Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([C:27](=[O:39])[NH:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=[CH:26][C:20]=3[N:19]=2)=[C:13]([CH3:40])[CH:12]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[CH3:40][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH:16]=[C:15]([CH3:17])[C:14]=1[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:27](=[O:39])[NH:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: CCOP(=O)(CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1cc(CCP(=O)(O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-ethyl)-phosphonic acid diethyl ester (270 mg, 0.49 mmol) in CH2Cl2 (10 mL) was added TMSBr (0.64 ml, 4.9 mmol) and the solution was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by HPLC to give (2-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-ethyl)-phosphonic acid as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (m, 3H), 8.08 (dd, 1H), 7.94 (m, 2H), 7.81 (dd, 1H), 7.77 (m, 1H), 7.56 (m, 1H), 7.13 (s, 2H), 2.95 (m, 2H), 2.18 (s, 6H), 2.01 (m, 2H). MS (m/z) 501.1 (M+1): Retention time: 1.12 min (Method 10).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([O:9]CC)=[O:8])[CH:3]=1.[OH-].[Na+].Cl.[Cl-].[Na+]>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)on1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)O)no1
Temperature: 0 °C

Procedure:
A mixture of 1.55 g of ethyl 5-methyl-3-isoxazolecarboxylate (1A) (P. G. Baraldi, et al., Journal of Heterocyclic Chemistry, volume 19, pages 557-560 (1982)) and 20 ml of 10% w:v sodium hydroxide in water was stirred at room temperature for 2 hours. The resulting mixture was cooled to 0° C., acidified with 6N hydrochloric acid to pH 3, saturated with sodium chloride and extracted with ethyl acetate. The extract was dried (MgSO4) and stripped of solvent to give 5-methyl-3-isoxazolecarboxylic acid (1B), as a solid, m.p.: 170°-172° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17]O)=[O:15]>OS(O)(=O)=O>[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17][C:10]1[C:2]([CH3:1])=[C:3]([C:7]([CH3:11])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 56519.7 %

Procedure:
To a solution of 2,6-dimethyl benzoic acid (6.8 g, 0.045 mmol) in conc. H2SO4 (100 mL), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (7.1 g, 0.049 mmol) was added and the reaction mixture was stirred at RT for 24 h. After completion of the reaction, the reaction mass was quenched in ice water and stirred for 15 minutes. The obtained solid product was filtered and dried to afford 7.0 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 2.26 (s, 6H), 4.36 (t, J=12.3 Hz, 2H), 7.09 (m, 1H), 7.15 (m, 1H), 9.89-9.94 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=[O:7])#[N:2].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([O:8][CH3:13])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(C#N)c1
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a 100 mL rbf was added 3-cyano-4-fluoro-benzoic acid (2.6 g, 15.9 mmol), potassium carbonate (6.6 g, 47.6 mmol), and DMF (30 mL) and the reaction was allowed to stir for 10 minutes. Iodomethane (1.1 mL, 17.5 mmol) was added dropwise and the reaction was allowed to stir for 1 h. The reaction was complete by 1 cms. The reaction was quenched with brine and extracted with EtOAC. The organic layer was washed with brine 3 times and the organic layer was dried over sodium sulfate and evaporated. Methyl 3-cyano-4-fluoro-benzoate (2.5 g, 62%) was isolated as a white solid. ESI-MS m/z calc. 179.0, found 180.0 (M+1)+; Retention time: 1.15 minutes (3 min run).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[C:22]([Zn]C#N)#[N:23].[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:22]#[N:23])=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#C[Zn]C#N
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 127 °C

