Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:41])=[CH:38][CH2:39]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH:38]=[C:37]([CH3:41])[CH3:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)=CCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CC(C)=CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3-methyl-2-buten-1-ol in place of isobutanol (yield: 0.1284 g, 88%). mp 128-132° C. 1H NMR (300 MHz, DMSO d6) δ 1.58 (s, 3H), 1.67 (s, 3H), 3.30 (s, 3H), 4.95 (d, J=7 Hz, 2H), 5.31 (m, 1H), 7.38 (m, 2H), 7.65 (m, 2H), 7.89 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.41; H, 4.95; N. 6.47.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].Cl[C:9]1[N:14]=[N:13][C:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[C:20]([CH:30]=2)[C:21]([N:23]2[CH2:29][CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]2)=[O:22])=[C:11]([CH2:32][CH3:33])[CH:10]=1.CC([O-])=[O:36].[Na+]>CC(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:32]([C:11]1[C:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[C:20]([CH:30]=2)[C:21]([N:23]2[CH2:29][CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]2)=[O:22])=[N:13][NH:14][C:9](=[O:36])[CH:10]=1)[CH3:33]
Reactant: CCc1cc(Cl)nnc1Cc1ccc(F)c(C(=O)N2CCC[NH2+]CC2)c1
Reactant: CC(=O)[O-]
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(=O)[nH]nc1Cc1ccc(F)c(C(=O)N2CCC[NH2+]CC2)c1
Temperature: 25 °C

Procedure:
A mixture of B2, NaOAc (2 eq) and AcOH (0.16 M) was heated at reflux for 4 h. The reaction mixture was cooled down to RT and concentrated under reduced pressure. The crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: Water X-Terra C18). The pooled product fractions were lyophilized to give the title compound. 1H NMR (600 MHz, DMSO-d6) δ: 12.80 (1H, m), 8.84 (2H, s), 7.38-7.28 (3H, m), 6.66 (1H, s), 4.01 (2H, s), 3.85-3.7 (2H, m), 3.55 (1H, m), 3.36-3.32 (2H, m), 3.27 (1H, m), 3.20 (1H, m), 3.16 (1H, m), 2.45-2.42 (2H, m), 2.06 (1H, m), 1.90 (1H, m), 1.11-1.07 (3H, m). MS (ES) C19H23FN4O2 required: 358. found: 359 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH:16]=1)=[O:10])(C)(C)C.C(OCC)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1.CCCCCCC>[Cl:24][C:19]1[CH:18]=[C:17]([C:15]2[CH:16]=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:31])=[O:5])=[O:10])[CH:12]=[N:13][C:14]=2[O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(O)CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Yield: 98.3 %

Procedure:
A solution of 4.00 g {[5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-amino}-acetic acid tert-butyl ester in 20 ml trifluoroacetic acid was kept at ambient temperature for 30 min. The solvent was evaporated and the residue was dried under high vacuum. The residue was taken up in toluene and the solvent was evaporated to leave a semi solid residue. The residue was taken up in toluene and dichloromethane and the solvents were evaporated to leave a crystalline residue which was taken up in heptane and ethyl acetate and stirred until homogenous slurry was obtained. The solid was collected by filtration, washed with heptane and dried to constant weight to yield 3.47 g of the title compound as white crystalline powder. MS (EI): 422 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH2:18][C:17]([C:20]3[C:21]([C:27]([F:30])([F:29])[F:28])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)(O)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:18]=[C:17]([C:20]3[C:21]([C:27]([F:29])([F:30])[F:28])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2=NOC(O)(c3ccc[n+]([O-])c3C(F)(F)F)C2)cc([N+](=O)[O-])c1OC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc(-c3ccc[n+]([O-])c3C(F)(F)F)on2)cc([N+](=O)[O-])c1OC
Reaction time: 0.17 h

