Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[CH:10][CH:9]=1)C>O.C(O)C>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:25])=[O:5])=[CH:9][CH:10]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4.75 g of potassium hydroxide in 20 cc of water is added to 7 g of 4-(2-carboxybenzyl-thio)phenyl-acetic acid ethyl ester in 50 cc of ethanol, and the mixture is stirred at room temperature for 20 hours. The solution is then concentrated at reduced pressure, the residue is taken up in water and extracted with ether. The aqueous phase is subsequently acidified with 5 N hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate extract with water and drying over sodium sulphate, the solvent is removed by distillation, whereby 4-(2-carboxy-benzyl-thio)phenyl-acetic acid is obtained as crystalline residue. M.P. 169° (from ethyl acetate/pentane).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([NH2:12])[CH:10]=[CH2:11]>O1CCCC1>[CH2:9]([NH:12][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:10]=[CH2:11]
Reactant: C=CCN
Reactant: CCCCCC(=O)Cl
Solvent: C1CCOC1
Product: C=CCNC(=O)CCCCC
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
Hexanoyl chloride (33 g, 0.25 mol) in 250 mL of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (28.6 g, 0.5 mol) in 200 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtration was concentrated under vacuum to yield 37 g of N-allyl hexanamide as a colorless viscous liquid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCNCCCN
Product: CCCCCCCCNCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 3-octylamino-propylamine comparable as in Example A.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]1(C)C=CC=C[CH:14]=1>>[CH:10]1[C:9]2[NH:8][C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1
Reactant: c1ccc(-c2ccccn2)nc1
Product: c1ccc2c(c1)[nH]c1ccccc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To an ampoule, Cu(I)Br (1 mmol), 2,2′-bipyridine (1 mmol), norbornene methylene bromide(NBMBr) (1 mmol) and styrene(St) (100 mmol) were added in 10 mL toluene. The heterogeneous mixture was placed under vacuum and degassed via a freeze-pump-thaw cycle thrice. After degassing, the reaction mixture in ampoule was stirred at 100° C. for 12 hrs. The macromonomer containing polystyrene segments (NBMPStBr) was precipitated from methanol. Polymer was dissolved in THF and reprecipitated from methanol three times. Number average molecular weight of (NBMPStBr) is 160000 and PDI is 1.28 (by GPC).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1>>[CH3:34][O:33][C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:22]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:12]=2[O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:23])[CH2:26]1)=[O:32]
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(OC(F)(F)F)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-[3-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)propoxy]benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-trifluoromethoxybenzene.
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[S:12](Cl)(=[O:14])=[O:13]>>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[S:12]([F:1])(=[O:14])=[O:13]
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Agent: [K+]
Product: O=S(=O)(F)c1cc(Cl)c(Cl)cc1Cl
Yield: 99 %

Procedure:
2,4,5-Trichlorobenzenesulfonyl fluoride was synthesized from potassium fluoride and 2,4,5-trichlorobenzenesulfonyl chloride using the procedure described in Example 1. A product with mp 80°-83° C was obtained in 99% yield. The chemical analysis, NMR and IR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.Br[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:17]([C:18]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[CH:1]=1)(=[O:19])[CH3:16]
Reactant: CC(=O)CBr
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc2oc(C(C)=O)cc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 246.8 %

