Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]4[N:52]=[C:51](Cl)[N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH:59]5[CH2:64][C:63]([CH3:66])([CH3:65])[N:62]([O:67][CH:68]6[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]6)[C:61]([CH3:75])([CH3:74])[CH2:60]5)[N:48]=4)=[CH:42][CH:41]=3)([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[N:3]=1.[NH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]([OH:84])=[O:83]>>[C:82]([CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][NH:76][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]4[N:52]=[C:51]([NH:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]([OH:84])=[O:83])[N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH:59]5[CH2:64][C:63]([CH3:66])([CH3:65])[N:62]([O:67][CH:68]6[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]6)[C:61]([CH3:75])([CH3:74])[CH2:60]5)[N:48]=4)=[CH:42][CH:41]=3)([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[N:3]=1)([OH:84])=[O:83]
Reactant: CC(C)(c1ccc(Oc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1)c1ccc(Oc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1
Reactant: NCCCCCC(=O)O
Product: CC(C)(c1ccc(Oc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1)c1ccc(Oc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1

Procedure:
The title compound is prepared from the reaction of 2,2-bis{4-[[2-chloro-4-[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl]oxy]phenyl}propane with 6-aminohexanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24]O)=[CH:21][C:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:19]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 2-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine to give (6-{2-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:8]1.Cl[CH:18]([F:20])[F:19].O>CN(C)C=O>[F:19][CH:18]([F:20])[N:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:8]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C(F)F)c1
Temperature: 135 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
6.0 g (43.5 mmoles) of anhydrous potassium carbonate was added to a solution of 3.0 g (21.4 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 100 ml of N,N-dimethylformamide. Thereinto was blown chlorodifluoromethane. The resulting mixture was stirred at 130 to 140° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.67 g (yield: 41.0%) of ethyl 1-difluoromethyl-1H-pyrazole-4-carboxylate as a colorless transparent oily substance.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:26])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15](OC)=[O:16].[Cl-].[NH4+]>C1COCC1>[CH3:13][C:14]([CH3:26])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)C(C)(C)Cc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of dimethyl methylphosphonate (2.4 ml, 21.8 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.49N, 14.7 ml, 21.8 mmol) at -78° C. under argon atmosphere. After the mixture was stirred for 30 minutes, methyl 2,2-dimethyl-3-phenylpropionate (1.75 g, 10.0 mmol) was added dropwise and the mixture was stirred at -78° C. for 20 minutes and then at room temperature overnight. To this reaction mixture was added an aqueous saturated solution of ammonium chloride, and the mixture was extracted with ethyl acetate (50 ml×4). Then, the combined ethyl acetate layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (silica gel, ethyl acetate) yielded a pure product of dimethyl 3,3-dimethyl-2-oxo-4-phenylbutylphosphonate (2.3144 g, 8.14 mmol, 89.5%). This compound was assigned the structure by the following data: m.p. 39° -46° C. (colorless needle-like crystal)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])[CH:28]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])[CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.316 mL, 0.316 mmol) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-pyran-4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 132-(1); 62.9 mg, 0.105 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at 0° C. for 10 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (44.0 mg, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[N:29][CH:30]=[C:25]([CH3:24])[CH:26]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: Cc1cncc(B(O)O)c1
Product: Cc1cncc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Yield: 17 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 5-methylpyridin-3-ylboronic acid were reacted to give 191 (0.027 g, 17%). 1H NMR (400 MHz, DMSO) δ 8.73 (d, J=2.4, 2H), 8.42 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.69 (dd, J=8.4, 2.3, 1H), 7.20 (d, J=8.4, 1H), 5.82 (dt, J=13.1, 6.5, 1H), 4.43 (t, J=4.8, 2H), 3.56-3.39 (m, 2H), 2.39 (s, 3H), 1.58 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.0 (M+H)
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:24]1([N:30]=[C:31]=[S:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[S:32])[NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: S=C=Nc1ccccc1
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1ccccc1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (252 mg, 1.06 mmol) in 13 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.16 ml, 1.16 mmol) and phenyl isothiocyanate (277 μl, 2.3 mmol). The mixture was stirred at 80° C. for 36 hours, concentrated and purified by column chromatography on silica gel (eluent: 4:1 diisopropyl ether/hexane). The product was obtained in a yield of 48 mg (12%).
