Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:22][CH2:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:45]=2)[C:40]1=[O:52])(=O)C>>[C:48]([C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:52])[N:39]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[NH:15][N:14]=[C:13]([CH:16]5[CH2:18][CH2:17]5)[CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:24]=1[CH2:23][OH:22])[CH2:47]2)([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: Cn1cc(Br)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Yield: 32.7 %

Procedure:
Using the same general procedure as Example 105, reaction of 110a (260 mg, 0.841 mmol) and 103f (429 mg, 0.926 mmol) afforded a 33% yield (144 mg) of 110 as an off-white solid: mp 178-180° C.; 1H NMR (500 MHz, DMSO-d6) δ 11.76 (d, 1H, J=2.0 Hz), 7.98 (d, 1H, J=2.0 Hz), 7.92 (s, 1H), 7.71 (m, 2H), 7.61 (dd, 1H, J=7.9, 1.6 Hz), 7.48 (m, 1H), 7.42 (dd, 1H, J=7.6, 1.1 Hz), 7.35 (dd, 1H, J=7.6, 1.1 Hz), 7.23 (d, 1H, J=2.1 Hz), 5.79 (d, 1H, J=2.2 Hz), 4.93 (s, 2H), 4.90 (t, 1H, J=4.9 Hz), 4.35 (d, 2H, J=4.6 Hz), 3.57 (s, 3H), 1.81 (m, 1H), 1.37 (s, 9H), 0.89 (m, 2H), 0.64 (m, 2H); MS (ESI+) m/z 524.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][NH2:32]>O1CCOCC1>[C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[O:17])#[N:2]
Reactant: COCCCN
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)Oc1ccccc1
Solvent: C1COCCO1
Product: COCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Temperature: 80 °C
Yield: 74.7 %

Procedure:
A mixture of phenyl (4-cyano-3-(4-nitrophenyl)isothiazol-5-yl)carbamate (37 mg, 0.10 mmol) and 3-methoxypropylamine (0.015 mL, 0.15 mmol) in 0.8 mL dioxane was heated at 80° C. After 2 hours the reaction mixture was evaporated to a solid film. The solid was triturated with dichloromethane and then 10% EtOAc in hexane to give a yellow-orange solid. This material was then chromatographed eluting with gradient 50% to 70% EtOAc in hexane. The filtrate from trituration and material from another reaction were combined and chromatographed with EtOAc/hexane. The clean product lots were combined to give the title compound as an off-white solid (27 mg).
Reaction SMILES: C(OC([N:8]([S:26]([CH2:29]P(OCC)(OCC)=O)(=[O:28])=[O:27])[CH2:9][CH2:10][N:11]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O)(C)(C)C.[H-].[Na+].C(O[CH:43](O)[C:44]([F:47])([F:46])[F:45])C>C1COCC1>[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:11]([CH2:10][CH2:9][NH:8][S:26](/[CH:29]=[CH:43]/[C:44]([F:47])([F:46])[F:45])(=[O:27])=[O:28])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:24]=1
Reactant: CCOC(O)C(F)(F)F
Reactant: CCOP(=O)(CS(=O)(=O)N(CCN(C(=O)OC(C)(C)C)c1cc(C)ccn1)C(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccnc(N(CCNS(=O)(=O)/C=C/C(F)(F)F)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.3 %

Procedure:
To a solution of tert-butyl N-[2-(tert-butoxycarbonyl(diethoxyphosphorylmethyl-sulfonyl)amino)-ethyl]-N-(4-methyl-2-pyridyl)carbamate (344 mg, 0.608 mmol) in anhydrous THF (30 ml) were added molsieve (4A) and sodium hydride (42.5 mg, 1.063 mmol, 60%) under nitrogen and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0° C. and 1-ethoxy-2,2,2-trifluoro-ethanol (220 mg, 1.525 mmol, 180 μl) was added. Stirring was continued for 30 minutes at 0° C. and overnight at room temperature. The mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient of 0 to 100% heptane in ethyl acetate) to yield 98 mg of a colourless oil (0.239 mmol, 39%) MS(ESI) m/z=410.1 [M+1]+.
Reaction SMILES: I.CS[C:4](=[N:18][CH2:19][CH3:20])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>C(O)(C)(C)C>[CH2:21]([NH:25][C:4]([NH:18][CH2:19][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: CCCCN
Agent: I
Solvent: CC(C)(C)O
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NCC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-ethyl-2-thiopseudourea hydroiodide (10 g prepared as described in Example 212), n-butylamine (2.7 g) and t-butanol (75 ml) was heated at 90°-95° C. for 172 hours to yield 1-(n-butyl)-2-(2-morpholinophenyl)-3-ethylguanidine which was converted into its monofumarate salt (m.p. 159°-160° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: F[S:2]([C:5]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:6]=1[NH2:7])(=[O:4])=[O:3].[CH3:14][Li]>CCOCC>[Br:13][C:8]1[CH:9]=[C:10]([Br:12])[CH:11]=[C:5]([S:2]([CH3:14])(=[O:4])=[O:3])[C:6]=1[NH2:7]
Reactant: Nc1c(Br)cc(Br)cc1S(=O)(=O)F
Reactant: [Li]C
Solvent: CCOCC
Product: CS(=O)(=O)c1cc(Br)cc(Br)c1N
Temperature: 0 °C

