Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1.Cl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: COc1ccc(C=O)c(Cl)c1O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)O)c(Cl)c1O
Temperature: 100 °C
Yield: 91.9 %

Procedure:
2-Chloro-3-hydroxy-4-methoxybenzaldehyde (1.86 g, 10 mmol) was dissolved in pyridine (7 ml), malonic acid (1.25 g, 10 mmol) and piperidine (0.1 ml) were added and the mixture was heated at 100° C. for 2 hrs, then it was poured in 100 ml HCl 1N and extracted with AcOEt. This was dried and evaporated, and the residue was triturated with diethyl ether and filtered, giving 2.10 g of (E)-3-(2-chloro-3-hydroxy-4-methoxy-phenyl)-acrylic acid as a white solid, which was used without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]([C@@H:26]([CH3:29])[CH2:27][OH:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:19]([N:18]([C@@H:26]([CH3:29])[CH:27]=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Dry DMSO (0.53 mL, 7.43 mmol) was added to a stirred solution of oxalyl chloride (0.31 mL, 3.6 mmol) in CH2Cl2 (7.5 mL) at −78° C. The solution was allowed to stir 15 minutes followed by the addition of 40 (740 mg, 2.90 mmol) in CH2Cl2 (7.5 mL). After 30 minutes, Et3N (1.0 mL, 7.2 mmol) was added and allowed to warm to rt. The solution was extracted with satd. NaHCO3 (20 mL) and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The organic layer was washed with satd. NaCl solution, dried with MgSO4 an concentrated in vacuo at rt to give 720 mg (98% yield) of a yellow oil which became a solid when cooled to −20° C. The aldehyde was used without further purification: mp 52-54° C. Lit. mp 55.5° C.; [α]26D=−36.0 (c 1,CHCl3 Lit. [α]20D=−35.1 (c 1, EtOAc); 1H NMR (400 MHz, CDCl3) δ 1.19 (d, 2H, J=7.0 Hz), 3.34 (q, 1H, J=7.0 Hz), 3.58 (d, 2H, J=13.7 Hz), 3.74 (d, 2H, J=13.7 Hz), 7.26 (m, 2H), 7.33 (m, H), 7.42 (m,4H), 9.74 (s, 1H); 13C NMR (100 MHz) δ 6.7, 54.9, 62.8, 3.3, 4.4, 4.8, 139.1, 204.6; FABMS m/z 408.2 (M+MB), 254.2 (M+H), 22.2 (M—CHO); HRFABMS calcd for C17H20NO Mr 254.1545 (M+H), found Mr254.1545. See, Dix et al., Arch Pharm (Weinheim) 1995, 328, 203-205.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:51]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>CN(C=O)C.O>[C:54]([O:53][C:51]([N:58]1[CH2:63][CH2:62][N:61]([C:20](=[O:22])[CH2:19][NH:18][C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[O:17])[CH2:60][CH2:59]1)=[O:52])([CH3:57])([CH3:55])[CH3:56]
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 0.03 h
Yield: 35.4 %

Procedure:
DIPEA (2.928 g, 22.66 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (2.892 g, 11.33 mmol) in DMF (30 mL). HOBT (1.835 g, 13.59 mmol) and EDCI.HCl (2.532 g, 13.59 mmol) were then added at room temperature. After 2 minutes, N-Boc-piperazine (3.381 g, 24.22 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine solution, dried over sodium sulphate and concentrated in vacuo to afford 1.7 g (37.5% yield) of 4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carboxylicacid tert-butyl ester. LC-MS purity: 82.06%
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[S:5][C:6]=1[C:7]([OH:9])=O.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:7]([C:6]1[S:5][C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)=[N:3][C:2]=1[CH3:1])=[O:9]
Reactant: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)O
Reactant: NCC(F)(F)F
Product: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)NCC(F)(F)F
Yield: 93 %

Procedure:
As described for example 19, 4-methyl-2-[2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (70 mg, 0.22 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (82 mg, 93%) which was obtained as an off white solid MS: m/e=397.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:7](=[O:9])[CH2:26][C:25]([O:31][CH2:32][CH3:33])=[O:30])[CH:10]=1
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Reaction time: 1.5 h

