Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[CH3:38][O:39][C:40]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH2:49].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:38][O:39][C:40]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH:49][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:18]
Reactant: COc1cc(Br)ccc1CCN
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4OC)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 1.90 g; 5.04 mmol), 1-hydroxybenzotriazole hydrate (0.85 g; 5.55 mmol) and 2-(2-methoxy-4-bromophenyl)ethanamine (Preparation 6; 1.28 g; 5.55 mmol) in dry dimethylformamide (15 mL) was added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.16 g; 6.05 mmol) at ambient temperature. After stirring at ambient temperature for 4 hours, the solution was diluted with 150 mL of water, stirred for 10 minutes longer and then extracted with ethyl acetate (3×15 mL). Aqueous HCl (1M, 50 mL) was added to enable layer separation. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with hexane and ethyl acetate to provide ethyl 7-(4-(2-methoxy-4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as a light yellow solid (1.81 g). MS (apci, pos) m/z=590.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([Cl:24])=[O:21])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Solvent: c1ccccc1
Product: Cn1c(C(=O)Cl)cc2c(OCc3ccccc3)cccc21
Temperature: 80 °C

Procedure:
To a stirred suspension of 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (0.75 g) in benzene (5 mL) was added thionyl chloride (2.8 mL) in benzene (5 mL) followed by heated at 80° C. for 45 min. to give a clear orange solution. Evaporation to dryness gave 0.80 g of the title compound as an orange solid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O[C:24]1[CH:65]=[CH:64][C:27]([CH2:28][N:29]([CH2:56][C:57]([O:59]C(C)(C)C)=[O:58])[C:30](=[O:55])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[C:48]([F:51])([F:50])[F:49])=[CH:33][C:32]=2[O:53][CH3:54])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:54][O:53][C:32]1[CH:33]=[C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[C:48]([F:50])([F:51])[F:49])[CH:35]=[CH:36][C:31]=1[C:30]([N:29]([CH2:56][C:57]([OH:59])=[O:58])[CH2:28][C:27]1[CH:64]=[CH:65][C:24]([O:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[O:16])=[CH:25][CH:26]=1)=[O:55]
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)c(OC)c2)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)c(OC)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
Prepared using General Procedures 2 then 8: To a stirring suspension of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (57 mg, 0.27 mmol) in DCM (5 mL) were added DMF (2 drops) and oxalyl chloride (25 μL, 0.29 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-24 (108 mg, 0.18 mmol) and TEA (62 μL, 0.45 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h then TFA (3 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to provide to afford 23.1 mg (17%) of 2-(2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-((4′-methyl-[1,1′-biphenyl]-4-carbonyl)oxy)benzyl)benzamido)acetic acid 314 as a white powder. LCMS-ESI (m/z) calculated for C41H35F3N2O8: 740; found 741 [M+H]+, tR=10.33 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 10.34 (s, 0.5H), 10.32 (s, 0.5H), 8.25-8.15 (m, 2H), 7.93-7.85 (m, 2H), 7.74-7.64 (dt, J=6.3, 2.3 Hz, 2H), 7.53-7.39 (m, 3H), 7.39-7.07 (m, 9H), 5.01 (br s, 1H), 4.42 (s, 1H), 3.90-3.65 (m, 10H), 2.38 (s, 3H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.ClCCl.N1C=CC=CC=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:67])[C:43]2[C:44]([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)=[C:45]3[C:53](=[CH:54][C:55]=2[CH:56]([CH3:58])[CH3:57])[O:52][C:48]2([CH2:51][CH2:50][CH2:49]2)[CH2:47][C:46]3=[O:59])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(OCC)(=O)C.[OH-].[Na+]>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:42]([C:43]2[C:44]([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)=[C:45]3[C:53](=[CH:54][C:55]=2[CH:56]([CH3:58])[CH3:57])[O:52][C:48]2([CH2:51][CH2:50][CH2:49]2)[CH2:47][C:46]3=[O:59])=[O:67])=[CH:40][CH:41]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