Procedure:
A solution of 2-fluorosulfonyl-4,6-dibromoaniline (7.19 g; 0.0216 mol) in ether (100 ml) is cooled to -65° C. under a nitrogen atmosphere and a solution of methyllithium in ether (37.5 ml of 1.8 M; 0.0675 mol) is added via a syringe. The mixture is allowed to warm to 0° C., the solution is poured into ice, and the ether layer is separated. The aqueous layer is extracted with ether (3×100 ml) and the ether layers are combined. The solvent is removed under reduced pressure and the residue crystallized from petroleum ether to afford the title product.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([N+:35]([O-])=O)[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[H][H]>[Pd].C1COCC1.CN(C=O)C>[C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([NH2:35])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 0.6 g of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine and 0.2 g of 10% palladium on carbon in 170 ml of THF and 10 ml of DMF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 4 hours. The reaction mixture was heated to dissolve the precipitated product and the catalyst was removed by filtration. The filtrate was concentrated at reduced pressure and the solid residue was dissolved in THF and the solution was passed through a SEP-PAK silica cartridge (Waters Associates). The eluent was concentrated at reduced pressure to a solid which was triturated with ethyl acetate and filtered to give 0.25 g (44% yield, mp 185°-195°) of N-(carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1C
Product: COc1ccc(C(=O)Nc2nc(C(Cl)(Cl)Cl)ns2)cc1

Procedure:
A solution of 11.0 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 12.8 g (0.08 mole) 4-anisoyl chloride in 200 ml xylene was heated at reflux for 20 hours. Cooling of the reaction mixture resulted in precipitation of the crude product, which was then isolated by filtration. Purification was achieved by washing the crude product with hot hexane. Yield was 12.0 g (82%); m.p. 172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:22]#[N:23])[N:14]2[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=12.[CH2:24]([CH:27]([NH2:31])[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:22]#[N:23])[N:14]2[C:19]([NH:31][CH:27]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=12
Reactant: CCCC(N)CCC
Reactant: Cc1cc(Cl)n2c(C#N)cc(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCC(CCC)Nc1cc(C)nc2c(-c3ccc(C(C)C)cc3Br)cc(C#N)n12
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 8-(2-bromo-4-isopropyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (300 mg), 1-propyl-butylamine (267 mg), N,N-diisopropylethylamine (300 mg) in ethanol (1.0 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=20:1) to give 8-(2-bromo-4-isopropyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (321 mg) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH:45][CH3:46])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27].CC(C)N=C=NC(C)C>>[Cl:1][C:2]1[C:15]([NH:16][C:17]2[N:45]([CH3:46])[C:22]3=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([C:26](=[O:27])[NH:28][C@H:29]4[CH2:30][CH2:31][C@H:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]4)[CH:39]=[C:21]3[N:20]=2)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)nc21

