Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([N:8]1[CH2:39][CH2:38][CH2:37][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][C:28]1[CH:36]=[CH:35][C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].NCC(O)=O.N[C@H](C(O)=O)C(C)C.[F:60][C:61]([F:66])([F:65])[C:62]([OH:64])=[O:63]>>[NH2:1][C@H:2]([C:6]([N:8]1[CH2:39][CH2:38][CH2:37][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[CH:35][CH:36]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5].[F:60][C:61]([C:62]([OH:64])=[O:63])([F:66])[F:65]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[C@H](N)C(=O)O
Agent: NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@H](C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
Boc-Val-Pro-Gly-Val-Gly-ONp (3.2 g, 4.93 mmol) prepared as described in Urry et al. (1975) J. Mol. Biol. 96, pp. 101-117, was dissolved in 99% trifluoroacetic acid (6 ml) and the mixture was treated in the same manner as described for the preparation of XI in part (j); yield 3.1 g (95%), m.p. 122-127° C., Rf1 0.13, Rf3 0.42. Calcd. for C27H37N6O10F3.1/2H2O: C, 48.29; H, 5.70; N, 12.51%. Found: C, 48.00; H, 5.86; N, 12.21%. Amino acid analysis: Pro, 1.00; Gly, 1.90; Val, 2.09.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C[C:13]1=O.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:25][CH2:24]1.NC1C=CC=CC=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:13][NH:39][C:36]3[CH:35]=[CH:34][C:33]([NH:32][CH2:31][CH2:30][CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:38][CH:37]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: CN1CCN(CCCNc2ccc(N)cc2)CC1
Solvent: Nc1ccccc1
Product: CN1CCN(CCCNc2ccc(NC=C3C(=O)Nc4cc(F)ccc43)cc2)CC1

Procedure:
The named compound is prepared by substituting 6-fluoro-1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (used for the preparation of Example 302) for aniline in the reaction of Example 1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH2:7][CH2:8][CH2:9]O.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[ClH:6].[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:9][CH2:8][CH2:7][Cl:6])[CH3:2]
Reactant: OCCCCl
Reactant: CCNCC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)CCCCl
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
10 ml toluene, 3 ml (28.9 mmol) of diethylamine and 2.9 ml (34.6 mmol) of 3-chloropropanol were added successively into a reaction flask, and the mixture was heated to the reflux temperature and reacted for 6 h. After cooling to room temperature, the mixture was washed with 5% NaOH solution and saturated saline solution, successively, and dried over anhydrous sodium sulfate, then filtered. 4.2 ml (57.7 mmol) of thionyl chloride was added dropwise into the filtrate in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated to dry in a reduced pressure and the residue was recrystallized with absolute ethyl alcohol to obtain 2.1 g white solid with the yield of 40%. m.p. 80-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]([C:13](N)=[O:14])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH2:16]>Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]([C:13]([OH:14])=[O:16])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC(C(N)=O)CO2
Reactant: O
Agent: Cl
Product: COc1cccc2c1OC(C(=O)O)CO2

Procedure:
8-Methoxy-1,4-benzodioxan-2-carboxamide (2.41 g.) in 50% hydrochloric acid (35 ml.) was stirred at 100° C. for 1 hour. The resulting solution was cooled, diluted with water (200 ml.), extracted with chloroform (3×100 ml.) then the extracts dried (MgSO4) and evaporated in vacuo. The solid residue (1.8 g.) was recrystallized from water (m.p. 75°-78° C.) then from ethyl acetate/hexane to give 8-methoxy-1,4-benzodioxan-2-carboxylic acid, m.p. 131°-132° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH3:19])=[CH:21][CH:22]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Cc1ccc(N)cc1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-methyl-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 115-117° C. (diethylether)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:3]1[N:2]([CH3:1])[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2[nH]c(=O)n(C)c12
Product: COC(=O)c1cccc2nc(Cl)n(C)c12
Yield: 81 %

