Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:24]1([O:27][CH2:28][CH3:29])[CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH:21][C:24]3([O:27][CH2:28][CH3:29])[CH2:26][CH2:25]3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: CCOC1(Br)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC1(Nc2cccnc2N(C)C2CCN(Cc3ccccc3)CC2)CC1

Procedure:
A mixture of 1-benzyl-4-[N-methyl-N-(3-amino-2-pyridinyl)amino]piperidine (EXAMPLE 122, 825 mg), 1-bromo-1-ethoxycyclopropane (919 mg) and triethylamine (0.78 ml) in dry tetrahydrofuran (1.4 ml) under nitrogen is refluxed for 48 hrs, cooled to 20°-25°, diluted with methylene chloride (30 ml), washed with saline (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The residue is chromatographed (silica gel, 70-230 mesh, 140 g; eluting with a gradient of methanol/methylene chloride (1/99-5/95)) to give the title compound, NMR (CDCl3) 7.80, 7.41, 7.25, 6.93, 5.62, 3.51, 3.48, 3.03, 2.87, 2.60, 1.98, 1.71, 1.64, 1.13 and 0.85δ.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:33]1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[CH2:33]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: NC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1nc(NC2CCCN(C(=O)OCc3ccccc3)C2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.2 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in 1,4-dioxane (5 ml) was added potassium carbonate (0.42 mmol) and benzyl 3-aminopiperidine-1-carboxylate hydrogen chloride (0.15 mmol). The reaction mixture was stirred at room temperature for 24 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (59 mg) which was characterized by its mass spectrum: MS m/z (%): 507 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH2:19][C@@H:20]([O:24][C:25]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:34](=[O:43])[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:29][CH2:28]2)=[O:26])[C:21]([OH:23])=O)[CH:3]=1.[F:44][C:45]1[CH:54]=[CH:53][C:48]([C:49](=[N:51]O)[NH2:50])=[CH:47][CH:46]=1.Cl.CN(C)CCCN=C=NCC>COCCOCCOC>[O:43]=[C:34]1[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C@@H:20]([C:21]3[O:23][N:51]=[C:49]([C:48]4[CH:53]=[CH:54][C:45]([F:44])=[CH:46][CH:47]=4)[N:50]=3)[CH2:19][C:4]3[CH:3]=[C:2]([CH3:1])[C:10]4[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])[N:9]=4)[CH:5]=3)=[O:26])[CH2:32][CH2:31]2)=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COCCOCCOC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)c2nc(-c3ccc(F)cc3)no2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A stirred solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (22.4 mg, 0.0370 mmol) in anhydrous diglyme (2 mL) was treated with 4-fluorobenzamidoxime (5.3 mg, 0.0389 mmol) and 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide hydrochloride (7.5 mg, 0.0389 mmol) to at room temperature. The mixture was stirred overnight. The stirred mixture was then heated to 110° C. overnight. After cooling to room temperature, the solvent was removed in vacuo and the crude product was purified using preparative HPLC to afford a tan gum (16.2 mg, 61%). 1H-NMR (CDCl3, 400 MHz) δ 8.8.06 (bs, 2H), 7.88 (s, 1H), 7.69-7.46 (m, 2H), 7.40 (s, 1H), 7.35-7.20 (m,2H), 7.18-7.07 (m, 2H), 7.07 (s, 1H), 6.19-6.15 (m, 1H), 5.79 (s, 2H), 4.40-4.20 (m, 2H), 3.55-3.40 (m, 4H), 3.20-2.83 (m, 4H), 2.70 (s, 3H), 2.72-2.35 (m, 2H), 2.08-1.9 (m, 2H), 0.90-0.77 (m, 2H), −0.11 (s, 9H). Mass spec. 723.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]N1C(=O)CCC1=O)=O.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)=[O:10]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CN1CCCC1=O)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1=O)N1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 14.4 g (60 mmol) of N-[2-(2-oxopyrrolidin-1-yl)-acetoxy]-succinimide and 10.6 g (60 mmol) of 1-benzylpiperazine in 125 ml of dimethylformamide is stirred for 16 hours at 20°. The reaction mixture is concentrated to dryness by evaporation under reduced pressure at 90°. The oily residue is taken up in 250 ml of water, and a solution of 5.4 g of oxalic acid in 5 ml of water is added, and then the whole is stirred in an ice bath. The resulting crystalline oxalate is filtered off with suction, dissolved in 400 ml of water and the pH is adjusted to 9 with concentrated ammonia solution The clear aqueous solution is washed twice with 30 ml of ether each time, the ethereal extracts are discarded and the aqueous layer is concentrated by evaporation under reduced pressure at 70°. The residue is composed of a sticky mass which is stirred into 400 ml of ethanol at 30° and the insoluble matter is filtered off with suction. After concentrating the clear ethanolic filtrate by evaporation, a slightly yellowish oil is obtained. This is boiled in 130 ml of ethyl acetate and filtered while hot, and the filtrate is stirred in an ice bath to complete the reaction. The precipitated crystals are filtered off with suction and dried on a water bath. 1-[2-(2-oxopyrrolidin-1-yl)-acetyl]-4-benzylpiperazine is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[O:19][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:21][N:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[O:19][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:21][N:22]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1cnc(N)o1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1cc(Nc2ncc(CC(=O)OC)o2)nc(-c2cccc(Cl)c2)n1
Temperature: 120 °C
Yield: 34.1 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol), methyl 2-(2-aminooxazol-5-yl)acetate (0.138 g, 0.89 mmol), palladium acetate (0.006 g, 0.029 mmol), rac-BINAP (0.028 g, 0.044 mmol) and cesium carbonate (0.482 g, 1.48 mmol) in dioxane (5 mL) under argon. The reaction mixture was heated to 120° C. under microwave irradiation for 2 h until the starting material was consumed (monitored by LCMS analysis). The reaction mixture was cooled and filtered through celite. The filtrate was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) to afford the title compound (0.075 g, 34%) as an off-white solid. MW=372.81. 1H NMR (CDCl3, 300 MHz) δ 8.65 (s, 1H), 8.37-8.33 (m, 1H), 8.25 (dt, J=7.2, 1.5 Hz, 1H), 8.02 (s, 1H), 7.49-7.38 (m, 2H), 6.40-6.35 (m, 1H), 4.08 (s, 2H), 3.41 (s, 3H), 2.91 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz, 3H); ESI MS m/z 373 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[N:7]=[C:6]([NH:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[CH:5]=1.[N-:18]=[N+:19]=[N-:20].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[N:18]=[N:19][NH:20][N:11]=2)[N:7]=[C:6]([NH:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(C#N)n1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
Heat a suspension of (S)-2-sec-butylamino-6-cyano-isonicotinic acid methyl ester (932 mg, 4.0 mmol), sodium azide (780 mg, 12 mmol), and triethylamine hydrochloride (1.65 g, 12 mmol) in toluene (13 mL) at 90° C. for 2 days. Cool to room temperature and extract with water (3×30 mL), acidify the combined aqueous layers to about pH=2 using 1 N HCl, extract the desired product with ethyl acetate (4×50 mL), dry (sodium sulfate) and concentrate to give the title compound (720 mg, 65%).
Reaction SMILES: CC(C)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][S:16][CH2:17][CH:18]=2)=[C:9]([F:19])[CH:8]=1.[C:22]([O:25][C@H:26]([CH2:32]Cl)[CH2:27][NH:28][C:29](=[O:31])[CH3:30])(=[O:24])C.CC(C)([O-])C.[Li+].C(O)(=O)C>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CO.CN(C)C=O.C1(C)C=CC=CC=1>[S:16]1[CH2:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:32][C@H:26]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:25][C:22]3=[O:24])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1
Reactant: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: 15 °C
Reaction time: 17 h
Yield: 78.5 %

