Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].Br[C:22]1[S:26][C:25]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24][CH:23]=1>>[C:28]([NH:27][C:25]1[S:26][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][N:24]=1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1ncc(Br)s1)c1ccccc1
Reactant: C#Cc1cncc(C(=O)N=S(C)(=O)c2ccccc2)c1
Product: CS(=O)(=NC(=O)c1cncc(C#Cc2cnc(NC(=O)c3ccccc3)s2)c1)c1ccccc1
Yield: 26.1 %

Procedure:
In a manner similar to that described in Example 462, 5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (74 mg, 0.26 mmol), N-(5-bromo-1,3-thiazol-2-yl)benzamide (74 mg, 0.26 mmol) were reacted to give the title compound as a cream solid (33 mg, 26%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:21][C:22](Cl)=[O:23].[NH2:25][CH2:26][CH2:27][SH:28].[Na]>ClCCl.C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:22](=[O:23])[CH2:21][S:28][CH2:27][CH2:26][NH2:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: NCCS
Reactant: N/C=C\CCOc1cccc(CN2CCCCC2)c1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.9 %

Procedure:
There was dissolved 15.0 g (0.0577 mol) of 4-[3-(piperidinomethyl)phenoxy]-cis-butenylamine in 150 ml of dichloromethane and added dropwise 6.52 g (0.0577 mol) of chloroacetyl chloride under cooling with ice. After dropping, the mixture was stirred for 3.5 hours under cooling with ice and then the solvent was removed under reduced pressure. The residue was dissolved in 150 ml of ethanol and this solution was added to a solution which was prepared by adding 4.44 g (0.0577 mol) of 2-aminoethanethiol to a solution of 2.65 g (0.115 mol) of sodium in 150 ml of ethanol and stirring for 30 minutes at room temperature, and the obtained mixture was refluxed with heating for 1 hour. After being allowed to cool at room temperature, the precipitate was filtrated off, and the solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate and washed with water, and dried over Glauber's salt. Then the solvent was removed under reduced pressure to give 18.5 g of the titled compound as oily matter.
Reaction SMILES: [C:1]([NH:4][CH:5]([S:16][CH2:17][CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].[OH2:19].C[OH:21]>>[C:1]([NH:4][CH:5]([S:16]([CH2:17][CH3:18])(=[O:21])=[O:19])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: O
Reactant: CO
Reactant: CCSC(NC(C)=O)C(=O)NCc1ccccc1
Product: CCS(=O)(=O)C(NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 18 h

Procedure:
An aqueous solution (20 mL) of NaIO4 (3.00 g, 14.02 mmol) was added to a MeOH solution (20 mL) of 2-acetamido-N-benzyl-2-(ethylmercapto)acetamide (0.95 g, 3.57 mmol). The initial homogeneous solution rapidly became turbid. H2O (~10 mL) was then added dropwise until the system became homogeneous. The solution was stirred (18 h) at 50°-60° C. MeOH (50 mL) was added to the reaction solution and the precipitated salt was filtered and washed with MeOH (10 mL). The filtrate was concentrated and the remaining solution was extracted with CHCl3 (3×50 mL). The combined CHCl3 extracts were dried (Na2SO4), and concentrated in vacuo. Time residue was purified by flash chromatography on SiO2 gel (1% MeOH/CHCl3) to give the desired product. The product was further purified by recrystallization from EtOH:.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:28].O>C1(C)C=CC=CC=1.CCCCCC>[C:11]1([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1CCN(CCc2ccccc2)CC1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: O=CC1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-cyano-1-(2-phenylethyl)piperidine (6.5 g, 30.3 mmol) in dry toluene (100 ml) cooled in an ice bath was added dropwise 43 ml (43 mmol) of 1M diisobutylaluminum hydride in hexane. After the addition was complete, the mixture was warmed to room temperature and stirred overnight (16 h). Methanol was added to decompose any unreacted reagent and H2O was added with vigorous stirring. The gelatinous aluminum salts were removed by filtration through Celite and the filtrate extracted with toluene (2×100 ml). The extracts were combined, washed with saturated aqueous NaCl, dried (MgSO4) filtered and evaporated to give a clear oil. This oil was flash chromatographed on silica gel using acetone as eluent to give product as a clear oil, which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=1)(=O)[CH3:2].C1(P(=C[C:46]#[N:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(C)C=CC=CC=1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[S:8][C:4]([C:1]([CH3:48])=[CH:2][C:46]#[N:47])=[CH:5][C:6]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: CC(=CC#N)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1