Procedure:
A solution of 2.00 g (9.70 mmol) of methyl 1-methyl-2-oxo-1,3-dihydro-2H-benzimidazole-7-carboxylate in 20 mL of phosphorous oxychloride was heated at 100° C. for 6 h. The reaction was concentrated in vacuo and the thus obtained residue was quenched with water and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The thus obtained residue was purified via flash chromatography eluting with a solution of 20% ethyl acetate/hexanes to give 1.77 g (81%) of the title compound as white solids.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].C(N(CC)CC)C>CCO>[CH2:25]([O:24][C:22](=[O:23])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1)[CH2:26][CH3:27]
Reactant: COc1ccc(-n2cc(C#N)c3ccc(N)cc32)cc1
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCOC(=O)Nc1ccc2c(C#N)cn(-c3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), was suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol) was added, and this mixture was stirred at room temperature overnight. The addition of triethylamine (300 μL), followed by another hour of stirring at room temperature, completed the reaction. This reaction mixture was loaded directly onto a silica column, and was eluted with CH2Cl2. Another silica column (3/2, ether/hexanes) was needed to fully purify the product, [3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:34]I.O>CN(C=O)C>[CH3:34][N:15]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:18])[N:13]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[C:14]1=[O:31]
Reactant: CI
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (100 mg) was dissolved in DMF (4 mL), and sodium hydride (60%, in oil) (10 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, methyl iodide (37 mg) was added at 0° C., and the mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction solution, and separated out white precipitates were filtered. Further recrystallization using hexane:ethyl acetate=1:1 afforded 64 mg of white crystals.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:12])[CH3:11].[OH-].[K+].Cl>O>[CH2:10]([O:12][C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=1)[C:11]#[C:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCO
Reactant: O=C([O-])c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCC#CC#CCOc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
In a flask were placed 4.0 g (0.014 mole) of the benzoate derivative obtained and 18 ml of ethanol and while stirring the mixture at room temperature, an aqueous solution composed of 2.0 g (0.36 mole) of potassium hydroxide and 20 ml of water was added to the mixture. After stirring the mixture for 24 hours at 40° C. Twenty (20) ml of water was added to the mixture followed by ice-cooled. When the reaction mixture was acidified with concentrated hydrochloric acid, white crystals formed. The crystals were recovered by filtration, washed with water, and dried. Thus, 3.2 g (yield 89.3%) of the desired product could be obtained. The melting point was 165°-166° C.
Reaction SMILES: [O:1]=[C:2]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[CH2:3][CH2:4][C:5]([OH:7])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.N1NC(CCC(O)=O)=C2C=1CCCC2.ClC1C=CC(C2CCNCC2)=CC=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]3=[O:14])[CH2:24][CH2:23]2)=[CH:20][CH:21]=1
Reactant: O=C(O)CCC(=O)C1CCCCC1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Clc1ccc(C2CCNCC2)cc1
Agent: O=C(O)CCc1[nH]nc2c1CCCC2
Product: O=C1CCCCC1C(=O)CCC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 102.8 %

