Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([NH:9]C=O)[N:6]=[C:5]([C:12](=[N:36][O:37][CH3:38])[C:13]([NH:15][CH:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH:23]([S:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH3:24])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:4]=1.C(OCC)C>CO>[ClH:2].[NH2:9][C:7]1[N:6]=[C:5]([C:12](=[N:36][O:37][CH3:38])[C:13]([NH:15][CH:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH:23]([S:25][C:26]4[NH:27][N:28]=[N:29][N:30]=4)[CH3:24])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:4]=[C:3]([Cl:2])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cc(Cl)nc(NC=O)n1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 156 %

Procedure:
Conc. hydrochloric acid (242 mg.) was added to a solution of 7-[2-(6-chloro-2-formamidopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.2 g.) in methanol (12 ml.), and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a foamy residue, which was pulverized with ethyl ether. This powder (1.1 g.) was dissolved in methanol (6 ml.), and to ethyl ether (50 ml.) was added dropwise the methanol solution. The precipitates were collected by filtration and then dried to give 7-[2-(2-amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (0.95 g.).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.[OH2:20]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:2]([OH:20])([C:1]#[CH:6])[CH3:3]
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: O
Solvent: CS(C)=O
Product: C#CC(C)(O)c1ccccc1-c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 46.6 g of p-phenylacetophenone in 250 ml. of dimethyl sulfoxide, there is added 65.5 g of lithium acetylide - ethylene diamine complex. After 18 hours at room temperature, the mixture is poured on 2 liters of iced water. The initial oil solidifies on standing, is filtered off and recrystallized from 150 mlof isopropyl alcohol to give 2-(p-biphenylyl)-3-butyn-2-ol, mp 75°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]=[N:26][NH:25][C:24]1=[O:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[C:24](=[O:28])[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:15])([F:30])[F:29])[CH:27]=[N:26]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccccc1C(F)(F)F
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccccc2C(F)(F)F)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 20.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.1 g of 4-(2-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(2-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone (0.4 g) was obtained as a colorless powder.
Reaction SMILES: CO[CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13].C([O:18][N:19]=O)CCC.[O-]CC.[K+]>>[OH:18][N:19]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13]
Reactant: CCCCON=O
Reactant: COC1CCc2ccccc2C1=O
Agent: CC[O-]
Agent: [K+]
Product: O=C1C(=NO)CCc2ccccc21

Procedure:
Most of the 5, 6, 7, and/or 8-methoxy-1-tetralones are known. See, e.g., Autrey & Scullard, J. Am. Chem. Soc. 90, 4924 (1968); Thomas and Nathan, J. Am. Chem. Soc. 70, 331 (1948); Thrift, J. Chem. Soc. C., 288 (1967). The appropriate methoxy 1-tetralone (Compound 1) is reacted with n-butylnitrite and potassium ethoxide to yield the 2-hydroxyimino-1-tetralone (Compound 2). The latter is reduced over palladium-barium sulfate to give the 2-amino-1-tetralone (Compound 3). ##STR10## Reduction with sodium borohydride leads to the trans 2-amino-1 tetralol (Compound 4). Treatment of Compound 4 with chloroacetyl chloride or a suitably substituted derivative yields the chloroacetamide (Compound 5). (The size of the heterocyclic ring may be increased by substituting chloropropionyl chloride for chloroacetyl chloride.) ##STR11## Reaction of (Compound 5) with sodium hydride or sodium hydroxide leads to ring closure to the lactam (Compound 6). Reduction of this lactam with lithium aluminum hydride gives the amine (Compound 7) in which A is --CH2 --. ##STR12## Alkylation with RI or RBr yields the tertiary amine (Compound 8). This can also be achieved by acylation of Compound 7 with an alkane carboxylic acid chloride followed by reduction with lithium aluminum hydride. (R5 ' is R5 less one methylene unit.) A third alternative is to directly alkylate Compound 7 with a NaBH4 -carboxylic acid complex. On treatment with boron tribromide the methoxy group (--OCH3) of Compound 8 is converted to a phenol (--OH) to yield Compound 9. (The numbering of the carbons corresponds to A=--CH2 --.) ##STR13##
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.9 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in acetonitrile (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopentylcarbamate (0.44 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered to afford N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopentylamino)carboxamide (0.2 g, 27%) as a white solid: mp 151-153° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 6.31 (t, 1H), 6.17 (d, J=6.9 Hz, 1H), 5.18-5.11 (dd, J=4.6 and 12.3 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 3.83 (q, J=6.4 Hz, 2H), 2.96-2.85 (m, 1H), 2.64-2.50 (m, 2H), 2.07-2.04 (m, 1H), 1.70-1.29 (m, 8H); 13C NMR (DMSO-d6) δ 172.77, 169.83, 167.59, 167.04, 157.63, 141.12, 134.64, 133.43, 131.52, 128.99, 121.64, 51.09, 48.83, 38.70, 32.91, 30.94, 23.16, 21.99; Anal. Calcd. For C20H22N4O5: C, 60.29; H, 5.57; N, 14.06. Found: C, 60.09; H, 5.66; N; 14.15.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[C:25]([F:26])=[CH:24][C:13]2[O:14][C:15]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=3[CH:17]=[N:18][C:12]=2[CH:11]=1.C(OCC)C>C1(C)C(C)=CC=CC=1>[Br:9][C:10]1[C:25]([F:26])=[CH:24][C:13]2[O:14][C:15]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=3[C@H:17]3[C@H:2]([C:1]([OH:7])=[O:8])[CH2:3][CH2:4][C:5](=[O:6])[N:18]3[C:12]=2[CH:11]=1
Reactant: Fc1ccc2c(c1)Oc1cc(F)c(Br)cc1N=C2
Reactant: O=C1CCCC(=O)O1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Temperature: 150 °C