Procedure:
To a mixture of [4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamic acid 2-methylpropyl ester (17.89 g, 57.83 mmol), (S)—N-[2-(acetyloxy)-3-chloropropyl]acetamide (22.35 g, 115.42 mmol, 2.00 eq), methanol (3.66 g, 114 mmol, 1.97 eq), 2,6-di-tert-butyl-4-methylphenol (0.1365 g, 0.6194 mmol, 0.0107 eq), toluene (52 ml), isooctanes (49 ml), and N,N-dimethylformamide (34.3 ml) is added a solution of lithium t-butoxide (13.94 g, 174.1 mmol, 3.01 eq) in isooctanes (130 ml) over 1.6 h while maintaining 15° C. Isooctanes (20 ml) is added and the mixture stirred at 15 to 19° C. for 17 h. The mixture is cooled to 0° C. and acetic acid (6.7 ml, 117 mmol, 2.02 eq) added. The mixture is warmed to 21° C. and methanol (29 ml) added. The phases are separated and the upper washed twice with a mixture of methanol (29 ml) and water (9 ml). To the combined lower phases is added water (69 ml) and methylene chloride (69 ml). The phases are separated and the upper phase washed twice with methylene chloride (29 ml). The combined lower phases are concentrated under reduced pressure to 112 ml total volume. Methanol (69 ml) is added and the mixture concentrated to 112 ml. Methanol (69 ml) is added and the mixture concentrated to 75 ml then toluene (65 ml) is added. Water (65 ml) is added over ½ h while maintaining 19 to 30° C. The mixture is cooled to 9° C. and isooctanes (56 ml) added. The slurry is cooled to 0° C. and the precipitate collected by vacuum filtration, washed with water (22 ml) and isooctanes (22 ml) and dried in a nitrogen stream to give the title compound (15.909 g, 78.5%): HPLC retention time=2.77 min (column=Phenomenex Luna 5.0 micron C-8(12) 150×4.6 mm, flow rate=2.0 ml/min, gradient elution from 40:60 A:B to 73.3:26.7 A:B over 15 minutes; A=acetonitrile; B=water).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([N+:11]([O-])=O)[C:8]=1[O:9][CH3:10].[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([NH2:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(N)c1OC