Procedure:
To a solution of ethyl 3-formyl-4-hydroxybenzoate (4.00 g, 11.5 mmol) in acetonitrile (85 mL) were added bromoacetone (9.68 g, 64.1 mmol) and potassium carbonate (14.7 g, 106 mmol), and the mixture was stirred at 70° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was passed through silica gel. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (6.59 g, yield 67%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19](O)=[O:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:28]CCl>CN(C)C=O>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([Cl:28])=[O:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a suspension of 3-[4-(biphenyl-4-sulfonylamino)-phenyl]-acrylic acid (82a) (0.27 g, 0.71 mmol) in dichloromethane (3 ml) oxalyl chloride (0.3 ml, 3.39 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.277 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]Br.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:18][CH:17]=[C:16]([CH3:20])[CH3:15])[CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Sc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-bromothiophenol (5.0 g) in 60 mL of DMF was treated with 3.75 g of ground potassium carbonate and 3.2 mL of 3,3-dimethylallyl bromide. The reaction mixture was stirred at room temperature for two hours, poured onto 75 mL of ice-water, acidified to pH 2.0 with 10% HCl and extracted with three 75 mL portions of ether. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by short path distillation (T=170° C. at 950 mTorr) to give 5.651 g of 1-bromo-3-(3-methyl-but-2-enylsulfanyl)-benzene as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:23][C:22]#[CH:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide is alkylated using 3-bromo-propyne and K2CO3. After aqueous work-up the crude material (5.11 g) is de-acetylated in MeOH (180 ml) using DBU (1,3 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-prop-2-ynyl-1,3-dihydro-indol-2-one (4.32 g) is obtained and used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[C:15]([N:22]1[CH2:28][CH2:27][CH2:26][C@H:23]1[CH2:24]O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:24][C@@H:23]1[CH2:26][CH2:27][CH2:28][N:22]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate (3.00 g, 15.29 mmol), (S)-N-Boc-prolinol (3.08 g, 15.30 mmol), Ph3P (4.81 g, 18.34 mmol) in THF (50 mL) was added DIAD (3.61 mL, 18.33 mmol) at 0° C. The resulting mixture was heated under reflux 6.5 hr. After cooling to room temp, the mixture was evaporated and purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give ethyl (S)-3-methoxy-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl methoxy]benzoate as a gum. The above ethyl (S)-3-methoxy-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate was dissolved in CH2Cl2 (50 mL) and TFA (45 mL). The mixture was stirred for 2 days at room temp. The resulting mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CH2Cl2, washed with brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (20:1, v/v) as eluent to give 3.27 g (77% for 2 steps) ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy) benzoate as a yellow oil. 1H-NMR (CDCl3) δ 1.39 (t, 3 H, J=7.1 Hz), 1.52–1.59 (m, 1 H), 1.76–1.88 (m, 2 H), 1.92–2.01 (m, 1H), 2.92–3.06 (m, 2 H), 3.56–3.63 (m, 1 H), 3.90 (s, 3 H), 3.91–4.02 (m, 2 H), 4.35 (q, 2 H, J=7.1 Hz), 6.89 (d, 1 H, J=8.3 Hz), 7.54 (d, 1 H, J=2.0 Hz), 7.65 (dd, 1 H, J=2.0, 8.3 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[NH:10]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]1.O>CN(C)C=O>[CH2:7]([N:10]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]1)[CH3:8]
Reactant: CCI
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.9 %

Procedure:
3.7 g (26.8 mmoles) of anhydrous potassium carbonate and 4.2 g (26.6 mmoles) of ethyl iodide were added to a solution of 1.5 g (10.7 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 20 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 1.6 g (yield: 88.9%) of ethyl 1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.
Reaction SMILES: [CH:1]1([N:5]2[C:9]([C:10](=O)/[C:11](/[F:16])=[CH:12]/N(C)C)=[CH:8][N:7]=[C:6]2[CH3:18])[CH2:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32]3[N:34]=[C:10]([C:9]4[N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:6]([CH3:18])=[N:7][CH:8]=4)[C:11]([F:16])=[CH:12][N:33]=3)=[CH:29][CH:30]=2)[CH2:20][CH2:21]1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C1CCC1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2F)n1C1CCC1

