Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:33][C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[CH:39][N:40]2[CH2:43][CH2:44][C@@H:45]([N:55]2[CH:59]=[C:58]([C:60]([NH2:62])=[O:61])[N:57]=[CH:56]2)[CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])=[CH:36][CH:35]=1>ClCCl>[Si:48]([O:47][CH2:46][C@H:45]([N:55]1[CH:59]=[C:58]([C:60]([NH2:62])=[O:61])[N:57]=[CH:56]1)[CH2:44][CH2:43][N:40]1[C:41]2[C:37](=[CH:36][CH:35]=[C:34]([NH:33][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:42]=2)[CH:38]=[CH:39]1)([C:51]([CH3:54])([CH3:52])[CH3:53])([CH3:49])[CH3:50]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(NC(=O)CCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100.3 %

Procedure:
To a stirred mixture of 3-phenylpropionic acid (46 mg, 0.304 mmol) and 1-hydroxybenzotriazol (45 mg, 0.334 mmol) in dichloromethane (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (52 mg, 0.334 mmol) at ice-bath temperature. The mixture was stirred for 40 minutes at room temperature. And then 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (130 mg, 0.304 mmol) was added to the mixture at ice-bath temperature. After adding, the resulting mixture was stirred for 4 hours at room temperature. The solvent was concentrated in vacuo. And then the residue was extracted with ethyl acetate and washed with water and brine. The organic layer was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel (6 g) column chromatography eluting with chloroform/methanol (30:1) to give 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-(3-phenylpropionylamino) indol-1-yl)-2-butyl]imidazole-4-carboxamide (170.6 mg, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C@@H:11]([C@@H:26]1[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:32][CH2:31]3)[CH2:28][CH2:27]1)[CH2:12][CH2:13][C:14]([F:25])([F:24])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])C>O1CCCC1.CCOCC>[CH2:22]([O:21][CH:19]([O:18][C:15]([C:14]([F:24])([F:25])[CH2:13][CH2:12][C@H:11]([C@@H:26]1[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:32][CH2:31]3)[CH2:28][CH2:27]1)[CH2:10][OH:9])([CH3:16])[CH3:17])[CH3:20])[CH3:23]
Reactant: CCOC(=O)[C@H](CCC(F)(F)C(C)(C)OC(C)OCC)[C@H]1CC[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.20 g (0.0053 mol) of lithium aluminum hydride and 10 mL of tetrahydrofuran at 0° C. was added 2.55 g (0.0034 mol) of [1α,3β]-1,3-bis[tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-oic acid ethyl ester in 35 mL of tetrahydrofuran. The mixture was heated at 50° C. for 1.5 hr, recooled to 0° C., and diluted with 120 mL of ether. The mixture was then quenched with the dropwise addition of 0.40 ml of water and 0.32 mL of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 1 hr and was filtered. The solids were triturated with ether and filtered. Evaporation of solvent afforded [1α,3β]-1,3-bis[tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21ol, [α]D20 +4° (c 1, CHCl3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:7][C@@H:8]([CH3:14])[C:9](OCC)=[O:10].C[O-].[Na+].O.O.O.C(O)(=O)C(O)=O>C(O)C>[OH:7][C@@H:8]([CH3:14])[C:9]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:10]
Reactant: C1CNCCN1
Reactant: CCOC(=O)[C@H](C)O
Agent: C[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](O)C(=O)N1CCNCC1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
A flask charged with piperazine (10.0 g, 116 mmol) and (S)-ethyl 2-hydroxypropanoate 7 (17.84 g, 151 mmol, 1.30 equiv) was cooled to 10° C. Sodium methoxide (25 wt % in MeOH) (12.55 g, 58.1 mmol, 0.50 equiv) was slowly added while maintaining the temperature below 20° C. The cold water bath was removed and the reaction mixture was allowed to warm to ambient temperature and aged for 19 h. Water (6.23 g, 346 mmol, 3.0 equiv) was added and the mixture was aged for 16 h. The mixture was diluted with ethanol (40 mL) and concentrated under reduced pressure. The residue was diluted with ethanol (40 mL) and treated with a solution of oxalic acid dihydrate (6.58 g, 52.2 mmol) in ethanol (30 mL) to adjust the pH to 7.5. The suspension was cooled to <10° C., filtered through a pad of CELITE® and washed with ethanol (2×60 mL). The filtrate and washes were combined and concentrated to 50 mL. The solution was cooled to 10° C. and a solution of oxalic acid dihydrate (16.1 g, 128 mmol) in ethanol (60 mL) was slowly added. The suspension was allowed to warm to ambient temperature and stirred for 1 h. The suspension was cooled to 10° C. and the solid was collected by filtration, washed with cold ethanol (2×18 mL) and dried under reduced pressure at 50° C. for 24 h to afford the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V as a white solid (15.2 g, 53%). 1H NMR (300 MHz, D2O) δ 4.73-4.51 (m, 1H), 3.93-3.59 (m, 4H), 3.26 (dd, J=8.8, 4.0 Hz, 4H), 1.27 (d, J=6.7 Hz, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:7]([N+:12]([O-])=O)=[N:8][CH:9]=[CH:10][CH:11]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: NCCc1cccnc1N
Yield: 90.7 %

