Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@H:14]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].Cl>O1CCOCC1.C(O)C.FC(F)(F)C(O)=O.[Pd]>[CH3:13][O:12][C:10]1[CH:11]=[C:6]2[C:7]([C@H:14]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH2:15][N:16]([C:17]([O:18][CH3:19])=[O:20])[CH2:2]2)=[CH:8][CH:9]=1
Reactant: COC(=O)NC[C@@H](c1ccc2ccccc2c1)c1ccc(OC)cc1C1OCCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1Cc2cc(OC)ccc2[C@H](c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
To a solution of Compound 24 (0.10 g, 0.25 mmol) in 1,4-dioxane (10 mL) at 0° C. was added concentrated HCl (0.8 mL). The reaction solution was stirred at room temperature for 20 min, and then quenched with aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The residue obtained was dissolved in a mixture of ethanol (30 mL) and trifluoroacetic acid (2 mL). Palladium on carbon (105 mg) was added and the reaction mixture was shaken under hydrogen (25 psi) for 15 min, then filtered through a pad of celite and concentrated in vacuo. The residue was dissolved in dichloromethane and the resulting solution was washed with aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. Purification by preparative thin layer chromatography (hexanes/ethyl acetate 75:25) provided Compound 25 (52 mg, 60%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.82-7.74 (m, 3H), 7.62-7.51 (m, 1H), 7.47-7.44 (m, 2H), 7.24 (d, J=9.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.80-6.68 (m, 2H), 4.83-4.60 (m, 2H), 4.40-3.90 (m, 2H), 3.81 (s, 3H), 3.76-3.42 (m, 4H); ESI MS m/z 348 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])[C:8]1=[O:30]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])[C:8](=[O:30])[C:7]2([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[NH:6][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: COC(=O)c1ccc(CN2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)NC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC)cc2OC)c2ccc(Cl)cc21
Reaction time: 24 h
Yield: 87.8 %

Procedure:
0.52 g of propionyl chloride is added at RT to a solution of 1.323 g of the compound obtained in EXAMPLE 89 in 5 ml of pyridine and the mixture is stirred for 24 hours. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 1.3 g of the expected product.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.C(N(CC)CC)C.CN(C)C=O>[C:1]([C:5]1[S:9][C:8]([C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: CC(C)(C)c1cnc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ncc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a N,N-dimethylformamide (25 mL) solution of 5-tert-butyl-1,3-thiazole-2-carboxylic acid (2.5 g), N,O-dimethylhydroxylamine hydrochloride (2.0 g), WSC.HCl (3.9 g), HOBt.H2O (3.1 g) and triethylamine (7.1 g) were added, and the resultant was stirred at room temperature for 1 day. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→50/50) to obtain the title compound (3.1 g) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](=O)[CH3:9])[CH:2]=1.S(Cl)(Cl)(=O)=O.[NH2:16][C:17]([NH2:19])=[S:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O1CCCC1.O>[NH2:19][C:17]1[S:18][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:8]([CH3:9])[N:16]=1
Reactant: CC(=O)Cc1cccnc1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)sc1-c1cccnc1
Yield: 39.5 %

