Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([SH:11])=[N:9][N:10]=2)[N:7]=1.[CH3:12][NH2:13].Cl>>[CH3:12][NH:13][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([SH:11])=[N:9][N:10]=2)[N:7]=1
Reactant: Sc1nnc2ccc(Cl)nn12
Reactant: CN
Agent: Cl
Product: CNc1ccc2nnc(S)n2n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (330 mg, 1.77 mmol) was treated with a 40% v/v aqueous solution of methylamine. The reaction mixture was stirred at 100° C. for 17 h, then it was cooled to room temperature and acidified to pH 1-2 with 1 N aqueous HCl. The resulting precipitate was filtered, washed with water, and dried in vacuo to give 185 mg of 6-methylamino-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow powder (58% yield): 1H NMR (DMSO-d6): δ 2.83 (d, 3H), 6.85 (d, 1H), 7.44 (broad q, 1H), 7.74 (d, 1H), 14.2 (s, 1H); MS (m/z) 182 [M+H+]+.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18]>>[OH:18][C@@H:17]([C:16]([CH3:20])([CH3:19])[CH3:15])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CC(C)(C)C=O
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@@H](O)C(C)(C)C

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with trimethylacetaldehyde. Rapid addition of the aldehyde to the enolate solution at 0° C. gave a 1:1 ratio of the (2R*,3S*) and (2R*,3R*) isomers. The desired isomer was isolated by silica gel chromatography, then crystallized. 1-NMR (CDCl3, 400 MHz): δ 8.05 (m, 1 H), 7.20–7.27 (m, 4 H), 4.24 (dq, J=7, 4 Hz, 1 H), 3.82 (br t, J=4 Hz, 1 H), 2.33 (br d, J=4 Hz, 1 H), 1.36 (d, J=7 Hz, 3 H), 0.99, (s, 9 H). 13C-NMR (CDCl3, 100 MHz): δ 175.3, 150.8, 142.2, 127.9, 125.4, 124.9, 116.2, 109.9, 77.6, 40.3, 35.8, 29.7, 26.7, 12.7.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[NH2:31][CH2:32][CH2:33][OH:34]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:32][CH2:33][OH:34])[N:3]=3)[N:20]=2)=[CH:29][CH:28]=1
Reactant: NCCO
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Solvent: C1CCOC1
Product: N#Cc1c(NCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (purity 91%, 0.186 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were initially charged in 5 ml of THF, 0.023 ml (0.373 mmol) of 2-aminoethanol was added and the mixture was stirred at room temperature for 30 min. The product was then isolated by preparative HPLC. This gave 64 mg (67% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[S:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([NH:20][CH2:2][C:3]2[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[S:5][C:4]=2[C:12]([O:14][CH3:15])=[O:13])[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1CBr
Reactant: Cc1c(N)cccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1sc(C(C)(C)C)cc1CNc1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A 250-mL single-necked round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 102c (1.09 g, 4.68 mmol), 3-bromo-2-methylaniline (2.61 g, 14.0 mmol) and acetonitrile (25 mL). Cesium carbonate (1.67 g, 5.15 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated under reduced pressure. Purification of the resulting residue by column chromatography afforded a 70% yield (1.30 g) of 102d as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 6.92 (m, 2H), 6.85 (s, 1H), 6.57 (dd, 1H, J=4.8, 2.1 Hz), 4.60 (s, 2H), 3.86 (s, 3H), 2.29 (s, 3H), 1.37 (s, 9H); MS (ESI+) m/z 396.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:2]=1.[Cl:13]C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O>[Cl:13][C:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: O=C1CCN(c2cccnc2)N1
Reactant: Clc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=NN(c2cccnc2)CC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To the paste-like solid obtained from Step 1 in a 4-neck round bottomed flask (500 mL) was added chlorobenzene (120 mL). Phosphoryl chloride (10.2 mL, 0.110 mol) was added dropwise to the thick mixture over 10 minutes. The temperature of the mixture went from 22° C. to 27° C. The slurry was heated at 80° C. for 1 hour. The mixture was cooled to 25° C., water (120 mL) was added to dissolve the solids, and the temperature rose to 28° C. The two phase mixture was brought to pH˜12 with sodium hydroxide (50% in water, 42.8 g) using an ice-bath cooling to keep the temperature below 40° C. After cooling to 30° C., the mixture was transferred to a separatory funnel. The phases separated rapidly, and the bottom aqueous layer (containing some suspended solids) was removed from the dark organic phase. Attempted re-extraction of the aqueous phase with chlorobenzene (30 mL) resulted in an emulsion with solids present. The mixture was filtered through Celite®, the phases allowed to settle, and the organics added to the above organic phase to give a solution of the title compound as a dark amber liquid containing a small amount of fine solids (319 g, LC internal standard analysis indicated 4.3 wt % (75.4 mmol) 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole in the solution, for an in-pot yield of 75% starting from 3-hydrazinopyridine).