Procedure:
A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1.8 g) and (triphenylphosphoranylidene)acetonitrile (3.2 g) in toluene (40 ml) was refluxed for 28 hours. The mixture was cooled and filtered. The filtrate was concentrated and the residue (4.2 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (10:1). The obtained crystals (1.8 g) were recrystallized from ethanol to give colorless crystals of 3-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}-2-butenenitrile (1.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10]([O:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>CN(C=O)C.C(#N)C>[Br-:25].[C:1]([O:5][C:6]([NH:8][CH:9]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][C@@H:13]1[CH2:17][CH2:16][N+:15]([CH3:18])([CH2:26][C:27](=[O:28])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CC[C@@H](OC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@@H]1CC[N+](C)(CC(=O)c2ccccc2)C1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.9 %

Procedure:
To a solution of (R)-1-methylpyrrolidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C61) (170 mg, 0.51 mmol) in DMF (5 ml) and acetonitrile (3 ml), was added 2-bromo-1-phenylethanone (111 mg, 0.56 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-methyl-1-(2-oxo-2-phenylethyl)pyrrolidinium bromide (152 mg; 56% yield).
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:40][CH:41]1[CH2:43][CH2:42]1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH:41]1([CH2:40][O:21][C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][N:9]3[C:10](=[O:11])[C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[S:38][C:6]=4[N:7]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:8]3=[O:22])=[CH:20][CH:19]=2)[CH2:43][CH2:42]1
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(O)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OCC4CC4)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 60 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a mixture of 4′-{[6-ethyl-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile, (bromomethyl)cyclopropane (0.42 mL) and N,N-dimethylformamide (7 mL) was added cesium carbonate (0.94 g), and the mixture was stirred at 60° C. for 12 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.61 g, 73%).
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][C@@H:11]([CH2:15][CH2:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])[C:12](O)=[O:13])=[CH:8][CH:7]=1.[NH2:31][C@H:32]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]1=[O:45]>CN(C=O)C.C(Cl)Cl>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@H:17]([CH2:16][CH2:15][C@H:11]([CH2:10][C:9]2[CH:29]=[CH:30][C:6]([F:5])=[CH:7][CH:8]=2)[C:12](=[O:13])[NH:31][C@H:32]2[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:45])[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1
Reactant: N[C@H]1CCCCN(c2ccccc2)C1=O
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)Cc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O)[C@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCCCN(c2ccccc2)C1=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
EDC (16 mg, 0.083 mmol) was added to a 0° C. solution of (2R,5R)-2,5-Bis(4-fluorobenzyl)hexanedioic acid (30 mg, 0.083 mmol) in DMF (1 mL) and DCM (5 mL). The ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to remove most of the DCM. (S)-3-Amino-1-phenylazepan-2-one (21 mg, 0.085 mmol) was added followed by TEA (18.4 mg, 0.182 mmol). The reaction mixture was left to stir at rt for 3 hr. The reaction mixture was partitioned between EtOAc and 5% aqueous KHSO4. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2R,5R)-2,5-bis(4-fluorobenzyl)-6-oxo-6-((S)-2-oxo-1-phenylazepan-3-ylamino)hexanoic acid (32 mg, 0.058 mmol, 71% yield) as a colorless syrup. Anal. Calcd. for C32H34F2N2O4 m/z 548.3. found: 549.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1>CN(C)C=O>[ClH:1].[CH3:24][O:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([F:25])=[CH:27][C:28]=1[CH3:33])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]1[CH3:22]
Reactant: COc1cccc2c(N3CCc4ccccc4C3C)nc(Cl)nc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3C)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 38 %