Procedure:
To a solution of 1-(3-pyridyl)-2-propanone (3.4 g) in methylene chloride (30 ml) was dropwise added a solution of sulfuryl chloride (4.0 g) in methylene chloride (5 ml) at 20° C. to 28° C. under stirring and the mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was added to a solution of thiourea (4.2 g) in a mixture of tetrahydrofuran (50 ml) and water (20 ml) and the mixture was adjusted to pH 7.0 to 7.5 with 20% aqueous potassium carbonate. After being stirred at ambient temperature for 2 hours, the mixture was evaporated in vacuo. The residue was dissolved in a mixture water and ethyl acetate, and the mixture was acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with 20% aqueous potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was washed with a mixture of diethyl ether and ethyl acetate, and recrystallized from tetrahydrofuran to give 2-amino-4-methyl-5-(3-pyridyl)thiazole (1.9 g). mp 190°-191° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[OH:41])(=[O:37])[CH3:36].[H-].[Na+].O>COCCOC>[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[O:41][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4])(=[O:37])[CH3:36]
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(CBr)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](OCC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-3′,4′,5′-tribenzyloxyacetophenone (11) (2.59 g, 5 mmol) and β-D-glucose-2,3,4,6-tetraacetate (8) (1.74 g, 5 mmol) were dissolved in dry DME (50 mL) and sodium hydride (0.18 g, 7.5 mmol) (0.3 g 60% NaH suspension in oil) was added in small portions. The reaction mixture was allowed to be stirred at room temperature overnight. Water (50 mL) was added and the water phase extracted with DCM (3×25 mL). The organic layers were combined and washed with water (2×50 mL), dried (MgSO4) and evaporated to give a dark viscous oil. The product was isolated by dry flash chromatography (PE/EtOAc 6:4) (PE=petroleum ether). Recrystallisation from a mixture of methylcyclohexane and ethyl acetate afforded the desired compound as white crystals, m.p. 156-158° C. Yield 0.51 g (13%). 1H NMR (300 MHz, CDCl3): δ=1.98 (3H, s), 2.00 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 3.63-3.73 (2H, m), 4.08-4.30 (5H, m), 4.62-4.94 (1H, m), 5.02-5.34 (7H, m), 7.20-7.56 (17H, m); 13C NMR (75 MHz): δ=20.5, 20.6, 61.6, 68.2, 70.5, 70.8, 71.2, 71.8, 72.4, 75.0, 100.1, 107.9, 127.4, 127.9, 128.0, 128.1, 128.4, 128.5, 129.6, 136.4, 137.1, 143.2, 152.6, 169.3, 169.5, 170.0, 170.5, 193.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N+:9]([O-])=[CH:10]2)=[O:4].O=P(Cl)(Cl)[Cl:18]>ClCCl>[Cl:18][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2c[n+]([O-])ccc12
Solvent: ClCCl
Product: COC(=O)c1cccc2c(Cl)nccc12
Temperature: 90 °C
Yield: 86 %

Procedure:
5-(Methoxycarbonyl)isoquinoline 2-oxide (2 g, 9.84 mmol) obtained in Step (4) of Preparation Example 1 was dissolved in dichloromethane (20 mL), added with POCl3 (20 mL) at room temperature, and stirred for 4 hours or more at 90° C. The temperature of the reaction mixture was lowered to room temperature, followed by quenching with distilled water. The reaction mixture was diluted with dichloromethane, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.86 g, 86%).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:12]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32].[OH-].[Li+].S(=O)(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:21]([O:20][C:18]([N:13]1[C@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C@H:11]([CH2:10][C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:33])=[O:2])[O:15][C:14]1([CH3:17])[CH3:16])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1cccnc1C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1Cc1ccccc1F
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)[C@H](Cc2ncccc2C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[(4R,5S)-3-tert-butoxycarbonyl-4-(2-fluoro-benzyl)-2,2-dimethyl-oxazolidin-5-ylmethyl]-nicotinic acid methyl ester (5.5 g, 12 mmol) in 100 mL of dioxane/water (2:1) is added lithium hydroxide (0.57 g, 24 mmol). The reaction is stirred at room temperature for 2 hr after which time the reaction is diluted and the pH adjusted to pH 4-5 with a 2M solution of sodium bisulfate. The product is extracted into dichloromethane and the combined organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the resultant residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[C:16]([I:17])[C:9]=23)[CH:7]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:15]=[C:16]([I:17])[C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]cc(I)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2c1c(I)cn2COCC[Si](C)(C)C
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 14B (15.1 g, 41.0 mmol) in tetrahydrofuran under nitrogen was cooled to −8° C. and 60% sodium hydride in mineral oil (2.461 g, 61.5 mmol) was added in portions at a rate such that the temperature was maintained at or below −5° C. The solution was stirred 30 minutes at −5° C. and 2-(trimethylsilyl)ethoxymethyl chloride (8.73 mL, 49.2 mmol) was added dropwise over 15 minutes. The mixture was stirred for 30 minutes at −5° C. and allowed to warm to ambient temperature and stirred overnight. The reaction was quenched carefully with aqueous saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified on an Analogix MPLC using a silica gel column eluting with 100% heptane followed by 7% ethyl acetate/heptanes to provide the title compound. MS (ESI+) m/z 498.8 (M+H)+.
Reaction SMILES: C(=O)=O.[S:4]([F:8])(F)([F:6])[F:5].[CH2:9]([N:11]([Si](C)(C)C)[CH2:12][CH3:13])[CH3:10]>ClC(Cl)(Cl)F>[CH2:9]([N:11]([S:4]([F:8])([F:6])[F:5])[CH2:12][CH3:13])[CH3:10]
Reactant: CCN(CC)[Si](C)(C)C
Reactant: FS(F)(F)F
Agent: O=C=O
Solvent: FC(Cl)(Cl)Cl
Product: CCN(CC)S(F)(F)F
Temperature: 25 °C
Yield: 80 %

