Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].O[NH:38]/[C:39](=[N:56]\[H])/[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([C:27]2[O:29][N:56]=[C:39]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43]4)[N:38]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])#[N:23]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: [H]/N=C(\NO)c1ccc2[nH]c(CCC(=O)OCC)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
EDCI (187 mg) and HOBT (149 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (100 mg) in THF (5 mL). The mixture was stirred at room temperature for 1 hour followed by addition of ethyl 3-{5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (201 mg). The resulting mixture was stirred at room temperature for 2 hrs followed by addition of TBAF (510 mg). The reaction vessel was sealed and heated in Biotage Initiator to 120° C. for 2 hrs. After cooling the reaction, THF was removed. The residue was dissolved in EtOAc. The organic solution was washed with saturated aqueous sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D114) (68 mg). The product was directly used in the next step without identification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH:24]=[O:25].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([CH:24]([C:23]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:22]=2[F:21])[OH:25])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Clc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: OC(c1cc(F)ccc1F)c1cc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10 mmol) was added n-butyl lithium (6.3 ml, 1.59M hexane solution) at −78° C. After stirring for 10 minutes, 2,5-dichloropyridine (1.48 g, 10 mmol) was added. Thirty minutes later, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added to the mixture. The resulting mixture was warmed gradually to 0° C. and stirring was conducted for further 10 minutes. An aqueous solution of ammonium chloride was added and the mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, washed with brine and dried. After filtration, the filtrate was concentrated under reduced pressure. The precipitate thus obtained was triturated with ethanol to yield the title compound (1.93 g, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 80 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide (1 g, 3.86 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 2,4-Difluorophenylboronic acid (0.727 g, 4.63 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.627 g, 0.769 mmol, 0.2 eq.) and aqueous sodium carbonate (1.22 g, 11.5 mmol, 3.0 eq.) were added sequentially and the mixture was further degassed for 5 min and then heated at 90° C. for 2 h. The mixture was quenched with water and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the crude residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 80% yield (0.9 g). 1H NMR (300 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.7-8.69 (m, 1H), 8.16 (d, 1H), 8.04 (s, 1H), 7.8-7.67 (m, 1H), 7.53 (m, 1H), 7.34 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: CC1(C)OC(=O)[C:5](=[CH:9][NH:10][C:11]2[S:15][C:14]([CH2:16][CH2:17][CH3:18])=[N:13][CH:12]=2)[C:4](=O)[O:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:16]([C:14]1[S:15][C:11]2[NH:10][CH:9]=[CH:5][C:4](=[O:3])[C:12]=2[N:13]=1)[CH2:17][CH3:18]
Reactant: CCCc1ncc(NC=C2C(=O)OC(C)(C)OC2=O)s1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1nc2c(=O)cc[nH]c2s1
Yield: 82.8 %

Procedure:
The product of Example 5E (230 mg, 0.7781 mmol) was added to refluxing diphenyl ether (5 mL) under a nitrogen atmosphere. After refluxing for 5 minutes, the solution was cooled in an ice bath and diluted with hexanes (50 mL). The resulting golden solid was collected by vacuum filtration and thoroughly washed with hexanes to give the title compound (125 mg, 0.644 mmol, 83%).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CCCCCC>[CH3:1][C:2]([O:11][C:18](=[O:25])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4]
Reactant: CCCCCCC(C)(O)CC
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCC(C)(CC)OC(=O)C1CCCCC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
36 G. (0.25 mole) of 3-methylnonan-3-ol, 20 g. of pyridine and 60 ml. of hexane are combined and cooled to 5° C. under agitation. To the resulting solution is added, under agitation over a period of 1 to 2 hours while maintaining the reaction temperature between 5°-15° C. a solution of 37 g. (0.25 mole) hexahydrobenzoyl-chloride dissolved in 60 ml. of hexane. The source of cooling is removed and the reaction mixture is agitated overnight, permitting the temperature of the reaction mixture to rise to room temperature (25°-30° C.). After completion of the reaction, the formed pyridine hydrochloride is removed by successive washings with 100 ml. portions of warm water. The solvent is removed by distillation and the desired ester is rectified by fractional distillation in a vacuum, preferably at 1 mm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:25]=[O:26])=[C:20](B(O)O)[CH:21]=1>COCCOC.O.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:19]([CH:25]=[O:26])=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Reactant: Brc1ccc(Br)cc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 52.1 %

