Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:23]([N:26]([CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:24][CH3:25].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH3:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCCN(CCC)CCCCN
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCNS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
The compound (150 mg) obtained in Example 24-2 was dissolved in chloroform (10 ml) and then added with the compound (131 mg) obtained in Example 1-2 and triethylamine (0.224 ml), followed by stirring at room temperature for 15 minutes. The solution was added with water and subjected to extraction. The organic layer was washed with saturated saline solution and then dried and concentrated with anhydrous sodium sulfate, thereby obtaining the subject compound (160 mg) as a colorless viscous liquid.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][C:6]1([CH2:11][CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[Br-].[OH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([S+:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]2=3)=[CH:17][C:16]=1[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.ClCCl>[Br-:1].[CH2:11]([C:6]1([O:5][C:3](=[O:4])[CH2:2][O:14][C:15]2[C:16]([CH3:35])=[CH:17][C:18]([S+:22]3[C:23]4[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=4)=[CH:19][C:20]=2[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:12]
Reactant: Cc1cc(-[s+]2c3ccccc3c3ccccc32)cc(C)c1O
Reactant: CCC1(OC(=O)CBr)CCCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(OC(=O)COc2c(C)cc(-[s+]3c4ccccc4c4ccccc43)cc2C)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
1-ethylcyclopentyl 2-bromoacetate (4.03 g, 17.1 mmol, 1.1 eq) was added dropwise to a solution of 5-(4-hydroxy-3,5-dimethylphenyl)-5H-dibenzo[b,d]thiophenium bromide (6.00 g, 15.6 mmol) and cesium carbonate (10.15 g, 31.1 mmol, 2 eq) in dimethylformamide (150 mL) under N2 at 0° C. The solution was slowly warmed to r.t. and stirred for 16 h. The reaction mixture was diluted with water (400 mL) and dichloromethane (400 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (4×150 mL). The combined organic layers were extracted with water (2×300 mL), dried (Na2SO4) and concentrated to the remaining DMF (−100 mL). This non-viscous solution was slowly poured onto MTBE (700 mL) under vigorous stirring. The precipitate was filtered, washed with MTBE (3×200 mL) and the residue dried in vacuo to afford the title compound (7.92 g, 94%) as a white solid. 1H NMR (500 MHz, d-DMSO) δ: 8.51 (d, J=8 Hz, 2H), 8.32 (d, J=7.5 Hz, 2H), 7.96 (t, J=7.5 Hz, 2H), 7.75 (t, J=7.5 Hz, 2H), 7.31 (s, 2H), 4.51 (s, 2H), 2.21 (s, 6H), 1.93-2.03 (m, 2H), 1.92 (q, J=7 Hz, 2H), 1.49-1.69 (m, 6H), 0.79 (t, J=7 Hz, 3H).
Reaction SMILES: COC(=O)[NH:4][C:5]1[C:10]([F:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13].O.[OH-].[Na+]>CO>[Cl:13][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[C:10]([F:11])[C:5]=1[NH2:4]
Reactant: COC(=O)Nc1c(Cl)ccc(C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)c(N)c1F
Temperature: 25 °C

Procedure:
N-(2-chloro-5-methyl-6-fluorophenyl)-carbamic acid methyl ester (39 g, 0.18 mmol) is dissolved in MeOH (150 mL), water (150 mL) and 30% NaOH solution (150 mL). The reaction mixture is heated to reflux temperature for 3 days and then cooled to room temperature. The reaction is concentrated by rotary evaporator to remove most of the methanol and then partitioned between Et2O (500 mL) and water (500 mL). The aqueous phase is extracted again with Et2O (250 mL) and the combined organic layers washed with brine (500 mL), dried and concentrated by rotary evaporator. The crude product is purified by bulb-to-bulb distillation to give 2-chloro-5-methyl-6-fluoroaniline as a colorless oil (b.p. 120–131° C. at ˜20 mm of Hg), which forms a white crystalline solid upon storage at 4° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14].Cl[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:18].ClC=C(C1C=CC=CC=1)C>CC(C)=O.CCOCC.O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:16]
Reactant: Sc1ccccc1Cl
