Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[C:16]([OH:17])[C:11]=3[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:23]/[N:24]=[N+:25](/[N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])\[O-:26])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:19]([O:23]/[N:24]=[N+:25](/[N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([O:17][C:16]1[C:11]2[CH2:10][O:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][C:15]=1[CH3:18])=[O:30])\[O-:26])[CH2:20][CH2:21][CH3:22]
Reactant: Cc1ncc2c(c1O)CO[C@H]2c1ccc(Cl)cc1
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)Oc1c(C)ncc2c1CO[C@H]2c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7-ol (346 mg, 1.32 mmol), 1-[(Z)-butoxy-NNO-azoxy]-L-proline (306 mg, 1.32 mmol), and triethylamine (369 mL, 2.65 mmol) in CH2Cl2 (10 mL) was added BOP-Cl (438 mg, 1.72 mmol). After stirring at rt over night, the mixture was purified by flash chromatography (Biotage 40+M) using 40-50% EtOAc/hexane gradient, affording the title compound: 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.35-7.33 (m, 2H), 7.28-7.25 (m, 2H), 6.19 (s, 1H), 5.21 (dd, J=2.4, 14.1 Hz, 1H), 5.07 (dd, J=1.9, 14.2 Hz, 1H), 4.78 (dd, J=4.5, 14.1 Hz, 1H), 4.20 (t, 6.7 Hz, 2H), 3.93-3.88 (m, 1H), 3.73-3.68 (m, 1H), 2.54-2.48 (m, 1H), 2.47 (s, 3H), 2.26-2.15 (m, 3H), 1.76-1.70 (m, 2H), 1.45-1.38 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[K+].C(#N)C.CC(N(C)C)=O.P(Cl)(Cl)([Cl:27])=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 0 °C
Yield: 84 %

Procedure:
To a mixture of 1280 g of potassium 4-chloro-3-nitrobenzenesulfonate, 1150 ml of acetonitrile, 250 ml of sulforan, and 30 ml of dimethylacetamide was added dropwise 1250 ml of phosphorus oxychloride while maintaining the internal temperature thereof at 60° C. to 70° C. Then, after performing reaction for 3 hours at 73° C., the reaction mixture was cooled with water and after gradually adding thereto 400 ml of water, the reaction mixture was poured into 5 liters of ice-water. Crystals deposited were filtered by filtration, washed with water, and then dried to provide 1060 g of the above-described product with a yield of 84%. The melting point thereof was 55° C. to 56° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)(=[O:4])=[O:3].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: CS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(C)(=O)=O)n1

Procedure:
A mixture of 4.1 g. 3-methylsulphonyl-1,2,4-triazole, 4.75 g. diallylcarbamoyl chloride, 20 ml. dry tetrahydrofuran and 5.5 ml. dry triethylamine was refluxed under anhydrous conditions for 1 hour. The reaction mixture was filtered and the filtrate was distilled to dryness under reduced pressure. The solid residue was recrystallized from a mixture of toluene and petroleum ether (b.p. 40° - 60° C.) to give 1-diallylcarbamoyl-3-methylsulphonyl-1,2,4-triazole, m.p. 52° - 54° C. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].Cl[CH2:13][CH:14]=[C:15]([CH3:35])[CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCOCC1>[CH3:35][C:15]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:14][CH2:13][C:8]2[C:6](=[C:5]([CH3:9])[C:4]([CH3:10])=[C:3]([OH:11])[C:2]=2[CH3:1])[O:7]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(=CCCl)CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
Fused zinc chloride (0.22 g), trimethylhydroquinone (2.47 g) and anhydrous dioxane (10 cc) are introduced into a 250 cc reactor. The mixture is heated to 40°-45° C. and a solution of 1,7,11,15-tetrachloro-3,7,11,15-tetramethylhexadec-2-ene (6.8 g) in dioxane (7 cc) is then added over the course of 20 minutes. Stirring is continued for 1 hour 30 minutes. This reaction mixture is poured into an aqueous solution (50 cc) of ammonium chloride (100 g/liter). The mixture is extracted with ethyl acetate (twice 50 cc) and the organic phases are then dried over magnesium sulphate. After filtration and evaporation of the solvent, 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-trimethyltridecyl)-chroman-6-ol is obtained in a yield of 43.5%.
Reaction SMILES: P(O[CH2:10][CH3:11])(OCC)(OCC)=O.Br[CH2:13][CH2:14][CH2:15][Si@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[CH:23]=2)[CH2:18][CH2:17]1>C1COCC1.[Cu]I>[F:33][C:24]1[CH:23]=[C:22]([C@H:19]2[CH2:20][CH2:21][Si@H:16]([CH2:15][CH2:14][CH2:13][CH2:19][C@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:29][CH2:10][CH3:11])[CH2:24][CH2:23]3)[CH2:17][CH2:18]2)[CH:27]=[C:26]([F:28])[C:25]=1[C:29]([F:32])([F:31])[F:30]
Reactant: Fc1cc([C@H]2CC[Si@H](CCCBr)CC2)cc(F)c1C(F)(F)F
Reactant: CCOP(=O)(OCC)OCC
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CCCC[Si@H]2CC[C@H](c3cc(F)c(C(F)(F)F)c(F)c3)CC2)CC1

