Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl-].[NH2:11][CH:12]([CH2:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]2[C:28]=1[CH:29]=[CH:30][N:31]2[S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14].[C:47]1([S:53](Cl)(=[O:55])=[O:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl.CCOCC>[C:47]1([S:53]([NH:11][CH:12]([CH2:26][C:27]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]3[C:28]=2[CH:29]=[CH:30][N:31]3[S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:14])(=[O:55])=[O:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(CC(N)C(=O)NCCCCc2ccccc2)c2ccn(S(=O)(=O)c3ccccc3)c12
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Hunig's base (2.1 g, 16 mmol) is added to a suspension of 2-amino-3-(1-benzenesulfonyl-7-methoxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide, hydrogen chloride salt (3.0 g, 5.6 mmol) in CH2Cl2. The resulting solution is cooled to 0° C. and benzenesulfonyl chloride (1.2 g, 6.9 mmol) is added. After being warmed to rt and stirred 2 h, the reaction mixture is diluted with Et2O and washed sequentially with 0.5 M HCl and saturated NaHCO3 solutions. The aqueous phases are extracted once with Et2O. The desired compound crystallizes at this point. The volatiles are removed in vacuo and the remaining residue is azeotroped sequentially with dioxane and toluene to provide 2-benzenesulfonylamino-3-(1-benzenesulfonyl-7-methoxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide as a solid which is used as is without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2([O:18][CH3:19])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:8]2([O:18][CH3:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: COC1(c2ncccc2Cl)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a solution of the product of Example 7A (2.147 g, 7.57 mmol) in dioxane (40 mL) was added 3N hydrochloric acid (25 mL). The reaction mixture was stirred at ambient temperature for 3 hours, quenched with 3N sodium hydroxide (35 mL), followed by addition of water (200 mL), extracted twice with ethyl acetate (200 mL), washed with water (200 mL) and brine, dried with anhydrous sodium sulfate, filtered and concentrated to a yellow oil. The residue was chromatographed on silica gel, eluting with 0-to-30% ethyl acetate in hexane to provide 1.698 g (94% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17-2.31 (m, 4H), 2.54-2.65 (m, 4H), 3.01 (s, 3H), 7.42 (dd, J=7.97, 4.58 Hz, 1H), 7.94 (dd, J=8.14, 1.36 Hz, 1H), 8.54 (dd, J=4.58, 1.53 Hz, 1H). MS (DCI) m/z 240.05 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:8](Cl)[C:9](=[CH2:11])[CH3:10].C(#N)CCCCC#N.[OH-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]([N:4]([CH2:10][C:9](=[CH2:8])[CH3:11])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C(C)CCl
Reactant: CC(C)NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: N#CCCCCC#N
Product: C=C(C)CN(C(C)C)C(C)C

Procedure:
A mixture of diisopropylamine (20.24 g, 0.2 mol), methallyl chloride (9.00 g, 0.1 mol), adiponitrile (10.81 g, 0.1 mol) and tetrabutylammonium iodide (3.69 g, 10 mmol) was refluxed for 5 h with vigorous stirring (two phases). The temperature of the mixture increased from 88° to 125° C. Potassium hydroxide solution (5M, 15 ml, 0.15 mol) was added. Three layers formed. The mixture was extracted with n-pentane (2×50 ml). Adiponitrile (the middle layer) was recovered. The pentane solution was dried with anhydrous magnesium sulfate and the product was isolated by distillation: 12.58 g (81%), bp 75-77° C/45 mm Hg. 1H NMR CDCl3 δ ppm, 0.98 (d, J=6.6 Hz, 12H, CH3), 1.70 (s, 3H, CH3), 2.97 (m, 4H, CH2, CH), 4.78 (s, 1H,=CH2), 4.93 (m, 1H,=CH2) .
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([O:11]CC)=[O:10])[N:3]=1.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[N:3]=1
Reactant: CCOC(=O)Cn1nc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.7 %