Procedure:
3-(3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxy-4,5-dihydroisoxazol-5-yl)-2-(trifluoromethyl)pyridine 1-oxide (2.14 g, 5 mmol) was heated in 20 mL of ethyl acetate to 70° C. To the resulting slurry was added trifluoroacetic acid (0.74 g, 6.5 mmol) dropwise. After 10 minutes, the reaction was evaporated to dryness and the residue was recrystallised from isopropanol to give 3-(3-(3,4-dimethoxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.27 g (62%).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])SC)#[N:2].[OH-].[NH4+:19]>C(O)C>[NH2:19][C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[N:3][C:1]#[N:2]
Reactant: COC(=O)c1cccc(NC(=NC#N)SC)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(NC(N)=NC#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound from Example D (1.0 g) and ammonium hydroxide (2 ml) in ethanol (20 ml) was heated at 70° in a sealed tube for 3.5 hours. The reaction mixture was cooled to room temperature and reduced to half its volume. After standing overnight at room temperature a white solid was obtained, which was isolated by filtration and washed with methanol. This afforded the title compound (389 mg) as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Prepared in the same manner as intermediate 18. To a solution of tert-butyl 1-piperazinecarboxylate (15.0 g. 80.5 mmol) and benzoic acid (8.94 g, 73.2 mmol) in CH2Cl2 (500 mL), was added DMAP (9.84 g, 80.5 mmol) and EDC (15.39 g, 80.5 mmol). The reaction mixture was stirred at rt for 17 h, and then washed with excess hydrochloric acid (5×250 mL, 1 N aq.) and water (350 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give N-Benzoyl-N′-Boc piperazine as an off white solid (21 g, 99%). 1H NMR (300 MHz, CD3OD) δ 7.46 (m, 5H), 3.80-3.30 (b m, 8H), 1.47 (s, 9H); LC/MS (ES+) m/z (M+H)+=291, (2M+H)+=581, HPLC Rt=1.430.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33](O)=[O:34])[N:16]=2)[CH:14]=1.Cl.[CH3:41][N:42]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33]([N:52]3[CH2:51][CH2:50][CH:49]([N:42]([CH3:41])[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH2:54][CH2:53]3)=[O:34])[N:16]=2)[CH:14]=1
Reactant: COC(=O)CCN(C)C1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCN(C)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid trifluoroacetate (100 mg, 0.17 mmol) in DMF (3 mL) was added methyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (62 mg, 0.26 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with ethyl acetate/petroleum ether (10:1). The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (37.0% up to 43.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 37.0% in 2 min); Detector, UV 254/220 nm. This resulted in 45.2 mg (38%) of the formic acid salt of methyl 3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoate as an off-white solid. LCMS (Method 24) [M+H]+=645.2, RT=1.64 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=4.5, 7.2 Hz), 7.04 (t, 1H, J=73.2 Hz), 5.33-5.27 (m, 2H), 4.52-4.48 (m, 1H), 4.10-4.06 (m, 1H), 3.66 (s, 3H), 3.51-3.34 (m, 2H), 3.16-3.08 (m, 2H), 2.86-2.51 (m, 6H), 2.28-1.99 (m, 2H), 1.73-1.70 (m, 1H), 1.55-1.45 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:38]=[CH:37][C:23]([CH2:24][O:25][C:26](SC2N=C(C)C=C(C)N=2)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].[OH-].[Na+]>O.O1CCOCC1.C(OCC)C>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])=[O:27])=[CH:37][CH:38]=1)([O-:19])=[O:18]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trans-4-Hydroxy-L-proline (6.55 g) and triethylamine (7.5 ml) were dissolved in 15 ml of water, and a solution of 15.95 g of S-p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 35 ml of dioxane was dropwise added thereto. The resulting mixture was stirred at room temperature for 1.5 hours and allowed to stand overnight. To the reaction mixture was added 30 ml of 2N sodium hydroxide solution under ice-cooling, and the resultant mixture was shaken with diethyl ether. The aqueous layer was separated from the ethereal layer, the ethereal layer was washed with 20 ml of 1m hydroxide solution, and the washing was combined with the aqueous layer. The combined mixture was made acidic with 100 ml of 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with 2N hydrochloric acid, dried over anhydrous sodium sulfate and distilled to remove the solvent. The resulting crude crystals were washed with ethyl acetate to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline. M.P., 134.3°-135.5° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[S:18]1(=[O:26])(=[O:25])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>C1COCC1.O>[O:25]=[S:18]1(=[O:26])[CH2:23][CH2:22][C:21](=[CH:9][C:7]#[N:8])[CH2:20][CH2:19]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCS(=O)(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=C1CCS(=O)(=O)CC1
Temperature: 0 °C