Procedure:
21.9 g (0.1 mol) of trans-4-bromomethyl-1-n-propyl-1-silacyclohexane was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was then dropped in a solution, in 500 ml of THF, of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 40.1 g (0.1 mol) of 4-(trans-4-(3-bromopropyl)-4-silacyclohexyl) -2,6-difluoro-1-trifluormethylbenzene. The resultant product was subjected to ordinary aftertreatments to obtain trans-4-(4-(trans-4-(3,5-difluoro-4-trifluoromethylphenyl)-1-silacyclohexyl)butyl)-1 -n-propylcyclohexane, followed by isolation through chromatography to obtain 37.2 g (yield: 81%) of the intended trans isomer product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=5[N:32]=4)[CH2:17][CH2:16]3)[C:7]=2[CH:34]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=5[N:32]=4)[CH2:17][CH2:16]3)[C:7]=2[CH:34]=1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(O)cc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-[({1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Example 22) (100 mg, 0.21 mmol) in dichloromethane was cooled to −78° C. and treated with 1M boron tribromide (0.63 mL, 0.63 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to −78° C. and an additional 1 equivalent of 1M boron tribromide was added. The reaction was stirred for 4 hours at room temperature, and then quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous phase was extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure to afford crude product, 11 mg (11%), as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([NH2:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:29][CH2:27][CH3:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2C=O)c1
Reactant: CCN
Product: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Yield: 95.3 %

