazol-5-ol, which is characterized.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]N(C)C=O.CI.[Cl-].[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([O:24][CH3:25])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc([C@@H](C)O)nc3N21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Product: CO[C@H](C)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.75 g (2.25 mmol) (4R,9aR)-6-(1-(R)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 5 mL N,N-dimethylformamide 0.12 g (2.70 mmol) sodium hydride (55–65% dispersion in oil) was added. After 30 min., 0.28 mL (0.64 g, 4.50 mmol) methyl iodide was added and the reaction mixture was stirred at 50 deg C. for 2 h. After cooling down to room temperature, the reaction mixture was poured into 10% aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-heptane (1:2) as eluant.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[O:15]1[CH2:16][CH2:17][O:18][C:19]2[C:10]([CH:2]3[N:1]([CH2:29][C:28]4[CH:31]=[CH:32][CH:33]=[C:26]([C:24]5[N:25]=[C:21]([CH3:20])[S:22][CH:23]=5)[CH:27]=4)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]3)=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: COC(=O)CCCC(N)c1cccc2c1OCCO2
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: Cc1nc(-c2cccc(CN3C(=O)CCCC3c3cccc4c3OCCO4)c2)cs1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 420.98 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH2:35][CH3:36]>>[CH2:35]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[CH3:36]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C(F)(F)F)cc4)cc3)c2)o1
Reactant: CCI
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.77-7.73,(3H, m), 7.60-7.46,(7H, m) 4.79-4.64,(2H, b), 3.41-3.26,(2H, b), 2.55,(3H, s), 2.32,(3H, s), 1.08,(3H, b). LCMS; retention time 3.78 min, MH+ 480.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)(O)=O.[N+:12]([CH2:15][CH3:16])([O-])=O.C([O-])(=O)C.[NH4+].CCCCCC.CCOC(C)=O>C(O)(=O)C>[NH2:12][CH:15]([CH2:7][C:6]1[CH:5]=[CH:4][CH:11]=[CH:10][CH:9]=1)[CH3:16]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(N)Cc1ccccc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 161.5 %

Procedure:
To a solution of 1.902 q (12.68 mmol) of 3-carboxybenzaldehyde in 10 mL of glacial acetic acid, was added 2.848 mL (2.970 g, 38.04mmol) of nitroethane and 1.080 g (13.95 mmol) of ammonium acetate. The solution was then heated with stirring under nitrogen in a 110° C. oil bath. Then, all of the solid went into solution near 60° C. and the mixture turned a deep yellow color. After 3 hours, thin layer chromatography with 3:1 hexane/EtOAc indicated that no starting material remained. The reaction mixture was cooled to room temperature, and then partitioned between water and methylene chloride, with acidification to about pH2 with 6 M HCl. The organic layer was washed with 6 M HCl, then dried with magnesium sulfate. The solvents were then removed with a rotary evaporator, yielding 2.768 g (98%) of crude material, which was carried on without further purification because of the difficulty of chromatographing the very polar carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3.FC(F)(F)[C:20](O)=[O:21].C1N2CN3CN(C2)CN1C3>>[CH:20]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[CH3:16])[C:3]1[C:2]([CH3:17])([CH3:1])[C:6](=[O:7])[O:5][C:4]=1[CH:8]=[CH:9]2)=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc2ccc3c(c2c1)C(C)(C)C(=O)O3
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc2c3c(ccc2cc1C=O)OC(=O)C3(C)C

Procedure:
A mixture of 1,1,8-trimethyl-2-(1H)-naphtho[2,1-b]furanone (3.85)g, trifluoracetic acid (25 ml) and hexamine (3.5 g) was stirred under reflux for 18 h. The bulk of the trifluoroacetic acid was evaporated under reduced pressure and the residue was treated with water and heated at 90° for 10 minutes. The mixture was neutralised with potassium hydrogen carbonate and extracted twice with chloroform. The combined extracts were dried and evaporated to dryness, and the residue was recrystallised from ethyl acetate to give 7-formyl-1,1,8-trimethyl-2(1H)-naphtho[2,1-b]furanone (2.2 g), m.p. 193°-195° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-]>CO.[Ni]>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:9]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(I)cc2)cn1
Agent: [Ni]
Solvent: CO
Product: NCc1cn(-c2ccc(I)cc2)cn1
Yield: 90.4 %

