Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.C(=O)(O)[O-].[Na+].[CH2:21]([O:28][C:29]1[CH:44]=[CH:43][C:42](Br)=[CH:41][C:30]=1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.COCCOC>[CH2:21]([O:28][C:29]1[CH:44]=[CH:43][C:42]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:41][C:30]=1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Water (1.2 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.25 g), sodium bicarbonate (0.21 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added to an ethylene glycol dimethyl ether (4 mL) solution of benzyl 2-(benzyloxy)-5-bromobenzoate (0.40 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g), sodium bicarbonate (0.10 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-45% hexane/ethyl acetate] to obtain 0.29 g of benzyl 2-(benzyloxy)-5-(pyridin-4-yl)benzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>COCCOC>[CH3:13][N:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:6]1=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(F)(F)F)cc(=O)[nH]1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C(F)(F)F)cc(=O)n1C
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To a suspension of 6-methyl-4-(trifluoromethyl)-1H-2-pyridone (2 g, 11.25 mmol) and potassium carbonate (4.68 g, 33.9 mmol) in DME (25 mL) was added iodomethane (9.62 g, 67.8 mmol) at room temperature and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine solution (200 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography on a Biotage (40 m) column to obtain 2.1 g (97% yield) of 1,6-dimethyl-4-(trifluoromethyl)-2-pyridone as a white solid: mp 80-82° C. EI-HRMS m/e calcd for C8H8F3NO (M+) 191.0558, found 191.0559.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:26])[CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:32][C:33]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:34]=1[O:35][C:36]1[C:41]([CH:42]=O)=[CH:40][N:39]=[C:38]([NH:44][C:45]2[S:46][CH:47]=[C:48]([CH3:50])[N:49]=2)[CH:37]=1.[NH4+].[Cl-:57]>O.C1COCC1>[ClH:57].[ClH:57].[F:32][C:33]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:34]=1[O:35][C:36]1[C:41]([CH:42]=[CH:6][CH2:5][CH2:4][N:3]([CH3:26])[CH3:2])=[CH:40][N:39]=[C:38]([NH:44][C:45]2[S:46][CH:47]=[C:48]([CH3:50])[N:49]=2)[CH:37]=1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Cl-]
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(C=O)cn2)n1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(C=CCCN(C)C)cn2)n1
Product: Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A flask was charged with (3-(dimethylamino)propyl)triphenylphosphonium bromide (0.555 g, 1.30 mmol) and THF (5 mL) and cooled to 0° C. Butyllithium (0.518 mL, 1.30 mmol) was added. The reaction was stirred at 0° C. for 20 minutes, and then 4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)nicotinaldehyde (Example 146; 0.150 g, 0.432 mmol) was added. The reaction was stirred at ambient temperature overnight. Water and saturated NH4Cl were added, and the reaction was extracted with ethyl acetate and dichloromethane. The organic layer was dried, filtered and concentrated, and the crude material was purified by silica gel column chromatography eluting with DCM-2-5% methanol/DCM. The isolated material was treated with 2M HCl in ether and dried over high vacuum to give the title compound (0.165 mg, 78% yield) as a white solid. 1H NMR (CDCl3) δ 8.43 (s, 0.5H), 8.22 (s, 0.5H), 7.29 (m, 1H), 7.25 (m, 1H), 7.08 (m, 2H), 6.95 (d, 0.5H), 6.68 (d, 0.5H), 6.38 (d, 1H), 6.31 (d, 1H), 3.16 (dt, 2H), 2.87 (s, 6H), 2.79 (m, 2H), 2.32 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N:15]1([CH2:20][C:21](O)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[N:15]1([CH2:20][C:21]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: Nc1ccc2sc3ccccc3c2c1
Reactant: O=C(O)Cn1cncn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1cncn1)Nc1ccc2sc3ccccc3c2c1
Yield: 84.3 %

Procedure:
2-Aminodibenzthiophene (Bull. Soc. Chim. Fr. (1 996), 133 (6), 597-610; 500 mg, 2.5 mmol) was dissolved DMF (10 ml) and 2-(1,2,4-triazol-1-yl)acetic acid (318 mg, 2.5 mmol) was added in one portion followed by 1-hydroxybenztriazole hydrate (383 mg, 5.0 mmol) and EDAC (960 mg, 5.0 mmol). The resultant mixture was stirred for 16 hours at ambient temperature then poured on to water (100 ml). A fine white solid was collected which was washed extensively with water, methanol (25 ml) and ether (25 ml) to leave a colourless solid (650 mg). NMR: 10.62 (brs, 1H), 8.18 (m, 2H), 8.16 (m, 3H), 7.99 (m,3H), 7.62 (dd, 1H), 7.50 (m, 2H), 5.20 (s, 2H); m/z 309.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]([N:14]=[C:15]=[S:16])(=[O:13])[O:10][CH2:11][CH3:12]>O1CCOCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:9]([NH:14][C:15]([NH:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[S:16])=[O:13])[CH3:12]
Reactant: Nc1cc(Cl)ccn1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 4-chloropyridin-2-amine (2.16 g, 16.8 mmol, Eq: 1.00) in dioxane (70 ml) was added O-ethyl carbonisothiocyanatidate (2.2 g, 1.9 ml, 16.8 mmol, Eq: 1.00) at 25° C. The resulting mixture was stirred for 2 hours at 25° C. The mixture was diluted with ethyl acetate and washed with water and brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 1-ethoxycarbonyl-3-(4-chloro-pyridin-2-yl)-thiourea (4.02 g/92.1%) as a green waxy solid. MS: m/e=257.9 (M−H+)
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][NH2:20].[CH2:23](N(CC)CC)C>>[CH2:4]1[CH2:3][CH2:2][CH:1]([O:7][C:8](=[O:14])[C@H:9]([CH2:10][C:11]([OH:13])=[O:12])[NH:20][CH2:19][CH2:18][CH:17]([NH:16][CH2:21][CH3:22])[CH3:23])[CH2:6][CH2:5]1
Reactant: O=C(O)/C=C\C(=O)OC1CCCCC1
Reactant: CCN(CC)CC
Reactant: CCN(C)CCCN
Product: CCNC(C)CCN[C@@H](CC(=O)O)C(=O)OC1CCCCC1

Procedure:
43.6 g (0.2 mol+10% excess) of maleic acid-monocyclohexyl ester, 40 ml of triethylamine and 23.2 g (0.2 mol) of 3-(methylethylamino)-propylamine are reacted in the manner described in Example 1 and analogously further processed. The yield is 36.3 g (57.7% of theory) of a crystalline aspartic acid derivative which, after recrystallisation in acetone, melts at 123.5°-127.5° C.
Reaction SMILES: C[O-].[Na+:3].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16]>C(O)C>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:13][CH:14]([CH3:18])[C:15]([O-:17])=[O:16])=[CH:7][CH:6]=1.[Na+:3]
Reactant: CC(S)C(=O)O
Reactant: ClCc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(SCc1ccncc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium methoxide (5.1 g., 94 mmoles) was dissolved in 50 ml. of absolute ethanol and cooled in an ice bath. A slurry of 4-picolyl chloride hydrochloride (5.0 g., 30.4 mmoles) in 45 ml. of ethanol was added and the chilled reaction mixture stirred for approximately 10 minutes. Finally, 2-mercaptopropionic acid (3.23 g., 30.4 mmoles) dissolved in 5 ml. of ethanol was added over a 10 minute period. The mixture was allowed to warm to room temperature and stirred overnight (approximately 16 hours). The reaction was filtered through filter aid to remove salts, carbon treated and concentrated to crude sodium 2-(4-picolylthio) propionate (approximately 7 g. of oil used directly in the next step).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](SC(C)C)[CH:5]=[CH:4][C:3]=1[CH3:12].O[O:14][S:15]([O-:17])=O.[K+].[CH2:19]1[CH2:23]OC[CH2:20]1>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:15]([CH:19]([CH3:23])[CH3:20])(=[O:17])=[O:14])[CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1ccc(SC(C)C)cc1Br
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A cooled (0° C.) solution of 2-bromo-4-(isopropylthio)-1-methylbenzene (123 mg) in THF (10 ml) was treated with a solution of oxone (580 mg) in water (6 ml). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated to give the title compound (120 mg, 92%).