Procedure:
Potassium tert-butoxide (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at 0° C. and THF (8 mL) was added. Diethyl (cyanomethyl)phosphonate (0.56 mL, 3.5 mmol) was added slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of dihydro-2H-thiopyran-4(3H)-one 1,1-dioxide (0.50 g, 3.4 mmol) in THF (5 mL). After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@@H:27](O)[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=[O:37]>C(OCC)(=O)C>[NH2:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C@@H:20]([OH:37])[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)[C@@H](O)C1CCCCC1

Procedure:
A solution of 2(S)-(N-t-butoxycarbonyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (383 mg) in trifluoroacetic acid (10 ml) was stirred at 0° C. for 30 minutes. After concentration of the mixture in vacuo, the residue was dissolved in ethyl acetate (20 ml). The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to give 2(S)-(L-histidyl)amino-1-cyclohexyl-(S)-hydroxy-6-methylheptane (275 mg) as an amorphous powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][C@@H:7]1[OH:17])=[O:4].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C=O)C>[CH2:24]([O:17][C@H:7]1[CH2:8][C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@H:6]1[NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)[C@@H](O)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO[C@H]1Cc2ccc(OC)cc2[C@H]1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Step AE (2): To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide in DMF (4.5 mL) at rt was added sodium hydride (95% purity, 205 mg). The resulting mixture was stirred at rt for 5 min. Allyl bromide (0.26 mL) was added, and the reaction mixture was stirred for 30 min. Water was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give N-((1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide as a slightly yellowish oil (660 mg). 1H NMR (400 MHz, CDCl3) δ 7.14 (1H, d), 6.85 (1H, d), 6.83 (1H, s), 5.88 (1H, m), 5.44 (1H, d), 5.28 (1H, dt), 5.12 (1H, dt), 4.38 (1H, q), 4.06 (1H, m), 3.76 (3H, s), 3.05 (1H, d).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1Br)=[O:3].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.ClCCl.[OH-].[Na+]>O1CCCC1.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]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(=O)c1cc(F)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)ccc1-c1ccc(F)cc1F
Temperature: 60 °C

Procedure:
A stirred solution of 2-bromo-5-fluoroacetophenone (11.72 g, 54 mmol) and 2,4-difluorophenylboronic acid (8.53 g, 54 mmol) in tetrahydrofuran (600 mL) was treated under nitrogen with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol, 5 mole %) and a 5 N sodium hydroxide solution (21.6 mL, 108 mmol). The reaction was heated at 60° C. for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in diethyl ether, filtered through a short column of silica gel, and the solvent evaporated in vacuo to a crude brown oil (11.72 g). The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 3% and 10% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford, after evaporation of the solvent, the title compound as a purified, colorless oil (7.11 g, 28.4 mmol, 52%);
Reaction SMILES: I[C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Si:16]([O:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[OH-].[Na+].CCOC(C)=O>C1COCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[Si:16]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:13]=[CH:14][C:15]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]3=2)[CH:28]=[C:29]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(B(O)O)c1
Reactant: Ic1cccc2c1ccc1ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccc4ccccc4c3c2)c1
Reaction time: 24 h
Yield: 107.2 %