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (1.6 g, 4.69 mmol) in DMF (8 mL), was added Pd(PPh3)4 (0.434 g, 0.375 mmol) and dicyanozinc (0.441 g, 3.75 mmol). The reaction mixture was heated to 127° C. for 4 h. NH4Cl(aq) was added to quench the reaction, followed by EtOAc. The reaction mixture was filtered through celite, washed with saturated NaHCO3 and NH4Cl. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give a crude product, which was purified with Analogix gel silica (Hexanes:EtOAc) to afford the title compound as a light yellow solid. LCMS (method B): [MH]+=288, tR=1.81 min.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[Sn:28]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:15][N:16]([CH3:24])[C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].O[N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50].CCN=C=NCCCN(C)C>C(#N)C>[F:42][C:2]([F:1])([F:41])[C:3]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:15][N:16]([CH3:24])[C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCC(=O)ON2C(=O)CCC2=O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
Compound 15 (170 mg, 236 mmol) was dissolved in acetonitrile (5 mL), N-hydroxysuccinimide (54 mg, 472 mmol) and EDCI (90 mg, 472 μmol) were added and the mixture stirred 6 h at 20° C. The solvent was removed under vacuum and the residue was purified over silica gel using dichloromethane/acetone (1/1) as eluant to give 155 mg (190 μmol, 80% yield) of a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[CH2:27][CH2:28][OH:29]>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:31]([NH:30][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][OH:29])=[C:21]([F:20])[CH:22]=3)=[O:32])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(CCO)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(CCO)c(F)c1
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (227 mg, 0.73 mmol, 1.0 eq) in THF (10 mL) was added TEA (147 mg, 1.45 mmol, 2.0 eq) followed by phenyl 3-fluoro-4-(2-hydroxyethyl)phenylcarbamate (200 mg, 0.73 mmol, 1.0 eq) at RT and the mixture was stirred for 16 h. The reaction mixture was concentrated under vacuum and the residue purified by CC using neutral alumina and EtOAc/PE (3:2) as eluent), followed by preparative HPLC to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(2-hydroxyethyl)phenyl)urea (150 mg; 45%, white solid; TLC system: EtOAc/PE (3:2); Rf: 0.2).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:47][C:48]([F:67])([C:63]([F:66])([F:65])[F:64])[CH2:49][CH2:50][CH2:51]OS(C1C=CC(C)=CC=1)(=O)=O>O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][N:38]([CH2:51][CH2:50][CH2:49][C:48]([F:67])([F:47])[C:63]([F:66])([F:65])[F:64])[CH2:39][CH2:40]3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(F)(F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN2CCN(CCCC(F)(F)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
7-(Methoxymethoxy)-3-(4-methoxymethoxyphenyl)-4-(9-piperazinylnonyl)-3-methylchroman (380 mg, 0.685 mmol), K2CO3 (190 mg, 1.375 mmol) and 4,4,5,5,5-pentafluoropentyl-4-methylbenzenesulfonate (460 mg, 1.384 mmol) were refluxed under acetone for 15 hours. After the mixture was cooled down to room temperature, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic solvent was removed under reduced pressure. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to give 238 mg (yield: 48%) of the title compound as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O.C(O)(=O)C.[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH2:53])[CH2:43][C@@H:42]1[CH2:54][CH3:55])=[O:40])([CH3:37])[CH3:36].[Cl-].[NH4+]>ClC(Cl)C>[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH:53][CH2:20][C:19]2[CH:18]=[C:17]([C:16]([F:30])([F:29])[F:15])[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=2)[CH2:43][C@@H:42]1[CH2:54][CH3:55])=[O:40])([CH3:37])[CH3:36]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[C@H]1C[C@@H](N)c2nc(OC)ccc2N1C(=O)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.1 %

Procedure:
Add sodium triacetoxyborohydride (0.091 mg, 0.409 mmol) to a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (0.045 mL, 0.273 mmol), acetic acid (0.018 mL, 0.303 mmol) and (+/−)-cis-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.08 mg, 0.273 mmol) in dichloroethane (3 mL). Stir the mixture at room temperature under an atmosphere of nitrogen for 14 h. Add a saturated solution of ammonium chloride, separate the layers, and extract the aqueous layer with dichloromethane. Dry the combined organic layers over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (125 mg, 88%). MS (ES+): 520 (M+H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:21]([O:23]C)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].Cl>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Sodium hydroxide (4.35 mL, 8.69 mmol) was added to a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (1.6 g, 4.35 mmol) dissolved in MeOH (30 mL). The resulting suspension was stirred at 23° C. for 16 hrs. The mixture was diluted with water and the pH adjusted to 3 with HCl 2N. The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide overnight to give 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (1.30 g, 84%) as a beige solid. Mass Spectrum: M+H+ 356
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[CH:30]1([C:34]2[N:35]=[C:36]([NH2:39])[S:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:27][C:25]([CH3:26])([CH3:28])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:1])[F:29])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:39][C:36]1[S:37][CH:38]=[C:34]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[N:35]=1)=[O:21])[CH:17]=[CH:16][S:15]2
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc(C2CCC2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C3CCC3)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 4-(cyclobutyl)-1,3-thiazol-2-amine (40 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol), DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 50 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 1.84-1.90 (m, 2H), 1.95-2.05 (m, 1H), 2.15-2.30 (m, 4H), 3.58 (s, 2H), 6.73 (s, 1H), 7.18 (t, J=75.0 Hz, 1H), 7.20-7.30 (m, 2H), 7.38-7.44 (m, 1H), 7.66-7.72 (m, 1H), 7.83 (d, J=16.2 Hz, 1H), 8.10-8.18 (m, 1H), 8.62-8.68 (m, 1H), 12.87 (br s, 1H); ESI-MS (m/z) 559.22 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1Cl.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>>[C:4]1([CH2:9][C:10]([NH2:15])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: NC(=O)Cc1ccccc1