Procedure:
A solution of 3-(2-azidoethyl)-2-nitropyridine (0.190 g, 0.98 mmol) in methanol (5 mL) was stirred at 20° C. with 10% palladium on carbon (50 mg) under 1 atm hydrogen for 96 h. The mixture was filtered through celite and the filtrate concentrated to give the title compound (0.122 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=2)(C(O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[Cl:23][C:19]1[CH:18]=[C:17]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccnc(Cl)c2)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccnc(Cl)c2)CC1
Yield: 87 %

Procedure:
The pure compound 1-(tert-butoxycarbonyl)-4-(2-chloropyridin-4-yl)piperidine-4-carboxylic acid (42 g, 0.12 mols, 1 equiv.) from Step B was dissolved in toluene (250 mL) and heated at 110° for 4 hours. The reaction was monitored by TLC (ethyl acetate/petroleum ether; 1/5). Once complete, the mixture was concentrated and purified by flash chromatography using silica gel (ethyl acetate/petroleum ether; 1/20) to give tert-butyl 4-(2-chloropyridin-4-yl)piperidine-1-carboxylate (31 g, 87%)
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17]C(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].F[C:23](F)(F)C(O)=O.C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[N:8][CH:7]=2)[CH2:10][CH2:11]1)(=[O:17])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (270.4 mg, 0.9281 mmol) in dichloromethane (2.5 ml) was added trifluoroacetic acid (2.5 ml) at 0° C. After stirring at 0° C. for 1 hr, the reaction mixture was concentrated under reduced pressure. Anhydrous dichloromethane (2.5 ml) was added to the residue, acetic anhydride (0.105 ml, 1.114 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 5 times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane=1:30) to give 5-(4-acetylpiperazin-1-yl)pyridine-2-carbaldehyde (147.0 mg, yield 67.9%) as a slightly yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])[CH3:5].[CH3:20]I>CN(C=O)C>[CH3:6][C:4]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]1)=[O:9])([CH3:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.0 g, 41 mmol, 2.5 equiv) in DMF (30 mL) at −10° C. was added cis-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexanecarboxylic acid (4.0 g, 16 mmol, 1.0 equiv). The reaction mixture was allowed to warm to room temperature and then was stirred for 1 h. The mixture was again cooled to −10° C., and MeI (25 g, 260 mmol, 16 equiv) was added dropwise. The cold bath was removed, and the reaction mixture was stirred for 3 h at room temperature. The mixture was poured onto ice, and then NaOH (1.5 g) was added to hydrolyze any undesired methyl ester that formed. This solution was stirred for another 4 hours. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure to remove the DMF. The resulting residue was diluted with water, and the pH was adjusted to ˜3-4. The desired product precipitated as a white solid which was collected by filtration (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([O-])([O-])OCC>>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:9])=[CH:7][N:6]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOC([O-])[O-]
Product: CNc1ccc(Cl)nc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To 5.0 g (0.039 mole) of 5-amino-2-chloropyridine was added 40 ml of ethyl orthoformate and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 50 ml of EtOH. After addition of 1.8 g of sodium borohydride, the mixture was stirred at 70-80° C. for 3 hours. The reaction mixture was concentrated and after addition of 50 ml of iced water and 5 ml of concentrated hydrochloric acid, the mixture was adjusted to pH 7-8 with NaHCO3 and extracted with AcOEt (50 ml×3). The AcOEt layers were pooled,washed with water and dried over MgSO4. The AcOEt was distilled off and hexane was added to the crystalline residue. The crystals are collected by filtration, washed with hexane and dried to give 5.1 g of the title compound as white crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][N:24]=CC=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[NH:34][N:24]=[CH:25][CH:26]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc2cc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2cc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-5-yl)naphthalen-2-yl)acetic acid (56) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of 1H-pyrazol-5-ylboronic acid for pyridin-4-ylboronic acid in step 5. The title compound (0.004 g) was isolated as an amorphous white powder. LCMS-ESI− (m/z): [2M−H]− calcd for C52H49Cl2N4O6: 895.30; found: 895.45. 1H-NMR: 400 MHz, (CD3CN) δ: 8.23 (br s, 1H); 7.93 (d, J=9.6 Hz, 1H); 7.79 (s, 1H); 7.68 (s, 1H); 7.61-7.53 (m, 3H); 7.40-7.35 (m, 1H); 7.30 (d, J=9.6 Hz, 1H); 6.78 (s, 1H); 5.22 (s, 1H); 2.57 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[CH:9]=1)[NH2:6].[CH:19]1([N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]2[CH:41]=[CH:40][O:39][CH:38]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:4]([CH:5]([NH:6][C:34]([C:32]1[CH:31]=[CH:30][C:29]2[N:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:26]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)=[N:27][C:28]=2[CH:33]=1)=[O:35])[CH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:14]([OH:16])=[O:15])([OH:3])=[O:18]
Reactant: COC(=O)c1cccc(C[C@H](N)C(=O)OC)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: Cl
Product: O=C(O)c1cccc(CC(NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)c1