Reaction SMILES: [OH:1][CH:2]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:20][CH3:21])[O:18][CH3:19])[CH2:3][N:4]=[C:5]([N:9]([CH3:11])[CH3:10])[N:6]([CH3:8])[CH3:7].[N:24]([CH2:27][CH2:28][CH2:29][Si:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[C:25]=[O:26]>C1(C)C=CC=CC=1>[CH2:35]([O:34][Si:30]([O:37][CH2:38][CH3:39])([O:31][CH2:32][CH3:33])[CH2:29][CH2:28][CH2:27][NH:24][C:25](=[O:26])[O:1][CH:2]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:18][CH3:19])[O:20][CH3:21])[CH2:3][N:4]=[C:5]([N:9]([CH3:10])[CH3:11])[N:6]([CH3:7])[CH3:8])[CH3:36]
Reactant: CO[Si](CCCOCC(O)CN=C(N(C)C)N(C)C)(OC)OC
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCCNC(=O)OC(CN=C(N(C)C)N(C)C)COCCC[Si](OC)(OC)OC)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A ten gram sample of N"-[2-hydroxy-3-[3-(trimethoxysilyl)propoxy]propyl]-N,N,N',N'-tetramethylguanidine, prepared in Example 2, was dissolved in 5 g of toluene. To this solution was added, under a stream of argon gas, 7.1 g of 3-isocyanatopropyltriethoxysilane. The resulting mixture was stirred at ambient temperature for one hour. At the end of this time, analysis of the reaction mixture by infrared spectroscopy indicated the absence of hydroxyl function. The reaction mixture, containing 71% by weight of [3-(triethoxysilyl)propyl]carbamic acid, [2-[[bis(dimethylamino)methylene]amino]-1-[[3-(trimethoxysilyl)propoxy]methyl]ethyl]ester, was used without further puriofication as an accelerator.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[CH3:13][N:14]=[C:15]=[O:16]>CCOCC>[CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:15](=[O:16])[NH:14][CH3:13])[CH2:5][CH2:4]1
Reactant: CN=C=O
Reactant: COC1CCC(N)c2ccsc21
Solvent: CCOCC
Product: CNC(=O)NC1CCC(OC)c2sccc21
Reaction time: 8 h
Yield: 75 %

Procedure:
Crude 4,5,6,7-tetrahydro-7-methoxybenzo[b]thiophen-4-amine (2.3 g, 12.57 mm) is dissolved in ether (50 ml) and the stirred solution treated with a solution of methyl isocyanate (2.9 ml) in ether (10 ml), added over a period of 20 minutes. After stirring overnight the product is filtered off, washed twice with ether (50 ml total) and air dried to afford the title compound (2.25 g, 75% Y) m.p. 152° C-159° C. The analytical sample is recrystallized from acetone and has m.p. 164° C-166° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]([CH3:47])[C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30]3[CH2:45][CH2:44][C:43](=[O:46])[C:31]3=[C:32]2[C:35]2[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][N:24]([CH3:47])[C:25]1[CH:34]=[C:33]2[C:28](=[CH:27][CH:26]=1)[CH:29]=[C:30]1[CH2:45][CH2:44][C:43](=[O:46])[C:31]1=[C:32]2[C:35]1[CH:36]=[CH:37][C:38]([CH:41]=[O:42])=[CH:39][CH:40]=1
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(CO)cc4)c2c1)C(=O)CC3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C)c1ccc2cc3c(c(-c4ccc(C=O)cc4)c2c1)C(=O)CC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
An oven-dried 25 mL one-necked round-bottomed flask equipped with a septum and a stir bar was charged with Dess-Martin periodinane (DMP, 0.063 g, 0.15 mmol) in dry CH2Cl2 (5 mL). The solution was cooled to 0° C. in an ice bath for 10 min, compound 15b (0.045 g, 0.14 mmol) in dry CH2Cl2 (5 mL) was added and the mixture mas stirred at 0° C. for 5 min. The reaction was then warmed to rt and stirred for an additional 15 min. