Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11](O)[C:10]2[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:40]=[N+:41]=[N-:42])[C:10]2[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Yield: 71.3 %

Procedure:
Heat a mixture of (R)-7-ethyl-5-hydroxy-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (7.59 g, 21.12 mmol), diphenylphosphoryl azide (DPPA, 5.50 mL, 25.64 mmol) and DBU (3.95 mL, 26.41 mmol) in toluene (200 mL) at 65° C. under nitrogen for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (5.79 g, 71%): 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 18H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 1H), 7.31-7.45 (m, 2H); APCI MS m/z 356 (M−N2)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:13]1[CH2:14][CH2:15][CH:10]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:11][CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A solution of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine (3.21 g, 0.0106 mol), triethylamine (2.5 g, 0.025 mol), and benzoyl chloride (1.70 g, 0.012 mol) in 400 mL of methylene chloride was stirred 16 h at room temperature. The reaction was concentrated to dryness and dissolved in chloroform. The chloroform layer was extracted successively with water, 1N sulfuric acid, and 5% sodium hydroxide. The chloroform layer was dried (Na2SO4) and filtered. The chloroform was removed to give a fluffy-white residue. This material was dissolved in methylene chloride and chromatographed by flash chromatography on silica gel. Elution was accomplished using methylene chloride, 1% acetone-methylene chloride, 2% acetone-methylene chloride, and 4% acetone-methylene chloride. Fractions of similar purity were combined, and solvents removed to give a fluffy-white residue. This material was triturated with isopropyl ether and chilled in a freezer. A white solid was isolated and dried, 16 h at 78° C. This furnished 1.40 g (32.5%) of white crystalline solid, mp 157°-158° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)C.[OH-].[K+].Cl>CO.O>[CH2:14]([C:9]1[CH:8]=[C:7]([CH2:6][CH:5]([O:21][CH2:22][CH3:23])[C:4]([OH:24])=[O:3])[CH:12]=[CH:11][C:10]=1[OH:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cc2ccccc2)c1)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester (0.38 g, 1.16 mmol) in MeOH (5 mL), a solution of KOH (1.62 g, 29 mmol) in H2O (5 mL) was added. The mixture was stirred for 2 h at room temperature then acidified with aq. HCl (10%) and extracted with dichloromethane. The combined organic layers were dried and evaporated and the remaining crude product was purified by column chormatography to yield the title compound as an oil (0.35 g, 74.8%). Mass Spectrum: M+H+ 300.94, M−H+ 298.99.
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]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:30]=[O:31])C>>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:10]([C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH:30]=[O:31])=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[CH2:17][CH2:16]1
Reactant: CN(C)C=O
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2C=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.206 g) in DMF (1.5 mL) at 0° C. was treated with phosphorus oxychloride (0.1 mL) over 10 min. The reaction mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was poured into water and adjusted to neutral pH by addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.108 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]4[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(C(F)(F)F)c1
Yield: 32 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(trifluoromethyl)benzoyl chloride to afford the title compound as an off-white solid (17 mg, 32%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.94 (d, 1H, Harom, J=8.0 Hz), 7.44 (ps t, 1H, Harom, J=8.0 Hz), 7.62 (s, 1H, Harom), 7.66 (d, 1H, Harom, J=7.5 Hz), 7.72-7.82 (m, 2H, Harom+Py,6), 7.96 (d, 1H, Harom, J=8.0 Hz), 8.24 (d, 1H, Harom, J=7.5 Hz), 8.26 (s, 1H, Harom), 10.55 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.62, 110.87, 113.79, 114.73, 116.37, 123.93, 124.26, 128.28, 129.19, 129.75, 130.25, 131.85, 135.54, 140.48, 141.35, 144.55, 147.17, 154.21, 154.78, 164.22. HRMS (EI): m/z [M+H] calcd for C20H14F3N4O3: 415.1018; found: 415.1010.
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:19])[C:12](=[CH:17][CH:18]=1)[C:13](OC)=[O:14]>CCOCC>[OH:19][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[CH:18]=[CH:17][C:12]=1[C:13]([NH:2][OH:3])=[O:14]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(=O)NO)c(O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Prepare 4-(6-methoxybenzo[d]isoxzaol-3-yl)piperazine by slowly adding a solution of hydroxylamine hydrochloride (57.2 g, 0.823 mol) and water (600 mL) to a solution of sodium hydroxide (76.9 g, 1.92 mol) and water (300 mL). Then add a solution of methyl 4-methoxysalicylate (100 g, 0.55 mol, Aldrich Chemical Co.) and ether (800 mL), stir overnight, evaporate the ether, acidify with dilute hydrochloric acid, cool to 0° C., and filter. Recrystallize the filter cake from methanol to afford the 2-hydroxy-p-anisohydroxamic acid (78 g). Treat a warm (50° C.) solution of the hydroxamic acid (78 g) and tetrahydrofuran (500 mL) under nitrogen with a solution of carbonyldiimidazole (138.1 g, 0.85 mol) and tetrahydrofuran (500 mL), reflux for 3.5 hours, quench by addition of water (1000 mL), acidify to pH 3, add water (1000 mL) and refrigerate overnight. Collect the solid, wash with water and recrystallize from methanol to afford 54 g of 3-hydroxy-6-methoxy-1,2-benzisoxazole. Heat a stirred mixture of 3-hydroxy-6-methoxy-1,2-benzisoxazole (54 g) and POCl3 (100.3 g, d 1.645) at 95° C. under nitrogen, cool to 30° C., add triethylamine (33 g), heat at 140° C. overnight, quench with stirring into ice water and filter. Dissolve the filter cake in cyclohexane (2000 mL), filter, concentrate and recrystallize the residue from petroleum ether to give 3-chloro-6-methoxy-1,2-benzisoxzole (33 g). Treat this product with piperazine as described in U.S. Pat. No. 5,852,022, the contents of which are herein incorporated by reference, to afford 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([O:31][C:32]3[C:37]4[N:38]=[C:39]([NH2:41])[S:40][C:36]=4[CH:35]=[CH:34][CH:33]=3)[CH:26]=2)=[CH:23][CH:22]=[C:21]([C:42]([F:45])([F:44])[F:43])[N:20]=1.C(=O)([O-])[O-].[K+].[K+].[C:52](OC(=O)C)(=[O:54])[CH3:53]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([O:31][C:32]3[C:37]4[N:38]=[C:39]([NH:41][C:52](=[O:54])[CH3:53])[S:40][C:36]=4[CH:35]=[CH:34][CH:33]=3)[CH:26]=2)=[CH:23][CH:22]=[C:21]([C:42]([F:45])([F:43])[F:44])[N:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCCCN1CCCNc1nc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(N)nc23)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NCCCN4CCCCC4C)ncn3)cccc2s1
Temperature: 90 °C