Reaction SMILES: OS([O-])=O.[Na+].O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:10]2.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>O.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][N:21]([CH3:20])[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:10]2
Reactant: CC(=O)c1ccc2cc(O)ccc2c1
Reactant: CNCCO
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc2cc(N(C)CCO)ccc2c1
Yield: 73 %

Procedure:
A mixture of 4.15 g (55.5 mmol) NaHSO3, 8 m L of water, 0.78 g (4.19 mmol) of 1-(6-hydroxy-2-naphthyl)-1-ethanone (prepared as described in Example 1(b)), and 8 mL of 2-methylaminoethanol was heated and stirred in a steel bomb at 140° C. for 28 hours. After cooling, the mixture was distributed between ethyl acetate and water (500 mL and 200 mL, respectively). The organic layer was dried and evaporated to leave raw 1-(6-(2-hydroxyethyl-methylamino)-2-naphthyl)-1-ethanone (0.749 g, 73%) of which was further purified by radial chromatography (4 mm SiO2, CH2Cl2).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]([F:42])([F:43])[F:44])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CCC(F)(F)F)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CCC(F)(F)F)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(3,3,3-trifluoropropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]#[N:29])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(C#N)ccc32)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 4a (0.29 g; 0.68 mmol) in DMF (7 mL) were added sodium azide (0.13 g, 2.0 mmol) and ammonium chloride (0.11 g; 2.06 mmol), and the mixture was heated at 120° C. for 16 h. The mixture was allowed to cool to rt, and filtered. The filtrate was acidified with 1N hydrochloric acid (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated, yielding 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a. MS m/z (M+Na) 456.9. The crude material was used as such for the next reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])[CH:7]=4)[NH:11][C:10]3=[O:15])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 54.2 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 100 mg (54%) of the title compound as a yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:64])([F:63])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:54][CH3:55])=[N:35][CH:36]=[C:37]([C:39]5[C:51]([CH3:52])=[CH:50][C:42]([C:43]([O:45]C(C)(C)C)=[O:44])=[CH:41][C:40]=5[CH3:53])[CH:38]=4)=[CH:31][CH:30]=[C:29]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[N:28]=3)[C@H:21]2[CH3:62])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>C(Cl)Cl>[F:19][C:16]([F:17])([F:18])[C:14]1[CH:13]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:54][CH3:55])=[N:35][CH:36]=[C:37]([C:39]5[C:40]([CH3:53])=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:50][C:51]=5[CH3:52])[CH:38]=4)=[CH:31][CH:30]=[C:29]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[N:28]=3)[C@H:21]2[CH3:62])[CH:11]=[C:10]([C:9]([F:64])([F:63])[F:8])[CH:15]=1
Reactant: COc1ncc(-c2c(C)cc(C(=O)OC(C)(C)C)cc2C)cc1-c1ccc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1ccc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Yield: 69.1 %

Procedure:
A solution of TFA (0.095 mL, 1.240 mmol) and tert-butyl 4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-methoxy-6′-(morpholin-4-yl)-3,3′-bipyridin-5-yl]-3,5-dimethylbenzoate (EXAMPLE 55, 44 mg, 0.055 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature overnight, after which time TLC and LCMS showed the reaction to be complete. After solvent was removed in vacuo, the crude was dissolved in CH3CN and purified by reverse phase HPLC (C18 stationary phase, using a gradient from 10-100% CH3CN/water (modified with 0.05% TFA) to give the titled compound (33 mg, 0.038 mmol, 70% yield) as white solid after lyophilization. LCMS (M+H)+: 731.0. 1H NMR (CD3OD, 500 MHz): δ 8.18 (d, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.91 (d, 1H), 7.89 (s, 2H), 7.63 (d, 1H), 7.51 (d, 1H), 7.38 (d, 1H), 6.88 (d, 1H), 5.79 (d, 1H), 4.73 (d, 1H), 4.20-4.31 (m, 1H), 4.03-4.17 (m, 1H), 3.99 (s, 3H), 3.83 (t, 4H), 3.60 (t, 4H), 2.38 (s, 3H), 0.66 (brd, 3H). RTA IC50: 9 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C(=O)CCC1=O.N>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: N