Procedure:
Glutaric anhydride (7.93 g, 69.5 mmol) was added to a stirred solution of 8-bromo-3,7-difluoro-dibenz[b,f][1,4]oxazepine (14.4 g, 46.4 mmol) in xylene (30 mL) and the mixture was heated to 150° C. for 72 h. The reaction mixture was allowed to cool to ambient temperature, and diethyl ether was added. The product was collected by filtration and dried to yield the title compound which was used without further purification (16.2, 82%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([F:13])([F:12])[F:1]
Reactant: Oc1ccc(C(O)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C(Cl)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (ice bath) mixture of 4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (4.3 g, 22 mmol) and anhydrous pyridine (1.8 ml, 22 mmol) in toluene was added thionyl chloride (SOCl2) (2.3 ml, 31 mmol) drop wise via a syringe. After stirred for 1 h at 0° C., the reaction was heated at 70° C. for 2 h. At this point, reaction did not go completion, indicated by LCMS. Heating was continued for 16 h. Reaction was quenched with ice water. The resulted mixture was diluted with EtOAc. The organic layer was washed with saturated Na2CO3, water and brine. After dried over Na2SO4, the solution was filtered and concentrated. The residue was purified on a silica gel column (5-10% EtOAc/hexane) giving the title compound as a light yellow oil. MS m/z: 21 1(M+1).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:11]([OH:15])(=[O:14])[CH:12]=[O:13]>CC(C)=O>[C:1]([NH:9][CH:12]([OH:13])[C:11]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(=O)O
Reactant: NC(=O)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(O)C(=O)O)c1ccccc1
Yield: 100 %