Procedure:
trans-2-(3,4-Dimethoxy-5-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene (0.3 g, 0.69 mmole) was suspended in 10 ml of ethanol. To this was added CaCl2 (72.63 mg, 0.65 mmole) in 2 mL water, followed by zinc metal (1.01 g). The suspension was refluxed for 5 hours, filtered, and the residue was washed with ethanol. The combined filtrate was washed with 10% NaHCO3, water and saturated aqueous sodium chloride, dried over MgSO4 and evaporated in vacuo to an oil that was purified by flash column chromatography using 1:1 hexane/ethyl acetate as solvent (30 mg, 10.8%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C)C=O.O>[CH2:11]([O:10][C:8]([C:7]1[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4][N:5]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (6.24 g, 30.0 mmol) in N,N-dimethylformamide (60 ml) was added under ice-cooling 60% sodium hydride (1.80 g, 45.0 mmol) by a small amount and the mixture was stirred for 30 min. tert-Butyl bromoacetate (5.32 mL, 36.0 mmol) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give tert-butyl [4-(ethoxycarbonyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (7.33 g, 75%) as a colorless oil. Trifluoroacetic acid (30 mL) was added to the present compound (3.22 g, 10.0 mmol), and the mixture was stirred under ice-cooling for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give the title compound (2.03 g, 76%) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:41][C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:56][CH2:55][C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[NH:52][C:51]3=[O:61])[CH2:46][CH2:45]2)=[O:43])[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])=[O:33])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:11][C:10]=1[CH3:62])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:41][C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:56][CH2:55][C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[NH:52][C:51]3=[O:61])[CH2:46][CH2:45]2)=[O:43])[C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])=[O:33])[CH2:28][CH2:27]3)[CH2:24][CH2:25]2)=[O:19])=[CH:11][C:10]=1[CH3:62]
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1O

Procedure:
95 mg (0.11 mmol) dimethylcarbamoylmethyl 1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate in 10 mL THF were combined with 50 mg 10% Pd/C and hydrogenated at 50° C. and 50 psi hydrogen for 6 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:9][C:8]([NH:10]C(=O)OC(C)(C)C)=[N:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O.Cl>O>[NH2:10][C:8]1[S:9][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][N:7]=1
Reactant: CNC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cnc(N)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 159 %

