Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](/[C:15](/[CH3:22])=[CH:16]/[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:30](=[NH:39])OCC1C=CC=CC=1>O>[CH:30]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1/[CH:16]=[C:15](/[C:7]1[CH2:6][C@@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([OH:14])=[O:13])\[CH3:22])=[NH:39]
Reactant: N=COCc1ccccc1
Reactant: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C/C(=C\[C@@H]1CCCN1C=N)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@@H]2C1
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (0.48 g) in water (30 ml) was adjusted to pH 8.5 with aqueous potassium carbonate at 0° C. and benzyl formimidate hydrochloride (2.7 g) was added in portions while adjusting around pH 8.5 with addition of aqueous potassium carbonate. After stirring for 15 minutes at pH 8.5, the reaction mixture was washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (50 ml) eluting successively with water and 3% aqueous acetone. The fractions containing the desired compound were collected and lyophilized to give (5S,6S)-3-[(E)-2-{(2S)-1-formimidoylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept- 2-ene-2-carboxylic acid (170 mg).
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:46]([N:53]=[C:54]=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC#N>[CH:41]1([N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:54]([NH:53][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:55])[CH2:20][NH:19][CH2:24]2)=[O:44])[CH2:42][CH2:43]1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)NCc3ccccc3)C2)C2CC2)ccc1C

Procedure:
The title compound is prepared analogously as described in Example 98 using (3R*,5S*)-3-amino-5-{cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 98A.) and benzylisocyanate. MS: 509.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.22 min.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O>CN(C=O)C.O>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1
Reactant: FC(F)(F)CS
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
2,2,2-Trifluoroethane-1-thiol (471 μL, 3.41 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in dry DMF (10 mL) at 0 C and the mixture was stirred for 15 min. A solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (prepared in an analogous manner to Intermediate 181, 1 g, 3.41 mmol) in DMF (5 mL) was added dropwise and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated aq. sodium bicarbonate (25 mL) then brine (25 mL), dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a light yellow oil (1.13 g, quant.). Method B HPLC-MS: MH+ requires m/z=314 Found: m/z=258 (MH+-tBu), Rt=2.39 min (98%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CCC.C[O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:19]2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[OH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(-n2nc(-c3ccccc3)c3cccnc32)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCS
Product: Oc1cccc(-n2nc(-c3ccccc3)c3cccnc32)c1
Temperature: 0 °C
Yield: 101.8 %

Procedure:
In 400 ml of dichloromethane was suspended 45.1 g of anhydrous aluminium chloride. While stirring, 45.1 ml of butylmercaptan was added thereto. After the mixture was stirred at room temperature for 1 hour, 34 g of 1-(3-methoxy- phenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine was added under ice-cooling. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into about 2 l of ice-water. The resulting crystals were collected by filtration, and washed with water to give 33.0 g of 1-(3-hydroxy- phenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine, m.p. 142°-144° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:11][C:9](=O)[C:6](=CO)[C:4](=[O:5])[O:3]1.[CH3:13]C(C1C(=O)OC(C)(C)OC1=O)=O>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[CH3:12][C:2]1([CH3:1])[O:3][C:4](=[O:5])[CH:6]=[C:9]([CH3:13])[O:11]1
Reactant: CC1(C)OC(=O)C(=CO)C(=O)O1
Reactant: CC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CC1=CC(=O)OC(C)(C)O1

Procedure:
The derivatives have not heretofore been known at all, but for the first time the present inventors have found a process for producing 2,2-dimethyl-1,3-dioxin-4-one as a compound belonging thereto. Namely, according to the process reported by the present inventors in Chem. Pharm. Bull. 31, (6) 1896 (1983), 2,2-dimethyl-1,3-dioxin-4-one was obtained from formyl Meldrum's acid in the presence of acetone and using a small amount of toluene or xylene as solvent, with a yield of 31%. This formyl Meldrum's acid seems to have a higher reactivity than that of similar acetyl Meldrum's acid. That is, in the case of the latter acid, its thermal decomposition yielded 2,2,6-trimethyl-1,3-dioxin-4-one, whereas in the case of the former acid, its mere heating in the absence of solvent formed only a resinous substance without yielding 2,2-dimethyl-1,3-dioxin-4-one, but when the former acid was heated in a xylene solvent containing acetone, the compound was obtained for the first time. However, its yield was not only low (yield: 31% as described above), but the loss of the raw material acid due to the resin formation was so great that the recovery of the raw material was impossible.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1-c1ccccc1
Temperature: 160 °C
Yield: 75.2 %