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution (20 mL) of 2-chloro-4,5-difluorobenzoic acid (1.0 g) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.15 g) and N-hydroxysuccinimide (717 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 28% aqueous ammonia solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-chloro-4,5-difluorobenzamide as a colorless solid (yield: 760 mg, yield: 76%). To a solution (5 mL) of 2-chloro-4,5-difluorobenzamide (300 mg) in N,N-dimethylformamide was added pyridine (0.253 mL), and oxalyl chloride (0.20 mL) was added dropwise thereto under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (yield: 250 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([F:24])=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.I[CH3:26]>CN(C=O)C>[Br:3][C:4]1[C:5]([F:24])=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14][CH2:13][C:9]=3[N:10]([CH3:26])[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)c(F)cc3c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(F)c(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.2 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 150 mg, 3.66 mmol) was added to a solution of tert-butyl 7-bromo-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.9 g, 2.44 mmol) in 20 ml of DMF, and the mixture was stirred for 40 min. at ambient temperature. Iodomethane (0.25 mL, 3.66 mmol) was added, and the resulting suspension was stirred for 2 h. The resulting mixture was concentrated under reduced pressure to ˜⅓ of initial volume and treated with water (20 mL). The resulting precipitate was collected by filtration, sequentially washed with water and diethyl ether and dried under vacuum to afford the title compound (0.75 g, 83%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=5.4 Hz, 1H), 7.17 (d, J=9.3 Hz, 1H), 4.45 (br s, 2H), 3.81 (br m, 2H), 3.60 (s, 3H), 2.78 (br m, 2H), 1.52 (s, 9H); ESI MS m/z 383 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1.[N+:41]([O-])([OH:43])=[O:42].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1)[N+:41]([O-:43])=[O:42]
Reactant: O=[N+]([O-])O
Reactant: O=C(NCCCCCCCCCCCO)c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=C(NCCCCCCCCCCCO[N+](=O)[O-])c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Reaction time: 6 h
Yield: 57 %

Procedure:
0.66 g of N-(11-hydroxy-1-undecanyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide were dissolved in 15 ml of methylene chloride and to the solution was added dropwise under ice-cooling a mixed solution of 0.2 ml of fuming nitric acid and 0.5 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 0.41 g (57%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:12]=1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NC(N)=S
Product: Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Yield: 77.8 %

Procedure:
