Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:20][C@@H:21]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([CH3:44])[O:24][C@H:22]2[OH:23])[C@@H:6]1[NH:45][C:46](=[O:51])[C:47]([Cl:50])([Cl:49])[Cl:48])(=[O:3])[CH3:2].[Cl:52][C:53]([Cl:57])([Cl:56])[C:54]#[N:55].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:52][C:53]([Cl:57])([Cl:56])[C:54]([O:23][C@@H:22]1[O:24][C@@H:25]([CH3:44])[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:21]1[O:20][C@@H:7]1[O:8][C@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]1[NH:45][C:46](=[O:51])[C:47]([Cl:50])([Cl:49])[Cl:48])=[NH:55]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
The hemiacetal 318 (539 mg, 0.68 mmol) was dissolved in CH2Cl2 (50 mL), placed under argon and cooled to 0° C. Trichloroacetonitrile (0.6 mL, 6.8 mmol), then DBU (10 μL, 70 μmol) were added. The mixture was stirred at 0° C. for 30 min. The mixture was concentrated and toluene was co-evaporated from the residue. The residue was eluted from a column of silica gel with 7:3 cyclohexane-EtOAc and 0.2% of Et3N to give 306 (498 mg, 78%) as a colourless foam; [α]D−18° (c 1, CHCl3). 1H NMR: δ 8.48 (s, 1H, NH), 7.40-7.15 (m, 10H, Ph), 6.75 (d, 1H, J2,NH=8.5 Hz, NHD), 6.18 (d, 1H, J1,2=1.1 Hz, H-1A), 5.15 (pt, 1H, J2,3=J3,4=9.5 Hz, H-3D), 5.07 (pt, 1H, J4,5=9.5 Hz, H-4D), 4.82-4.50 (m, 4H, CH2Ph), 4.62 (d, 1H, J1,2=8.5 Hz, H-1D), 4.20-4.03 (m, 2H, J5,6=4.5, J6a,6b=12.3 Hz, H-6aD, 6bD), 3.98 (m, 1H, H-2D), 3.85 (dq, 1H, J3,4=9.5, J5,6=6.2 Hz, H-5A), 3.84 (dd, 1H, J2,3=3.3 Hz, H-2A), 3.83 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.55 (m, 1H, H-5D), 3.45 (pt, 1H, H-4A), 1.98, 1.96, 1.93 (3s, 9H, OAc), 1.23 (d, 3H, H-6A); 13C NMR: δ 171.1, 170.0, 169.6, 162.1 (C═O), 138.4-127.2 (Ph), 101.7 (C-1D), 97.2 (C-1A), 92.6 (CCl3), 80.5 (C-4A), 79.1 (C-3A), 76.2 (C-2A), 76.2, 74.1 (2C, CH2Ph), 74.4 (C-3D), 74.1 (C-5D), 71.3 (C-5A), 68.6 (C-4D), 62.3 (C-6D), 56.3 (C-2D), 21.1, 21.0, 20.9 (3C, OAc), 18.2 (C-6A). Anal. Calcd for C36H40Cl6N2O13: C, 46.93; H, 4.38; N, 3.04%. Found: C, 46.93; H, 4.52; N, 2.85%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]3[N:29]=[CH:30][CH:31]=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl.CN([CH:40]=[O:41])C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:40]=[O:41])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3ccnn23)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=O)cnn23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12 %

Procedure:
To tert-butyl 3-(5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (965 mg, 2.2 mmol) in DMF (8.2 mL), POCl3 (1.2 mL, 13.3 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred for 3 days at room temperature. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, tert-butyl 3-(5-(3-chlorophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was collected as a solid in 12% yield after purification by column chromatography on silica using 5% acetone/dichloromethane as the eluent. LCMS (M+1=464)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[F:19][C:20]([F:27])([F:26])[C:21]1[N:22]=[CH:23][NH:24][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:24]2[CH:25]=[C:21]([C:20]([F:27])([F:26])[F:19])[N:22]=[CH:23]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1c[nH]cn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cnc(C(F)(F)F)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
In a similar way a solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 5.62 mmol), 4-trifluoromethyl-imidazole (0.945, 6.74 mmol) and ethyl-diisopropyl-amine (3.94 ml, 22.5 mmol) in 10 ml of dioxane is heated to reflux for 48 hours. After a similar workup procedure 1.4 g (3.65 mmol, 65%) of amorphous 5-(4-trifluoromethyl-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester are obtained, ES-MS: m/z 384 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:13](=[O:15])=[O:14].C(OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: COc1cccs1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 31 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of dry ice and diethyl ether, and warmed to room temperature with stirring. The solvent was distilled off, and the residue was acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-methoxy-2-thiophenecarboxylic acid (5.62 g).
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.[CH3:21][C:22](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:21]([N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN1C(=O)C(C)Oc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.82 g) in dry tetrahydrofuran (150 ml) was added potassium tert-butoxide (2.42 g), with stirring. After 20 mins, bromoethane (5.37 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, concentrated, and the residue was adhered to silica and flash chromatographed (30% ethyl acetate/hexane). The appropriate fractions were concentrated. Trituration of the residue with diethyl ether/pentane (1/1) gave 4.51 g (85%) of 1-ethyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19]([O:21]C1C=C2C(=CC=1)NC(C)=C2C=O)C>>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][NH2:18])=[CH:14][CH:15]=2)[C:10]([CH:19]=[O:21])=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CN)ccc21
Product: CC(C)(C)OC(=O)n1cc(C=O)c2cc(CN)ccc21
Yield: 73 %