Procedure:
2-Bromobenzaldehyde (315 μL, 2.70 mmol), phenylboronic acid (395 mg, 3.24 mmol), Pd(PPh3)4 (31 mg, 0.027 mmol) and Na2CO3 (430 mg, 4.05 mmol) were dissolved in N,N-dimethylformamide (20 mL) in a reaction vessel and refluxed at 160° C. for 6 hours. After the reaction was completed, the reaction mixture was diluted with EtOAc and saturated NaHCO3 solution was added. The organic layer obtained by extracting the aqueous layer with EtOAc was dried with anhydrous MgSO4 and then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography (hexane:diethyl ether=8:1) to obtain 369 mg of the target compound (2.03 mmol, 75.0%).
Reaction SMILES: Cl.C([C:4](=[NH:11])[CH2:5][C:6](OCC)=[O:7])C.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH2:25].C([O-])(=O)C.[Na+].[Na]>CO.O.C(O)(=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]1[C:6](=[O:7])[CH:5]=[C:4]([NH2:11])[NH:25]1
Reactant: COC(=O)c1cc(Cl)c(NN)c(Cl)c1
Reactant: CCOC(=O)CC(=N)CC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(-n2[nH]c(N)cc2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 27.5 g of ethyl β-ethyl-β-iminopropionate hydrochloride, 30 g of 2,6 -dichloro-4-methoxycarbonylphenylhydrazine [Intermediate (h) as in Method (a) in Syntheses Example 1-(1)] and 11.5 g of anhydrous sodium acetate in 100 ml of methanol as stirred at room temperature for 2 hours. A solution containing 7 g of metallic sodium dissolved in 70 ml of methanol was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. After adding 60 ml of acetic acid, the reaction mixture was poured into 1 liter of water. The crystals formed were collected and recrystallized from acetonitrile to obtain 21 g of 1-(2,6 -dichloro-4-methoxycarbonylphenyl)-3-amino-5-pyrazolone having a melting point of 225°-229°C.
Reaction SMILES: OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.C(=O)([O-])[O-].[K+].[K+].[I:19][C:20]1[C:29]([C:30]([NH:32][CH3:33])=[O:31])=[C:28]([I:34])[C:27](N=C=O)=[C:26]([I:38])[C:21]=1[C:22]([NH:24][CH3:25])=[O:23]>CN(C)C=O>[I:19][C:20]1[C:21]([C:22]([NH:24][CH3:25])=[O:23])=[C:26]([I:38])[CH:27]=[C:28]([I:34])[C:29]=1[C:30]([NH:32][CH3:33])=[O:31]
Reactant: CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NC)c1I
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(I)cc(I)c(C(=O)NC)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A slurry of glucosamine (0.591 g.; 0.0033 mole) and potassium carbonate (1.242 g.; 0.009 mole) in dimethylformamide (30 ml.) was heated rapidly to 75° C. (to dissolve the glucosamine) and quickly cooled in an ice bath to 25° C. 2,4,6-Triiodo-5-isocyanato-N,N'-dimethylisophthalamide (IV; 1.83 g.; 0.003 mole) dissolved in dimethylformamide (9 ml.) was added dropwise over a five minute period. After being stirred overnight at room temperature, the reaction mixture was filtered and concentrated to a foam under reduced pressure employing a 50° C. water bath. The residue was dissolved in water (24 ml.), and the aqueous solution was adjusted to pH 1 with concentrated hydrochloric acid. The solution was extracted with aqueous 90% phenol (4×10 ml.). The combined phenolic layers were washed with water (4×10 ml.), diluted with ether (120 ml.) and extracted with water (4×10 ml.). The combined aqueous extracts were washed with chloroform-isopropyl alcohol (3/1; 10×40 ml., contact time 15 min.). The aqueous solution was evaporated under reduced pressure at 40° C. (water bath) to give 5-{3-[3-D-gluco-2-deoxy-3,4,5,6-tetrahydroxy-1-oxohexyl)]ureido}-2,4,6-triiodo-N,N'-dimethylisophthalamide (V) as a colorless foam, 1.3 g. (55% yield), m.p. 175°-230° C. (dec.). The infrared and nuclear magnetic resonance spectra were consistent with the assigned structure. The material was homogeneous by thin-layer chromatography (chloroform-methanol-trimethylamine, 65:35:5; and ethanol-concentrated ammonium hydroxide, 50:50), and the aqueous solubility was determined to be 2.7-8% depending upon the method employed.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:30]=[C:29]2[CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>C(OCC)(=O)C.O.CN1CCCC1=O>[CH3:12][C@H:11]1[C:3]2[C:2]([N:42]3[CH2:41][CH2:40][CH:39]([C:29]4[N:28]([CH2:27][CH2:26][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH:32]=[C:31]([CH:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[N:30]=4)[CH2:44][CH2:43]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1
Reactant: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C5CCOCC5)cn4CCN4CCCC4)CC3)c21
Temperature: 110 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
Combine (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (15.69 g, 1.2 eq), triethylamine (10.14 mL, 1.1 eq), 4-[1-(2-pyrrolidin-1-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-1H-imidazol-2-yl]-piperidine (22 g, 66.17 mmol) and N-methylpyrrolidinone (66 mL). Stir at 110° C. for 16 hours, then allow to cool to room temperature. Dilute with ethyl acetate (110 mL) and water (220 mL). Add 5 M aqueous sodium hydroxide to adjust the pH to 12. Extract with ethyl acetate (2×200 mL). Wash the organics with saturated aqueous sodium chloride. Add water (220 mL) to the organics and aqueous 85% phosphoric acid to adjust the pH to 3. Wash the resulting acidic aqueous layer with ethyl acetate (2×100 mL). Add 5 M aqueous sodium hydroxide to adjust the pH to 12. Extract with ethyl acetate (3×70 mL). Wash the organics with saturated aqueous sodium chloride (50 mL). Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give the final compound as a light brown solid (21.5 g, 64%). MS (ES) m/z=494 [M]+.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[H+].Cl[Au-:17](Cl)(Cl)Cl.[Cl-].[NH4+]>O>[Au:17].[N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Au-](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [H+]
Agent: [NH4+]
Solvent: O
Product: [Au]
Temperature: 60 °C