91 mg (0.21 mmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are dissolved in 1.4 ml of abs. dichloromethane and cooled to −30° C. 12 μl (0.14 mmol) of pyridine are added, followed by the dropwise addition of 68 mg (0.14 mmol) of 6-[(4-tert-butylphenyl)(hydroxy)-methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A), dissolved in 0.6 ml of abs. dichloromethane. The mixture is slowly warmed to 0° C. and stirred at this temperature for 1.5 h. The mixture is diluted with ethyl acetate, 5 ml of 1 N aqueous sodium hydroxide solution are added and the mixture is then extracted twice with ethyl acetate. The combined organic phases are washed once with 1 N hydrochloric acid and twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product is dried under high vacuum and then reacted without further purification. This gives 81 mg (>100% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[OH:8][CH2:7][C@H:5]([NH:6][C:29]([C@H:28]1[CH2:32][CH2:33][CH2:34][N:27]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:30])[C:4]([O:3][CH3:2])=[O:9]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of L-Serine methyl ester hydrochloride (Aldrich, 5.0 g, 32.0 mmoles), in CH2Cl2 (150 mL) at 0° C., were added Et3N (4.88 mL, 35.2 mmoles), Cbz-D-Proline (8.01 g, 32.0 mmoles) and DCC (7.26 g, 35.2 mmoles) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and chromatographed on silica gel (70% ethyl acetate/30% chloroform) to yield 8.5 g of (R)-benzyl 2-((S)-3-hydroxy-1-methoxy-1-oxopropan-2-ylcarbamoyl)pyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[ClH:26].[OH-].[Na+:28]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Na+:28].[Cl-:26]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Fc1ccc(-c2nnc(C3CCNCC3)o2)cc1
Product: [Cl-]
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (210 mg, 0.605 mmol) in dioxane (1 mL) was added 4N HCl in dioxane (0.756 mL, 3.0 mmol) and the mixture was stirred for 48 h. 1N NaOH (2.4 mL, 2.4 mmol) was added to neutralize the mixture. The solvent was evaporated, ether was added to the resulting white precipitate and the mixture sonicated. This white precipitate was filtered, washed with ether to give the title compound as a white powder as a NaCl salt (171 mg) and used without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 8.00-8.16 (m, 2H) 7.24-7.41 (m, 2H) 3.42-3.58 (m, 3H) 3.15-3.29 (m, 3H) 2.31-2.53 (m, 2H) 2.11 (m, 2H); MS (m/z, MH+): 248.3
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C[OH:11]>>[CH3:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N+:1]=1[O-:11]
Reactant: CO
Reactant: Cc1cc(C)nc(C)c1
Product: Cc1cc(C)[n+]([O-])c(C)c1

Procedure:
In a 500 mL round bottom flask equipped with a magnetic stirrer and thermometer were added 36.7 g (164 mmol) of 77% 3-chloroperbenzoic acid (Aldrich) and 200 mL of methylene chloride. This slurry was cooled to 5° C. and a solution of 16.6 g (137 mmol) of collidine (Aldrich) in 50 mL of methylene chloride was added over 30 min while maintaining the temperature at 5-10° C. The mixture was then allowed to warm to room temperature over 1 hr and then stirred overnight. The crude reaction mixture was transferred slowly to a beaker containing 200 g of basic alumina, which resulted in a slight warming of the mixture. The mixture was stirred and filtered and the alumina was mixed with 300 mL of 2:1 CHCl3:CH3OH. The solvent was removed on a rotary evaporator at room temperature. The alumina was washed with ether and the solvent was removed to yield 24.7 g of a clear liquid, which solidified to give a white, waxy solid. This yield was slightly high due to the presence of some salt. TLC (silica gel developed with methanol) showed a single major spot (Rf=0.45) along with a minor spot (Rf=0.55). The major spot was the desired N-oxide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.96 (s), 2.51 9(s) and 2.28 (s). The minor spot corresponded to the starting collidine. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.78 (s), 2.48 (s) and 2.26 (s).