Procedure:
0.122 g (5 mol %) of Pdcl2 (dppf) was added to 0.742 g (2.44 mmol) of iodophenanthrene in a darkroom, and dissolved with 12 ml of THF/H2O. 0.90 g (2.19 mmol) of 3,5-bis-tert-butyldimethylsilyloxymethyl Phenylboronic acid dissolved in 12 ml of THF/H2O was added, 3.66 ml (3 eq) of 2N NaOH aq was injected, the reaction was initiated in a 65° C. oil bath with light shielding, and the mixture was agitated for 24 hours. Completion of the reaction could not be confirmed because the raw material iodophenanthrene overlaps the target product in TLC (Hex:EtOAc=1:1). Fluorescence was confirmed with the naked eye. This was extracted with EtOAc, and the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure to obtain 1.2749 g of a mixture of the target product and iodophenanthrene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[S:17][C:18]([C:20]([O:22]CC)=[O:21])=[CH:19][C:13]=3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[S:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:13]=3[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(s1)CCN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCc3sc(C(=O)O)cc3C2)cc1

Procedure:
A solution of ethyl 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (1 eq) obtained from step B1 and NaOH (1.5 eq.) in ethanol was refluxed for 2 h. Reaction mixture was concentrated under reduced pressure and neutralized to get 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]([CH:5]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]2[N:19]=[CH:18][NH:17][N:16]=2)=[CH:11][CH:10]=1)[CH2:6][CH3:7])=O.[NH3:22].C(O)C>CC(C)=O>[C:3]([CH:5]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]2[N:19]=[CH:18][NH:17][N:16]=2)=[CH:11][CH:10]=1)[CH2:6][CH3:7])(=[O:2])[NH2:22]
Reactant: CCC(Oc1ccc(C=Cc2nc[nH]n2)cc1)C(=O)OC
Reactant: N
Solvent: CC(C)=O
Solvent: CCO
Product: CCC(Oc1ccc(C=Cc2nc[nH]n2)cc1)C(N)=O

Procedure:
3-[4-(1-methoxycarbonylpropoxy)styryl]-1,2,4-triazole (0.5 g--prepared as the intermediate for Example 22 above), concentrated ammonia (5 ml) and ethanol (10 ml) were placed in a Carius tube, and further saturated with gaseous ammonia for 20 minutes. The tube was cooled in acetone/solid carbon dioxide and sealed, and then heated at 110° for 24 hours. The tube was cooled and opened, and the contents were evaporated to dryness to give the required 3-[4-(1-carbamoylpropoxy)styryl]-1,2,4-triazole, crystallised from methanol, softened at 50° and mp~150°.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=1.[NH4+].[Cl-]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (1.86 g, 9.99 mmol, supplier Aldrich) and DIPEA (2.62 ml, 14.98 mmol) in dry DCM (20 ml) at 0° C. under argon was added 4-bromo-2-methylbenzenesulfonyl chloride (2.96 g, 10.99 mmol) and the resulting yellow solution allowed to warm to rt, then stirred at rt for 18 h. Semi-saturated NH4Cl (40 ml) was added, then the aq extracted with DCM (30 ml). The combined organics were passed through a hydrophobic frit, then concentrated in vacuo to give the title compound as a yellow gum that became a solid on standing (4.72 g).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH3:27])[C:12]([CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.Cl>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH2:18][C:12]1[N:11]([CH3:27])[C:10]([CH2:9][OH:8])=[N:14][C:13]=1[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)c1nc(COCc2ccccc2)n(C)c1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(CO)n(C)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
In 3 ml of ethanol was dissolved 470 mg (1.17 mmol) of 2-benzyloxymethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (58), followed by addition of 10 ml of concentrated hydrochloric acid (36% aqueous solution), and the mixture was refluxed under heating at 110° C. After 3 hours, the reaction mixture was concentrated under reduced pressure, neutralized with aqueous sodium hydroxide, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. To the crude crystals, 5 ml of diethyl ether was added, and filtered to give 350 mg of [5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (59a) (yield 95.9%).