Procedure:
A solution of 1,4-dibromobenzene (8.3 g, 35.3 mmol), potassium carbonate (11.3 g, 81 mmol) and 5-chloro-2-formylphenylboronic acid (5 g, 27.1 mmol) in DME (150 mL) and water (30 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(PPh3)4 (0.94 g, 0.814 mmol) was added and the reaction heated to 80° C. overnight. The reaction was cooled to r.t. and evaporated on the rotovap. The residue was diluted in EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (0-15% EtOAc:Hex) to give 4′-bromo-5-chlorobiphenyl-2-carbaldehyde (4.17 g, 14.11 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.28 (m, 2H) 7.42 (d, J=2.01 Hz, 1H) 7.50 (ddd, J=8.41, 2.01, 0.88 Hz, 1H) 7.59-7.69 (m, 2H) 7.98 (d, J=8.53 Hz, 1H) 9.92 (s, 1H).
Reaction SMILES: N1CC[O:4]CC1.[Li]CCCC.CCCCCC.Br[C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22].[N+](C1C=CC=CC=1)([O-])=O.Cl>C1COCC1>[OH:4][C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: COc1cc(C=O)c(Br)c(OC)c1
Reactant: C1COCCN1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O=[N+]([O-])c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C=O)c(O)c(OC)c1
Temperature: -50 °C
Reaction time: 0.58 h

Procedure:
Morpholine (2.05 g, 24 mmol) and THF (40 mL) were placed in a three-necked, round bottomed flask equipped with a stirring bar, septum cap, dropping funnel, thermometer, and argon inlet. The flask was cooled in a dry ice-acetone bath to −50° C., and a solution of n-BuLi in hexane (1.6M, 15 mL, 24 mmol) was added all at once. After 10 min a solution of 1 (4.9 g, 20 mmol) in THF (30 mL) was added dropwise via a syringe over a period of 4 min, and the mixture was cooled to ˜−75° C. over 20 min. n-BuLi in hexane (1.6M, 20 mL, 32 mmol) was then added dropwise over 45 min, keeping the temperature at −75° C. After complete addition of n-BuLi the solution was stirred for 35 min. A solution of nitrobenzene (6.90 g, 46 mmol) in 10 mL THF was added from the dropping funnel, keeping the temperature at −75° C. The resulting dark mixture was stirred at −75° C. for 4 h and then allowed to warm to room temperature. It was acidified to pH 1 with 6N HCl and stirred for 15 min. After dilution with brine (100 mL), THF was removed in vacuo. The aqueous solution was extracted with diethyl ether (4×40 mL). The combined organic layers were extracted with 2 N NaOH (3×40 mL). The combined NaOH extracts were washed with diethyl ether (3×20 mL) and then acidified to pH 1 with concentrated HCl. The resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine, dried (MgSO4) and adsorbed on silica gel. The product was purified by flash chromatography, eluting with EtOAc/hexane (1:2). Pure 2 was obtained (2.0 g, 55%) as a yellow solid. m/z=183.06 (M+H). 1H NMR (500 MHz, CDCl3): δ: 10.71 (1H, s, OH), 9.91 (1H, s, CHO), 6.77 (1H, d, J4,6=2.8 Hz, H-6), 6.61 (1H, d, J4,6=2.8 Hz, H-4), 3.92 (3H, s, OMe), 3.84 (3H, s, OMe). 13C NMR CDEPT135 (500 MHz, CDCl3): δ: 196.11 (CHO), 107.93 (C-6), 103.90 (C-4), 56.29 (OMe), 55.83 (OMe).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)#[N:21].C([O-])([O-])=O.[K+].[K+]>>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]([CH2:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc(C#N)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 4-cyanobenzylbromide (216 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.127 g (34.7%); MS m/z: 367.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): (Rotamers) δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.63 (s, 0.7H); 4.66 (s, 1.3H); 4.72 (s, 0.7H); 4.76 (s, 1.3H); 6.61 (br s, 0.7H); 6.67-6.68 (m, 0.7H); 6.75-6.77 (m, 0.3H); 6.81 (br s, 0.3H); 7.14 (d, 2H, 3J=7.9 Hz); 7.19 (d, 2H, 3J=7.9 Hz); 7.25-7.27 (m, 0.3H); 7.36 (d, 0.7H, 3J=8.9 Hz); 7.46 (d, 2H, 3J=8.2 Hz); 7.77 (d, 2H, 3J=8.2 Hz); 7.87 (s, 0.7H); 7.97 (s, 0.3H); 11.85 (s, 0.7H); 12.04 (s, 0.3H); HPLC (METHOD [A]): rt 17.49 min (98.4%)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[C:35]([F:44])[CH:34]=1>>[F:44][C:35]1[CH:34]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:30]=2)[CH:38]=[CH:37][C:36]=1[N:39]1[CH:43]=[N:42][N:41]=[N:40]1
Reactant: Fc1cc(Br)ccc1-n1cnnn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)c(F)c4)ccc3o2)CC1
Yield: 20.6 %

