Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][O:12][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)[P:14]([O:18][CH2:19][CH3:20])(=[O:21])[O:15][CH2:16][CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: COc1cccc(C(OC)OC)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC)c1cccc(OC)c1
Reaction time: 15 h

Procedure:
m-Methoxybenzaldehyde dimethyl acetal from Example 4 (271.4 g, 1.49 mol), triethyl phosphite (250.3 g, 1.51 mol), and methylene chloride (600 ml) were charged into a 3 liter 3-necked flask which was outfitted with a dropping funnel, an argon inlet, and an argon outlet. The flask was flushed with argon and the funnel was capped with a septum. The mixture was stirred and cooled to -40° in a liquid nitrogen-acetone bath. Boron trifluoride etherate (198.1 ml, 1.61 mol) was then added dropwise from the funnel over a 25 minute period. The mixture was allowed to slowly warm up to 5° over 3 hours. Stirring was then continued at room temperature for another 15 hours. The light yellow solution was then stirred rapidly as 500 ml saturated sodium bicarbonate solution was added. After 1 hour the mixture was transferred to a separatory funnel. The organic layer was isolated and washed with 500 ml water, 2×300 ml saturated sodium bisulfite, and 300 ml saturated bicarbonate solution. Drying was accomplished over 30 g anhydrous sodium sulfate just before decolorizing carbon (3 g) was added to the solution, and the whole was filtered under vacuum through celite. Concentration on the rotory evaporator and high vacuum pumping to a final pressure of 0.15 mm Hg at 100° C. provided a light yellow oil weighing 380 g (90%). I.R. (neat, cm-1): 2974, 1596, 1582, 1480, 1255 (P=O ), 1098, 1050, 1020, 965, 1HNMR (400 MHz, CDCl3): δ1.21 and 1.25 (6H, two t, 7 Hz, OCH2CH3); 3.37 (3H, s, ArCHOCH3); 3.80 (3H, s, ArOCH3); 3.90-4.10 (4H, m, OCH2CH3); 4.46 (1H, d, 15.6 Hz, ArCHPO); 6.85 (1H, m); 7.00 (2H, m), 7.26 (1H, m). This product was sufficiently pure for use in a Horner-Emmons reaction. However, further purification to remove a trace of a non-polar fluorescent impurity may be accomplished with silica gel chromatography using dichloromethane to elute the impurity and subsequent elution with 20% ethyl acetate in dichloromethane to elute the phosphonate. ##STR29##
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26](=[O:34])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:14]([C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:3]2[N:4]=[CH:5][N:6]([CH3:7])[C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([CH:19]=2)[C:26]([NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:34])[CH:13]=1)#[N:15]
Reactant: O=C(Nc1ccccc1)c1cc(B(O)O)ccc1F
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(C(=O)Nc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 4-fluoro-3-(phenyl carbamoyl)phenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H16FN5O, 398. Found, 398.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Si:14]([O:31][C@H:32]([CH3:44])[C@H:33]([NH2:43])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C=O)C>[Si:14]([O:31][C@H:32]([CH3:44])[C@H:33]([NH:43][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Cesium carbonate (242 mg) and ethyl bromoacetate (103 μl) are added to a solution of (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine obtained in Example 26 (274 mg) in DMF (5 ml), and the reaction solution was stirred at room temperature for 11 hours. Ice water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with half-saturated brine and brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:diethyl ether=19:1) to obtain 190 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].S(=O)(=O)(O)O.[CH3:27]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH3:27])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 2-[(4-amino-3-nitrophenyl)carbonyl]benzoic acid (4.60 g, 16.00 mmol) in methanol (300 mL) in the presence of catalytic amount of cc. sulfuric acid was heated to reflux for 18 h. The solution was cooled to room temperature and the solvent was evaporated. The yellow precipitate formed was collected by filtration, washed with water and dried in vacuo to provide methyl 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (4.8 g, quantitative). MS (EI) for C15H12N2O5: 301 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([NH2:23])([CH2:21][OH:22])[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH3-]C#N.[Na+].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.[ClH:70]>CCO.CCOCC.O.C1(C)C=CC=CC=1>[ClH:70].