Procedure:
0.5 g of 1,10-phenanthroline (made by Wako Pure Chemical Industries, Ltd.) and 80 ml of distilled water were put in a 300-ml glass-made reaction vessel equipped with a reflux condenser, and the mixture was heated at 60° C. to dissolve the phenanthroline and cooled to room temperature. While the solution was stirred, a solution obtained by dissolving 1 g of tetrachloroauric acid (III) tetrahydrate in 17.2 ml of distilled water was gradually added dropwise over a period of 30 minutes. After completion of the dropwise addition, the temperature was raised to 110° C., the mixture was refluxed for 5 hours, and, then, 150 g of ammonium chloride was added to the resulting reaction solution to deposit orange powder. The deposited powder was filtered, washed with cold methanol and then with cold diethyl ether, and then dried to obtain 0.79 g of a gold-phenanthroline complex (hereinafter abbreviated as [Au(phen)Cl2]+Cl—).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([O:17]CC)=O)[CH:12]=[CH:11][C:9]=2[CH:10]=1.[CH3:20][NH:21][CH3:22].[O-]CC.[Na+]>C(O)C>[CH3:20][N:21]([CH3:22])[C:15]([C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[O:7][C:8]=2[CH:14]=1)=[O:17]
Reactant: CCOC(=O)c1ccc2cc(CCCCN)oc2c1
Reactant: CNC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)C(=O)c1ccc2cc(CCCCN)oc2c1

Procedure:
A solution of ethyl 2-(4-aminobutyl)benzofuran-6-carboxylate (13.0 g., 0.05 mole), dimethylamine (35 g.), and a catalytic amount of sodium ethoxide (approximately 100 mg.) in ethanol (100 ml.) is heated in a sealed pressure bottle at 65° C. for 18 hours. Evaporation of the solvent provides N,N-dimethyl-2-(4-aminobutyl)benzofuran-6-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]=[C:20]=[O:21])=[CH:14][C:13]=1[Cl:22].CCCCCC>C1COCC1>[Cl:22][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[Cl:11])[CH2:18][NH:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[O:21]
Reactant: Nc1cccc2[nH]ccc12
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1cccc2[nH]ccc12