Procedure:
In a similar manner, 4.40 g of 3,4-dichlorophenylacetic acid, 3.47 g of carbonyldiimidazole and 2.97 g of the (-) amine from Part D, above, were reacted to yield the above-named (+)-benzeneacetamide product. This product was chromatographed on silica gel (2% methanol (which was saturated with ammonia gas)/98% ethyl acetate) to yield 3.22 g of pure benzeneacetamide product, [α]D25 +34° (8.2 mg/ml in methanol). This benzeneacetamide product was treated with 1.011 g of maleic acid in methanol and the mixture was diluted with diethyl ether to yield 3.56 g of the above named product salt, mp 174°-175° C., [α]D25 +35.3° (10.0 mg/ml in methanol).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C1(C#C)C=CC=CC=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1C#N>C(#N)C1C=CC=CC=1>[CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[C:4][C:16]1[O:15][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccco1
Reactant: C#CC(C)(C)C
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CC(C)(C)C#Cc1ccco1
Reaction time: 16 h
Yield: 91 %

Procedure:
The procedure was identical to Example 1, with the exception that 3,3-dimethyl-1-butyne (0.488 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 16 h at 65° C. showed the presence of 1.82 mmol (91% yield) of 2-(3,3-dimethyl-1-butynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1
Reactant: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(C)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A mixture of ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylate (400 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at 60° C. for 5 hrs. To the reaction mixture was added 1N hydrochloric acid (3 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylic acid (350 mg, yield 93%). The crystals were recrystallized from acetone-hexane. melting point: 169-170° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[C:20]3[CH:19]([N:27]([CH:29]4[CH2:31][CH2:30]4)[CH3:28])[CH2:18][CH2:17][C:16]([CH3:33])([CH3:32])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH:29]1([N:27]([CH3:28])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:33])([CH3:32])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[C:21]([O:23][CH:24]([CH3:25])[CH3:26])[C:20]2=3)[CH2:30][CH2:31]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC(C)C)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 129, 0.045 g, 0.098 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as a white solid (0.027 g, 61%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:18])[N:7](CCCN(C)C)[C:8]2=[O:11])=[CH:4][C:3]=1S(N)(=O)=O.ClC1C=C2C(=O)NC(=O)C2=CC=1S(=O)(=O)N.CN(C)CCCN>>[O:18]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:11])[NH:7]1
Reactant: CN(C)CCCN1C(=O)c2cc(Cl)c(S(N)(=O)=O)cc2C1=O
Agent: CN(C)CCCN
Agent: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: O=C1NC(=O)c2ccccc21
Yield: 95 %

Procedure:
6-Chloro-2-[3-(dimethylamino)propyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide. Reaction of a mixture 4-chloro-5-sulfamoylphthalimide and 3-(dimethylamino)propylamine according to the procedure of Example 1(a) afforded a 95% yield of the 1,3-dioxoisoindole intermediate. Crystallization of this material from dimethylformamide-ethanol provided analytically pure 6-chloro-2-[3-(dimethylamino)propyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 192°-194°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][C:14]([OH:18])([C:16]#[CH:17])[CH3:15].C(NC(C)C)(C)C>CN(C)C=O.[Cu]I.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]#[C:16][C:14]([OH:18])([CH3:15])[CH3:13])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
2-Amino-5-bromobenzenesulfonamide (2 g, 7.96 mmol), copper(I) iodide (0.076 g, 0.40 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.280 g, 0.40 mmol) were slurried in anhydrous N,N-dimethylformamide (6 mL) in a microwave vial. 2-Methyl-3-butyn-2-ol (2.316 mL, 23.89 mmol) followed by diisopropylamine (3.37 mL, 23.89 mmol) were added, the vial was capped, purged with argon and the mixture was heated in a microwave at 100° C. for 30 min. The mixture was filtered and the solvent was evaporated in vacuo. Purification by column chromatography, using a gradient of 60-70% ethyl acetate in heptane as the eluent, gave 0.92 g (46% yield) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[O:14]([CH2:13][CH2:12][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1CCOc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of ethyl imidazole-2-carboxylate (0.505 g, 3.60 mmol) in N,N-dimethylformamide (6 ml) were added β-bromophenetole (0.804 g, 4.00 mmol) and potassium carbonate (0.598 g, 4.32 mmol), and the mixture was stirred at 80° C. for 1 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give ethyl 1-(2-phenoxyethyl)imidazole-2-carboxylate (0.869 g, 3.34 mmol, yield 93%). This was dissolved in methanol (9 ml), 1N-aqueous sodium hydroxide solution (9 ml) was added at room temperature, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 5%-aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 1-(2-phenoxyethyl)imidazole-2-carboxylic acid (0.573 g, 2.47 mmol, yield 74%).