Procedure:
The title compound is prepared from N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (120 mg, 0.38 mmol) and 5-amino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-nicotinamide (150 mg, 0.38 mmol) with DIC in analogy to examples 8a/8b.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]([NH:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([O:16][C:17]2[CH:22]=[C:21]([I:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=2[CH:26]([CH3:28])[CH3:27])=[CH:11][N:10]=1)=[O:7].[OH-].[Li+]>C1COCC1.O>[NH2:15][C:13]1[C:12]([O:16][C:17]2[CH:22]=[C:21]([I:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=2[CH:26]([CH3:27])[CH3:28])=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:29])=[O:2])[N:14]=1
Reactant: COC(=O)CCC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCC(=O)O)nc2N)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
To a solution of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-succinamic acid methyl ester (0.54 g, 1.05 mmoles) in THF (20 ml) was added a solution of Lithium hydroxide (0.33 g, 13.8 mmoles) in water (10 ml). The mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure. The aqueous residue was pH adjusted to pH=8, washed with EtOAc, and lyophilized for 36 hours. The resulting solid was washed with 30% methanol in ethyl acetate, and filtered. The filtrate was evaporated and the residue was washed twice with dichloromethane, dissolved in water and pH adjusted pH=7 by addition of 0.5 N HCl aqueous solution. The resulting precipitate was recrystallized from water, and the crystals were washed with dichloromethane/ether to give 40 mg of N-[4-Amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-succinamic acid as a light yellow solid. MS (M+H)=501.
Reaction SMILES: [C:1]1([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:4][C:3]1[CH:2]=[C:1]([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.4 %

Procedure:
A 0° C. mixture of orcinol (10.0 g, 80.6 mmol) and 325 mesh potassium carbonate (12.25 g, 88.6 mmol) in DMF (100 mL) is treated dropwise with benzyl bromide (6.91 g, 40.4 mmol). The mixture was then warmed to rt and stirred for 20 hours under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 5/1 hexanes/ethyl acetate to afford 4.88 g (57%) of the title compound. Rf=0.40 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C14H14O2 214, found 215 (M+1, 100%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][OH:13])=[O:6])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>N1C=CC=CC=1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:34])[O:13][CH2:12][C:11]2[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[N:9]=[N:8][C:7]=2[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:28][CH:27]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COC(=O)Nc2ccc(F)cc2)cc1
Temperature: 60 °C
Yield: 35.7 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (200 mg) obtained in Example 112 in pyridine (5 ml) was added 1-fluoro-4-isocyanatobenzene (125 mg) and the mixture was heated at 60° C. for 18 hr. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (101 mg).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1>C1(C)C=CC=CC=1>[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][B:19](/[CH:2]=[CH:1]/[C:3]2[CH:15]=[CH:14][C:6]([CH2:7][N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:5][CH:4]=2)[O:18]1
Reactant: C#Cc1ccc(CN2CCOCC2)cc1
Reactant: CC1(C)OBOC1(C)C
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
An oven-dried round-bottom flask was cooled under N2 (g) and then charged with 4-(4-ethynylbenzyl)morpholine (120 mg, 0.596 mmol), toluene (2.5 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.43 mL, 2.98 mmol). The mixture was stirred for 15 min while purging the solution with N2 (g). HRuCl(CO)(PPh3)3 (29 mg, 0.030 mmol) was then added and the reaction heated to 50° C. for 18 h. The reaction was quenched with NaHCO3 (sat.) (10 mL), extracted with EtOAc, and the organic layer washed with brine (2×) and then dried over MgSO4. The solvent was removed and the resulting residue purified by column chromatography (silica gel, Hexanes/EtOAc, 2:3 to 1:2) to give a white solid (155 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=18.8 Hz), 7.30 (m, 2H), 6.15 (d, 1H, J=18.5 Hz), 3.72 (bs, 4H), 3.49 (bs, 2H), 2.45 (bs, 4H), 1.31 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.22.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH2:18]([N:13]1[C:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:28])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccccc1B(O)O
Product: CCn1nc2c(c1-c1ccccc1C)CCNCC2
Yield: 108.5 %