Procedure:
Racemic 3-(carbomethoxy)phenylalanine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the title compound of example 1234.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]1[S:10](=[O:12])(=[O:11])[O:9][CH2:8][CH2:7][CH2:6]1>CO>[CH2:1]([NH:4][CH:5]([S:10]([OH:12])(=[O:11])=[O:9])[CH2:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=S1(=O)CCCCO1
Solvent: CO
Product: C=CCNC(CCC)S(=O)(=O)O
Yield: 36.3 %

Procedure:
A solution of 57 g of allylamine and 136 g of butanesultone in 1 l of methanol was stirred for 48 h at room temperature. After evaporation, washing the residue with ether and drying under vacuum, 70 g of N-allyl-aminobutane sulfonic acid were obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:31])[CH2:7][CH:6]2[CH:8]([CH3:30])[C:9]([S:14]([NH:17][C:18](=[NH:29])[NH:19][CH2:20][CH2:21][CH2:22][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[NH2:24])(=[O:16])=[O:15])=[C:10]([CH3:13])[C:11]([CH3:12])=[C:5]2[O:4]1.C(N(CC)CC)C.[F:39][C:40]1[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=1[CH:42]=[CH:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:39][C:40]1[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=1[CH:42]=[CH:43][C:44]([NH:24][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:21][CH2:20][NH:19][C:18](=[NH:29])[NH:17][S:14]([C:9]1[CH:8]([CH3:30])[CH:6]2[CH2:7][C:3]([CH3:31])([CH3:2])[O:4][C:5]2=[C:11]([CH3:12])[C:10]=1[CH3:13])(=[O:15])=[O:16])=[O:45]
Reactant: COC(=O)[C@@H](N)CCCNC(=N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2C1C
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCNC(=N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2C1C)NC(=O)C=Cc1ccccc1F
Yield: 98.9 %

Procedure:
The same procedures as in Example 2 were carried out from methyl Nω-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-L-argininate hydrochloride (5.0 g), triethylamine (1.8 mL), 2-fluorocinnamic acid (2.1 g), WSC.HCl (2.4 g), and methylene chloride (150 mL), to give the captioned compound (6.1 g, 99%) as an amorphous solid product.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:18]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[Cl:26][C:24]1[CH:23]=[CH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])[C:18]=2[CH:25]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: O=C(O)c1cc2ccccc2n1Cc1csc2ccc(Cl)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-chloro-benzo[b]thiophene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 340.0 ([M−H]−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12].C([O-])(=O)C.[NH2+]1CCCCC1>C1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:17]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8](=[O:10])[CH3:9])[CH:19]=[CH:20][CH:21]=1)([O-:13])=[O:12]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cc1ccncc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)c1ccncc1

Procedure:
4.62 g (34 mmole) of 1-(4-pyridyl)-2-propanone and 5.14 g (34 mmol) of 3-nitrobenzaldehyde were dissolved in benzene. To this solution, 0.49 g (3.4 mmol) of piperidinium acetate was added, and the mixture was refluxed with application of heat for 6 hours for dehydration. The reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The benzene contained in the reaction mixture was distilled off under reduced pressure and the remaining reaction product was chromatographed on a silica gel column, whereby the captioned compound was obtained. The yield was 7.695 g (87.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[N+]=[N-]>C(O)(=O)C>[CH:5]1[C:4]2[C:3](=[N:12][O:10][N+:9]=2[O-:11])[C:2]([Cl:1])=[CH:7][C:6]=1[Cl:8]
Reactant: [N-]=[N+]=Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: [O-][n+]1onc2c(Cl)cc(Cl)cc21
Temperature: 0 °C
Yield: 92.1 %

