Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].[C:20]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].O>O1CCCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][CH:2]([O:1][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:31][CH:30]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(COC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.25 g of 1-[2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole and 0.26 g of sodium hydride (50% dispersion in mineral oil) in 20 ml of tetrahydrofuran was stirred under nitrogen at room temperature for one hour, and at 60° C. for one hour. The mixture was then cooled to 0° C. and treated dropwise with stirring with 4-acetylaminobenzyl chloride in 10 ml tetrahydrofuran, keeping the temperature below 10° C. After stirring for one hour, the mixture was heated to 60° C. for 2 hours and poured into water. The product was extracted with ethyl acetate and the extracts dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with 2% water in ethyl acetate to give 1-[4-(4-chlorophenyl)-2-(4-acetylaminobenzyloxy)-n-butyl]imidazole.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][C:3]#[CH:4].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[C:24]#[N:25])/[C:17](/Cl)=[N:18]/[OH:19]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:17]2[CH:4]=[C:3]([CH2:2][CH2:1][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[O:19][N:18]=2)[CH:21]=[CH:22][C:23]=1[C:24]#[N:25]
Reactant: C#CCCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(/C(Cl)=N/O)cc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1cc(-c2ccc(C#N)c(Cl)c2)no1
Temperature: 40 °C
Yield: 54.2 %

Procedure:
tert-Butyl but-3-yn-1-ylcarbamate (0.7 g, 4.14 mmol) was dissolved in toluene (20 ml) and trietyhylamine (0.87 ml) was added at RT. (Z)-3-chloro-4-cyano-N-hydroxybenzimidoyl chloride (0.98 g, 4.55 mmol) was added in DMF (2 ml) to reaction mixture. After one hour in RT the reaction mixture was heated to 40° C. for 2 h. The white precipitate was filtered and the filtrate was washed with 1 M HCl, water and brine. Dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by Flash chromatography (Heptane-EtOAc 2:1). Product fractions were combined and evaporated to give pure title compound (0.78 g). 1H-NMR (400 MHz; d6-DMSO): δ 1.35 (s, 9H), 2.95 (t, 2H), 3.30 (m, 2H), 7.04 (m, 2H), 8.00 (d, 1H), 8.12 (d, 1H), 8.18 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-]S([O-])(=O)=O.[Mg+2].[C:22]([C:26]1C=C(O)C(=[CH:31][CH:32]=1)O)(C)([CH3:24])[CH3:23].II>CC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:22]([CH3:24])([CH3:23])[CH:26]=[C:32]2[CH3:31])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Agent: II
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21

Procedure:
A mixture of N-Boc-1,4-phenylenediamine (75 g), MgSO4 (216 g), 4-tert-butylcathechol (1.8 g) and iodine (4.7 g) in anhydrous acetone (600 ml) was heated under reflux for 20 h. The MgSO4 was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a short plug of silicagel using heptane/ethyl acetate=8/2 (v/v) as the eluent to give the product as a brown oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH3:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (95 μL, 0.68 mmol) in methylene chloride (20 mL) was added dropwise 4-ethylbenzoyl chloride (81 mg, 0.48 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (66%) of the title compound as white crystals: mp 177-178° C.; [α]21D -43° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 377 (27, M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:24]([CH3:23])[CH:25]=[CH:26]4)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: Cn1ccc2cc(B(O)O)ccc21
Product: CC(On1ccc2ncc(-c3ccc4c(ccn4C)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (1-methyl-1H-indol-5-yl)boronic acid according to the procedure described in example 4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16](=O)[C:15]2[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][CH:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16]2=[N:30][NH:31][C:18](=[O:20])[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=32)[NH:9][CH:8]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg) in 85% hydrazine monohydrate (3 mL) and methanol (5 mL) was stirred at room temperature for 2 days. The resulting mixture was filtered and the residue was washed with water (20 mL) and methanol (5 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (95 mg, yield 74%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 3.40 (s, 3H), 4.64-4.67 (d, J=10.8 Hz, 1H), 4.92-4.94 (d, J=10.4 Hz, 1H), 6.72 (s, 1H), 6.87 (s, 1H), 7.15-7.17 (d, J=8.4 Hz, 2H), 7.26-7.30 (m, 3H), 7.38 (s, 3H), 7.55-7.59 (t, J=7.6 Hz, 1H), 12.15 (s, 1H); LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([CH2:18][NH:19][OH:20])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[O:23]([C:25]#[N:26])[K]>O.C(O)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([OH:20])[C:25]([NH2:26])=[O:23])=[CH:21][CH:22]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CNO)cc1
Reactant: N#CO[K]
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CN(O)C(N)=O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl hydroxylamine (303 mg, 1.0 mmol) (obtained from preparation 18) in a mixture of water (2 ml) and acetic acid (0.5 ml) was added a solution of KOCN (343 mg, 3.0 mmol) in water (1 ml) and stirred for 1 h at 30° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the compound (295 mg, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3](C(N)=O)[C:2]=1[C:10]([NH2:12])=[O:11].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C[N:31](C)[CH:32]=[O:33]>>[NH:31]1[C:3]2[N:4]=[CH:5][CH:6]=[N:1][C:2]=2[C:10](=[O:11])[NH:12][C:32]1=[O:33]
Reactant: NC(=O)c1nccnc1C(N)=O
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=c1[nH]c(=O)c2nccnc2[nH]1
Reaction time: 0.25 h