Procedure:
1,1-Dimethylethyl 4-[(3′-cyano-3-biphenylyl)methylidene]-1-piperidinecarboxylate (0.517 g, 1.381 mmol) in methanol (138 mL) was applied to H-Cube hydrogenation apparatus. This resultant mixture was run with a Pd(OH)2 cartridge at 1 mL/min, with 1 atmosphere at 20° C. HCl (1.38 mL, 1 N) was then added. One portion was run one time with Pd(OH)2 cartridge at 1 mL/min, 1 atmosphere at 20° C. Another portion was run with 1 run, Pd(OH)2 cartridge at 1 mL/min with 50 atmosphere and 20° C. Both portions were combined for 1 run, Pd(OH)2 cartridge, 1 mL/min with 1 atmosphere at 20° C. The reaction mixture was concentrated to afford the title compound (0.501 g, 87%). LC-MS m/z 381 (M+H)+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH2:24]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:33][CH:34]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCCCCCc1ccc(N)cc1
Product: CCCCCCCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 20 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-octylaniline (70.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-octylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.8 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]([C:9]1[N:10]([CH3:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)=[O:8]>CC(O)=O>[CH3:5][O:6][C:7]([C:9]1[N:10]([CH3:20])[C:11]2[C:16]([CH:17]=1)=[C:15]([N+:1]([O-:4])=[O:2])[C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)=[O:8]
Reactant: COC(=O)c1cc2cc(OC)ccc2n1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc2c([N+](=O)[O-])c(OC)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of concentrated HNO3 (2 mL) in AcOH (9 mL) was added to a solution of 8 (830 mg, 3.79 mmol) in AcOH (54 mL) at 0° C. Following the addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was poured over ice, filtered and the precipitate washed with H2O. The precipitate was dissolved in CH2Cl2 and filtered through a short column of silica gel to afford 9 (780 mg, 78%) as a yellow solid; Rf=0.53 (50% EtOAc/hexanes); 1H NMR (CDCl3): δ 7.58 (1H, d), 7.55 (1H, s), 7.18 (1H, d), 4.11 (3H, s), 4.02 (3H, s), 3.94 (3H, s).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].C([O:11][C@@H:12]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:13]1[O:31][C:32]1[C:36]([CH2:37][C:38]2[CH:43]=[CH:42][C:41](/[CH:44]=[CH:45]/[C:46](O)=[O:47])=[CH:40][CH:39]=2)=[C:35]([CH:49]([CH3:51])[CH3:50])[NH:34][N:33]=1)(=O)C.C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OC1C(CC2C=CC(/C=C/CC(O)=O)=CC=2)=C(C(C)C)NN=1)(=O)C>>[C@@H:13]1([O:31][C:32]2[C:36]([CH2:37][C:38]3[CH:43]=[CH:42][C:41](/[CH:44]=[CH:45]/[C:46](=[O:47])[NH:1][C:2]([CH2:5][OH:6])([CH3:7])[CH2:3][OH:4])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:51])[CH3:50])[NH:34][N:33]=2)[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@H:12]1[OH:11]
Reactant: CC(N)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/C(=O)NC(C)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 2-amino-2-methyl-1,3-propanediol and 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of ammonium chloride and 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole, respectively.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH2:29]1[O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30]1.CC(C)([O-:50])C.[K+:52]>C1C=CC=CC=1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[CH2:32]1[O:31][CH2:30][CH2:29][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33]1.[OH-:50].[K+:52]
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Solvent: c1ccccc1
Product: [OH-]

Procedure:
A solution of 2 parts 4-cholesten-3-one, 2 parts 18-crown-6 and 1.5 parts potassium t-butoxide in 400 parts benzene was stirred for 30 minutes at room temperature under an oxygen atmosphere and worked up in the usual manner. The product, 2-hydroxycholesta-1,4-dien-3-one, was purified by preparative TLC recrystallized from ligroin [M.P. 112.5-113.5] and identified by its spectral data: 1H NMR (CDCl3) δ 6.13 (s,H-4) 6.30 (s,H-1); MS (70 ev)m/e 398 (M+); IR (CHCl3): 3420, 1620, 1605 cm-1. The same enol was obtained when a solution of 1.7 parts of 4-cholesten-3-one, 2.4 parts of 18-crown-6 and 1 part of potassium hydroxide in 350 parts benzene was stirred for 3 days at room temperature under an oxygen atmosphere and worked up in the usual manner. The rate of reaction in this and similar cases can be increased if the oxygen pressure is increased above one atmosphere. :
Reaction SMILES: CC(C)=O.[F:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]([OH:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=O.C(OC(=O)C)(=O)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[F:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[NH:8][C:9](=[O:13])[NH:10][C:11]1=[O:12]
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1O
Reactant: C1CCNCC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1N1CCCCC1
Reaction time: 24 h