Procedure:
A mixture of 4-(6-(2-(3-(2-methylpiperidin-1-yl)propylamino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo [d]thiazol-2-amine trifluoroacetic acid salt, Example 80, (29 mg, 0.052 mmol), potassium carbonate (35 mg, 0.253 mmol) and acetic anhydride (2 mL) was heated at 90° C. in a microwave synthesizer for 10 min. to give MS (ESI, pos. ion.) m/z: 658 (M+1). The reaction mixture was dissolved in DCM (10 mL), filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Prodigy 5μ ODS-3 100 Å column, gradient: 20-100% CH3CN (0.1% TFA)/H2O (0.1% TFA) over 15 min) to give the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 700 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.O[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
A solution of 116 mg (0.5 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoic acid, 58 mg (0.5 mmol) of ethyl 4-hydroxybenzoate, 117 mg (0.56 mmol) of 1,3-dicyclohexylcarbodiimide and 30 mg (0.25 mmol) of 4-dimethylaminopyridine in 15 ml of methylene chloride was stirred at room temperature for 12 hours. The reaction mixture was then filtered and the filtrate concentrated in-vacuo. The resultant residue was purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as white crystals.
Reaction SMILES: [ClH:1].[CH2:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2OC)(=[O:12])[CH3:11]>O.C(O)CCC>[ClH:1].[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[NH:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: COc1cc(C)nc2ccc(NC(C)=O)cc12
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CC(=O)Nc1ccc2nc(C)cc(NCc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 96 h
Yield: 70.6 %