Procedure:
Following the General Procedure-3, the titled compound (22 mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and 1-(4-bromo-2-fluorophenyl)-1H-tetrazole (56 mg, 0.23 mmol) as a pale-yellow solid. M.P.: 154-159° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.14 (d, J 2.5, 1H), 8.04 (t, J 7.8, 1H), 7.91 (d, J 3.9, 1H), 7.64-7.54 (m, 4H), 4.16 (d, J 10, 2H), 3.21-3.13 (m, 1H), 3.01 (t, J 11.9, 2H), 2.21-2.12 (m, 2H), 2.00-1.87 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]4[CH2:33][CH2:32][S:31][CH2:30][C:29]4=[O:34])=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]>C(Cl)Cl>[C:1]([C:3]1[C:4]([NH:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]4[CH2:33][CH2:32][S:31][CH2:30][C:29]4=[O:34])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCSCC4=O)c(C(OC)OC)nc32)ncc1C#N
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCSCC4=O)c(C=O)nc32)ncc1C#N

Procedure:
From intermediate 207, reacted in an analogous manner to the preparation of Example 92. The crude material was dissolved in DCM and Et2O and precipitated by slow evaporation of solvents. The resulting solid was filtered and dried to yield the title compound as a pink solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Br.[OH-].[Na+].[CH3:12][O:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[O:26])=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[CH:19]=2)=[O:15].C([O-])([O-])=O.[K+].[K+]>CCOCC.CN(C=O)C>[CH:25]([C:24]1[C:23]2[C:18](=[CH:19][C:20]([O:27][CH3:28])=[CH:21][CH:22]=2)[N:17]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:16]=1[C:14]([O:13][CH3:12])=[O:15])=[O:26]
Reactant: BrCc1ccccn1
Reactant: COC(=O)c1[nH]c2cc(OC)ccc2c1C=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1c(C=O)c2ccc(OC)cc2n1Cc1ccccn1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
General Procedure J. 2-Bromomethylpyridine.HBr salt (7.0 g, 27.7 mmol) was treated with NaOH (4M, 6.9 ml, 27.6 mmol) in Et2O (20 ml). The ether layer was separated, washed with brine, and dried over MgSO4, filtered into a flask containing a suspension of methyl3-formyl-6-methoxy-1H-indole-2-carboxylate (Compound 90, 1.29 g, 5.54 mmol) and K2CO3 (2.3 g, 16.6 mmol) in DMF (25 ml). The reaction was stirred at 60° C. for 3 h, cooled to room temperature, quenched with H2O and extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by washing with H2O (×3) and filtration to yield the title compound as a golden brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH2:13][CH2:14][C:15](NN)=[O:16])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2[O:30][C:29](CCC(O)=O)=NN=2)C=CC=1.IC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:30][C:15](=[O:16])[CH2:14][CH2:13][C:11]1[O:12][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][N:10]=1
Reactant: NNC(=O)CCc1nnc(-c2cccc(Cl)c2)o1
Reactant: O=C(O)CCc1nnc(-c2cccc(Cl)c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1nnc(-c2cccc(Cl)c2)o1