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 4:6). The reaction was then quenched with sat'd aq NaHCO3 solution (20 mL). The aqueous layer was extracted with Et2O (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, gravity filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography, eluting with AcOEt/n-hexane 3:7, to provide 0.031 g of the title compound as an orange solid in a 67% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].CO>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CC(=O)N(C)C)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 2-chloro-N,N-dimethylacetamide, the crude product subjected to flash chromatography (SiO2, gradient 0 to 6% MeOH in DCM) to give 198 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1H, d, J=8.28 Hz), 7.84 (1H, d, J=0.71 Hz), 7.60 (1H, s), 7.10 (1H, dd, J=8.33, 1.81 Hz), 6.97 (1H, d, J=1.72 Hz), 6.01-5.91 (1H, m), 4.48-4.39 (4H, m), 3.99-3.90 (2H, m), 3.86-3.77 (1H, m), 3.46-3.38 (4H, m), 3.00 (3H, s), 2.93 (3H, s), 1.56 (6H, d, J=6.63 Hz). LCMS: RT=5.87 min, M+H+=436.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](Cl)=[N:30][CH:29]=1.O>CN(C)C=O>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[NH:12][CH:11]=[C:10]3[CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])([CH3:21])[CH3:20])=[N:30][CH:29]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cccc3c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c23)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (104 mg, 0.342 mmol) in dimethylformamide (10 mL) is added sodium hydride (10 mg, 0.410 mmol). The mixture is stirred at ambient temperature for 30 minutes under nitrogen. 6-Chloro-nicotinic acid methyl ester (99 mg, 0.581 mmol) is added and the mixture is heated in an oil bath to eighty degrees Celsius for 15 hours, under nitrogen. The mixture is then heated an additional 5 hours at eighty-five degrees Celsius. Water (100 ml) is added to quench the reaction and the mixture is extracted three times with 50 mL of ethyl acetate. The organic layers are combined and washed twice with 50 mL of 1.00 N sodium hydroxide. The organic layer is dried with sodium sulfate, filtered and the solvent evaporated. The residue is dissolved in dichloromethane and purified using silica gel chromatography (6% 2M ammonia in methanol, 94% dichloromethane used as mobile phase) to give 87 mg (58%) of 6-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-nicotinic acid methyl ester. FDMS m/e=440 (M++1).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]([CH3:41])([C:37]([O:39][CH3:40])=[O:38])[C:32]([O:34][CH2:35]I)=[O:33].[K+].[Br-]>CC(C)=O>[CH3:40][O:39][C:37]([C:31]([CH3:41])([CH3:30])[C:32]([O:34][CH2:35][O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])=[O:33])=[O:38]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: COC(=O)C(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)C(=O)OCOC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
To a dry round bottomed flask equipped with a reflux condenser and stirring bar were added piroxicam (1.50 g, 4.53 mmol), potassium carbonate (1.24 g, 8.98 mmol), iodomethyl methyl 2,2-dimethylmalonate (1.48 g, 5.17 mmol) and dry acetone (15 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere for 3 hours. Chromatographed title product was isolated according to the method of Example 5, 0.95 g (43.2%) light yellow solid which was recrystallized from toluene-hexane to give light yellow crystals: mp 112°-114° C.; IR (KBr) 1690, 1680 cm-1 ; 1H NMR (CDCl3) delta 1.28 (s, 6H), 3.11 (s, 3H), 3.62 (s, 3H), 5.76 (s, 2H), 7.08-7.18 (m, 1H), 7.70-7.88 (m, 4H), 7.89-7.99 (dd, J=8 Hz, J=4 Hz, 1H), 7.30-7.44 (m, 2H), 9.42 (s, 1H); precise mass calcd for C22H23N3O6S m/e 489.1205, found 489.1230.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+]>O>[CH:18]1([O:24][C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Reaction time: 1 h
Yield: 61 %

Procedure:
To dimethylformamide solution (35 ml) containing 2-chloro-5-nitrobenzonitrile (14.1 g) and cyclohexanol (8.5 g) was added sodium hydride (60% content, 3.7 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give 2-cyclohexyloxy-5-nitrobenzonitrile (11.6 g), melting point: 97–98° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][OH:22])[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:5].[OH-].[Na+].O[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>CO>[OH:29][C:28](=[N:2][C@@H:3]([CH2:21][OH:22])[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:5])[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:26]=1
Reactant: CCCCCCCCCCCCCCNC(=O)[C@@H](N)CO
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCNC(=O)[C@H](CO)N=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General procedure for synthesis of hydroxy-substituted (S)-2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamide (Compounds II-19, II-20, and II-21): A mixture of 0.40 g (1.00 mmol) of (S)-2-amino-3-hydroxy-N-tetradecylpropanamide hydrochloride, 0.04 g (1.00 mmol) of NaOH, 1.00 mmol of hydroxybenzaldehyde, and 40 mL of methanol was stirred at room temperature for eight hours. The solvent was then evaporated under reduced pressure, and the residue was washed with cooled methanol to yield (S)-2-(hydroxybenzylideneamino)-3-hydroxy-N-tetradecylpropanamide as powder.
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:3].BrC#[N:16].C(Cl)Cl>CCOCC>[CH3:3][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:16]
Reactant: CN(C)c1cccc2ccccc12
Reactant: N#CBr
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C#N)c1cccc2ccccc12
Yield: 48 %

Procedure:
In a 2 neck round bottom flask, equipped with a magnetic stir bar and reflux condenser, was placed N,N-dimethyl-1-naphthylamine (4.35 g, 25.4 mmol, and BrCN (2.99 g, 28.2 mmol) in a single portion. This suspension was placed in an oil bath (preheated, 90° C.) and allowed to stir and reflux under N2 for 21 hours. During this time a gas was given off, detected by bubbler placed over the reflux condenser. The reaction was followed by TLC, using methylene chloride as the solvent and viewed under UV. After the 21 hours, the mixture was cooled, 100 ml of ether was added and the insoluble quaternary salt (669 mg) was filtered off. The ether filtrate was extracted with an aqueous 5M HCl solution (4×, 30 ml) and washed with water (5×, 20 ml). The ether was dried over anhydrous granular K2CO3, filtered, then concentrated to dryness, then distilled by bulb to bulb distillation at reduced pressure to afford the yellow oil of the N-methyl-N-(1-naphthyl)cyanamide (2.22 g, 48%. b.p. 180° C./1.5 mm Hg (Cressman, Homer, W. J., Org. Synth. collective vol.3, 608), 170°-171° C./1 mm Hg).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:35]=[CH:34][C:11]2[N:12]=[C:13]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH3:24])=[CH:17][C:16]=3[F:33])[O:14][C:10]=2[CH:9]=1.Cl.[C:38](OCC)(=O)C>C(OCC)(=O)C>[F:1][C:2]1([F:36])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[CH3:38])[CH3:24])=[CH:17][C:16]=3[F:33])[O:14][C:34]=2[CH:35]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCCC4CC4(F)F)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl {(1S)-2-[(6-{6-[2-(2,2-difluorocyclopropyl)ethoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate (910 mg), 4 M hydrogen chloride/ethyl acetate (10 mL), and ethyl acetate (10 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (10 mL) and acetic anhydride (5 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallization (ethyl acetate/hexane) to give the title compound (475 mg) as white crystals.