Procedure:
4-Oxo-4-(2-oxocyclohexyl)-n-butyric acid (4.0 g) and 1-(4-fluorophenyl)piperazine (3.6 g) were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Example 102 and 4-(4-chlorophenyl)piperidine, 7.4 g of 4-(4-fluorophenyl)-1-(4-oxo-4-(2-oxocyclohexyl)butyryl)piperazine was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH:37]=O)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([O:7]C)=[O:6].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][S:50](=[O:54])(=[O:53])[CH2:49][CH2:48]1>>[O:53]=[S:50]1(=[O:54])[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][CH2:44][NH:43][CH2:37][C@:21]23[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]2[C@@H:23]2[C@@:18]([CH3:39])([CH2:19][CH2:20]3)[C@@:17]3([CH3:40])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:41])([CH3:42])[C:12]([C:11]3[CH:10]=[CH:9][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[F:1])=[CH:29][CH2:28]4)[CH2:25][CH2:24]2)[CH2:52][CH2:51]1
Reactant: NCCCN1CCS(=O)(=O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following steps 5 and 6 using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (70 mg, 68.0%). LCMS: m/e 737.5 (MH+), 2.59 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.8 Hz, 1H), 7.19-7.31 (m, 1H), 5.38 (d, J=4.8 Hz, 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.41 (br. s., 4H), 3.30-3.38 (m, 4H), 3.27 (d, J=12.5 Hz, 1H), 3.21 (br. s., 2H), 3.00 (t, J=6.4 Hz, 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.10 (br. s., 4H), 1.84 (br. s., 3H), 1.75 (br. s., 7H), 1.54 (br. s., 8H), 1.36 (br. s., 3H), 1.20 (br. s., 5H), 1.11 (br. s., 3H), 1.07 (br. s., 3H), 0.98 (br. s., 3H), 0.94 (br. s., 3H). 19F NMR (376 MHz, MeOD) δ ppm −113.31 (s, 1 F).
Reaction SMILES: C([O:4][C:5](=[O:9])[CH2:6][C:7]#N)CC.C[O:11]C(=O)CCC(O)=O.CN[C:21](=[O:24])[CH2:22][CH3:23]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH2:21]([O:24][C:7](=[O:11])[CH2:6][C:5]([OH:4])=[O:9])[CH2:22][CH3:23]
Reactant: COC(=O)CCC(=O)O
Reactant: CCC(=O)NC
Reactant: CCCOC(=O)CC#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCCOC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 10-mL volumetric flask was added 0.1271 g (1.00 mmol, 0.100 M) of cyanoacetic acid propyl ester, 9.689 mL of potassium phosphate buffer (50 mM, pH 7.0), and 0.20 mL of a 50 wt % cell suspension (0.10 g wet cell weight, 0.024 g dry cell weight) of Acidovorax facilis 72W (ATCC 55746) cells in 0.35 M potassium phosphate buffer (pH 7.0, previously heat-treated at 50° C. for 1h), and the resulting 10 mL suspension stirred at 25° C. Samples (0.180 mL) were mixed with 0.020 mL of 0.750 M N-methylpropionamide (HPLC external standard solution). The resulting solution was analyzed by HPLC. After 5 h, the conversion of cyanoacetic acid propyl ester was complete, and the yield (determined by HPLC and NMR) of propanedioic acid monopropyl ester was 100%, with no production of cyanoacetic acid or propanedioic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([NH:7][N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=1)[CH:9]([CH3:11])[CH3:10])=[O:6].[C:35]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH:9]([N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=1)[NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][CH:34]=[C:2]([O:1][CH3:35])[CH:3]=1)([CH3:11])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Temperature: 85 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in anhydrous acetonitrile (10.0 ml), iodomethane (0.0673 ml, 1.08 mmol) was added drop-by-drop at 0° C. The reaction mixture was refluxed for 12 hr at 85° C. After concentration under reduced pressure, the solution was separated through the silica gel chromatography (30% EtOAc) so that ivoty solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (43.5 mg, 42.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[N+:27]([O-])([O-:29])=[O:28].[K+]>ClCCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:27]([O-:29])=[O:28])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Product: O=C(O)c1cc(Oc2cc(C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The acid from (b) (2.0 g) was added to a mixture of concentrated sulphuric acid (15 ml) and 1,2-dichloroethane (10 ml) kept at 0°. Potassium nitrate (1.2 g) was then added in portions with stirring over a period of 30 minutes, keeping the temperature at 0°. The mixture was stirred for a further hour at 0° and then for 3 hours at room temperature. The mixture was then poured on to ice and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give a dark gum. This was extracted several times with boiling cyclohexane. The residue crystallised on cooling and was identified as the required nitro-acid, with a melting point of 147°-148°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)C#N.C[Mg]Br.CCCCCC.CC[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:22](=[O:21])[CH3:23])[CH:7]=[CH:8][N:9]=1
Reactant: N#Cc1ccnc(F)c1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: CCCCCC
Product: CC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoroisonicotinonitrile (10 g, 82 mmol) in anhydrous Et2O (250 mL) cooled in an ice-H2O bath was slowly added 3M methyl magnesium bromide in hexane (40 mL, 120 mmol). The mixture was stirred at 25° C. overnight. The reaction was quenched slowly with 1N aq. citric acid solution at 0° C. until all solids dissolved. Brine was added and the two phases were separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1-(2-fluoropyridin-4-yl)-ethanone (6.2 g) as a brown oil. The aqueous phase was stirred at 25° C. for 3 h, then extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4, filtered, and concentrated in vacuo to give an additional 1.1 g of the product, for a total of 7.3 g, used in the next step without further purification: EIMS m/z 139 ([M]+). 1H NMR (CDCl3): δ 8.25 (dd, 1H), 7.47 (d, 1H), 7.21 (m, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:4].Cl.Br[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:3]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:4]
Reactant: O=C(NCc1nnc(-c2ccc(O)cc2)s1)C(O)CCCCCCc1ccccc1
Reactant: BrCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1nnc(-c2ccc(OCc3ccncc3)cc2)s1)C(O)CCCCCCc1ccccc1