Procedure:
To a stirring solution of 5-chloro-2-methoxybenzoic acid (1.87 g, 10.0 mmol, 1 eq) in 20 mL tetrahydrofuran was added N,N-carbonyldiimidazole (1.64 g, 10.1 mmol, 1.01 eq), and stirring was continued for twenty minutes to generate the acyl-imidazole. Separately, potassium ethyl malonate (4.08 g, 24.0 mmol, 2.39 eq) and magnesium chloride (1.15 g, 12.1 mmol, 1.20 eq) were suspended in 20 mL tetrahydrofuran. To the magnesium chloride mixture was added the acyl-imidazole solution. Stirring was continued at 50° C. for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion dried over magnesium sulfate, filtered through a pad of celite, and concentrated to provide ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate, which was used without further purification. LCMS (ESI) m+H=257.2
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:27]1[CH:28]=[N:29][N:30]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[C:31]=1[CH3:32].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:27]2[CH:28]=[N:29][N:30]([CH:33]3[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]3)[C:31]=2[CH3:32])=[CH:15][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Cc1c(Br)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4o3)c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 41.8 %

Procedure:
3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (400 mg), tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (371 mg), tris(dibenzylideneacetone)dipalladium (49 mg), tricyclohexylphosphine (30 mg) and potassium phosphate (389 mg, 1.83 mmol) in dioxane (2.4 ml) and water (0.4 ml) were stirred at 100° C. for 3 h under argon. The reaction mixture was filtered and purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 micron silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/min) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (214 mg). NMR Spectrum: (DMSOd6) 1.43 (s, 9H), 1.83-1.92 (m, 4H), 2.42 (s, 3H), 2.95 (bs, 2H), 4.02-4.14 (m, 2H), 4.39-4.48 (m, 1H), 7.42-7.49 (m, 2H), 7.66 (s, 1H), 7.67 (bs, 2H), 7.79 (d, 1H), 7.84 (d, 1H), 8.22 (d, 1H), 8.29 (d, 1H); Mass spectrum: M+H+ 475 TFA (1 ml) was added to a solution of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (126 mg) in dichloromethane (1 ml). The solution was stirred at 25° C. for 1 hour. After evaporation of the solvents, the crude mixture was diluted in dichloromethane and 7N methanolic ammonia was added. After evaporation of the solvents, the residue was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane and 10 to 25% methanolic ammonia (7N) in dichloromethane. The solvent was evaporated to dryness and triturated in acetonitrile to afford 3-(1,3-benzoxazol-2-yl)-5-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (66 mg). NMR Spectrum: (DMSOd6) 1.79-1.87 (m, 2H), 1.90-2.01 (m, 2H), 2.40 (s, 3H), 2.65-2.75 (m, 2H), 3.07-3.15 (m, 2H), 4.23-4.33 (m, 1H), 7.40-7.49 (m, 2H), 7.65 (s, 1H), 7.67 (bs, 2H), 7.79 (dd, 1H), 7.84 (dd, 1H), 8.21 (d, 1H), 8.29 (d, 1H); Mass spectrum: M+H+ 375.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:9][CH2:10][CH3:11])[O:5][P:6](Cl)Cl)#[N:2].C[Si]([C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)(C)C>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH:4]([CH2:9][CH2:10][CH3:11])[O:5][P:6]([C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)#[N:2]
Reactant: CCCC(CC#N)OP(Cl)Cl
Reactant: Cc1c[nH]c([Si](C)(C)C)n1
Solvent: Cc1ccccc1
Product: CCCC(CC#N)OP(c1nc(C)c[nH]1)c1nc(C)c[nH]1
Reaction time: 0.08 h

Procedure:
To toluene (5 ml) there were added 0.267 g (1.25 mmol) of 2-cyano-1-n-propylethoxydichlorophosphine and 0.425 g (2.75 mmol) of trimethylsilyl-4-methylimidazole under an argon atmosphere at room temperature, and reaction was conducted for 5minutes. After by-product chlorotrimethylsilane and toluene were removed under reduced pressure for 10 minutes at room temperature, the residual toluene and excess trimethylsilyl-4-methylimidazole were removed under reduced pressure for 2 hours at 35° C. to obtain 2-cyano-1-n-propylethoxybis (4-methylimidazolyl)phosphine as a colorless transparent oil. This was dissolved in 2.5 ml of chloroform-d, and the solution (0.5 M) was added to 0.678 g (1.25 mmol) of 5′-O-(4,4′-dimethoxytrityl)thymidine that had been dried under reduced pressure for 2 hours, under an argon atmosphere at room temperature. Upon reaching homogeneity, the mixture was allowed to stand overnight for reaction to obtain a phosphorazolide compound represented by the formula (1-18) above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:28])=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:28])=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc(F)cc3)nc2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)c(O)cc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-7-hydroxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.39 mmol) in methanol (30 ml) and water (1 ml) was added sodium hydroxide (19.5 mg, 0.49 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(4-fluorophenyl)-7-hydroxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](C23NCCN2C(=O)C2C3=CC=CC=2)=[CH:4][CH:3]=1.F[C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[CH:24][CH:23]=1.C1(O)C=CC=CC=1.ClCC#N.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:22]1([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:30]=[CH:29][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C1c2ccccc2C2(c3ccc(O)cc3)NCCN12
Agent: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: c1ccc(Oc2ccccc2)cc1