Using 3′,4′-dichloroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][CH:27]=1)([OH:25])[CH2:23][OH:24]>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:22]([OH:25])([CH2:21][OH:20])[CH2:23][OH:24])=[CH:31][CH:30]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(C(O)(CO)CO)cc1)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C(O)(CO)CO)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred THF (10 mL) solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (102 mg, 0.33 mmol, 1.0 eq), TEA (0.1 mL, 0.66 mmol, 2.0 eq) followed by compound phenyl 4-(1,2,3-trihydroxypropan-2-yl)phenylcarbamate (100 mg, 0.33 mmol, 1.0 eq) was added at RT and the mixture stirred for 16 h, then it was concentrated under vacuum and the residue was purified by CC using MeOH/CHCl3 (3:17) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,2,3-trihydroxypropan-2-yl)phenyl)urea (120 mg; 75%, white solid; TLC system: MeOH/CHCl3 (1:4); Rf: 0.3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH3:17])([OH:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (1.83 g, 7.49 mmol) in THF (100 mL) was added methylmagnesium bromide (21.4 ml of 1.4M solution, 29.96 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added aqueous saturated NH4Cl solution and EtOAc. The organic phase was washed with brine and dried with MgSO4, filtered and concentrated in vacuo. The two spots were separated by silica gel chromatography (120 g silica gel column).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[N:3]1[CH2:8][CH2:7][C:6]([NH:11][OH:12])([C:9]#[N:10])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[CH2:28][C:29](Cl)=[O:30].O>O1CCCC1>[C:9]([C:6]1([N:11]([OH:12])[C:29](=[O:30])[CH2:28][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][C:22]=2[CH3:27])[CH2:7][CH2:8][N:3]([N:2]([CH3:13])[CH3:1])[CH2:4][CH2:5]1)#[N:10]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CN(C)N1CCC(C#N)(NO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(CC(=O)N(O)C2(C#N)CCN(N(C)C)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4.31 g 1-Dimethylamino-4-hydroxyamino-piperidine-4-carbonitrile (from Step 2) is dissolved in 70 ml tetrahydrofuran. 3.34 g sodium bicarbonate is added, and the mixture cooled to 0° C. Then at 0° C., a solution of (2,4,6-trimethyl-phenyl)-acetyl chloride in 30 ml tetrahydrofuran is added slowly. The mixture is allowed to warm to room temperature and stirred for 4 hours. The water is added and three times extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over sodium sulfate, and the solvent is evaporated. The residue is purified by chromatography, with ethyl acetate/cyclohexane (2:1) as a solvent. Thus, 3.9 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-N-hydroxy-2-(2,4,6-trimethyl-phenyl)-acetamide is obtained. 1H-NMR (CDCl3): 8.18 ppm (s, broad, 1H), 6.86 ppm (s, 2H), 3.81 ppm (s, 2H), 2.97 ppm (m, 2H), 2.72 ppm (m, 2H), 2.52 ppm (m, 2H), 2.40 ppm (s, 6H), 2.25 ppm (s, 3H), 2.21 ppm (s, 6H), 2.12 ppm (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:7]=1.[Cl:26][C:27]([O:29][CH3:30])=[O:28].Cl>N1C=CC=CC=1>[ClH:26].[CH:23]([S:20]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:28])[O:29][CH3:30])=[CH:7][C:6]=1[C@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)(=[O:21])=[O:22])([CH3:24])[CH3:25]
Reactant: COC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(N)cc1[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1F (0.1 g, 0.27 mmol) in pyridine (1 mL) at 0° C. was added methyl chloroformate (57 (μL, 0.54 mmol). After 2.0 h of stirring at rt the reaction was acidified with 1M HCl to pH 3-4. The product was extracted with ethyl acetate and was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was redissolved in ethyl acetate (1.5 mL) and hydrogen chloride (2 mL, 4M in dioxane) was added. The reaction was stirred for 3 h at rt. The solvent was removed and placed on the lyophilizer to give 0.15 g white solid 1G. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.25 (t, J=7.09 Hz, 3H) 1.37 (d, J=6.85 Hz, 3 H) 2.13-2.31 (m, 1H) 2.31-2.47 (m, 2H) 2.47-2.63 (m, 1H) 3.36-3.56 (m, 3H) 3.73-3.91 (m, 3H) 5.43 (t, J=7.70 Hz, 1H) 7.66 (dd, J=8.80, 2.20 Hz, 1H) 7.97 (d, J=8.80 Hz, 1H) 8.11 (d, J=1.96 Hz, 1H).