Procedure:
A dry 1-l. four-necked round-bottomed flask is equipped with a thermometer (-100° to 50°), a solid carbon dioxide-cooled reflux condenser (protected from the atmosphere through a drying tube), a gas inlet tube above the liquid level, and a magnetic stirrer. The apparatus is flushed with dry nitrogen, and 300 ml of trichlorofluoromethane is added to the flask. As the nitrogen atmosphere is maintained, the trichlorofluoromethane is cooled to -70° by means of a solid carbon dioxide-acetone bath and 119 g (1.1 mole) of sulfur tetrafluoride is added from a cylinder through the gas inlet tube. The gas inlet tube is then replaced with a 250-ml pressure-equalized dropping funnel charged with a solution of 145 g (1 mole) of N,N-diethylaminotrimethylsilane in 90 ml trichlorofluoromethane. This solution is added dropwise, with stirring, to the sulfur tetrafluoride solution at a rate slow enough to keep the temperature of the reaction mixture below -60° (about 40 minutes). The cooling bath is removed, and the reaction mixture is allowed to warm spontaneously to room temperature. The condenser is replaced with a simple distillation head, and the solvent (bp 24°) and by-product fluorotrimethylsilane (bp 17°) are distilled off into a well cooled receiver by warming the reaction mixture gently to 45° by means of a heating mantle. The yellow to dark brown residual liquid is transferred and distilled at reduced pressure through a spinning band column to give 129-145 g (80-90%) of diethylaminosulfur trifluoride as a light yellow liquid, bp 46-47 (10 mm).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C:11]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])=[O:13])=[C:5]2[N:4]=1.CN(C=O)C.O=S(Cl)[Cl:37]>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C:11]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])=[O:13])=[C:5]2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CO)nc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CCl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 5-(hydroxymethyl)-N-(4-methoxy-3-pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide prepared in step 2 above (50 mg, 0.1219 mmol) and DMF (44.55 mg, 47.19 μL, 0.6095 mmol) were suspended in dry DCM (1.25 mL). SOCl2 (72.51 mg, 44.46 μL, 0.6095 mmol) was added dropwise and the resulting mixture was stirred at RT for ˜2 h. The bright yellow suspension was filtered and the collected solid was washed with DCM (1 mL) and ether (3×1 mL) to give a light yellow powder (49.6 mg). LC-MS (M+H)+ 429.1; 1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.60 (s, 1H), 9.63 (s, 1H), 9.50 (d, J=7.1 Hz, 1H), 8.71 (d, J=6.4 Hz, 1H), 7.80 (d, J=6.6 Hz, 1H), 7.62 (d, J=7.1 Hz, 1H), 5.07 (s, 2H), 4.34 (s, 3H).
Reaction SMILES: [N:1]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:9][C:8]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N=C(N)N1CCCCCC1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(N2CCCCCC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=366.0 (M+H+), was prepared from azepane-1-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1ccccc1O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 22.7 g of 2-naphthalenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 15.0 g of an end product. Melting point 136.0° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:15]>>[CH2:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[CH2:1][CH2:2][NH:15][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCC2CCCCC2)cc1