Procedure:
A solution of ethyl 3,5-dichloro-1H-pyrazole-1-acetate (1.29 g, 5.8 mmol) (i.e. the product of Example 12, Step E) in tetrahydrofuran (10 mL) was treated with sodium hydroxide (5 mL, 15% aqueous solution) in water (3 mL), and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was then diluted with water (15 mL) and was concentrated under reduced pressure. The aqueous solution was acidified with concentrated hydrochloric acid to pH 1. The reaction mixture was then extracted with ethyl acetate and the extract was dried over MgSO4. The extract was then concentrated and recrystallized from 20% ethyl acetate in hexanes to give 370 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH:22]2[CH2:24][CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Reactant: NC1CC1
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(NC3CC3)nc(N)nc21

Procedure:
A solution of 2-amino-4-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 4, Step B) (21 mg, 0.07 mmol) in cyclopropylamine (0.5 mL) was heated at 70° C. for two days, then evaporated to an oily residue and purified on a silica gel column with CH2Cl2/MeOH, 20/1, as eluent to give the title compound as a white solid (17 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[S:41]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42]1>O1CCCC1.O>[F:25][C:11]1[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13][N:14]([S:46]([C:43]2[CH:44]=[CH:45][S:41][CH:42]=2)(=[O:48])=[O:47])[C:10]=1[C:9]1[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccsc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a suspension of sodium hydride (60% in oil, 37 mg) in tetrahydrofuran (2 mL) were added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate in tetrahydrofuran (1 mL), 15-crown-5 (205 mg) and 3-thiophenesulfonyl chloride (136 mg) at room temperature and the mixture was stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 264 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH:9][C:10]([CH3:43])([CH3:42])[CH2:11][C@:12]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:17][CH2:16][N:15]([C@H:18]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)[CH3:19])[C:14](=[O:35])[CH2:13]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:9][C:10]([CH3:43])([CH3:42])[CH2:11][C@:12]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:17][CH2:16][N:15]([C@H:18]([C:20]2[CH:21]=[CH:22][C:23]([C:2]3[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=3)=[CH:24][CH:25]=2)[CH3:19])[C:14](=[O:35])[CH2:13]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Reactant: O=c1ccc(Br)c[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (30 mg, 0.17 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under N2. The mixture was stirred at rt for 1 h. (R)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)piperidin-2-one (25 mg, 0.05 mmol) in EtOH (2 mL) was added, followed by satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for another 2 h under N2. The reaction was quenched with H2O, and extracted with EtOAc (3×). The combined organic phase was dried and concentrated to give the crude final product, which was purified by preparative TLC to give 5-(4-((S)-1-((R)-4-(2-hydroxy-2-methylpropyl)-2-oxo-4-phenylpiperidinyl)ethyl)phenyl)pyridin-2(1H)-one (4.5 mg, 20%). LC-MS Method 2 tR=1.034 min, m/z=445.2; 1H NMR (CDCl3): δ 0.86 (s, 3H), 1.02 (s, 3H), 1.41 (d, 3H), 1.82 (d, 2H), 2.00 (m, 2H), 2.11 (m, 2H), 2.62 (d, 1H), 2.85 (m, 1H), 3.42 (d, 1H), 6.0 (m, 1H), 6.69 (m, 1H), 6.88 (m, 2H), 7.09 (m, 2H), 7.17 (m, 1H), 7.25 (m, 4H), 7.51 (m, 1H), 7.78 (m, 1H).
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=1.[ClH:17]>CO>[ClH:17].[ClH:17].[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][NH:3][O:2][CH3:1])=[CH:12][CH:11]=1
Reactant: CONCCCc1ccc(NC(C)=O)cc1
Agent: Cl
Solvent: CO
Product: CONCCCc1ccc(N)cc1
Temperature: 60 °C