Procedure:
A 50 ml. flask was charged with 0.90 g. pyrazine-2,3-dicarboxamide dissolved in 16 ml. dimethylformamide. A 2.4 g. portion of lead tetra-acetate was added to the solution and the reaction mixture was stirred at 40° for 15 minutes. The reaction mixture was cooled, 30 g. of ice was added and after 1 hour the mixture was filtered. Crystallization of the residue from water gave, after drying in vacuo, a yield of 0.64 g. of pyrazino[2,3-d]pyrimidine-2,4(1H,3H)-dione, melting point 364°-365°, which represented 71 percent of theory. The structure was confirmed by infra-red spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6](SC#N)[N:5]2[N:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[N:5]2[N:18]=1
Reactant: Cc1nc2n(n1)C(SC#N)=Nc1ccccc1C2
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nc2n(n1)C(N1CCN(C)CC1)=Nc1ccccc1C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.25 g of 2-methyl-5-cyanothio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine in 7.3 ml of hexamethylphosphoramide is added dropwise, at 0°, 4.94 g of N-methylpiperazine over a period of 5 minutes. The mixture is stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and evaporated to dryness to give 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine, m.p. 185°-187°. This material is treated with an equivalent amount of maleic acid to give 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine monomaleate of example 1.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[NH2:9][C:10]1[C:11]([OH:16])=[N:12][CH:13]=[CH:14][CH:15]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[O:16][C:11]3[C:10]([N:9]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1cccnc1O
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3cccnc3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 5 mL of trimethylsilyl polyphosphate was added 3-aminopyridin-2-ol (150 mg, 1.59 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (229 mg, 1.0 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was taken up in a minimum of EtOAc and purified by prep TLC (1:1 EtOAc/hexanes) to give 2-(3-methoxy-4-pyridin-2-ylphenyl)[1,3]oxazolo[5,4-b]pyridine as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.73 (dq, 1H), 8.43 (dd, 1H), 8.32 (dd, 1H), 8.02 (d, 1H), 7.99–7.93 (m, 2H), 7.92–7.85 (m, 2H), 7.55 (dd, 1H), 7.40 (ddd, 1H), 4.01 (s, 3H); MS (ESI) 304 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:22]3[CH:23]=[C:24]4[N:31]([CH3:32])[CH2:30][CH2:29][N:25]4[C:26](=[O:28])[N:27]=3)=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(Cl)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(Cl)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (5.52 mg, 0.230 mmol) in THF (5 mL), 2-((5-chloropyridin-3-yl)oxy)-5-(hydroxymethyl)ben-zonitrile (30 mg, 0.115 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidi-n-5(1H)-one (21.4 mg, 0.115 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:60][CH2:59][CH:58]([C:61]2[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[NH:63][CH:62]=2)[CH2:57][CH2:56]1>CN(C=O)C>[NH:63]1[C:64]2[C:69](=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:61]([CH:58]2[CH2:59][CH2:60][N:55]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[C:1]#[N:2])=[O:8])[CH2:56][CH2:57]2)=[CH:62]1
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Cyano-benzoic acid (0.09 g, 0.6 mmol) is dissolved in 3 ml of DMF, then HBTU (0.28 g, 0.75 mmol), HOBt (0.10 g, 0.75 mmol) and DIPEA (0.26 g, 2.0 mmol) are added. The mixture is stirred at RT for 20 min before adding the 3-piperidin-4-yl-1H-indole (0.09 g, 0.6 mmol). The reaction was stirred at RT for 3 hours, monitored with LC/MS. The organic solvent is removed under the reduced pressure and the residue is purified by a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].[C:23]([C@@H:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:27]=1)#[N:24].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([O:19][C@H:25]([C:23]#[N:24])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=1)=[O:18]
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
Into 4.5 ml of methylene chloride containing 22.5 mg of 4-dimethylaminopyridine are added 439 mg (1.48 mmol) of (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid and 329 mg (1.46 mmol) of (S)-α-cyano-3-phenoxybenzyl alcohol. The solution is cooled in an ice bath and 380 mg (1.82 mmol) of dicyclohexylcarbodiimide is added. The mixture is stirred at 0° for 1 hour and is then worked up by partition between ether/hexane. The aqueous phase is extracted with ether, and the ether extract is washed with water (2×) and brine, dried over magnesium sulfate, filtered and evaporated. The product is purified by radial thin layer chromatography (2 mm silica gel rotor eluting with 12% ether/hexane). Higher diastereomeric purity is obtained by further radial tlc, yielding the final product (S)-α-cyano-3-phenoxybenzyl (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, specific rotation=+46.3° (in CHCl3), diastereomer purity=~98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:30][C:29]#[CH:28])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
First, 150 mg of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 58 mg of propargyl bromide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 160 mg (yield, 96%) of 3-[2,4-dichloro-5-(propargyloxy)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-370; m.p., 123.7° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH3:17])=[CH:4][CH:3]=1
Reactant: CCC(=O)C(C)Br
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)C(C)Oc1ccc(F)cc1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
To a solution of 4-fluorophenol (8.0 g, 71.4 mmol) in dimethylformamide (130.0 mL) was added potassium carbonate (13.5 g, 97.4 mmol) and 2-bromopentan-3-one (836) (10.7 g, 64.9 mmol). The suspension was heated at 70° C. for 18 h, cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-20% EtOAc in hexanes) to provide the desired 2-(4-fluorophenoxy)pentan-3-one (837) (5.2 g, 40.8%) as a colorless oil.
Reaction SMILES: C(C([CH:9]=[CH:10][C:11]([C:17]#[N:18])=[C:12](O)[C:13]([OH:15])=[O:14])=C(O)C(O)=O)#N.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C1(C)C=CC=CC=1>O>[C:17]([C:11]1[CH:10]=[CH:9][N:23]([C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)[C:12]=1[C:13]([OH:15])=[O:14])#[N:18]
Reactant: N#CC(C=CC(C#N)=C(O)C(=O)O)=C(O)C(=O)O
Reactant: Nc1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccn(-c2cccc(Cl)c2)c1C(=O)O