Reactant: C=C(CCl)c1ccccc1
Agent: CC(=CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=C(CSc1ccccc1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Potassium carbonate (4.6 g, 0.033 mole) is suspended in acetone (100 cc) and the whole is heated to 50°-60° C. An acetone (30 cc) solution of 2-chlorothiophenol (4.3 g, 0.03 mole) and of a mixture (9.1 g, 0.03 mole) containing 1-chloro-2-phenyl-2-propene (50%) and 1-chloro-2-phenyl-1-propene (50%) is added dropwise under nitrogen. After 1 h of stirring at 50°-60° C. the reaction mixture is poured into water and ice (150 g) and is then reextracted with ether (3×100 cc). It is washed with water (2×150 cc) and dried over MgSO4. The crude (11.7 g) is distilled in a ball oven to give 1-[2'-chlorophenylthio]-2-phenyl-2-propene (6.3 g, 80%) Bp0.5 =180° C. nD24 =1.6340.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[Cl-].[NH4+].C(O)C>[Cl-].[Na+].O.[Fe].C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc([N+](=O)[O-])c(N)c1)c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccc(N)c(N)c1)c1ccccc1
Temperature: 80 °C

Procedure:
tert-Butyl [(1R)-2-(3-amino-4-nitrophenoxy)-1-phenylethyl]carbamate (Intermediate 5) (346 mg, 0.93 mmol) was placed in a microwave reaction vial (10-20 mL), followed by iron (259 mg, 4.63 mmol), water (4 mL), ammonium chloride (40 mg, 0.74 mmol) and finally ethanol (4 mL). The reaction vial was sealed, and set to heat at 80° C. for twenty hours. The reaction was added to a separatory funnel containing ethyl acetate (100 mL) and brine (75 mL); the phases were separated, and the organic layer was washed again with brine (75 mL). The ethyl acetate layer was then concentrated in vacuo to afford tert-butyl [(1R)-2-(3,4-diaminophenoxy)-1-phenylethyl]carbamate as an orange solid. LRMS (ESI) cale'd for (C19H26N3O3) [M+H]+, 344.2; found 344.2.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1([C:40]2[C:41]3[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=3[S:43][C:44]=2[CH:45](O)[CH3:46])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[N:66]([CH:45]([C:44]1[S:43][C:42]2[CH:48]=[CH:49][CH:50]=[CH:51][C:41]=2[C:40]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:46])=[N+:67]=[N-:68]
Reactant: CC(O)c1sc2ccccc2c1-c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1sc2ccccc2c1-c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
DIAD (556 mg, 2.75 mmol) was added to a solution of triphenylphosphine (722 mg, 2.75 mmol) in dioxane (5 mL) at 0° C. under a nitrogen atmosphere. After 10 min, 1-(3-phenylbenzo[b]thiophen-2-yl)ethanol (350 mg, 1.37 mmol) was added followed by diphenylphosphoryl azide (454 mg, 1.65 mmol). The reaction mixture was stirred 20° C. for 16 h then concentrated in vacuo. The crude reaction mixture was purified by column chromatography (Si—PCC, gradient 0-20% DCM in cyclohexane) affording the title compound as a colourless oil (211 mg, 55%). 1H NMR (CDCl3, 400 MHz): δ 7.88 (1H, d, J=7.87 Hz), 7.54-7.42 (4H, m), 7.41-7.29 (4H, m), 4.97 (1H, q, J=6.80 Hz), 1.58 (3H, d, J=6.80 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13](OC)=[O:14].[CH3:24][NH2:25].CO>CO>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:25][CH3:24])=[O:14]
Reactant: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reactant: CN
Solvent: CO
Product: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reaction time: 22 h
Yield: 82.1 %

Procedure:
A solution of methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate (0.44 g, 1.40 mmol) in methanol (5 ml) was stirred at room temperature. 40% methylamine/methanol solution (0.33 g, 4.2 mmol) was added thereto. After 22 hours, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide (0.36 g, 82%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:35][C:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)=[O:37]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:42]5[CH:41]=[CH:40][CH:39]=[C:38]([C:36](=[O:37])[NH2:35])[CH:43]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C(N)=O)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-aminocarbonyl-phenylboronic acid.