Procedure:
3-Chloro-benzoic acid hydrazide (3.4 g, 20 mmol) and succinic anhydride (2. g, 20 mmol) was mixed in ethyl acetate (50 ml) at room temperature for 15 min. The reaction mixture was diluted with ether and the precipitate was filtered to give 5.1 g of 4-[N′-(3-chloro-benzoyl)-hydrazino]-4-oxo-butyric acid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 10.01 (s, 1H), 9.53 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H) and 2.35 (m, 4H). This solid was mixed with conc. H2SO4 and stirred at room temperature for 45 min and the reaction mixture was carefully added to crashed ice (400 g). The precipitate was filtered to give 4.07 g (80.6%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid as white solid. 1H-NMR(DMSO-d6) d(ppm): 12.4 (w, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 3.15 (t, 2H) and 2.82 (t, 2H). Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid (2.52 g, 10 mmol) was mixed with iodomethane (5.68 g, 40 mmol) and K2CO3 (5.52 g, 40 mmol) in DMF (25 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water 3 times, dried with MgSO4 and concentrated to give 2.57 g of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid methyl ester. The methyl ester (2.54 g, 9.52 mmol) was mixed with 98% hydrazine hydrate (4.76 g, 95.2 mmol) in methanol (10 ml) for an h. The reaction mixture was concentrated, diluted with water, filtered to give 2.17 g (81.4%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide as white solid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 8.75 (w, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.42 (m, 2H), 3.45 (w, 2H), 3.19 (t, 2H) and 2.68 (t, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:28])[CH3:31]
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Reaction time: 0.5 h

Procedure:
Benzyl indole-2-carboxylate (10 g) was dissolved in DMF (100 ml). Sodium hydride (60% oil, 1.8 g) was added under ice-cooling, and the mixture was stirred for 30 minutes. Ethyl 5-bromopentanoate (6.7 ml) was further added and the mixture was stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent to give 12.44 g of benzyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[F:18][C:19]1[N:30]=[CH:29][CH:28]=[CH:27][C:20]=1[C:21](N(OC)C)=[O:22]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:21]([C:20]2[C:19]([F:18])=[N:30][CH:29]=[CH:28][CH:27]=2)=[O:22])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1I
Reactant: CON(C)C(=O)c1cccnc1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1cccnc1F)c1nc(Cl)ccc1C(F)(F)F
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a solution of 6-chloro-2-iodo-3-(trifluoromethyl)pyridine (described in the literature: Eur. J. Org. Chem. 2004, 3793) (1.9 g, 6.180 mmol) in tetrahydrofuran (20 mL), cooled to −78° C., was added isopropyl magnesium chloride 2M in tetrahydrofuran (3.152 mL of 2 M, 6.304 mmol). The reaction mixture was stirred for 15 minutes. A solution of 2-fluoro-N-methoxy-N-methylnicotinamide (1.252 g, 6.798 mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was partitioned between a saturated solution of ammonium chloride and ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (1.14 g, 61% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH2:11])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][CH2:13][C:14](=O)[CH2:15][CH3:16].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:13]([CH:14]([NH:11][C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)[CH2:15][CH3:16])[CH3:12]
Reactant: Cc1nn2ccccc2c1N
Reactant: CCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(CC)Nc1c(C)nn2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a suspension of 2-methyl-3-amino-pyrazolo[1,5-a]pyridine (0.158 g, 1.07 mmol) and 3-pentanone (0.11 g, 0.14 mL, 1.29 mmol) in methanol (5.0 mL) was added NaCNBH3 (0.095 g, 1.5 mmol) and a drop of acetic acid. The mixture was stirred at room temperature for 18 h. The reaction was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined and dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (15% ethyl acetate/hexane) to give 0.196 g (85%) of a yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=7.0 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 6.99–6.95 (m, 1H), 6.59 (t, J=6.8 Hz, 1H), 2.87 (quintet, J=5.9 Hz, 1H), 2.44 (s, 3H), 1.57–1.47 (m, 4H), 1.01 (t, J=7.4 Hz, 6H); HRMS (FAB) calcd for C13H19N3+H 218.1657. found 218.1647.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOCC.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-fluoro-benzaldehyde (1 eq), 4-chloro-benzenethiol (1.0 eq) and sodium carbonate (1.5 eq) in DMF (0.16 M) was heated at 100° C. for 3 h then 18 h at rt. The mixture was diluted with ether and water, the organic phase washed with brine and the solvents evaporated. The residue was purified by stirring vigorously in hexane-ether followed by filtration to give the title compound as a white solid.