[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][NH:23][C:18]([CH3:17])([CH2:21][OH:22])[CH2:19][OH:20])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a 2 L Erlenmeyer flask was added 9-anthracenecarbaldehyde (Aldrich Chemical Co., Milwaukee, WI, 53201, 20.63 g, 0.1 mol) 2-methyl-2-amino-1,3-propanediol (Aldrich, 9.13 g, 86.8 mmol), p-toluenesulfonic acid.H2O (Eastman Kodak Co., Rochester, NY, 14650, 0.1 g, 0.5 mmol), and PhCH3 (500 mL). The mixture was warmed to reflux for a few minutes and H2O (2-3 mL) was driven off. The resulting golden colored solution was allowed to cool to RT, diluted with absolute EtOH (500 mL) and stirred overnight. NaBH3CN (Aldrich, 95%, 2.51 g, 42 mmol) was added to the reaction. After the NaBH3CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting blue solution was added 5 drops of 1M solution of HCl gas in absolute EtOH every 15 minutes. After 3 days the indicator turned green then yellow and voluminous white precipitate was present in the flask. To the flask was then added 1M HCl gas (10 mL) in absolute EtOH. The reaction was diluted to 4 L with Et2O and stirred for 1 h. The precipitate was then collected by filtration through a medium porosity glass fritted funnel and pressed dry. The filter cake was washed with CH2Cl2 (4×500 mL), pressed and sucked dry, and dried (100°). The crude solid was recrystallized from EtOH/Et2O (3×) to give 13.44 g (40%) of 2 -((9-anthracenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 139°-140° (dec), (C, H, Cl, N).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Cl[CH2:12][C:13]1[C:14]([CH3:19])=[N:15][O:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl>[CH3:19][C:14]1[C:13]([CH2:12][N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)=[C:17]([CH3:18])[O:16][N:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2c(C)noc2C)c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
Ethyl 1H-pyrazole-4-carboxylate (4.2 g, 30 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (5.1 g, 35 mmol), and cesium carbonate (9.8 g, 30 mmol), in DMF (50 mL), were stirred at 80° C. for 12 hours. The reaction was cooled to ambient temperature, diluted with 0.1 N HCl (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The solid product was triturated with ethyl acetate/hexanes (1/9) and collected by filtration to afford ethyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carboxylate (6 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ1.34 (t, J=7.2 Hz, 3H), 2.19 (s, 3H), 2.43 (s, 3H), 4.29 (q, J=7.2 Hz, 2H), 5.06 (s, 2H), 7.77 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:12][C:11]3=[N:20]S[N:22]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1>N.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:22])[C:11]([NH2:20])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2nc3nsnc3nc2-c2ccncc2)c1
Agent: N
Solvent: O
Product: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 5-(3-fluorophenyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine (Preparation 11) (1.6 g, 5.2 mmol) in ammonia solution (32%, 30 mL) was stirred and heated under reflux for 1 h. The reaction was allowed to cool to room temperature, diluted with water and the suspension obtained was filtered to provide the title compound as a brown solid (0.7 g, 48%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([C:10](OCC)=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)c1ncn2cc(Br)sc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ncn2cc(Br)sc12
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
A solution of ethyl 2-bromoimidazo[5,1-b] thiazole-7-carboxylate (52 mg, 0.19 mmol) in toluene (7 ml) was cooled to −78° C. A toluene solution of diisobutylaluminium hydride (1.01 M solution; 0.65 ml, 0.64 mmol) was added dropwise to the cooled solution, and the mixture was stirred at the same temperature for 40 min. After the completion of the reaction, a saturated aqueous potassium sodium tartrate solution was added thereto, and the mixture was stirred at room temperature for one hr and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give 2-bromo-7-hydroxymethylimidazo[5,1-b]thiazole (44 mg, 99%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=O.P([Cl:32])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]=[C:3]([Cl:32])[C:2]([F:15])([F:14])[F:1]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccccc1NC(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1N=C(Cl)C(F)(F)F
Temperature: 82 °C
Yield: 84 %

Procedure:
Five grams (22.8 mmol) of 2,2,2-trifluoro-N-(2-methoxyphenyl)acetamide, 12.24 g (45.6 mmol) of diphenyl chlorophosphate, 4.64 g (45.6 mmol) of triethylamine, and 25 ml of acetonitrile were introduced into a 100 ml flask and reacted for 22.5 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.55 g of N-(2-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 84.3%).