Reaction SMILES: Cl[C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:18][C:15]1[CH:14]=[CH:13][C:3]2[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:11][O:12][C:2]=2[C:16]=1[Cl:17])[CH3:27]
Reactant: ON=C(c1ccccc1)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3)noc2c1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 2,3-dichloro-4-hydroxybenzophenone oxime and 2.6 g of sodium hydride in 50 ml of dimethylformamide and 50 ml of toluene is heated to 118° C. and maintained at this temperature for 50 minutes. Thereafter, the reaction is permitted to cool prior to the dropwise addition of 7.9 g of ethyl bromoacetate in 50 ml of dimethylformamide. After the addition is complete the reaction mixture is stirred at ambient temperature for 40 minutes. To the well stirred mixture water is added dropwise to decompose any excess sodium hydride. The toluene is evaporated under vacuum and the resulting precipitate is collected by filtration and then rinsed with ether to yield the product ethyl[(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetate having a melting point of 130° to 132° C.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1CCN2C(=NCCC2)CC1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25]>C(#N)C>[C:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc(CS)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Into a 500-mL round bottom flask, was placed a solution of 3-(mercaptomethyl)benzoic acid (12 g, 71.43 mmol, 1.00 equiv) in acetonitrile (200 mL), tert-butyl acrylate (60 mL), and DBU (21.7 g, 142.76 mmol, 2.00 equiv). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of water and adjusted to pH 2-3 with 10% hydrochloric acid. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (50:1) to give 10.5 g (47%) of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid as red oil. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.08 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.46 (t, 1H), 3.81 (s, 2H), 2.68 (t, 2H), 2.50 (t, 2H), 1.48 (s, 9H). MS (ES, m/z): 295 [M−H]−.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]([CH3:30])[O:10][C@H:9]1[O:31][C@@H:32]1[C@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:40]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:39]([CH3:58])[O:38][C@H:33]1[O:34][CH2:35][CH:36]=[CH2:37])(=O)C>CO>[CH2:15]([O:14][C@@H:13]1[C@@H:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:11]([CH3:30])[O:10][C@@H:9]([O:31][C@@H:32]2[C@H:41]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C@@H:40]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@H:39]([CH3:58])[O:38][C@H:33]2[O:34][CH2:35][CH:36]=[CH2:37])[C@@H:8]1[OH:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A 1M solution of sodium methoxide in methanol (1.1 mL) was added to a solution of 322 (3.10 g, 4.13 mmol) in methanol. The mixture was stirred at rt for 3 h. The mixture was neutralised with Amberlite IR-120 (H+) resin, filtered and concentrated to give 323 (2.72 g, 93%) as a colourless syrup which crystallised on standing; mp 98-99° C.; lit. (Pinto, B. M.; Reimer, K. B.; Morissette, D. G.; Bundle, D. R. J. Org. Chem. 1989, 54, 2650-2656) mp 100° C. (hexane); [α]D−30° (c 0.5, CHCl3), lit. (Pinto, B. M.; Reimer, K. B.; Morissette, D. G.; Bundle, D. R. J. Org. Chem. 1989, 54, 2650-2656) [α]D−32.5° (c, 0.4, CHCl3); 1H NMR: δ 7.42-7.30 (m, 20H, Ph), 5.90-5.80 (m, 1H, All), 5.32-5.20 (m, 2H, All), 5.13 (d, 1H, J1,2=1.4 Hz, H-1A), 4.82 (d, 1H, J1,2=1.6 Hz, H-1B), 4.95-4.60 (m, 8H, CH2Ph), 4.20-4.12 (m, 1H, All), 4.19 (m, 1H, J2,3=3.2, J2,OH=1.8 Hz, H-2A), 4.09 (d, 1H, J2,3=3.2 Hz, H-2B), 4.00-3.95 (m, 1H, All), 3.95 (dd, 1H, J3,4=9.4 Hz, H-3A), 3.93 (dd, 1H, J3,4=9.4 Hz, H-3B), 3.87 (dq, 1H, J4,5=9.4, J5,6=6.2 Hz, H-5A), 3.74 (dq, 1H, J4,5=9.4, J5,6=6.2 Hz, H-5B), 3.53 (pt, 1H, H-4A), 3.46 (pt, 1H, H-4B), 2.52 (d, 1H, OH), 1.35 (m, 6H, H-6A, 6B); 13C NMR: δ 138.4-117.1 (Ph, All), 101.2 (C-1A), 98.4 (C-1B), 80.8, 80.4 (2C, C-4A, 4B), 80.3 (C-3B), 80.0 (C-3A), 75.8, 75.7 (2C, CH2Ph), 75.0 (C-2B), 72.7, 72.6 (2C, CH2Ph), 69.1 (C-2A), 68.4 (C-5B), 68.3 (C-5A), 68.1 (All), 18.4, 18.3 (2C, C-6A, 6B). CI-MS for C43H50O9 (M, 710) m/z 728 [M+NH4]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2C(OCC)=O)[CH:7]=1.Br.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnn2cc(Br)cc(OC)c12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(Br)cn2nccc12
Temperature: 0 °C
Yield: 59.8 %

Procedure:
A solution of ethyl 6-bromo-4-methoxylpyrazolo[1,5-a]pyridine-3-carboxylate (15, 5.2 g, 18.24 mmol) in HBr (100 ml, 884 mmol) was heated to 100° C. for 1 hour. After cooling to 0° C., 1M NaOH (182 ml, 912 mmol) was used to neutralize the solution. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydroxide (1N) and brine then dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (0-35% EtOAc in hexanes, linear gradient) to give 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (16, 2.475 g, 10.90 mmol, 60% yield). MS APCI: [M+H]+ m/z 228.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([O:14]C)[CH:7]=1)[CH3:2].OC1C=C(CC(O)=O)C=CC=1O>>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:14])[CH:7]=1)[CH3:18]
Reactant: CCN(CC)C(=O)Cc1ccc(OC)c(OC)c1
Agent: O=C(O)Cc1ccc(O)c(O)c1
Product: CCN(CC)C(=O)Cc1ccc(O)c(O)c1
Yield: 67 %

Procedure:
This compound was prepared from Compound H using a procedure analogous to that of Compound A, with a yield of 67%.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].[O-]CCCC.[CH3:20][N:21]=[C:22]=[S:23]>O1CCCC1.C(Cl)(Cl)Cl.O>[CH3:20][NH:21][C:22]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])=[S:23]
Reactant: CN=C=S
Reactant: O=C1CCCCC1c1ccccc1
Agent: CCCC[O-]
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CNC(=S)C1(c2ccccc2)CCCCC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
A solution of (±)-2-phenylcyclohexanone (3.0 g, 17.2 mmol) at -15° C. in tetrahydrofuran (40 ml) was treated with potassium t.-butoxide (1.9 g, 17.2 mmol) during 2 minutes. After 15 minutes at -15° C., a solution of methyl isothiocyanate (1.38 g, 19 mmol) in tetrahydrofuran (20 ml) was added dropwise during 2 minutes and the resulting solution was stirred for 3 hours at 0° C. Water (200 ml) followed by chloroform (200 ml) were added to the reaction mixture and the aqueous layer was extracted with chloroform (200 ml). The combined organic extracts were washed with brine (150 ml) then dried over sodium sulphate. Concentration in vacuo (30° C.; 14 mm Hg) afforded a crude oil (4.2 g) which was purified by flash chromatography over silica gel eluting with a 1:1 mixture of diethyl ether and hexane to give (±)-N-methyl-2-oxo-1-phenylcyclohexanecarbothioamide (1.5 g, 6.1 mmol) m.p. 86° C. N.M.R. (CDCl3) 1.62-2.05 (c, 4H), 2.42-2.56 (m, 2H), 2.64-2.84 (ddd, 1H), 3.0-3.18 (c, 4H), 7.23-7.45 (c, 5H) 8.72-9.06 (broad singlet, 1H). Found C, 68.3; H, 7.2; N, 5.8; S, 13 0%, C14H17NOS requires C, 68.0; H, 6.9; N, 5.7; S, 13.0%.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:20])[N:3]=1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CO.CC(O)=O>[F:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1ccc(-c2cn(CCC=O)c(=O)[nH]c2=O)c(F)n1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)c(F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A solution of 3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep117, 0.46 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 104 mg, 0.46 mmol), and AcOH (32 μl) in dichloroethane-MeOH (10-0.5, 4 ml) was cooled to 0° C. NaBH(AcO)3 (102 mg, 0.48 mmol) was added portionwise. The mixture was stirred at 0° C. for one hour and then basified with 1N NaOH. The product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred overnight in the presence of PS-isocyanate (300 mg). The mixture was filtered and the solvent evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) and then SCX cartridge to give 90 mg of the title compound (40% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:10]([Si:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)Cl)([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+]>CN(C)C=O>[Br:1][CH2:2][CH2:3][O:4][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Separately, 2.50 g (corresponding to 20.0 mmol) of 2-bromoethanol and 2.72 g (corresponding to 40.0 mmol) of imidazole were dissolved in 10 mL of dimethylformamide, and cooled to 0° C. Then, 5.50 g (corresponding to 20.0 mmol) of t-butyldiphenylchlorosilane was added thereto. After the reaction mixture was stirred at room temperature for 18 hours, a saturated sodium chloride aqueous solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1) to obtain 7.04 g (corresponding to 19.4 mmol) of 1-bromo-2-(t-butyldiphenylsiloxy)ethane (FIG. 8, Step 3).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[C:5]([CH3:12])=[CH:4][N+:3]=1[O-:13].C([Cl:17])(=O)C>>[Cl:17][C:6]1[C:5]([CH3:12])=[CH:4][N+:3]([O-:13])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Product: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reaction time: 0.33 h

Procedure:
The 2,3,5-trimethyl-4-nitropyridine1-oxide (13.4 g, 73.6 mmol) obtained in the step (11c) was added to acetyl chloride (80 ml, 1,125 mmol) at −30° C. in a nitrogen atmosphere. The mixture was stirred at −30° C. to room temperature for 4 hours and 20 minutes. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography (NH silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=10/1) to obtain fractions containing a pure product of the title compound and fractions containing a crude product of the title compound.