Reaction SMILES: C([NH:8][C:9]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[CH2:10]O)C1C=CC=CC=1.[CH3:18][C:19]([OH:21])=[O:20]>[Pd].CCO>[C:19]([O:21][CH2:10][C:9]([NH2:8])([CH2:15][O:16][CH3:17])[CH2:12][O:13][CH3:14])(=[O:20])[CH3:18]
Reactant: COCC(CO)(COC)NCc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: COCC(N)(COC)COC(C)=O
Yield: 48.6 %

Procedure:
A mixture of crude 4-aza-3,3-bis-(methoxymethyl)-1-oxaspiro[4.5]decane (66A, 40.0 g, 0.174 mol) and 6N HCl (100 mL) was refluxed for 1 h. The mixture was cooled and washed with Et2O (3×100 mL). The volume of the aqueous layer was reduced to 25 mL by rotary evaporation, basified with excess 50% NaOH solution and extracted with a mixture of Et2O/CH2Cl2 (3:1, 2×200 mL). The organic layers were combined, the solvent removed and the resulting crude oil distilled to give 16.4 g (63.2%) of 2-amino-2,2-bis-(methoxymethyl)ethanol, (bp 109°-110°/15 mm). This material also contains some of the --NCH3 compound. This material was further purified by conversion to the --NCH2Ph derivative. Thus, a mixture of crude 2-amino-2,2-bis-(methoxymethyl)ethanol (15.0 g, ~0.10 mol), benzaldehyde (Aldrich, 7.42 g, 0.07 mol), NaBH3CN (Aldrich, 4.4 g, 0.07 mol) and CH3OH (100 mL) was stirred at 5° for 15 min then at RT for 2 h. H2O (50 mL) then excess 12N HCl was then added to the flask. The volume of the mixture was reduced to 50 mL by rotary evaporation. The mixture was washed with Et2O (100 mL), basified with 50% NaOH solution and extracted with Et2O (200 mL). After removal of the solvent the crude oil (15.54 g) was distilled to give 11.64 g of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol, bp 118°-119°/0.10 mm, shown to 99.7% pure by GLC (10% OV-17 on Chromasorb W at 250°), (C,H,N). A mixture of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol (8.25 g, 0.0345 mol), 5% Pd/C (Aldrich, 1.0 g), abs. EtOH (250 mL) and glacial HOAc (25 mL) was hydrogenated in a Parr apparatus at 40 psi for 15 min. The catalyst was removed by filtration through a pad of Celite® and the solvent removed to give the crude product which after crystallization from abs. EtOH gave a 48.6% yield of 2-amino-2,2-bis-(methoxymethyl)ethanol acetate, mp 119.5°-120.5°, (C,H,N).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CO>[OH:20][C:6]1[C:5]([CH2:22][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]([OH:21])[C:3]([O:2][CH3:1])=[C:8]2[C:7]=1[C:12](=[O:13])[CH:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:9]2
Reactant: C=O
Reactant: C1CCNC1
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Solvent: CO
Product: COc1c(O)c(CN2CCCC2)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.1 ml), pyrrolidine (7.1 g) was stirred under for 4 hours at 55° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as orange red solid 35.4 g of purity 99.1%. MS: (API-ES) m/z 368.5[M+H]+, 390.5[M+Na]+; 1H NMR (DMSO-d6, 400 MHz) δ 8.03˜8.04 (m, 2H, Ar-2′,6′-H), 7.59˜7.60 (m, 3H, Ar-3′,4′,5′-H), 6.79 (s, 1H, 3-H), 4.09 (s, 2H, CH2), 3.81 (s, 3H, 8-OCH3), 3.03 (s, 4H, CH2), 1.90 (s, 4H, CH2).