Reaction SMILES: [F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C([NH2:23])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][C@H:7]([NH2:23])[C@H:2]([F:1])[CH2:3]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A mixture of (+/−)-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.33 g, 1.52 mmol), benzylamine (0.16 mL, 1.52 mmol) and sodium triacetoxyborohydride (0.382 g, 1.8 mmol) in dry 1,2-dichloroethane (6 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aq. K2CO3 solution (25 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhyd. Na2SO4 and concentrated under vacuum. The crude product obtained was purified by flash chromatography to give the cis isomer of the title compound (200 mg, 42.6%) as the major product and the trans isomer of the title compound (20 mg, 4.26%) as the minor product. Cis isomer: HPLC (condition D): retention time=10.20 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.32-7.37 (m, 4H), 7.24-7.29 (m, 2H), 4.69-4.82 (m, 1H), 4.32 (s, 1H), 4.11-4.16 (m, 1H), 3.88 (s 2H), 2.91-3.04 (dd, J=35.6 Hz, J=14 Hz, 1H), 2.66-2.80 (m, 2H), 1.78 (bs, 1H), 1.63-1.72 (m, 1H), 1.47 (s, 9H). 19F-NMR (400 MHz in CDCl3): δ ppm: −204.51 (1F). Trans isomer: HPLC (condition D): retention time=11.05 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.99 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.31-7.37 (m, 4H), 7.25-7.28 (m, 1H), 4.25-4.30 (m, 2H), 3.89-3.93 (d, J=13.6 Hz, 2H), 2.93 (bs, 1H), 2.80-2.89 (m, 2H), 1.96-2.01 (m, 1H), 1.48 (s, 9H), 1.37-1.40 (d, J=13 Hz, 1H). 19F-NMR (400 MHz in CDCl3): δ ppm: −189.58 (1F).
Reaction SMILES: N[C:2]1[NH:3][C:4]2[CH:10]=[C:9](C(=O)C(C)(C)C)[CH:8]=[CH:7][C:5]=2[N:6]=1.O.N#CBr>CC#N.CCO>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][CH:2]=1
Reactant: CC(C)(C)C(=O)c1ccc2nc(N)[nH]c2c1
Agent: N#CBr
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: c1ccc2[nH]cnc2c1
Reaction time: 20 h

Procedure:
2-Amino-5-(2′,2′-dimethylpropionyl)benzimidazole: To a flask containing 60 mL H2O was added 11.32 mL of a 5.0 M solution of cyanogen bromide in CH3CN followed by the addition of 10.71 g 4-(2′,2′-dimethylpropionyl)-1,2-aminobenzene (51.5 mmol, prepared above in step (b), 1.0 equiv) in 60 mL EtOH over 30 min via addition funnel. After stirring for 20 h the solution was concentrated under reduced pressure to remove the EtOH. The resulting aqueous solution was washed (2×EtOAc), and the EtOAc fractions were back extracted 2×H2O. The combined aqueous layers were made basic with sat. NaHCO3, and then extracted (3×EtOAc). The organic layer was then washed (1×brine), dried (MgSO4), and concentrated under reduced pressure to give the product benzimidazole as a brown solid (8.59 g, 36.8 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 7.04 (d, J=8.3 Hz, 1 H), 6.79 (d, J=2.2 Hz, 1 H), 6.53 (dd, J=2.2, 8.3 Hz, 1 H), 6.31 (broad s, 2 H), 1.28 (s, 9 H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 69 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1.COC(C)(C)C>C1(C)C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[C:29]([C:26]1[CH:25]=[CH:24][C:23]([N:13]2[CH2:12][CH2:11][CH:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:15][CH2:14]2)=[CH:28][CH:27]=1)([OH:38])[C:34]([F:35])([F:37])[F:36]