Procedure:
A solution of 4-azidomethyl 1-(4-iodophenyl)imidazole 1-4 (0.725 g, 2.23 mmol) over Ra—Ni (50% aq. slurry, 300 mg) in MeOH (12 mL) was hydrogenated under balloon H2 for 3 h. The mixture was filtrated through CELITE. The filtrate was concentrated in vacuo to give 4-aminomethyl 1-(4-iodophenyl)imidazole 1-2 as a solid (0.603 g). MS 300.0 (M+H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][NH2:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Na].[CH3:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17].C1(OC2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[CH3:12][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][CH2:10][NH2:11])[CH:7]=[C:2]([O:17][CH2:16][CH:15]([CH3:14])[CH2:18][CH3:19])[N:3]=1
Reactant: CCC(C)CO
Reactant: Cc1cc(NCCN)cc(Cl)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCC(C)COc1cc(NCCN)cc(C)n1
Temperature: 160 °C
Yield: 70 %

Procedure:
N-(2-Chloro-6-methyl-4-pyridyl)ethane-1,2-diamine (0.205 g, 1.2 mmol) was combined with the sodium salt of 2-methylbutan-1-ol (0.66 g, 6 mmol, that had been obtained by treating 2-methylbutan-1-ol with sodium hydride dispersion in THF), diphenylether (2.2 g) and DMSO (0.75 ml). The mixture was heated at 160° C. for 16 hours and purified by column chromatography (silica, ethyl acetate/methanol, 1% concentrated NH3) to yield 200 mg of a brown oil (0.84 mmol, 70%). MS (APCI) m/z=237.9 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:18])[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][CH2:17][CH:12]([N:11]([CH3:18])[CH3:10])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CN(C)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C1CCN(Cc2ccc(Br)cc2)CC1
Yield: 85.8 %

Procedure:
4-Bromobenzyl bromide (0.5 g, 2.0 mmol) was stirred with 4-dimethylaminopiperidine (0.51 g, 4.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) in THF (20 mL) at ambient temperature for 96 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound (0.51 g, 86%). 1H NMR (CDCl3, 400 MHz): 7.44-7.40 (m, 2H), 7.21-7.16 (m, 2H), 3.43 (s, 2H), 2.91-2.85 (m, 2H), 2.27 (s, 6H), 2.17-2.07 (m, 1H), 2.00-1.91 (m, 2H), 1.80-1.72 (m, 2H), 1.58-1.45 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][C:26](O)=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:26](=[O:27])[CH2:25][CH2:24][C:20]3[CH:21]=[N:22][O:23][C:19]=3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A mixture of 4-(1-imidazolyl)aniline (0.51 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.60 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.75 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(1-imidazolyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.95 g, yield 83%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 176–177° C.
Reaction SMILES: O.NN.[OH-].[K+].O=[C:7]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:8][CH:9](C(O)=O)[C:10]([OH:12])=[O:11].Cl.[Na+].[Cl-]>C(O)CO>[S:18]1[CH:19]=[CH:20][C:16]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:17]1
Reactant: O=C(CC(C(=O)O)C(=O)O)c1ccsc1
Agent: Cl
Agent: NN
Agent: [Cl-]
Solvent: O
Solvent: OCCO
Product: O=C(O)CCCc1ccsc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Hydrazine hydrate (1.3 mL, 1.34 g, 26.8 mmol) was added dropwise to a solution of KOH (3.54 g, 63 mmol) and 2-[2-oxo-2-(3-thienyl) ethyl] malonic acid 8(c) (4.00 g, 17.5 mmol) in ethylene glycol (30 mL). This solution was heated at reflux for 6 hours. After cooling to room temperature, the crude reaction mixture was poured into a mixture of 6N HCl (50 mL) and ice (200 g). This aqueous mixture was saturated with NaCl, then extracted with ether (3×70 mL). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to provide an orange oil (2.61 g) of sufficient purity to be employed in the-subsequent reaction without any further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[N:15]=[C:14]([C:16]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH:13]=[CH:12][C:11]=1[O:24][CH3:25].[Cl-].[NH4+]>O1CCCC1>[CH:3]1([O:8][C:10]2[N:15]=[C:14]([C:16]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[CH:13]=[CH:12][C:11]=2[O:24][CH3:25])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc(C(=O)OC2CCCC2)nc1Cl
Reactant: OC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)OC2CCCC2)nc1OC1CCCC1
Reaction time: 1.5 h

Procedure:
Sodium hydride (887 mg of a 60% dispersion in oil) is added to a solution of cyclopentanol (3.35 mL) in dry tetrahydrofuran (127 mL) and the mixture stirred for 1.5 hours. Cyclopentyl 6-chloro-5-methoxypyridine-2-carboxylate (6.3 g) is added and the mixture is stirred at room temperature for 21 hours. The mixture is poured into saturated aqueous ammonium chloride (500 mL) and the resulting mixture extracted with ethyl acetate (2×500 mL). The combined extracts are washed with saturated aqueous sodium bicarbonate (500 mL) and water (500 mL). After drying (MgSO4) the solution is evaporated to dryness to give a yellow oil which is purified by flash chromatography (silica with pentane/ethyl acetate 9:1 v/v as eluent) affording cyclopentyl 6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) as an oil.