Procedure:
4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.25 g of the title compound as a tan solid. mp 201° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0 (dd, 1H), 7.25 (m , 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H, 3.68; N, 11.97.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:20]1[C:28]2[C:23](=[CH:24][C:25](Cl)=[CH:26][CH:27]=2)[NH:22][N:21]=1)=O)(C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:20]2[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][N:21]=2)=[CH:10]3)=[O:18])[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2n[nH]c3cc(Cl)ccc23)cc2cc(C(=O)O)ccc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3[nH]c(-c4n[nH]c5ccccc45)cc3c2)CC1

Procedure:
A solution of 1-(tert-butoxycarbonyl)-2-(1H-indazol-3-yl)-1H-indole-5-carboxylic acid (4-5, 100 mg, 0.265 mmol), N-methyl piperazine (40 μL, 0.32 mmol), EDC (61 mg, 0.32 mmol), and HOAt (43.3 mg, 0.32 mmol)in 5 ml of DMF was treated with triethylamine (90 μL, 0.66 mmol) and mixed for 24 h. The solution was partitioned between ethyl acetate (3×50 mL) and water (75 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residual oil was dissolved in a 1:1 mixture of dichloromethane/trifluoroacetic acid and mixed for 45 min. The solvent was removed in vacuo and the residue was purified by reverse phase liquid chromatography (H2O/CH3CN gradient with 0.1% 1TFA present) to provide 3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}-1H-indazole (4-6); 1H NMR (500 MHz, CD3OD) δ 11.36 (s, 1H), 8.14 (d, 1H, J=8.3 Hz), 7.83 (s, 1H), 7.58 (dd, 2H, J=8.5 Hz), 7.45 (t, 1H, J=8.3 Hz), 7.30 (dd, 2H, J=8.06 Hz), 7.17 (s, 1H), 4.55 (bs, 2H), 3.45 (bs, 2H), 3.25 (bs, 2H), 2.98 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=2)[CH2:10][CH:11](C(OC)=O)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Li+]>O.CS(C)=O>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1cccc(-c2ccccc2)c1
Temperature: 165 °C
Yield: 80.7 %

Procedure:
A mixture of dimethyl (m-phenylbenzyl)malonate (1.00 g) and lithium chloride (0.285 g) in water (0.12 ml) and dimethylsulphoxide (8.5 ml) was heated at 165° C. for 3 hours then allowed to cool, poured into water and extracted with ether. The extracts were washed with water, dried, concentrated, and chromatographed using 10% ether in petrol as eluant to give methyl 3-(m-phenylphenyl)propanoate (0.65 g, 81%) as a colourless oil which solidified on standing, melting point 29°-30° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH:15][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(OC)c(NC(=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of phenylacetyl chloride (1.07 g, 6.6 mmol) in dry benzene (7 ml) was added drop by drop for 10 minutes to a cooled solution of 2,5-dimethoxyaniline (1 g, 6.5 mmol) in dry benzene (7 ml). The reaction mixture was agitated at room temperature for 1 hour and then the reaction was stopped with cold 24% aqueous sodium carbonate (10 ml.) After vigorously agitating the two-phase system for 30 minutes, the benzene layer was separated and the aqueous phase was extracted with ether (3×50 ml). The combined organic layers were dried over sodium sulfate and evaporated and the residue was crystallized from petroleum ether, yielding 1.61 g 91%) of N-(2',5'-dimethoxyphenyl)-2-phenylacetamide. m.p. 85° C. (petroleum ether).
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:22](=[O:23])[CH2:21][C:20]([CH3:26])([CH3:25])[CH3:19])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]1)=[O:23]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C1COCCOCCNCCOCCOCCN1
Product: CC(C)(C)CC(=O)N1CCOCCOCCN(C(=O)CC(C)(C)C)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:23])([F:24])[F:25])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:4]
Reactant: NCCCO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCCO)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), 3-aminopropan-1-ol (10.47 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were dissolved in DMF (1 mL). It was stirred for 20 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.1 min) to provide (R/S)-2-hydroxy-N-(3-hydroxypropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.032 mmol, 34.4% yield): LCMS=488.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.42-8.50 (1 H, m), 8.12 (2 H, dd, J=8.57, 3.30 Hz), 7.51-7.73 (7 H, m), 5.11 (1 H, s), 3.58 (2 H, t, J=6.15 Hz), 3.35 (2 H, t, J=6.81 Hz), 1.74 (2 H, quin, J=6.59 Hz); HPLC peak RT=6.8 min (Method A).