Procedure:
A warm solution of benzylamine hydrochloride (1.5 g, 10.4 mmol) in water (2 mL) was added to a mixture of 6-acetamido-4methoxy-2-methylquinoline (2.0 g, 8.7 mmol) in n-butanol (20 mL). The mixture was stirred for 4 days at 100° C., cooled in an ice bath, and the resulting precipitated solid was filtered, washed with ether, and dried by suction to afford 2.1 g (71%) of 6-acetamido-4-benzylamino-2-methyl-quinoline hydrochloride. This material was heated in 25% hydrochloric acid (33 mL) for 5 h at 90° C. After cooling, the separated solid was filtered, washed with ether, and dried by suction. The solid was dissolved in water, made basic (pH >10) with 5N sodium hydroxide to afford a yellow solid that was filtered, washed with water, and dried. 6Amino-4-benzylamino-2-methyl-quinoline was obtained in 43% yield (0.98 g). 0.5 Grams (1.9 mmol) of this material was dissolved in glacial acetic acid, and the solution was treated with oxalyl chloride (0.17 mL) for 1 h at room temperature with stirring. Ether was then added (25 mL) and the mixture stirred for 30 min. The solid was filtered, washed with ether, and dried by suction. It was dissolved in water (25 mL) and warm ethanol (200 mL) with additional water added to achieve complete solution. After cooling to room temperature, 5N sodium hydroxide was added to give a yellow precipitate that was filtered, and dried under high vacuum to yield 0.46 g (41%) of the title compound; m.p. 292-294° (dec.); MS (FAB): m/z 581 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14](=O)[CH3:15])=[CH:8][CH:7]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(SCC(C)=O)cc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [4-(2-Oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:41][CH2:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(CCN)cc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc(CCNC(=O)[C@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 47 %

Procedure:
Prepared analogously to Example 8a) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4-methoxybenzenethanamine and TBTU in a yield of 47% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1.[CH3:26][NH:27][CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([N:27]([CH3:28])[CH3:26])=[O:18])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 1 dram vial was added 4-[2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-benzoyl chloride (300 mL, 0.3 mmol) as a 0.1M solution in Dichloromethane, Dimethyl-amine (27 mg, 0.6 mmol) and N,N-Diisopropylethylamine (77.4 mg, 0.6 mmol). The reaction was stirred at room temperature for 30 min and then placed directly on silica and purified using a gradient of Hexane to Ethyl Acetate 0-50% over 10 CV. The relevant fractions were combined and dried in vacuo to give 108.6 mg (92%) of an off white solid; MS (ES): 394 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 7.84 (dd, J=7.8 Hz; 1.7 Hz 1H), 7.73-7.58 (m, 3H), 7.45-7.35 (m, 5H), 3.00 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([CH:10]([F:12])[F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](I)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC([O-])(C)C.[K+]>CN(C=O)C>[C:1]1([S:7]([C:10]([F:12])([F:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCI
Reactant: O=S(=O)(c1ccccc1)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCC(F)(F)S(=O)(=O)c1ccccc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Typical Procedure for Nucleophilic Substitution Reactions of Difluoromethyl Phenyl Sulfone with Alkyl Iodides. Under an argon atmosphere, into a Schlenk flask containing difluoromethyl phenyl sulfone (192 mg, 1 mmol) and n-heptyl iodide (904 mg, 4 mmol) in DMF (4 mL) at −50° C., was added dropwise via a syringe t-BuOK (224 mg, 2 mmol) in DMF (4 mL). The reaction mixture was stirred at −50° C. for 1 h, and the completion of the reaction was monitored by 19F NMR. The reaction was then quenched by adding 1N HCl aqueous solution (5 mL) at −50° C., followed by warming to room temperature. A saturated NaCl aqueous solution (10 mL) was added, and the mixture was extracted with Et2O (15 mL×3). The combined organic phase was dried over MgSO4, filtered, and the solvent was removed in a rotary evaporator. The residue was further purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1,1-difluorooctyl phenyl sulfone (4a) (230 mg, 79% yield) as a colorless oily liquid. 1H NMR (500 MHz, CDCl3): δ 0.88 (t, J=6.9 Hz, 3 H); 1.28 (m, 8 H); 1.64 (m, 2 H); 2.33 (m, 2H); 7.60 (t, J=8.3 Hz, 2H); 7.73 (t, J=7.3 Hz, 1H); 7.99 (d, J=7.9 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9; 20.7 (t, J=3.4 Hz); 22.4; 28.7; 29.0; 29.1; 31.4; 124.6 (t, J=286 Hz); 129.1; 130.6; 132.7; 135.1. 19F NMR (470 MHz, CDCl3): δ −104.2 (t, J=19 Hz). GC-MS (EI, m/z): 291 (M++1); 142; 77. HRMS (EI): m/z calcd for C14H21F2O2S (M++H) 291.1230, found 291.1222.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(Cl)cccc2Cl)N2CCCOCC2)cn1