Procedure:
A mixture of N-[4-(3-methoxyamino-propyl)-phenyl]-acetamide (0.50 mmol) and 20% aqueous hydrochloric acid (2 mL) in methanol (8 mL) is heated for 18 hours at 60° C. and then concentrated under reduced pressure to give N-[3-(4-amino-phenyl)-propyl]-O-methyl-hydroxylamine dihydrochloride (62 mg, 0.24 mmol) and is used in the following step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[C:9]([CH3:21])=[N:8][CH:7]=1.[OH:22][C:23]1[CH:24]=[CH:25][C:26]([I:32])=[C:27]([CH:31]=1)[C:28](O)=[O:29].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][NH:3][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([OH:22])[CH:24]=[CH:25][C:26]=3[I:32])=[CH:7][N:8]=[C:9]2[CH3:21])=[CH:13][C:14]=1[F:20])#[N:17]
Reactant: Cc1ncc(CCN)n1Cc1ccc(C#N)c(F)c1
Reactant: O=C(O)c1cc(O)ccc1I
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(CCNC(=O)c2cc(O)ccc2I)n1Cc1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-[5-(2-amino-ethyl)-2-(methyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride as prepared in Example 10, Step A (2.00 g, 6.038 mmol), 5-hydroxy-2-iodobenzoic acid (1.594 g, 6.038 mmol), 1-Hydroxybenzotriazole hydrate (816 mg, 6.038 mmol), and triethylamine (2.52 mL, 18.114 mmol) in dry DMF (12.0 mL) was cooled to 0° C., and EDC (1.158 g, 6.038 mmol) was added. After stirring at 0° C. for 15 minutes, the reaction mixture was stirred at ambient temperature overnight, then poured into water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was preabsorbed onto silica gel and purified by flash chromatography eluting with a gradient of 6-9% MeOH/CH2Cl2 to give the titled product.
Reaction SMILES: CO[C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:24])(=[O:23])[NH:10][C:11]3[C:20]2=[CH:19][CH:18]=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4].[CH3:25][NH2:26]>>[CH3:25][NH:26][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:23])(=[O:24])[NH:10][C:11]3[C:20]2=[CH:19][CH:18]=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Reactant: CN
Product: CNC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 81.3 %

Procedure:
In a similar fashion using route 53 general procedure 122,6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 307 (20 mg, 0.058 mmol), methylamine (33% in EtOH; 4 ml, 0.58 mmol) at 100° C. gave the title compound (16 mg 84%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][O:14][NH2:15].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:15][O:14][CH3:13])=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a mixture of 2,5-difluorobenzoyl chloride (1.77 g, 10 mmol) and O-methylhydroxylamine hydrochloride (830 mg, 10 mmol) in methylene chloride (25 mL) at 0° C. was added dropwise triethylamine (2.8 mL, 20 mmol) and the mixture was stirred at room temperature for 8 h. The mixture was then washed with water, brine, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed (hexane-EtOAc 2:1) to afford 1.4 g of the title compound. 1H NMR (300 MHz-DMSO-d6) δ 3.70 (s, 3H), 7.42 (m, 3H), 11.64 (s, 1H); MS (DCI/NH3) m/z 188 (M+H)+, 205 (M+NH4)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[CH3:19][CH:20]([NH2:22])[CH3:21]>O1CCCC1>[CH:20]([NH:22][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:21])[CH3:19]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])c(NC(C)C)c1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A mixture of 2-fluoro-4-methyl-1-nitrobenzene (250 mg, 1.6 mmol), triethylamine (200 mg, 2.0 mmol), and 2-propanamine (200 mg, 3.4 mmol) in tetrahydrofuran (1 mL) was heated at 25° C. for 5 hours. The crude product was purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (1:2)], giving the desired product (150 mg, 48%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:22]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[N:25]=3)[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:22]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[N:25]=3)[CH:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CN1CCC(n2cc(-c3ccc(F)cc3)nc2-c2ccnc(NC3CCN(Cc4ccccc4)CC3)n2)CC1
Agent: [Pd]
Product: CN1CCC(n2cc(-c3ccc(F)cc3)nc2-c2ccnc(NC3CCNCC3)n2)CC1
Reaction time: 18 h