Procedure:
The titled compound 65 was prepared according to a procedure described by Zoller et al.209 A mixture of benzamide 35 (5.00 g, 41.3 mmol) and glyoxylic acid monohydrate 41 (4.32 g, 46.9 mmol) in anhydrous acetone (70 mL) was heated at reflux for 19 h. The reaction mixture was evaporated under reduced pressure to afford the desired product 65 as a colourless solid (8.06 g, 100%), m.p. 198-200° C. (lit.209 200-201° C. (dec)) Spectroscopic data indicated the crude product 65 did not require purification and was used directly in the subsequent reaction (Section 7.11.4). νmax (KBr): 3310 bs, 3058w, 1728s, 1646s, 1602w, 1582w, 1535s, 1491w, 1452w, 1315m, 1292w, 1254m, 1161m, 1097s, 1040m, 1002w, 957m, 805w, 770w, 728m, 692m, 654m, 609w, 515m, 483w cm−1. 1H n.m.r. (300 MHz, D6-DMSO): δ 5.60 (d, J=7.8 Hz, 1H, H2), 7.41-7.49 (m, 2H, H3′, 5′), 7.55 (m, 1H, H4′), 7.86-7.92 (m, 2H, H2′, 6′), 9.26 (d, J=7.8 Hz, 1H, NH), two exchangeable OH protons not observed. 13C n.m.r. (75 MHz, D6-DMSO): δ 71.7 (C2), 127.6, 128.3, 131.7 (Arom CH), 133.7 (C1′), 166.0, 171.5 (C1, CONH). Mass Spectrum (ESI+, MeOH): m/z 218.2 (M+Na)+, C9H9NNaO4 requires 218.2.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([O:21][C:22]([CH2:24][S:25][C:26]1[S:27][C:28]([SH:31])=[N:29][N:30]=1)=[O:23])[CH3:20].COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.N>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:31][C:28]3[S:27][C:26]([S:25][CH2:24][C:22]([O:21][CH2:19][CH3:20])=[O:23])=[N:30][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCOC(=O)CSc1nnc(S)s1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: CCOC(=O)CSc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 40 °C
Reaction time: 0.13 h
Yield: 92.8 %

Procedure:
A 8.0 ml portion of acetonitrile was added to 1.36 g of 7-ACA and 1.54 g of 2-ethoxycarbonylmethylthio-5-mercapto-1,3,4-thiadiazole, and the mixture was cooled to -40° to -30° C., followed by adding thereto dropwise 5.40 g of DCPA under stirring. The external bath was removed and the reaction mixture was stirred for 8 minutes, then warmed at 40° C. and stirred for 20 minutes to allow the reaction to proceed. The reaction solution was poured into 10 ml of ice-water, which was adjusted to pH 4.4 with 25% aqueous ammonia. The precipitated powder was recovered by filtration, washed with water and dried, thereby affording 2.08 g (92.7% of yield) of 7-amino-3-[(2-ethoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid in the form of mud yellow powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][C:42]([F:43])([F:44])[F:45])[C:38]=1[O:39][CH3:40])[C:33]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:34]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1OC(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (278 mg) and 37% formalin (0.18 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6.5 mL), and diisopropylethylamine (0.50 mL) and 3-chloro-4-methoxy-5-trifluoromethoxybenzoyl chloride (436 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (k).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(Cl)c1
Product: COc1cnc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
0.24 g of 5-(4-chlorophenyl)-4-(3-chloro-5-methoxy-2-pyridyl)-6-methyl -2H-pyridazin-3-one and 6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.12 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.07 g of 3-chloro-5-(4-chlorophenyl)-4-(3-chloro-5-methoxy-2-pyridyl) -6-methylpyridazine (hereinafter, described as compound (10) of the present invention.).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=O)=[CH:27]3)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=[C:10]2[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=4)[NH:3][C:2]2=[O:1])=[CH:27]3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCOCC4)ccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 73.7 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (27 mg, 0.12 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (30 mg, 0.11 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 90° C. for 2 hours. The reaction was cooled at 0° C. for overnight. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 38 mg (62%) of the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-fluorophenol (4.52 g, 40.29 mmol), 4-fluorobenzaldehyde (5.00 g, 40.29 mmol) and potassium carbonate (6.70 g, 48.35 mmol) in DMAC (40 mL) was refluxed for 12 h and cooled to room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccccc1

Procedure:
The title compound, MS: m/e=308.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and benzylbromide.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)=[CH:3]1
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.1 %

Procedure:
A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromene-8-carboxylic acid 35 (0.5 g, 1.5 mmol), 3-aminopyridine 36 (0.28 g, 3 mmol), HATU (1.14 g, 3 mmol) and DIPEA (0.78 g, 6 mmol) in DMF (4 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered and the solid was washed with H2O and dried under vacuum to give Compound 224 as a yellow solid (0.13 g, 23% yield). MS (ESI) calcd for C22H13F3N2O3: 410.09. found: 411 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: Nc1ccccc1
Product: Nc1ccc(C(=O)c2cc(F)ccc2F)cc1
Reaction time: 1 h
Yield: 209.6 %