Procedure:
Compound 239 was prepared from 9b-(4-hydroxyphenyl)-1,2,3,9b-tetrahydroimidazo[2,1-a]isoindol-5-one using Method L. The tetrahydroimidazoisoindolone was bis-acylated with 4-fluorobenzoyl chloride according to Method H and the resulting phenolic ester function was converted to a phenol by basic hydrolysis. The product was then treated with chloroacetonitrile and K2CO3 in acetone and heated to reflux for 30 h to yield phenyl ether compound 239.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[N+:10]([O-])([OH:12])=[O:11].O>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1F
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1F
Reaction time: 15 h

Procedure:
To a cold (-2°), stirred solution of 285 g. (2.26 mol) of 2-fluoroanisole in 1.1 L of acetic anhydride was added, dropwise, 114 mL of fuming nitric acid (sp. gr. 1.59) at such a rate that the reaction temperature remained between -2° and 0°. The reaction mixture was stirred for 5 hours at this temperature then poured into 4.0 L of water. The suspension was stirred for 1.5 hours, stored for 15 hours, then extracted with methylene chloride (2×1.0 L). The combined extracts were washed with water (2×500 mL), dried over anhydrous magnesium sulfate, then concentrated in vacuo (475 g.). Crystallization from ethanol gave 147.4 g. (38%) of material suitable for further transformation. Additional material (34.5 g.) was obtained from three scouting runs.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=2)[CH:3]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>>[CH2:19]([NH:21][C:22]([N:6]1[C:2]([CH3:1])=[CH:3][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:5]1)=[O:23])[CH3:20]
Reactant: COc1cc(Oc2cc(C)[nH]n2)ccc1[N+](=O)[O-]
Reactant: CCN=C=O
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])c(OC)c2)cc1C
Yield: 62.9 %