Procedure:
The title compound (138 mg) was prepared according to Example 263 using 206 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 95 mg of 2-methylphenylboronic acid. MS (ESI): exact mass calculated for C16H21N3, 255.17; found, m/z 256.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.42 (m, 2H), 7.38-7.35 (m, 1H), 7.25-7.24 (m, 1H), 4.69 (br s, 2H), 4.03-3.17 (m, 5H), 2.76-2.68 (m, 2H), 2.15 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][C:24](=[N:54]O)[C:25]1[CH:52]=[CH:51][C:28]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39](=[O:50])[C@H:40]([NH:42][C:43]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)=[O:44])[CH3:41])[CH2:35][CH2:34]2)=[CH:27][C:26]=1[F:53]>CN(C=O)C>[F:53][C:26]1[CH:27]=[C:28]([CH:51]=[CH:52][C:25]=1[C:24]1[N:54]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[O:7][N:23]=1)[O:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][N:36]([C:39](=[O:50])[C@H:40]([NH:42][C:43]([C:45]2[S:46][CH:47]=[CH:48][CH:49]=2)=[O:44])[CH3:41])[CH2:37][CH2:38]1
Reactant: C[C@@H](NC(=O)c1cccs1)C(=O)N1CCN(CCCOc2ccc(C(N)=NO)c(F)c2)CC1
Reactant: Cc1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(OCCCN4CCN(C(=O)[C@@H](C)NC(=O)c5cccs5)CC4)cc3F)no2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Methylbenzoic acid (0.3 mmol) was treated with a 0.4 M solution of 1,1′-carbonyldiimidazole (CDI) (0.75 mL, 0.3 mmol) in DMF in a 4 mL vial. After mixing for 30 minutes, a 0.22 M solution of Example 187C (0.75 mL, 0.16 mol) in DMF was added to the vial. The mixture was stirred for 4 hours at room temperature and a 0.4 M solution of CDI (0.5 mL, 0.2 mmol)in DMF was added to the vial. After heating the mixture at 115° C. for 7 hours, the mixture was allowed to cool to room temperature and then was concentrated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product. 1H NMR (CDCl3) δ1.50 (d, 3H), 2.35 (m, 2H), 2.45 (s, 3H), 3.05-3.60 (m, 6H), 3.80-4.25 (m, 6H), 5.05 (m, 1H), 6.80 (m, 2H), 7.00 (m, 1H), 7.08 (m, 1H), 7.40 (m, 2H), 7.50 (m, 1H), 7.60 (m, 1H), 8.00 (m, 2H), 8.05 (m, 1H); MS (APCI+) m/z 564 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH-].[K+]>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCC(Br)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.38 g, 0.01 mole) and ethyl 2-bromopentanoate (2.09 g, 0.01 mole) in acetone (100 ml) was added potassium hydroxide flakes (1.68 g, 0.03 mole) The mixture was stirred at room temperature for one hour and then concentrated in vacuo to an oil. The oil was added to water (50 ml) and extracted with diethyl ether, dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:18]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)=[O:19])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH2:2][CH3:3].Cl.[NH2:30][OH:31]>CCO.N1C=CC=CC=1>[CH2:1]([C:4]1[C:5]([C:18]([C:20]2[CH:28]=[CH:27][C:23]([C:24](=[N:30][OH:31])[OH:25])=[CH:22][CH:21]=2)=[O:19])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(cc1C(=O)c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCc1cc2c(cc1C(=O)c1ccc(C(O)=NO)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthyl)carbonyl]benzoic acid (101) (12.6 mmol) in EtOH (10 mL) and pyridine (15.3 mL) was treated with hydroxylamine hydrochloride (4.38 g, 63 mmol), and the mixture was heated at reflux. After 6 h, the mixture was cooled to room temperature and the ethanol was removed in vacuo. The residue was taken-up in water and the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated to give a foamy white solid. Recrystallization (CH2Cl2/ether/hexanes) gave 4-[(3-n-propyl,5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (104), as white crystals (85%): mp 255-257°C.; 1H-NMR (400 MHz, CDCl3) δ8.19 (½ABq, J=8.3 Hz, 2H, ArH), 7.89 (½ABq, J=8.3 Hz, 2H, ArH), 7.23 (s, 1H, ArH), 7.20 (s, 1H, ArH), 2.65 (m, 2H, CH2), 1.70 (m, 4H, 2CH2), 1.56 (m, 2H, CH2), 1.32 (s, 6H, 2CH3) 1.20 (s, 6H, 2CH3), 0.88 (t, J=7.3 Hz, 3H, CH3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[NH:14])OCC.C(O)C.[NH2:18][NH:19][C:20]([NH2:22])=[S:21]>C(O)(=O)C>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:18][NH:19][C:20]([NH2:22])=[S:21])=[NH:14]
Reactant: NNC(N)=S
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S

Procedure:
To a stirred solution of ethyl 1-methyl-5-nitro-2-imidazolecarboximidate (0.198 g., 0.001 mole) in 10 ml. of absolute ethanol is added thiosemicarbazide (0.091 g., 0.001 mole) and 1 ml. of glacial acetic acid. The mixture is heated at reflux for 11/4 hours and is cooled in an ice bath. The orange-red solid is filtered washed and dried affording 0.173 g. of the title compound, melting point 210°-214°, dec.