Procedure:
tert-Butyl 5-(methylcarbamoyl)thiazol-2-ylcarbamate (0.77 g, 3.0 mmol) was added to TFA (1.5 mL) that was cooled in a water bath. The solution obtained was stirred at room temperature for 1.5 h. A second batch of TFA (1.5 mL) was added and the reaction mixture was stirred at 40° C. for 30 min and then concentrated in vacuo. To the residue was added 1 M aqueous solution of HCl (3.0 mL, 3.0 mmol) and deionized water (2.0 mL) and the solution concentrated under reduced pressure. Lyophilization gave 2-amino-N-methylthiazole-5-carboxamide (HCl salt, 750 mg) as a white powder. MS found: (M+H)+=158. The crude product was used as such in the next step without further purification.
Reaction SMILES: S([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)(=O)(=O)N.NC1C=CC(S(NC2SC(S(N)(=O)=O)=NN=2)(=O)=O)=CC=1.C(N(CC)CC)C.[C:59](Cl)(=[O:69])CCCCCCCCC>C(#N)C>[OH:69][CH2:59][C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Agent: Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
N-(4-(N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)decanamide 139). 5-(4-Aminophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide (7, 50 mg, 0.15 mmol) was suspended in anhydrous acetonitrile (5 mL). Triethylamine (17.1 mg, 0.17 mmol) was added with stirring at 0° C. A solution of decanoyl chloride (32.4 mg, 0.17 mmol) dissolved in anhydrous acetonitrile (1 mL) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 h and overnight at room temperature. Volatiles were removed in vacuo and the residue was washed with water (5 mL). The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1, giving the pure product as a solid (42 mg, 0.09 mmol, 60% yield), mp 242-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=6.9 Hz), 1.24 (m, 12H), 1.56 (m, 2H), 2.32 (t, 2H, J=7.5 Hz), 7.66 (s, 4H), 7.91 (s, 2H), 10.13 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 22.3, 25.2, 28.8, 29.0, 31.5, 36.6, 118.6, 127.0, 137.4, 142.2, 157.8, 170.8, 172.1; LRMS (LCQ, ESI−) calcd for C18H26N5O5S3 488.1, found 488.1 (M−H)−; HRMS (ESI−, m/z) calcd for C18H26N5O5S3 488.1102, found 487.1101 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13]
Reactant: C#CCCCO
Reactant: Brc1ccccn1
Product: OCCCC#Cc1ccccn1
Yield: 87.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (4.46 g, 28.2 mmol) and pent-4-yn-1-ol (2.50 g, 29.7 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/MeOH 97:3) to yield 4.00 g (24.8 mmol, 88%) of 5-pyridin-2-yl-pent-4-yn-1-ol as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](N)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=[O:24].[Na+]>O.S(=O)(=O)(O)O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([OH:24])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 8 h

Procedure:
Add 2 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide to 4.7 ml of concentrated sulfuric acid while cooling on ice and then add thereto a solution of 0.78 g of sodium nitrite in 2 ml of water slowly and dropwise at a temperature not exceeding 7° C. Allow the resulting mixture to stand overnight; dilute with from 4 to 5 ml of concentrated sulfuric acid and then mix it (while cooling with ice) with 0.39 g of sodium nitrite in 1 ml of water. Allow the thus-prepared solution to stand at a temperature of 0° to 5° C for 2 days in a refrigerator and then pour it onto ice. Vacuum filter to separate formed precipitate and chromatograph with chloroform/ethanol (9:1) on a silica gel column to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid [m.p. 250° to 252° C].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[CH:35](O)=[O:36].C(N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([CH:35]=[O:36])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Reactant: O=CO
Agent: O=C(n1ccnc1)n1ccnc1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCN(C=O)CC3)CC2)CC1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) and formic acid (5.37 μL, 140 μmol) in methylenehloride (0.7 mL) was added carbonyldiimidazole (23.4 mg, 140 μmol). The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using a gradient from methylenechloride to a mixture of methylenechloride/methanol (v:v 19:1) as solvent to yield the title compound as a white solid (25 mg, 67%). MS ISP (m/e): 534.2/536.3 (100/29) [(M+H)]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][O:16]1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:24][C:23]1[NH:22][CH:21]=[C:20]3[C:15](=[O:14])[O:16][CH2:17][CH2:18][C:19]=13)[C:7](=[O:13])[NH:8]2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1[nH]cc2c1CCOC2=O
Yield: 424.3 %

Procedure:
4-(2-Hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.1 g, 0.6 mmol) was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde (1.2 eq, 0.06 g) to give 0.5 g (28%) of the title compound as a yellow solid.