Reactant: O=S(=O)(c1ccccc1)C1CCNCC1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A 15-mL reaction vial was charged with 4-(phenylsulfonyl)piperidine (1.05 g, 4.66 mmol, BetaPharma, Brandford, Conn.), sodium t-butoxide (0.98 g, 10.24 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.50 g, 4.66 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (0.170 g, 0.233 mmol, Strem Chemicals, Inc, Newburyport, Mass.), and toluene (10 mL). The vial was closed and purged with nitrogen for several minutes. The reaction mixture was heated at 100° C. for 2.5 h and allowed to cool to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (5 mL) and dried over Na2SO4. The solution was filtered and concentrated and then absorbed onto a plug of silica gel and purified by column chromatography (40 g of silica gel, 10 to 30% EtOAc in hexanes) to provide 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol (1.94 g) as white solid
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])[N:9]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:8][C:7]1([CH2:21][CH2:20][CH2:19]1)[CH2:6]2.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[N:9]([CH2:15][CH2:16][CH2:17][NH:18][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][C:7]1([CH2:19][CH2:20][CH2:21]1)[CH2:6]2
Reactant: COc1cc2c(c(C)c1C)N(CCCN)CC1(CCC1)C2
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(C)c1C)N(CCCNC(=O)c1ccccc1)CC1(CCC1)C2
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 3-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)propan-1-amine (80 mg) prepared as described herein, dissolved in 2 mL dichloromethane, was added benzoic acid (67.6 g), 1,3-dicyclohexylcarbodiimide (68.4 mg), 4-dimethylaminopyridine (18 mg) at room temperature. After 2 hours, more dichloromethane was added and the mixture was filtered. The filtrate was concentrated onto silica gel and purified through a column (Hexane/EtOAc, 10:6-10:7), to give N-(3-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)propyl)benzamide (95 mg). Demethylation as described herein gave N-(3-(6′-hydroxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)propyl)benzamide (62.4 mg, Hexane/EtOAc, 10:12 as a light yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)n1ccnc1
Yield: 68.6 %

Procedure:
A mixture of imidazole (25.6 g, 0.4 mol), triethyl orthoformate (236.8 g, 1.6 mol) and p-toluenesulfonic acid (2 g) was heated at 130° C. overnight with no condenser so ethanol can boil off. The excess orthoformate was removed by rotary evaporation and the residue was purified by vacuum distillation to give 1-(diethoxymethyl)-1H-imidazole (46.7 g). To a solution of the resulting protected imidazole (46.7 g) in anhydrous THF (350 mL) under N2 cooled at −40° C., was added n-butyllithium (2.5 M in hexane, 110 mL) at such a rate that the temperature did not rise above −35° C. After complete addition, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (18.25 g, 91.5 mmol) in anhydrous THF (70 mL) under N2 was added dropwise over 10 minutes keeping the temperature below −40° C. The reaction was stirred at 40° C. for 2 hours then 350 mL of 0.1 N HCl added and stirred for 15 minutes, ethyl acetate (350 mL) added and stirred for 5 minutes. The organic layer was separated and aqueous extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 10% methanol in ethyl acetate with 0.5% ammonia hydroxide to give tert-butyl 4-hydroxy-4-(1H-imidazol-2-yl)piperidine-1-carboxylate (10.5 g).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]=1[CH3:32])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:11]2[NH:12][C:13]3[C:18]([C:9](=[O:8])[C:10]=2[CH3:32])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:30][CH:29]=1
Reactant: Cc1c(C=CCCCOc2ccc(F)cc2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(CCCCCOc2ccc(F)cc2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
4-(Benzyloxy)-2-[5-(4-fluorophenoxy)pent-1-en-1-yl]-3-methylquinoline (E/Z mixture, 810 mg) was dissolved in ethanol-THF (1:1, 20 mL), and 10% palladium-activated carbon (200 mg) was added thereto. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2-[5-(4-fluorophenoxy)pentyl]-3-methylquinolin-4(1H)-one (572 mg).