Reaction SMILES: C(N(CC)C(C)C)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>C(Cl)Cl>[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]
Reactant: O=C1OCC[C@H]1O
Reactant: Fc1ccc2c(c1Cl)CCN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Temperature: -40 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −40° C., N,N-diisopropylethylamine (34.1 mL, 196 mmol) was added dropwise to a solution of solution of (R)-dihydro-3-hydroxyfuran-2(3H)-one (10.0 g, 98 mmol) in CH2Cl2 (100 mL). Trifluoromethanesulfonic anhydride (17.3 mL, 103 mmol) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. Upon completion of addition, the mixture was stirred at −40° C. for 1 h. A solution of 4-chloro-5-fluoroindoline (27.6, 147 mmol) in CH2Cl2 (40 mL) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. The reaction was allowed to warm up to −20° C. and was kept at this temperature for 48 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate (2×), brine, dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 0-40% ethyl acetate in hexane gave (5)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one as a white solid (22.9 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 7.07-7.02 (m, 1H), 6.50 (dd, J=3.6, 8.6 Hz, 1H), 4.88 (dd, J=9.0, 11.4 Hz, 1H), 4.44-4.39 (m, 1H), 4.29-4.22 (m, 1H), 3.60-3.54 (m, 1H), 3.28 (dd, J=8.6, 17.8 Hz, 1H), 3.07-2.92 (m, 2H), 2.43-2.28 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=256.1; tR=1.54 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][NH:13][CH2:14][C:15]1[N:16]=[CH:17][N:18](S(N(C)C)(=O)=O)[C:19]=1[CH3:20].[C:27](Cl)(Cl)=[O:28].[Cl-].[Cl-].[Cl-].[Al+3].CO>ClCCl>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:27](=[O:28])[N:13]([CH2:14][C:15]3[N:16]=[CH:17][NH:18][C:19]=3[CH3:20])[CH2:12][CH2:11][C:3]1=2
Reactant: Cc1c(CNCCc2cc3ccccc3n2C)ncn1S(=O)(=O)N(C)C
Reactant: O=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[[[(1-methyl-1H-indol-2-yl)ethyl]amino]methyl]-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (140 mg) in dry dichloromethane (15 ml) was cooled to 5° and the mixture was stirred under nitrogen while phosgene (12% w/w solution in toluene; 1 ml) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, aluminium trichloride (60 mg) was powdered and added, and stirring was continued overnight. After this time methanol (1 ml) was added and the reaction mixture was adsorbed onto FCC silica and purified by FCC eluting with System A (150:8:1) to give the protected derivative of the title compound (42 mg), as a solid, identical (by t.l.c. and m.p.) to the product of Intermediate 27. Deprotection as described in either of Examples 25 or 26 gives the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[OH-].[Na+].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21][CH2:22][CH2:23][OH:24].CCCCCC>CCOCC.O>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:24][CH2:23][CH2:22][S:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: BrCCCCCCBr
Reactant: OCCSc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCSc1ccc2ccccc2c1
Reaction time: 4 h

Procedure:
A mixture of 1,6-dibromohexane (9 ml), 50% w/v sodium hydroxide (40 ml), 2-(2-naphthalenyl)thioethanol (4 g), TAB (0.8 g) and hexane (30 ml) was stirred vigorously at 20°, under nitrogen for 4 h. Water (100 ml) and ether (100 ml) were added and the mixture was further extracted with ether (100, 2×50 ml). The combined, dried ether extracts were evaporated in vacuo to give a yellow oil. Purification by FCC eluting with light petroleum (b.p. 60°-80°):ether (30:1→1:1) gave the title compound as a white crystalline solid (5.7 g), m.p. 38°-40° (softens 36°).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([OH:11])[CH:10]=1)=[O:5])C.CCO.O.[OH-].[Li+]>O>[OH:11][N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]1