Procedure:
A solution of 4-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)phenol (1.74 mmol), 2-hydroxy-8-phenyloctanoic acid (1.74 mmol), HOBt (2.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.1 mmol) and DIPEA (6.94 mmol) in DMF (4 mL) was stirred at room temperature overnight. The resulting mixture was diluted with NaHCO3 (saturated) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The resulting residue was purified by chromatography (silica gel, methanol-CH2Cl2) to yield 2-hydroxy-N-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)-8-phenyloctanamide. A solution of 2-hydroxy-N-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)-8-phenyloctanamide (0.18 mmol), 4-bromomethypyridine hydrochloride (0.26 mmol), and potassium carbonate (0.53 mmol) in DMF (4 mL) was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated to yield 2-hydroxy-8-phenyl-N-((5-(4-(pyridin-4-ylmethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)octanamide, which was used in the next step without purification. To a solution of 2-hydroxy-8-phenyl-N-((5-(4-(pyridin-4-ylmethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)octanamide (0.16 mmol) in CH2Cl2 (5 mL) was added the Dess-Martin periodinane (0.23 mmol). The resulting mixture was stirred overnight, then quenched with an excess of a solution of sodium thiosulfate in saturated NaHCO3 (aqueous). The mixture was then extracted twice with ethyl acetate and the combined extracts were washed with brine, dried (Na2SO4) and concentrated. The resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C1COCC1>[C:1]([NH:5][S:17]([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)(=[O:18])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)Cl)cc1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
To a solution of tert-BuNH2 (15.6 mL, 148 mmol) in THF (50 mL) at 0° C., 2-(4-nitro-phenyl)-ethanesulfonyl chloride (WO 2006010079, 1.9 g, 7.6 mmol) was added portionwise. The resulting mixture was stirred for 24 h at RT. The solvent was removed in vacuo and the residue was taken up in DCM (50 mL) and cold 0.5 N HCl (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated to obtain 2-(4-nitro-phenyl)-ethanesulfonic acid tert-butylamide (1.3 g, 62%) which was used directly without further purification.
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[CH2:7]([S:9][CH:10](SCC)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:8]>CCOCC>[CH2:7]([S:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:8]
Reactant: CCCCCCCCCCCCCCCCCC(SCC)SCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCC=CSCC
Temperature: 195 °C

Procedure:
Potassium bisulfate (4 g.) is added to 1,1-di(ethylthio)-octadecane (20 g.) and the resulting mixture is heated under vacuum (200-250 mm.) at 195° C for 6 hrs., cooled to room temperature and dissolved in ether (100 ml.). The ether solution is washed with aqueous sodium bicarbonate and water and then dried over MgSO4. The solvent is removed and the residue is distilled twice to afford 1-ethylthio-1-octadecene (b.p. 181°-183°, 0.8 mm.) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16]([CH3:17])=[O:31])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)O)cc1Cl
Reaction time: 5 h

Procedure:
In DCM (20 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylic acid (200 mg, 0.59 mmol). The solution was cooled in an ice bath and m-CPBA (101 mg, 0.59 mmol) was added. The reaction was conducted at ambient temperature for 5 h, followed by addition of water and extraction with DCM. The organic phase was dried and concentrated to give a solid which was used in the subsequent procedure without further purification.