Procedure:
In accordance with the same procedures as in Example 8, except that to a mixture of 1.50 g of the compound (4.41 mM) prepared in Example 5 and 15 ml of dimethyl-formamide, 0.75 ml of 4-fluoro-2-methylaniline(9.27 mM) was added, 0.78 g of the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[C:8]([CH:31]3[CH2:34][CH2:33][CH2:32]3)=[CH:9][C:10]([CH2:29][CH3:30])=[C:11]([CH:28]=2)[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])=[N:4][N:3]=1.[OH-:35].[K+].[CH2:37](O)[CH3:38]>>[CH:31]1([C:8]2[C:7]([C:5]3[NH:1][C:2]([O:6][CH2:37][CH3:38])=[N:3][N:4]=3)=[CH:28][C:11]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([C:20]4[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:35])=[CH:22][CH:21]=4)[CH2:18][CH2:19]3)=[O:13])=[C:10]([CH2:29][CH3:30])[CH:9]=2)[CH2:32][CH2:33][CH2:34]1
Reactant: CCc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C(N)=O)cc4)CC3)c(CC)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a 10-mL sealed tube, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile (compound 215.7, 228 mg, 0.500 mmol, 1.00 equiv) in ethanol (5 mL). This was followed by the addition of potassium hydroxide (280 mg, 4.99 mmol, 10.0 equiv) in portions. The resulting solution was stirred for 5 h at 80° C. behind a blast shield. After cooling to ambient temperature, the reaction was then quenched by the addition of 15 mL of water and extracted with 2×20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 200 mg (80%) of 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:15])[CH2:8][C:9]2=[O:14])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].Cl>CCOCC>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:15])[CH:8]([N+:16]([O-:18])=[O:17])[C:9]2=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc2c1C(=O)CC2=O
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CCOCC
Product: CC(C)Oc1cccc2c1C(=O)C([N+](=O)[O-])C2=O

Procedure:
4-Isopropyloxy indane-1,3-dione (0.16 g; 0.003 mole) suspended in dry ether (5 ml) was treated dropwise and with stirring with fuming nitric acid (1.0 ml) at 10°C. The resulting dark solution was treated with 5N hydrochloric acid and evaporated to a yellow crystalline product; m.p. (water, hydrochloric acid) 80°-81°C. (Found: C, 57.94; H, 4.43; N, 5.46; C12H11NO5 requires: C, 57.83; H, 4.45; N, 5.62%).
Reaction SMILES: [F:1][C:2]1[C:12]([CH3:13])=[C:11](F)[C:10]([F:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:16]=[N+:17]=[N-:18].[Na+].C(OCC)(=O)C.O>CS(C)=O>[N:16]([C:11]1[C:10]([F:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[C:12]=1[CH3:13])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(F)c(F)c(C)c1F
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N=[N+]=[N-])c(C)c1F
Temperature: 55 °C
Reaction time: 14 h