Procedure:
This compound was prepared from 416 (297 mg, 1.21 mmol) in a manner similar to that for 409a to yield a cream-colored solid (243 mg, 73%): mp 126-128° C. TLC Rf 0.50 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 12.10 (s, 1H), 9.91 (s, 1H), 8.27 (m, 1H), 8.00 (s, 1H), 7.45-7.43 (m, 2H), 7.17-7.15 (d, 1H, J=8.4 Hz), 4.22-4.20 (d, 2H, J=6 Hz), 1.40 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 184.7, 155.7, 138.6, 136.0, 134.0, 124.0, 123.1, 119.2, 118.0, 112.0, 77.6, 43.7, 28.2. Elemental analysis calculated for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.75; H, 6.61; N, 10.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Cl[C@H:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27]>O>[CH2:29]([C@H:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH3:30]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC[C@@H](Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (7.50 g) in a mixed solvent of ethyl acetate (60 ml) and water (60 ml) were added sodium hydrogen carbonate (5.20 g) and (R)-2-chlorobutyryl chloride (7.50 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (90 ml), to the solution was added potassium carbonate (6.20 g) and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and the resulting crystals were taken by filtration to give (S)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (9.38 g).
Reaction SMILES: C(C1C=CC2OC(C)(C)[C@@H](Br)[C@H](O)C=2C=1)#N.[H-].[Na+].[C:19]([C:21]1[CH:33]=[CH:32][C:24]2[O:25][C:26]([CH3:31])([CH3:30])[CH:27]3[O:29][CH:28]3[C:23]=2[CH:22]=1)#[N:20].[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>CS(C)=O.O>[C:19]([C:21]1[CH:33]=[CH:32][C:24]2[O:25][C:26]([CH3:31])([CH3:30])[C@@H:27]([OH:29])[C@H:28]([N:34]3[CH2:38][CH2:37][CH2:36][C:35]3=[O:39])[C:23]=2[CH:22]=1)#[N:20]
Reactant: O=C1CCCN1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-bromo-4-hydroxy-2H-benzo[b]pyran (4 g, 14.2 mM) in dimethylsulphoxide (20 ml) was stirred and sodium hydride (60% dispersion in oil, 0.6 g, 15 mM) added. The suspension was stirred for 1 hour when a solution of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran resulted. 2-Pyrrolidone (1.8 g, 21 mM) and further sodium hydride (0.8 g, 21 mM) were introduced and the mixture stirred at room temperature for an additional 16 hours. Water (40 ml) was slowly added to the mixture to induce crystallisation of the product after which it was cooled in ice and filtered under suction. Crystallisation from ethanol (20 ml) gave the title compound as a cream coloured solid in 60% yield. Recrystallisation from ethyl acetate afforded the pure product as needles, m.p. 226.5°-227.5° having an nmr spectrum and t.l.c. characteristics identical to those of the compound of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH:31]=[C:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Fc1ccc(C2=CCNCC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CC=C(c2ccc(F)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 47.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-fluoro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.63 g, 9.3 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.63 g of the intended substance (yield 47.8%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=2)=O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:37][C:38]#[N:39])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=2)=[CH:37][C:38]#[N:39])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])([CH3:6])([CH3:5])[CH3:7]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Yield: 74.1 %

Procedure:
[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-(3,5-dimethoxyphenyl) methanone (0.74 g, 1.84 mmol), cyanomethylphosphonic acid diethyl ester (0.58 ml, 3.68 mmol) in anhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 3.70 ml, 3.68 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)-acrylonitrile. The crude was purified via flash column chromatography (100% hexane gradient to 20% EtOAc in hexane in about 40 min.) to give 3-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrile as an clear colorless oil (0.58 g, 74%): 1HNMR (CDCl3) δ 7.09-6.78 (m, 3H, Ar), 6.53-6.51 (m, 2H, Ar), 6.41 (d, J=2 Hz, 1H, Ar), 5.60 (s, 1H, CH), 3.86-3.76 (multiple singlets, 9H), 0.97 (s, 9H, 3OCH3), 0.14 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH3:35])[N:28]4[CH:36]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH3:35])[N:28]4[CH:36]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(OCC)cccc4n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cn4c(OCC)cccc4n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-ethoxyimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (441 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-ethoxyimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (335 mg, yield: 81%). This was recrystallized from ethanol-hexane. Melting point: 197–198° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][C:36](=[O:38])[CH2:37][CH:30]2[CH2:31][O:32][CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].C1COCC1.[BH4-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:30]3[CH2:37][CH:36]([OH:38])[CH2:35][CH:34]2[CH2:33][O:32][CH2:31]3)[CH2:10]1)(=[O:7])=[O:8]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(=O)C3)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(O)C3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.8 %