Procedure:
To stirred 90° C. polyphosphoric acid (125 g) was added 2,5-difluoro-benzoic acid (10.0 g, 6.32 mmol) and aniline (5.87 g 6.3 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 50 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 45 mL of 3N HCl added, the mixture poured into 650 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the mixture filtered through a pad of Celite. The Celite pad was washed well with methylene chloride, the methylene chloride dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash column chromatography (methylene chloride) followed by recrystallization twice from 50% ethanol (80 mL) yielded the aniline as a yellow solid (3.08 g, 21%); mp 101°-103° C. 1H-NMR (300 MHz, CDCl3): 4.27 (s, 2H, NH2) 6.63-6.67 (m, 2H, aromatic) 7.09-7.19 (m, 3H, aromatic) 7.68-7.71 (m, 2H, aromatic). MS (CI, CH4): 234 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([NH:22][NH2:23])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:21][C:34](=[O:36])[NH:23][N:22]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)NN)c3c2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4n[nH]c(=O)o4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
To a solution of 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carbohydrazide (1 g, 3.2 mmol) in DCM (100 mL) and DIPEA (1.19 mL, 19 mmol) was added a solution triphosgene (1.1 g, 3.7 mmol) in DCM (3 mL) dropwise. The reaction was stirred at RT for 2 h, then the solution was concentrated in vacuo. The residue was purified with silica gel chromatography (eluting with 0-10% MeOH in DCM) to give 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (50 mg, 5%) as a white solid. MS (ESI, pos. ion) m/z: 338.0 (M+1); 1H NMR (DMSO-d6) δ ppm: 12.32 (s, 1H), 12.1 (s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 8.00-8.17 (m, 3H), 7.6 (d, J=8.4 Hz, 1H), 5.38-5.45 (m, 1H), 1.49 (d, J=6.0 Hz, 6H).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C@@H:6]1[CH2:28][C:27]2[C:29](=[O:30])[C:22](=[CH:23][C:24]([C:26]=2OC)=[O:25])[NH:21][C:19](=[O:20])[C:18]([CH3:33])=[CH:17][CH:16]=[CH:15][C@H:14]([O:34][CH3:35])[C@@H:13]([O:36][C:37]([NH2:39])=[O:38])[C:12]([CH3:40])=[CH:11][C@H:10]([CH3:41])[C@@H:9]([OH:42])[C@@H:8]([O:43][CH3:44])[CH2:7]1.[CH2:45]([NH2:48])[CH2:46][CH3:47].Cl>O>[CH3:47][CH2:46][CH2:45][NH:48][C:26]1[C:24](=[O:25])[CH:23]=[C:22]2[C:29](=[O:30])[C:27]=1[CH2:28][CH:6]([CH3:5])[CH2:7][CH:8]([O:43][CH3:44])[C@@H:9]([OH:42])[C@H:10]([CH3:41])[CH:11]=[C:12]([CH3:40])[CH:13]([O:36][C:37]([NH2:39])=[O:38])[CH:14]([O:34][CH3:35])[CH:15]=[CH:16][CH:17]=[C:18]([CH3:33])[C:19]([NH:21]2)=[O:20]
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Reactant: CCCN
Agent: CCCNC1=C2CC(C)CC(OC)[C@@H](O)[C@H](C)/C=C(\C)C(OC(N)=O)C(OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCNC1=C2CC(C)CC(OC)[C@@H](O)[C@H](C)C=C(C)C(OC(N)=O)C(OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 50 ml. of chloroform, 280 mg. of Geldanamycin was dissolved and then, 1 ml. of n-propylamine was added. The mixture was stirred at room temperature for 1 hour and the mixture was charged into 50 ml. of cold water and then, pH was adjusted 3 with 6 N-HCl. The chloroform layer was separated and the water layer was extructed with 50 ml. of chloroform. Both chloroform layers were combined and dehydrated over anhydrous sodium sulfate for 2 hours. Chloroform was distilled off under a reduced pressure to remain a reddish violet solid product. The solid product was recrystallized from acetone-n-hexane to obtain 286 mg. (yield 98%) of 17-n-propylamino-Geldanamycin as reddish violet acicular crystal.