Procedure:
The title compound was prepared from (2Z)-1-(1-cyclobutyl-2-methyl-1H-imidazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (Method 16; 234 mg) and N-(4-morpholin-4-ylphenyl)guanidine (Method 4; 410 mg) by the procedure of Example 111 to yield a white solid (288 mg, 76%). NMR: 1.61-1.72 (m, 2H), 2.29-2.45 (m, 4H), 2.75 (s, 3H), 3.26-3.34 (m, 4H), 3.90-3.97 (m, 4H), 5.22 (quintet, 1H), 7.38-7.45 (m, 2H), 7.68 (d, 2H), 8.08 (d, 1H), 8.73 (d, 1H), 9.95 (brs, 1H); m/z 409.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:16]=1[N:26]1[C:30]([CH2:31][CH3:32])=[C:29]([CH2:33]O)[C:28]([CH2:35][CH3:36])=[N:27]1.C(N(CC)CC)C.CS(Cl)(=O)=O>CCOCC>[CH2:35]([C:28]1[C:29]([CH2:33][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]=2[OH:11])=[C:30]([CH2:31][CH3:32])[N:26]([C:16]2[C:15]([Cl:14])=[CH:20][C:19]([C:21]([F:22])([F:24])[F:23])=[CH:18][C:17]=2[Cl:25])[N:27]=1)[CH3:36]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CO
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1Cc1c(O)ccc2ccccc12
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of 303 mg (2.1 mmol) of 2-naphthol in 5 mL of dry ether was treated with 50 mg (2.1 mmol) of sodium hydride and the mixture was stirred for 15 minutes. A solution of 368 mg (1.0 mmol) of the compound of step C in 5 mL of dry ether and 126 mg (0.174 mL, 1.22 mmol) of triethylamine was cooled to 0° C. and treated with 114 mg (0.077 mL, 1.0 mmol) of methanesulfonyl chloride. Triethylamine hydrochloride was removed by filtration and the filtrate was added to the above suspension of sodium 2-naphthoxide and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then partitioned between water and ether and the organic extracts were dried and evaporated to give the desired product in 29% yield. 1H-NMR (CDCl3) δ1.00 (3H, t, J=7), 1.20 (3H, t, J=7), 2.44 (2H, q, J=7), 4.58 (2H, s), 6.96-7.84 (8H, m).
Reaction SMILES: Cl[P:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH:6]([CH3:22])[C:5]2[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:4]=2[O:3]1.[OH2:35].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:35]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH:6]([CH3:22])[C:5]2[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:4]=2[O:3]1
Reactant: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(Cl)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Reactant: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2O[PH](=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of 5.5 g (11 mmol) of the compound of Example 7 in 100 mL of toluene at ambient temperature is added dropwise a solution of 0.20 mL (11 mmol) of distilled water in 3.0 mL (22 mmol) of triethylamine. After the addition is complete, the reaction mixture is stirred at room temperature for 15 minutes. The toluene is removed under vacuum and the residue is recrystallized twice from 50 mL of diethyl ether. The ether is removed in vacuo and the residue is dried under vacuum to give 3.95 g (74% yield) of the title compound as an off-white solid melting at 209° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:10]([C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:13])[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]=12
Reactant: N#Cc1ccsc1N
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2sccc2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A mixture of 2-amino-3-thiophenecarbonitrile (2 g, 16.11 mmol), ethyl acetoacetate (2.24 mL, 17.72 mmol) and SnCl4 (3.78 mL, 32.2 mmol) in toluene (120 mL) was stirred at RT for 30 min and then at reflux for ca. 4 h. After cooling to RT, the mixture was quenched with 6M NaOH (ca. 80 mL), diluted with ethyl acetate (80 mL) and then filtered through celite. The organic layer of the filtrate was separated and the aqueous layer was re-extracted with ethyl acetate (50 mL×5). The combined organics were dried and concentrated. Purification by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (960 mg). LCMS (A) m/z: 237 [M+1]+, Rt 0.67 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:22](O)=[O:23])[C:5]=1[C:25](O)=[O:26])[CH3:2].[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:29]>C(O)(=O)C.[Cl-].[Na+].O>[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[C:22](=[O:23])[C:6]3[C:7]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]4=[C:4]([O:3][CH2:1][CH3:2])[C:5]=3[C:25]2=[O:26])=[CH:37][CH:38]=1)[CH3:29]
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCc2ccccc2)c2ccccc12
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCC)C2=O)cc1
Yield: 74.2 %

Procedure:
A mixture of 1-(ethyloxy)-4-[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (2.55 g, 6.97 mmol) and ethyl(4-aminophenyl)acetate (2.49 g, 13.9 mmol) were heated to 120° C. in acetic acid (20 ml) for 18 hours. The reaction mixture was diluted with brine and extracted with ethyl acetate twice. Combined organics were washed with water then dried over magnesium sulphate, the solvent evaporated to give a brown oil. This was purified by chromatography on silica gel, eluting with ethyl acetate (0-30%) in hexane to give the title compound as a peach coloured solid (2.63 g, 5.17 mmol). LC/MS: Rt=3.95, [MH]+ 510.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)cc1
Temperature: 110 °C
Yield: 72.8 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), [4-(methyloxy)phenyl]boronic acid (78 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was then heated in an aluminum block at 110° C. for 3 h. The resulting yellow slurry was diluted with ethanol then evaporated to dryness under reduced pressure. The residue was triturated from dichloromethane then the decanted solution was applied directly to a standard stock silica column (Analogix SF25-40 g) and eluted first with 100% ethyl acetate for 5 min and then with 7% methanol in dichloromethane. The combined desired fractions were evaporated to a colorless oil that was crystallized from hexanes/ethyl acetate to afford the title compound as a white solid (78 mg, 72.2%). MS(ES)+ m/e 419.2 [M+H]+.