Procedure:
A mixture of 0.63 g (2.7 mmol) of 2,4-dichloro-6-nitroazidobenzene and 25 ml glacial acetic acid is made and is refluxed for three to six hours. This is then poured over ice water, filtered and washed with water to yield 0.51 g (92.1% yield) of 4,6-dichlorobenzofuroxan, having a melting point of 105 to 105.5° C. Experimental runs result in yields ranging from 75 to 92%. The material can be recrystallized from ethanol/water if desired.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:11](=O)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:17]N>CCO>[CH2:12]([C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][NH:2][N:17]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)CC(C)C
Reactant: NN
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1CC(C)C
Yield: 74.7 %

Procedure:
According to Scheme 1 Step 2: A solution of ethyl 2-((dimethylamino)methylene)-5-methyl-3-oxohexanoate (11.6 mmol, 2.64 g) and hydrazine (11.6 mmol, 1.47 mL) in EtOH (10 mL) was stirred for 1 hour at room temperature. After evaporation of the solvent, the resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (80:20) as eluent to yield ethyl 3-isobutyl-1H-pyrazole-4-carboxylate (8.66 mmol, 1.70 g, 75%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:38])([F:37])[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]([F:38])([F:37])[F:23])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (23.4 g, 78.7 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (54.0 g, 394.0 mmol) at room temperature. The mixture was warmed up to 90° C. and stirred for 30 min, and then 2,2,2-trifluoroethyl-p-toluensulfonate (20 g, 78.7 mmol) was added. The reaction mixture was warmed up to 140° C. and stirred for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between ethylacetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE to give the title compound 17c as a white solid (26.0 g, 87.2%, HPLC: 97.45%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.54 (d, 1H), 7.45 (m, 1H), 7.40 (d, 1H), 7.18 (d, 2H), 7.00 (d, 2H), 4.80-4.64 (m, 2H), 4.01 (s, 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([O:32]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:37][NH2:38].[C-]#N.[Na+].NN>CCO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([NH:37][NH2:38])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reactant: NN
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCN(C(=O)CC(=O)NN)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 60 °C
Yield: 72 %

Procedure:
A solution of (S)-Ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (120 mg, 0.25 mmol) in EtOH (4 mL) was treated with hydrazine hydrate (24 μL, 0.50 mmol), a catalytic amount of sodium cyanide, and heated in a sealed tube at 50° C. for 24 hr after which time and additional amount of hydrazine was added (48 μL, 1.0 mmol) and the reaction mixture heated at 60° C. for 48 h. After this time the reaction mixture was evaporated, triturated with water and dissolved in EtOAc (2 mL), which was dried over MgSO4, filtered, and evaporated to afford the title compound as a foam (84 mg, 72%). LC/MS (Method B) 3.04 min, [M+1]+ 467.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(O)(=O)C.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:8]([NH:7][C:6]1[CH:11]=[C:2]([F:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]=1[OH:9])[CH3:10]
Reactant: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
5-Fluoro-2-methyl-6-nitro-benzoxazole (2.556 g, 13.03 mmol) was dissolved in Tetrahydrofuran (90 mL) and Acetic acid (4.5 mL, 79 mmol). Sodium borohydride (1.48 g, 39.1 mmol) was added and the reaction was stirred at room temperature for 90 min, then poured into 100 mL satd. sodium bicarbonate. The solution was extracted 3×50 mL DCM and the combined organics were washed with 1:1 brine:satd. sodium bicarbonate (50 mL) and dried over sodium sulfate, then conc. onto 10 g Celite. The crude product was chromatographed (120 g silica gel, ISCO, 0-20-40% EtOAc:Hex) to afford 2-Ethylamino-4-fluoro-5-nitro-phenol as a yellow solid (2.20 g, 84%). 1H-NMR (CDCl3): 7.55 (d, 1H, J=6.8 Hz), 6.26 (d, 1H, J=13.2 Hz), 5.51 (s, 1H), 5.05 (s, 1H), 3.26 (m, 2H), 1.34 (t, 3H, J=6.8 Hz).