Procedure:
In 20 ml. of acetone is dissolved 4.40 g. of ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxo-pyrimidine-5-carboxylate, followed by the addition of 2.5 ml. of acetic anhydride. To this is further added dropwise 2 ml. of pyridine and the mixture is allowed to stand at room temperature for 24 hours. To the colorless reaction mixture thus obtained is added dropwise 5.9 ml. of piperidine, whereby the reaction takes place with evolution of heat. After 5.5 hours' standing at room temperature, volatiles are distilled off under reduced pressure and the yellow oily residue is dissolved in chloroform. The solution is subjected to column chromatography on silica gel (80 g., solvent:chloroform). The fractions rich in the desired compound are concentrated under reduced pressure to recover 5.20 g. of a white solid. Upon recrystallization from chloroform-hexane, 3.0 g. of ethyl 5-fluoro-6-piperidino-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate is obtained as colorless needles.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH2:70])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>>[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH:70][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (28.7 mg, 66.4 μmol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (37.8 mg, purity 98.5%). MS m/z [M+H]+ calc'd for C29H25ClN4O8, 593.14. found 593.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[C:6]2=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CC([O-])(C)C.[Na+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[C:11]=3[CH3:14])[C:6](=[O:18])[C:7]3([CH2:15][CH2:16][CH2:17]3)[CH2:8]2)=[CH:22][CH:21]=1
Reactant: Clc1ccc(I)cc1
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1cc2c(c(C)c1C)N(c1ccc(Cl)cc1)CC1(CCC1)C2=O
Temperature: 105 °C
Yield: 65.5 %

Procedure:
6′-Methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (300 mg) was mixed with 1-chloro-4-iodobenzene (465 mg), NaOtBu (187.4 mg) and [PdBr(tBu3P)2]2 (20 mg). The reaction tube was then sealed with rubber septum, the air was evacuated, then it was flushed with nitrogen. This process was repeated three times, and then toluene (1.5 mL) was added. The reaction tube was then heated in a 105° C. bath for 2 hours. The mixture was then cooled, quenched with water, and extracted with EtOAc. The organic phase was washed with brine, dried and evaporated to give a crude mixture, that was eluted on a silica column (Hexane: EtOAc; 10:1.5-10:2) to give 1′-(4-chlorophenyl)-6′-methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (285 mg) as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=7.399 (s, 1H), 7.16-7.09 (m, 2H), 6.81-6.73 (m, 2H), 4.07 (s, 2H), 3.86 (s, 3H), 2.36-2.23 (m, 2H), 2.13 (s, 3H), 1.99-1.78 (m, 1H), 1.76 (s, 3H), 1.69-1.42 (m, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=198.29, 154.39, 149.44, 141.4, 134.46, 132.07, 129.25, 125.87, 124.07, 121.47, 105.15, 60.96, 55.62, 48.86, 28.59, 15.55, 15.52, and 13.09 ppm.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][N:27]2[CH2:32][C@H:31]3[CH2:33][C@@H:28]2[CH2:29][O:30]3)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CN2C[C@H]3C[C@@H]2CO3)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CN2C[C@H]3C[C@@H]2CO3)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:35][C:2]([F:1])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:14][C@H:13]2[CH2:26][N:27]2[CH2:32][C@H:31]3[CH2:33][C@@H:28]2[CH2:29][O:30]3)=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C[C@H]3C[C@@H]2CO3)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C[C@H]3C[C@@H]2CO3)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2C[C@H]3C[C@@H]2CO3)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2C[C@H]3C[C@@H]2CO3)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.90 (dd, J=1.0, 5.1 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.47 (t, J=8.1 Hz, 2H), 7.28 (dd, J=3.8, 5.0 Hz, 1H), 6.99-6.87 (m, 2H), 4.38-4.36 (m, 1H), 4.05-3.90 (m, 2H), 3.80-3.71 (m, 2H), 3.60-3.44 (m, 3H), 3.27-3.20 (m, 1H), 3.06-3.02 (m, 2H), 2.76-2.51 (m, 3H), 2.40-2.38 (m, 1H), 1.84-1.64 (s, 5H). m/z (ESI, +ve ion) 532.2 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.670 μM; GK-GKRP EC50 (LC MS/MS)=0.880 μM.