Procedure:
A 25-mL round-bottomed flask was charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (60 mg, 0.11 mmol, Example 106), THF (3 mL) and MeOH (0.5 mL). NaBH4 (39.6 mg, 1.05 mmol) was added and the reaction stirred at room temperature for 20 min. MeOH (50 mL) was added and then the mixture was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (10 mg) as a mixture of two isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[C:3]=1[CH3:12].I[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[CH:19][CH:20]=2)=[C:3]([CH3:12])[C:4]=1[OH:11])(=[O:10])[CH3:9]
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CI)cc2)c1
Reactant: CC(=O)c1ccc(N)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C)c1O
Temperature: 50 °C
Yield: 63.5 %

Procedure:
To a solution of 1-(4-amino-2-hydroxy-3-methyl-phenyl)-ethanone (300 mg, 1.8 mmol) and 3-[(4-Iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (865 mg, 2.0 mmol)) in anhydrous DMF (1.5 mL) under Ar gas at RT is added K2CO3 (303 mg, 2.2 mmol). The reaction mixture is heated at 50° C. overnight. The reaction mixture is quenched into water and extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried over Na2SO4 and concentrated. The residue is purified by flash chromatography using 25% EtOAc/hexane as eluent. Obtained is the title compound as a yellow foam (538 mg, 64%). LC-MS (m/e): 469 (M−1).
Reaction SMILES: [CH:1]1[C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][C:4]([I:18])=[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)[C:6]=1[I:7].[CH2:23](OC(Cl)=O)C1C=CC=CC=1>CO>[CH3:23][O:21][C:20](=[O:22])[CH2:19][C:2]1[CH:1]=[C:6]([I:7])[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)=[C:4]([I:18])[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: CO
Product: COC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
In anhydrous conditions, Tetrac (1.0 g, 1.3 mmol, 1.0 eq.) was suspended in MeOH (20 mL). TEA (181.4 μL, 1.3 mmol, 1.0 eq.) was then added dropwise followed by benzylchloroformate 184.8 μL, 1.3 mmol, 1.0 eq.). After stirring for 30 minutes, the solution was filtered, the solvent was removed from the residue and the product was separated by silica gel chromatography (eluent=DCM). The collected fractions were then evaporated to give a white powder which was recrystallized to give orange crystals (990 mg, 1.3 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 4-(4-chlorophenyl)cyclohexanecarboxylic acid (0.5 g, 2.095 mmol) in methanol (10 mL) was added one drop of conc. sulfuric acid. After stirring overnight at room temperature, the reaction mixture was extracted with ethyl acetate and washed with water, saturated sodium bicarbonate and brine. It was then dried over anhyd. magnesium sulfate, concentrated and dried in vacuo to yield methyl 4-(4-chlorophenyl)cyclohexanecarboxylate a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.23-7.30 (2H, m), 7.10-7.17 (2H, m), 3.70 (3H, s), 2.44-2.56 (1H, m), 2.36 (1H, tt, J=12.13, 3.60 Hz), 2.07-2.16 (2H, m), 1.92-2.01 (2H, m), 1.38-1.67 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]2[CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:8]1[N:7]([CH2:9][CH:10]2[CH2:11][O:12][CH2:13]2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnn(CC2COC2)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(CC2COC2)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of 4-nitro-1-(oxetan-3-ylmethyl)pyrazole (3200 mg, 17.47 mmol) in THF (80 mL) was added LHMDS (1M solution in THF, 22.7 mL, 22.7 mmol) dropwise at −78° C. over a period of 15 min. The resulting mixture was stirred at −78° C. for 30 min. Hexachloroethane (5.38 g, 22.7 mmol.) in THF (20 mL) was added at −78° C. dropwise. The resulting mixture was stirred at −78° C. for another 40 min. The reaction mixture was quenched with aqueous ammonium chloride and extracted with Ethyl acetate (×3). Combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography with 0 to 75% ethyl acetate in heptane as eluent to give 5-chloro-4-nitro-1-(oxetan-3-ylmethyl)-1H-pyrazole (3.60 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]([CH:14]([CH:6]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=1)[CH2:7][N+:8]([O-:10])=[O:9])[C:13]([O:20][CH3:21])=[O:19])=[O:16]
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Reactant: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc(C)cc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), 4-methyl-β-nitrostyrene (1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the isolation yield of the product was 71%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 92% ee.