Procedure:
The title compound was prepared according to example 1063B, replacing p-toluenesulfonyl chloride with p-tert-butylbenzenesulfonyl chloride to afford a white crystalline solid. MS (DCI/NH3) m/e 341 (M+NH4)+.
Reaction SMILES: I[C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:3]=1.[CH3:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:7]([C:6]1[CH:2]=[N:3][N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:18]=1[CH3:17])[C:22]([O:24][CH3:25])=[O:23])#[N:8]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(I)n1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2c(C#N)cnn2COCC[Si](C)(C)C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (compound 256.2, 2.73 g, 7.82 mmol, 1.00 equiv) in dioxane (30 mL). Methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.59 g, 9.38 mmol), Pd(dppf)Cl2 (570 mg, 0.78 mmol), and a solution of potassium carbonate (3.24 g, 23.4 mmol) in water (3 mL) were added to the reaction. The resulting mixture was stirred overnight at 90° C., then cooled and diluted with EtOAc (500 mL). The resulting mixture was washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (40:1) as eluent to obtained the title compound as a yellow oil (1.9 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[N:16]=[C:10]2[CH:9]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COS(C)(=O)=O
Temperature: 0 °C

Procedure:
To a 0° C. solution of 100 mg (0.31 mmol) of 7-N-(tert-butoxycarbonyl)-8-(hydroxymethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine in 1.0 mL of dichloromethane was added sequentially 0.047 mL (0.341 mmol) of triethylamine and 0.029 mL (0.372 mmol) of methanesulfonyl chloride. The reaction mixture was stirred at 0° C. and allowed to warm to room temperature for 4 h. Aqueous sodium bicarbonate solution was added, and the resultant mixture was extracted with three portions of dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, and concentrated to give a yellow oil which was used without further purification. LC/MS 401 (M+1).
Reaction SMILES: C1(=O)[O:6][C:4](=O)[CH:3]2[CH2:7][CH2:8][CH:9]=[CH:10][CH:2]12.C1(=O)O[C:15](=[O:16])C2CCCCC12>>[CH:3]1([CH2:4][OH:6])[CH2:2][CH2:10][CH:9]([CH2:15][OH:16])[CH2:8][CH2:7]1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: O=C1OC(=O)C2CCC=CC12
Product: OCC1CCC(CO)CC1

Procedure:
Tetrahydrophthalic anhydride was obtained from Janssen Chemical. Hexahydrophthalic anhydride and hydrogenated bisphenol A were obtained from Milliken Chemical. 1,4-Cyclohexanedimethanol was obtained from either Aldrich Chemical Co. or from Eastman Chemical Co. 1,4-Cyclohexane dicarboxylic acid was provided by Eastman Chemical Co. Trimethylolpropane mentioned in the examples below was obtained from Aldrich Chemical Co. Tin catalyst (Fascat 4100) was obtained from Elf Atochem. Equilibrium peracetic acid (35%) was purchased from Aldrich Chemical Co.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH3:52].Cl>CN(C=O)C.C(Cl)CCl>[C:56]([O:55][C:53](=[O:54])[C@H:51]([NH:50][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH3:52])([CH3:59])([CH3:58])[CH3:57]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
To a solution of 500 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 186 mg HOBt, 232 mg EDC, 0.50 ml DIPEA and 220 mg D-Ala-OtBu×HCl. After stirring for 12 h it was concentrated and the residue dissolved in ethyl acetate. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.