Procedure:
From 2,6-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:9][C@@H:10]1[N:15]([C:16]2[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)[S:5]([CH3:8])(=[O:7])=[O:6])[CH3:3].C(O)(C(F)(F)F)=O.[Cl:46][C:47]1[N:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>C(Cl)Cl>[Cl:46][C:47]1[N:52]=[CH:51][C:50]([S:53]([N:12]2[CH2:13][CH2:14][N:15]([C:16]3[N:17]=[CH:18][C:19]([C:22]([OH:31])([C:23]([F:25])([F:26])[F:24])[C:27]([F:29])([F:30])[F:28])=[CH:20][N:21]=3)[C@@H:10]([CH2:9][N:4]([CH:2]([CH3:3])[CH3:1])[S:5]([CH3:8])(=[O:6])=[O:7])[CH2:11]2)(=[O:55])=[O:54])=[CH:49][CH:48]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A 5-mL vial was charged with tert-butyl (3R)-3-(((1-methylethyl)(methylsulfonyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.150 g, 0.259 mmol, step 2), TFA (1.0 mL, 13 mmol) and CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature for 30 min and then the volatiles were removed in vacuo. To the resulting residue was added CH2Cl2 (2 mL) followed by TEA (0.40 mL, 2.9 mmol). The mixture was stirred at room temperature for 10 min and then 6-chloropyridine-3-sulfonyl chloride (0.0627 g, 0.296 mmol, Organic Process Research & Development 2009, 13, 875) was added. After 10 min at room temperature, the mixture was concentrated and the crude product was purified by column chromatography (25 g of silica gel, 0 to 50% EtOAc in hexanes) to afford N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide (0.163 g) as a light-yellow solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1.[Cl:22][C:23]1[CH:36]=[C:35]([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:34]([Cl:43])=[CH:33][C:24]=1[O:25][C@H:26]1[CH2:29][C@H:28]([CH2:30][NH:31][CH3:32])[CH2:27]1>C1COCC1>[Cl:22][C:23]1[CH:36]=[C:35]([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:34]([Cl:43])=[CH:33][C:24]=1[O:25][C@H:26]1[CH2:27][C@H:28]([CH2:30][N:31]([CH3:32])[C:19]([CH:16]2[CH2:15][CH2:14][O:13][CH2:18][CH2:17]2)=[O:21])[CH2:29]1
Reactant: CNC[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1
Reactant: O=C(O)C1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1)C(=O)C1CCOCC1

Procedure:
CDI (71 mg, 0.43 mmol) was added to a solution of tetrahydropyran-4-yl-carboxylic acid CAS 5337-03-1 (57 mg, 0.43 mmol) in THF (2 ml) at RT under stirring, the mixture was stirred at RT for 1 h. Example 381, ({trans-3-[2,5-dichloro-4-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (100 mg, 0.29 mmol) was added to the mixture and the solution was stirred at RT for 20 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 5 g, hexane/CHCl3 20:80→0:100, then CHCl3/MeOH 100:0→95:5). The residue was dissolved in ether (1 mL). 4N HCl/dioxane (0.20 mL) was added, and the reaction mixture was evaporated to dryness. The obtained crystals were washed with ether and dried in vacuo to give the title compound (70 mg, 50% yield). LC/MS data: 455.1 (M+H) (calculated for C23H32Cl2N2O3 455.43). 1H NMR-data (DMSO-d6): 10.64 (br. s, 1H, NH+); 7.88-8.09 (m, 1H, Ar—H); 7.00-7.13 (m, 1H, Ar—H); 4.88-5.37 (m, 1H), 4.32-4.44 (m, 2H); 3.79-3.91 (m, 2H); 3.33-3.56 (m, 6H); 2.98-3.15 (m, 4H); 2.76-2.93 (m, 2H); 2.56-2.65 (m, 1H); 2.10-2.33 (m, 4H); 1.81-2.07 (m, 4H); 1.46-1.69 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH3:9])[N:3]=1.[NH4+:16].[OH-]>>[N:10]1([CH:8]([C:4]2[N:3]=[C:2]([NH2:16])[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(c1cccc(Br)n1)N1CCCCC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(c1cccc(N)n1)N1CCCCC1

Procedure:
In a manner similar to that described in Preparation BW, 2-bromo-6-(1-piperidin-1-yl-ethyl)-pyridine (370 mg, 1.37 mmol) was heated with NH4OH (18 mL), IpOH (10 mL), and Cu (30 mg) in sealed tube to give a brown oil. MS m/z: 206.1 (M+H). Calc'd. for C12H19N3-205.16.