Procedure:
A mixture of 5-[(2-(1-benzyl-4-piperidinylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole (0.50 g, 0.95 mmol) and 10% palladium on carbon (10%) was stirred under an atmosphere of H2 for 18 h. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was recrystallized from EtOAc/hexanes to afford the title compound as a white solid; yield 0.98 g (24%): mp=201°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:29]([C:35]([F:38])([F:37])[F:36])([C:31]([F:34])([F:33])[F:32])[OH:30])=[N:9]1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:29]([C:31]([F:34])([F:32])[F:33])([C:35]([F:36])([F:38])[F:37])[OH:30])=[N:9]1
Reactant: COC(=O)c1cncc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cncc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-(4-(5-methoxycarbonyl-pyridin-3-yl)-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (6.0 mg, 0.01 mmol) prepared in Example 273 in methanol (0.5 mL), was added a solution of potassium hydroxide (2.0 mg, 0.03 mmol) in distilled water (0.5 mL). The reaction mixture was stirred at 70° C. for 2 hours and then washed with diethyl ether. A 1N hydrochloric acid solution was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:42][CH2:43][CH2:44][OH:45]>C(Cl)Cl>[OH:45][CH2:44][CH2:43][NH:42][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:20][CH:21]=1)=[O:24]
Reactant: NCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (50 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride(0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. And then, triethylamine (0.7 ml) and 2-aminoethanol(1.27 g) were added in order, the solution was stirred at 0~5° C. for 2 hours and heated slowly to 20~25° C. and stirred for 30 minutes. The reaction mixture was washed with water twice and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using isopropanol and ether. The recrystallized product was filtered and dried to give 1.34 g (yield: 80%) of the desired compound as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:44])([CH3:43])[CH2:7][N:8]([S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[CH2:9][C@@H:10]([OH:31])[C@@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.Cl[C:55]([O:57][CH3:58])=[O:56]>C1COCC1>[CH2:12]([C@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:10]([OH:31])[CH2:9][N:8]([CH2:7][C:6]([CH3:44])([CH3:43])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:55]([O:57][CH3:58])=[O:56])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cl
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCN)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCNC(=O)OC)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 55 mg (0.087 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((6-amino-2,2-dimethylhexyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17.0 μL (0.091 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 7.0 μL (0.091 mmol) of methyl chloroformate. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 55 mg (92%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.34-7.12 (m, 6H), 7.02 (d, 1H), 6.94 (s, 1H), 6.78 (d, 1H), 5.60 (d, 1H), 5.17 (d, 1H), 5.02-4.70 (m, 2H), 4.14 (s, 1H), 4.02 (m, 1H), 3.89 (dd, 1H), 3.79 (m, 2H), 3.72-3.55 (m, 5H), 3.28-2.91 (m, 6H), 2.83 (s, 3H), 2.89-2.64 (m, 3H), 1.65-1.18 (m, 8H), 0.91 (s, 3H), 0.88 (s, 3H). MS (ESI): 691 (M+H).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][SH:8].[CH3:15]I>CO.C[O-].[Na+]>[CH3:15][S:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1-c1ccccc1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCc1ccccc1-c1ccccc1
Temperature: 60 °C
Yield: 77 %

Procedure:
A mixture of biphenyl-2-yl-methanethiol (4 g, 20 mmol) in methanol (27 mL) and sodium methoxide in methanol (0.5 M, 40 mL) was heated at 60° C. for 0.5 h, cooled, treated with methyl iodide (3.7 mL, 60 mmol) and re-heated at 60° C. for 0.5 h. After cooling to room temperature, the reaction mixture was quenched with ice-water, acidified (pH˜2) and extracted with ethyl acetate (3×50 mL). Combined organic layer was washed with water (1×50 mL) and brine (1×50 mL), dried (MgSO4), and concentrated to give a crude product that was passed through a bed of silica (solvent: ethyl acetate) to give 3.3 g of 2-methylsulfanylmethyl-biphenyl (yellow oil) that was directly used in the next step.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:27](I)[CH3:28].NO.[H-].[Na+]>[Pd].CS(C)=O.O1CCCC1.O>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH2:27][CH3:28])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CCI
Agent: [Pd]
Agent: NO
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 48.5 %

Procedure:
A mixture of 28.3 grams (102 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 5.0 grams of magnesium sulfate, 1.0 gram of 5% palladium on carbon, and 100 ml of anhydrous tetrahydrofuran is hydrogenated (50 psi, room temperature) on a Parr apparatus. Solids are removed by filtration, and ethyl iodide (32.1 grams, 206 mmol) is added to the crude hydroxylamine solution. A solution obtained by refluxing a suspension of 3.7 grams (154 mmol) of sodium hydride in 10 ml of dimethyl sulfoxide and 50 ml of tetrahydrofuran is then added over 30 minutes to the hydroxylamine solution. The reaction mixture is diluted with water (1 liter) and extracted with ether (2×150 ml). The combined organic layers are washed with water (2×1000 ml), washed with saturated sodium chloride solution (500 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel; 9:1 hexane:ethyl acetate) and crystallized from methanol to afford 15.1 grams (48% yield) of the title compound as a white solid melting at 76°-78° C.