Procedure:
In 308 ml of dimethyl sulfoxide was dissolved 61.7 g of ethyl 2,4,5-trifluoro-3-methylbenzoate, and 42.3 g of sodium azide was added to the solution, after which the resulting mixture was stirred at 55° C. for 14 hours. The reaction mixture was cooled to room temperature and thereafter added to a mixed solvent of 500 ml of ethyl acetate and 1200 ml of water. The organic layer formed was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 65.3 g of pale yellow, oily ethyl 4-azido-2,5-difluoro-3-methylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2(C(OCC)=O)[CH2:12][CH2:11][CH2:10][N:9]3[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]5)=[C:18]([O:28][CH3:29])[N:17]=4)=[N:14][N:15]=[C:8]23)=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH3:41][Mg]Br.[Cl-].[NH4+].[CH2:46]1[CH2:50][O:49]CC1>>[F:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2([C:50]([OH:49])([CH3:46])[CH3:41])[CH2:12][CH2:11][CH2:10][N:9]3[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]5)=[C:18]([O:28][CH3:29])[N:17]=4)=[N:14][N:15]=[C:8]23)=[CH:4][C:3]=1[C:37]([F:39])([F:40])[F:38]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C1(Oc2ccc(F)c(C(F)(F)F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1nc(-c2nnc3n2CCCC3(Oc2ccc(F)c(C(F)(F)F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 8-[4-fluoro-3-(trifluoromethyl)phenoxy]-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (103.1 mg) in THF (1.8 mL) was added methylmagnesium bromide (1M THF solution, 920 μL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (31.5 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CNS(C)(=O)=O)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 (0.050 g, 0.14 mmol) and triethylamine (0.0235 mL, 0.169 mmol) in methylene chloride (0.902 mL) was added methanesulfonyl chloride (13.1 uL, 0.169 mmol) dropwise. The reaction was stirred at room temperature for 1 hour. Water was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 533 as a white solid (24 mg). MS (ESI+) 434.1. 1H NMR (400 MHz, DMSO) δ 8.31 (d, J=8.2 Hz, 1H), 7.61 (t, J=6.3 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.06 (br, 1H), 5.76 (hept, J=6.1 Hz, 1H), 4.36 (t, J=5.0 Hz, 2H), 4.17 (d, J=6.2 Hz, 2H), 3.43 (t, J=4.9 Hz, 2H), 2.89 (s, 3H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15]C=[CH:13][CH:12]=1.[CH2:20](N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=2)=[C:4]([O:10][CH3:20])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCN(CC)CC
Reactant: COc1ccc(Br)cc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.4 %

Procedure:
A mixture of 4-bromoguaiacol (2.23 g, 11 mmol), phenyl boronic acid (4.03 g, 33 mmol), copper(II) acetate (2.18 g, 12 mmol) and 4A powdered molecular sieves (20 g) in dichloromethane (100 mL) was treated with triethylamine (5.5 g, 55 mmol) then stirred at ambient temperature for 20 hours. The mixture was filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel using heptane/ethyl acetate (75:25) as an eluent to give 4-bromo-2-methoxy-1-phenoxybenzene (350 mg, 12%): 1H NMR (DMSO-d6, 400 MHz) δ 7.3-7.4(m, 3H), 7.15(d, 1H), 7.05(t, 1H), 6.98(d, 1H), 6.85 (d, 2H), 3.77(s, 3H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.12 min.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].O[CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16]>CO>[C:1]([O:10][CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: C[N+](C)(C)CCO
Agent: O=C(O)c1ccccc1O
Agent: [OH-]
Solvent: CO
Product: C[N+](C)(C)CCOC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Salicylic acid (5 or 10 mmol) and choline hydroxide (5 mmol, 40% solution in MeOH) were dissolved in 20 ml of methanol and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[OH:16][CH:17]([CH2:20][OH:21])[CH2:18][NH2:19]>>[OH:16][CH:17]([CH2:20][OH:21])[CH2:18][N:19]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: NCC(O)CO
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC(O)CO

Procedure:
102 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are heated with 45.55 g of 2,3-dihydroxypropylamine to 200° C., and the pressure is lowered to 47 Pa. The yield is 138 g (96.5% of theory) of a highly viscous product having η80 =605 mPa.s and n25D =1.5380.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCSc1ccc(Cl)c(C#N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)n1
Yield: 53.5 %

Procedure:
Following a procedure substantially the same as that described in Example 20, 8.0 g of 3-chloro-6-ethylthio-2-pyridinecarbonitrile was reacted with 8.2 g of 3,4-dichlorophenol in the presence of 5.6 g of t-BuOK in 60 ml of THF and 30 ml of DMSO. The reaction was allowed to proceed at boiling temperature for about 40 hours. The product, an oil, was purified by distillation on a Kugelrohr distillation apparatus, separated on a Water's Prep LC 500 instrument, and again distilled on a Kugelrohr apparatus to give about 7 g (54%) of the desired 3-(3,4-dichlorophenoxy)-6-ethylthio-2-pyridinecarbonitrile, having a boiling point (b.p.) of 160° C. at 0.01 mm Hg pressure.