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(OCC)(=O)C.ClCCl>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][O:7][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: OCc1ccco1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COCc1ccco1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine furfuryl alcohol (1 mL, 11.6 mmol) and tetrahydrofuran (20 mL). Add portionwise sodium hydride (0.57 g, 60% in oil, 14 mmol). After gas evolution ceases, add ethyl bromoacetate (1.3 mL, 11.7 mmol). Heat to reflux. After 2.5 hours cool to ambient temperature. After 18 hours, partition the reaction mixture between ethyl acetate and water. Separate the aqueous layer and extract twice with ethyl acetate. Combine the organic layers and extract with saturated aqueous sodium chloride solution, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1% ethyl acetate/dichloromethane to give ethyl fur-2-ylmethoxyacetate: Rf=0.62 (silica gel, 5% ethyl acetate/dichloromethane).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH2:12][C@@:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]1[OH:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCCC1.CO>[Br:26][C:22]1[CH:21]=[C:20]([C@:13]2([NH:12][C:10]([NH2:9])=[S:11])[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[OH:19])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Benzoyl isothiocyanate (7.20 g) was added to a suspension of (±)-(3R*,4R*)-4-amino-4-(3-bromophenyl)tetrahydropyran-3-ol (10.9 g) in toluene (200 mL). The mixture was stirred at room temperature overnight and then diluted with tetrahydrofuran, followed by addition of silica gel. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain an intermediate crude product. The resulting intermediate was suspended in methanol (300 mL), and potassium carbonate (20.0 g) was added. The mixture was stirred at room temperature overnight. Then, the insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the resulting solid was removed by filtration through celite. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (8.63 g).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:17][C:13](=[O:16])[C:14]([C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)=[CH2:15])[CH3:19]
Reactant: Brc1cnc2c(c1)OCCCN2
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: C=C(C(=O)OCC)c1cnc2c(c1)OCCCN2
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 3-bromo-6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene (1.1 g, 4.80 mmol), ethyl acrylate (1.5 mL, 14.4 mmol) and diisopropylethylamine (2.5 mL, 14.4 mmol) in propionitrile (100 mL) was purged with an Argon stream for 10 min. Pd(OAc)2 (108 mg, 048 mmol) and P(o-tol)3 (292 g, 0.96 mmol) were added and the Argon purge was repeated. The mixture was stirred at 100° C. for 8 h under Argon. Upon cooling, the resultant mixture was filtered through celite; the filtrate was evaporated. The crude product was purified by chromatography (silica, 0-2% MeOH CH2Cl2) to afford the title compound (0.753 g, 63%). 1H NMR (300 MHz, DMSO-d6, δ): 7.98 (d, J=1.9 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.51 (d, J=16 Hz, 1H), 6.83 (s, br, 1H), 6.42 (d, J=16 Hz, 1H), 4.15 (m, 4H), 3.34 (m, 2H), 1.98 (m, 2H), 1.25 (t, J=2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 3 h

Procedure:
A stirred solution of the product of Example 11 (70 mg) in methanol (0.5 ml) was treated with a M sodium hydroxide solution (0.19 ml) and stirring continued for 3 hours. The methanol was removed in vacuo and the residue diluted with water (1 ml), then a M hydrochloric acid solution (0.19 ml) added. On cooling to 4° C. a solid precipitated which was collected, washed with ice-water, then dried to give the title compound, 36.5 mg: m.p. 245°-247° C.; NMR (d6DMSO) δ 8.05(2H,d), 7.91(2H,d), 7.36(2H,d), 6.86(2H,d), 3.89(2H,s), 3.34(4H,t), 2.87(2H,t), 2.62(4H,t), 2.58(2H,t); m/e 354 (H+H)+ : calculated for C20H23N3O3.0.2 H2O: C, 67.2; H, 6.6; N, 11.8. found: C, 67.6; H, 6.6; N, 11.4%.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:3])[N:33]([C:32]4[CH:34]=[CH:35][C:29]([O:28][C:27]([F:36])([F:37])[F:26])=[CH:30][CH:31]=4)[CH2:23][CH2:22][CH2:21]3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCCC12CCN(S(=O)(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