Reactant: CCOC(=O)c1cn(O)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
1-Hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (2.0 g, 13 mmol) and EtOH (25 mL) were combined with a pre-dissolved solution of lithium hydroxide monohydrate (1.6 g, 38.2 mmol) and water (10 mL), and stirred at room temperature for 4 hours. The mixture was partially concentrated and acidified with HCl to cause precipitation. The solid was filtered and dried under vacuum to yield the title compound (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:38][C@H:37]([C:36]([O:35][CH3:34])=[O:41])[CH2:39][OH:40])=[O:19])=[C:5]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (287 mg, 852 μmol, Example 1 A-C) was dissolved in 1,4-dioxane (852 μL) and N-ethyl-N-isopropylpropan-2-amine (445 μL, 2557 μmol). L-Serine methyl ester hydrochloride (199 mg, 1278 μmol) was added, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the 180 mg of the title compound as a white solid after flash chromatography. MS m/e=410 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[C@@H:23]([N:25]1[CH2:30][C@@H:29]2[CH2:31][C@H:26]1[CH2:27][NH:28]2)[CH3:24]>C(Cl)Cl.C([O-])(O)=O.[Na+].[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:28]2[CH2:27][C@@H:26]3[CH2:31][C@H:29]2[CH2:30][N:25]3[C@H:23]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:17]([CH3:18])[C:12]=2[CH3:11])[CH3:24])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3)c(C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2ccc(Cl)nc2)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloronicotinoyl chloride (151 mg, 0.86 mmol) in 2 mL CH2Cl2 is added to a mixture of (1S,4S)-2-((S)-1-(2,3-dimethyl-4-propoxyphenyl)ethyl)-2,5-diaza-bicyclo[2.2.1]heptane in 5 mL of CH2Cl2 and aqueous NaHCO3 (saturated solution, 3 mL). The mixture is stirred vigorously at room temperature for 1 h. The mixture is then diluted with 1N NaOH (5 mL) and extracted CH2Cl2 (2×25 mL). The combined extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by flash chromatography on silicagel, eluting with CHCl3-MeOH (40:1 to 20:1) to afford the title compound. LC/MS: 428 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([N:14]3[CH2:18][CH2:17][O:16][C:15]3=O)=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CS(OCC[C@H]1C2C=CC(C([NH2:44])=O)=CC=2CCO1)(=O)=O>>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([N:14]3[CH2:18][CH2:17][NH:44][C:15]3=[O:16])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1)(=[O:23])=[O:22]
Reactant: O=C1OCCN1c1ccc2c(c1)CCO[C@H]2CCO
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N3CCNC3=O)ccc21

Procedure:
Prepared from 3-[(1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]-1,3-oxazolidin-2-one and methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:24])[CH:14]([C:22]#N)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-:25].[Na+].[OH2:27]>C(O)C>[C:1]1([CH2:11][NH:12][C:13]([CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:27])=[O:25])=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CC(Cc1ccccc1)C(=O)NCc1cccc2ccccc12
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)C(=O)NCc1cccc2ccccc12

Procedure:
In a mixture of 1 ml of ethanol and 2 ml of water were dissolved 123 mg of the amide obtained and 0.66 g of sodium hydroxide, and the solution was heated under reflux for 16 hours. After removal of ethanol, the residue was washed with diethyl ether, and then adjusted to a pH of 2 by adding a 2N-hydrochloric acid. The solution was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 103 mg of (±)-2-(1-naphthylmethylcarbamoyl)-3-phenylpropionic acid as colorless crystals.