Procedure:
A mixture of 9.2 g of the diethyl ester of 3,6-dicyano-2,7-dihydroxy-2,4,6-octatrienedioic acid, 7.0 g of 3-chloroaniline and 75 ml of dry toluene was stirred at reflux for 3 hours, water of reaction being distilled from the mixture as it was formed. The resulting mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 35 ml of hot ethanol and the solution was chilled in a freezer. The resulting solid was filtered and dried under vacuum to give the ethyl ester of 3-cyano-1-(3-chlorophenyl)-1H-pyrrole-2-carboxylic acid (5A), m.p.: 113°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[OH:56]>>[OH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[O:56][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1
Reactant: OCc1ccccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CO)cc1

Procedure:
Analogously to Method G, 1.0 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.37 g of 2-hydroxymethylphenol are reacted. The title compound is obtained as an opaque oil. Rf=0.16 (1:2 EtOAc-heptane); Rt=5.71.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[OH:9][CH2:8][C:3]1[C:2]([NH:1][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1CO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1CO)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (3-amino-pyridin-2-yl)-methanol (0.310 g, 2.54 mmol) and Et3N (0.570 g, 5.33 mmol) in dry CH2Cl2 (20 mL) was added benzoyl chloride (0.700 g, 5.08 mmol) dropwise. After the mixture was stirred for 18 h CH2Cl2 was removed, and then MeOH (5 mL) and saturated aqueous K2CO3 (25 mL) were added. The mixture was stirred for 2 h, and then extracted with CH2Cl2 (5×50 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (2:1 CH2Cl2/Et2O), affording N-(2-hydroxymethyl-pyridin-3-yl)-benzamide as a white solid. The white solid was dissolved in CH2Cl2 (15 mL), and activated MnO2 (0.660 g, 7.68 mmol) was added. The suspension was stirred for 64 h, and then filtered through a celite cake. The filtrate was concentrated by evaporation under vacuum, and a brown residue was purified by flash chromatography on a silica gel column (4:1 CH2Cl2/Et2O), affording N-(2-formyl-pyridin-3-yl)-benzamide as a pale yellow solid (0.139 g, 24% two steps). 1H NMR (CDCl3) δ 7.54-7.62 (m, 4H), 8.07 (d, 2H, J=7.2 Hz), 8.54 (d, 1H, J=4.2 Hz), 9.32 (d, 1H, J=8.7 Hz), 10.19 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12]O)=[CH:4][CH:3]=1.O1CCCC1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH2:12][C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCc1cnoc1-c1ccc(Cl)s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClCc1cnoc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a mixture of 5-(5-chloro-2-thienyl)-4-isoxazolylmethanol (6.54 g), tetrahydrofuran (20 ml) and toluene (100 ml) was added dropwise thionyl chloride (5.41 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals of 4-chloromethyl-5-(5-chloro-2-thienyl)isoxazole (6.98 g, yield 98%) were obtained from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio) and recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 70–71° C.