1-Benzenesulfonyl-4-(3-methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (0.3 g) was dissolved under an argon atmosphere in toluene (10 ml), 4-(trifluormethoxy)-aniline (0.173 g) was added followed by dimethylaluminium chloride in heptane (1.8 ml, 0.9 molar). The mixture was refluxed 3 hours, more 4-(trifluormethoxy)-aniline (0.173 g) and dimethylaluminium chloride in heptane (1.8 ml) were added and refluxing was continued for further 3 hours. The reaction mixture was then cooled to RT, water (1 ml) was added and the mixture was stirred for 10 minutes. The solvent was evaporated off, the residue absorbed on silica gel and purified by flash-chromatography (AcOEt/heptane, gradient from 0 to 25%) to give the desired 9-benzenesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,9-diaza-spiro[5.5]undecan-1-one (0.215 g) as a white solid. MS (ESI): 469.13 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:11]([OH:28])=[C:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[CH2:16]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:33])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[C:1]([O:5][C:6]([N:8]1[CH:17]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:11]([O:28][CH3:33])=[C:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[CH2:16]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1O)C1CCC(C2)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(NC(=O)OC(C)(C)C)ccc2c1C1CCC(C2)N1C(=O)OC(C)(C)C

Procedure:
4-tert-Butoxycarbonylamino-3-hydroxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester (260 mg, 0.67 mmol), dimethyl sulfate (0.13 mL, 1.3 mmol), cesium carbonate (430 mg, 1.3 mmol) and dioxane (3 mL) were stirred together at 90° C. for 20 h. The reaction mixture was then diluted with water (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified with silica gel chromatography (0-50% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-3-methoxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a yellow, foamy residue (198 mg, 74%). 1HNMR (400 MHz, CDCl3) δ 7.6 (s, 1H), 7.4 (d, 1H, J=8.0 Hz), 7.1 (d, 1H, J=8.0 Hz), 4.5 (m, 1H), 4.1 (m, 1H), 3.3 (s, 3H), 3.1 (dd, 1H, J=14.4, 4.8 Hz), 2.9 (dd, 1H, J=14.5, 5.0 Hz), 2.7 (dd, 1H, J=17.9, 7.8 Hz), 2.6 (dd, 1H, J=18.4, 10.4 Hz), 2.2 (m, 1H), 1.5-1.4 (m, 19H); MS (m/e) 349 (M-C4H7).
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NN[C:7]=2[CH:6]=CC=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([OH:53])=O)=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1.N[C@@H](CC)CO>C1COCC1>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([NH:10][C@H:11]([CH2:3][OH:2])[CH2:7][CH3:6])=[O:53])=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: CC[C@H](N)CO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Hydroxybenzotriazole hydrate (45.3 mg, 0.29 mmol), N-ethyldiisopropylamine (253 μL, 1.45 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56.7 mg, 0.29 mmol) were added at 0° C. to a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) and (S)-(+)-2-amino-1-butanol (34.0 μL, 0.35 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature overnight. Extraction with 1 N aqueous hydrochloric acid/ethyl acetate and chromatography (silica, ethyl acetate:heptane=0:100 to 100:0) afforded the title compound (75 mg, 62%) as a white solid. MS: m/e=414.2 [M−H]−.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1>[CH3:16][S:17]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Temperature: 5 °C

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (5 grams) in 15 milliliters of pyridine was cooled to 5° C. with stirring and methylsulfonyl chloride (5 milliliters) was added in 1-milliliter portions, maintaining the temperature at about 5° C. After the addition was completed, the reaction mixture was stirred for 2 hours at 5°-10° C., then poured into 30 grams of ice and 20 milliliters of concentrated hydrochloric acid. The desired 1-(methylsulfonyloxy)-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product precipitated and was separated by filtration and washed with water. The washed product was taken up in diethyl ether with a trace of acetone, dried over magnesium sulfate and the solvent evaporated under vacuum. The product so obtained melted at 136.7° C.