Procedure:
Reaction of 5-methyl-3-(3-methoxy-4-nitrophenyloxy)pyrazole with ethyl isocyanate was carried out in the same manner as in Example 96, to give a yellow viscous substance of N-ethyl-5-methyl-3-(3-methoxy-4-nitrophenyloxy)pyrazole-1-carboxamide (yield: 62.9%). 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.2 Hz, 3H), 2.63 (d, J=0.6 Hz, 3H), 3.40 (dq, J=5.9 and 7.2 Hz, 2H), 3.95 (s, 3H), 5.81 (q, J=0.6 Hz, 1H), 6.75 (dd, J=2.4 and 9.0 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.93 (br s, 1H), 7.96 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(CC)CC)C.CS(C)=O.O>[CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in WO2010079443A1. To a solution of compound 1-benzhydrylazetidin-3-ol (20 g, 28.4 mmol) in the triethyl amine (60 mL) was added a solution of sulfur trioxide pyridine complex (SO3.Py) (40 g, 251.6 mmol) in dimethylsulfoxide (260 mL) under a nitrogen atmosphere at 25° C. The reaction was stirred at 50° C. for 2 h. Then the reaction mixture was cooled back to 25° C., diluted with water (500 mL), and extracted with ethyl acetate (2×500 mL). Organic part was dried over sodium sulfate, filtered, and concentrated under a vacuum to give a crude compound which was further purified by column chromatography using silica gel (100 to 200 mesh) eluting with 0% to 20% ethyl acetate in hexanes to provide 1-benzhydrylazetidin-3-one (11.7 g) as a white solid. MS (ESI, positive ion) m/z (M+1): 238.30. 1H NMR (400 MHz, DMSO) δ 7.50 (d, J=7.5 Hz, 4H), 7.30 (t, J=7.5 Hz, 4H), 7.20 (t, J=7.3 Hz, 2H), 4.82 (s, 1H), 4.00 (s, 4H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1ccccc1F
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(N)c1ccc2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(2-fluorophenyl)quinoline (0.033 g, 0.11 mmol) in tetrahydrofuran (0.3 mL) and water (0.0813 mL) was added 1.00 M trimethylphosphine in tetrahydrofuran (0.135 mL, 0.135 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue had two peaks with the same desired mass and was used directly in next step (25 mg, 83%). LCMS calculated for C17H16FN2(M+H)±: m/z=267.1; found: 267.1.
Reaction SMILES: [CH3:1][CH:2]([NH:5][C:6](=S)[NH:7][NH2:8])[CH2:3][CH3:4].[Cl:10][CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>C(O)C>[ClH:10].[CH3:19][C:17]1[NH:8][N:7]=[C:6]([NH:5][CH:2]([CH3:1])[CH2:3][CH3:4])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCC(C)NC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NC(C)CC)n[nH]c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
A stirred solution of 5.1 g (0.035 mole) of 4-(2-butyl)-3-thiosemicarbazide in 40 mL of absolute ethanol was treated with 5.7 g (0.035 mole) of ethyl 2-chloroacetoacetate and stirred at ambient temperature for 3 hr. The mixture was treated with 20 mL of 2N ethanolic hydrogen chloride, heated at reflux for 1 hr and stirred for ~16 hr at ambient temperature. The reaction mixture after filtering and concentrating in vacuo gave a crude orange solid. A second reaction mixture was prepared with 8.0 g (0.054 mole) of crude 4-(2-butyl)-3-thiosemicarbazide, 50 mL of absolute ethanol, 8.9 g (0.054 mole) of ethyl 2-chloroacetoacetate, and 25 mL of 2N ethanolic hydrogen chloride as described above and gave a crude orange solid. The TLC of both crude products (10% methanol/benzene; silica gel) were identical. Recrystallization of the first batch from acetone/isopropyl ether gave 4 g of fine white crystals, mp 147°-148.5° C. Recrystallization of the second batch from benzene/ligroin gave 2.5 g of pale yellow crystalline product, mp 146°-148.5° C. The 2 solids were combined (6.5 g) and recrystallized from 200 mL of acetone/isopropyl ether (3:1) to give 3.6 g of white fluffy crystals, mp 147°-149° C.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21]CC)=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>C(O)C>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18](=[N:24][O:25][CH3:26])[C:19]([OH:21])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(C(=NOC)C(=O)OCC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCn1nnc(C(=NOC)C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
The 2-(2-dodecyl-2H-tetrazol-5-yl)-2-methoxyiminoacetic acid, ethyl ester (20.1 g, 54.6 mmol) was dissolved in ethanol (200 mL) and treated with 2 equivalents of sodium hydroxide pellets (4.37 g, 110 mmol). Dissolution gradually occurred and the solution was stirred at room temperature for overnight. The ethanol was concentrated in vacuo and the viscous liquid was taken up in water and acidified (pH 3.0) with concentrated HCl. The product was extracted from the aqueous media with 2 portions of ethyl acetate, which were combined and washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to give 17.5 g (94%) of 2-(2-dodecyl -2H-tetrazol-5-yl)-2-methoxyimino-acetic acid as a viscous liquid;
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([Li:18])=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1cccc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
Into a solution of dibenzo[b,d]thiophene (4.80 g, 26.1 mmol) in ether (70 mL) was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise at −78° C., and the solution was allowed to warm to room temperature and then heated at 35° C. oil bath for 2 h to yield a red solution of dibenzo[b,d]thiophen-4-yl lithium.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:12]([C:14]([C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])=[CH:18][CH:17]=1)=[O:15])[NH2:13]>CS(C)=O>[OH:27][NH:26][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]1[CH:18]=[CH:17][C:16]([C:14]([NH:12]/[N:13]=[CH:4]/[C:3]2[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([OH:10])[C:2]=2[OH:1])=[O:15])=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccc(/C=C/C(=O)NO)cc1
Reactant: O=Cc1ccc(O)c(O)c1O
Solvent: CS(C)=O
Product: O=C(/C=C/c1ccc(C(=O)N/N=C/c2ccc(O)c(O)c2O)cc1)NO
Temperature: 70 °C
Yield: 23.3 %

Procedure:
Compound 6a was resynthesized and purified to be re-subjected to the biochemical assay to confirm the results from the initial library screen. To a 4 dram vial charged with 2,3,4-trihydroxybenzaldehyde (25.9 mg, 0.168 mmol) was added 420 μL of a 200 mM solution of hydrazine 5a (0.084 mmol) in DMSO. The solution was heated on a rotating heating block at 70° C. for 16 h. Reaction progress was monitored via LCMS. Following purification by reverse phase preparatory LCMS (44 mL/min, CH3CN/H2O with 1% formic acid, 5 min gradient), 6a (7 mg) was isolated as a yellow powder (98% pure, by analytical LCMS). 1H NMR (300 MHz, DMSO) δ 12.01 (s, 1H), 11.51 (s, 1H), 10.84 (s, 1H), 9.49 (s, 1H), 9.13 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 7.96 (d, J=8.3, 2H), 7.73 (d, J=8.2, 2H), 7.53 (d, J=16.2, 1H), 6.80 (d, J=8.6, 1H), 6.59 (d, J=15.9, 1H), 6.40 (d, J=8.4, 1H); m/z (ES−) 356 ([M-H]).