Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.[H-].[Li+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>>[CH3:28][N:29]([CH3:33])[C:30]([C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1)=[O:31]
Reactant: O=C(O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2c(c(C(=O)O)c1)OC(c1ccccc1)(c1ccccc1)O2

Procedure:
6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.486 mmol), LiH (10 mg, 0.97 mmol, 2 eq.) and dimethylcarbamoylchloride (0.18 mL, 1.94 mmol, 4 eq.) as the electrophile were reacted according to GP4, Method B. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH 67:30:3) to give the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15]>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][O:15][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: OCc1cccs1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCc2cccs2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and thiophen-2-methanol by the method of Example 10 (b).
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:3]=1[N:4]([CH3:15])S(C1C=CC(C)=CC=1)(=O)=O.S(=O)(=O)(O)O.N>O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:3]=1[NH:4][CH3:15]
Reactant: Cc1ccc(S(=O)(=O)N(C)c2cccc([N+](=O)[O-])c2N)cc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CNc1cccc([N+](=O)[O-])c1N
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
0.0716 mol (23 g) of 2-amino-3-nitro-N-methyl-N-tosylaniline is added gradually, in the course of 10 minutes whilst stirring, to 230 ml of concentrated sulphuric acid to which 23 ml of water has been added and which has been heated to 90° C. beforehand. When the addition has ended, the reaction medium is kept at 90° C. for 5 minutes and then poured onto crushed ice. The acid aqueous solution obtained is rendered alkaline with the aid of ammonia solution in order to precipitate the expected product. The latter is filtered off, washed with water and recrystallised from 40 ml of alcohol. After drying in vacuo, it melts at 93° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C:14]#[CH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:2]1([C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 15 %

Procedure:
To an ethanol solution (3 ml) containing iodobenzene (102 mg), phenylacetylene (56.1 mg), and potassium carbonate (138 mg) the mesh catalyst precursor (12 mm by 14 mm, wire diameter of 0.1 mm, opening of 0.154 mm) prepared in Example 3 was added to be heated for 12 hours at 80° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was washed with ethanol to be taken off from the mixture. The solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane) to give an intended product, diphenylacetylene with 15% yield.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO)NC(=O)CCl
Temperature: -20 °C
Yield: 106.3 %

Procedure:
To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and triethylamine (28.56 ml, 0.204 mol) in CH2Cl2 (500 ml) at -78° C. was added chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes. The cooling bath was removed and the solution allowed to warm to -20° C. The mixture was diluted with EtOAc and washed sequentially with 1M HCl, and brine and dried (Na2SO4). Evaporation in vacuo afforded the amide title compound (35 g, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1([C:17]([OH:33])([CH2:26][N:27]2[C:31]([SH:32])=[N:30][CH:29]=[N:28]2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH2:16][CH2:15]1>ClCCl>[Cl:13][C:14]1([C:17]([OH:33])([CH2:26][N:27]2[C:31]([S:32][C:2]([O:4][CH3:5])=[O:3])=[N:30][CH:29]=[N:28]2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH2:16][CH2:15]1
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Sc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
At temperatures between 0 and 5° C., first a solution of 1.28 ml (6 mmol) of methyl chloroformate in 10 ml of absolute dichloromethane and then 0.84 ml (6 mmol) of triethylamine are added dropwise with stirring to a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol and 10 ml of absolute dichloromethane. After the addition, the reaction mixture is stirred at room temperature for a further 2 hours and then diluted with dichloromethane and washed with ice-cold aqueous sodium carbonate solution. The organic phase is dried over sodium sulphate and subsequently concentrated under reduced pressure. The 1.7 g of crude product that remain are chromatographed over silica gel using a mixture of petroleum ether/ethyl acetate=1:1. Concentration of the eluate gives 0.7 g (35% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methoxycarbonylthio-1,2,4-triazol-1-yl)-propan-2-ol in the form of an oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:9]=1.[CH3:20]I>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[C:6]([CH2:14][O:15][CH3:20])[C:5]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: CI
Reactant: COCOc1cc(Br)c(OCOC)c(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(Br)c(OCOC)c(COC)c1
Yield: 88 %

Procedure:
Add sodium hydride (0.430 g of 60% in oil, 10.75 mmol) to DMF (100 mL) at −5° C. Add (3-bromo-2,5-bis-methoxymethoxy-phenyl)-methanol (3.00 g, 9.77 mmol) in DMF (20 mL) in portions and stir the resulting solution at −5° C. for 1 hour. Add methyl iodide (0.67 mL, 10.75 mmol) and stir the reaction for 1 hour. Pour the reaction into ice-H2O (200 mL) and extract with EtOAc (2×50 mL). Combine the extracts and wash with H2O (2×100 mL) and brine (50 mL) then dry (MgSO4), filter and concentrate. Purify the residue by silica gel chromatography eluting with Hex:EtOAc (80:20) to provide the subtitled product (2.76 g, 88%) as an oil. 1H NMR (CDCl3) δ 3.41 (s, 3H), 3.47 (s, 3H), 3.62 (s, 3H), 4.54 (s, 2H), 5.03 (s, 2H), 5.13 (s, 2H), 7.06 (d, J=2.9 Hz, 1H), 7.20 (d, J=2.9 Hz, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21]>C1(C)C=CC=CC=1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[O:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(-c2ccc(Br)o2)cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)nc3)o2)cc1
Temperature: 80 °C
Yield: 64 %

Procedure:
Continuing with Scheme 3, to a stirred solution of 15 (1.245 g, 5 mmol), and tetrakis(triphenylphosphine) palladium (288 mg) in toluene (15 mL) under a nitrogen atmosphere was added 10 mL of a 1 M aqueous solution of NaHCO3 followed by 4-cyanophenyl boronic acid (821 mg, 4.6 mmol) in 5 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 24 h, then cooled, and the precipitate was filtered. The precipitate was partitioned between methylene chloride (300 mL) and 1 M aqueous NaHCO3 (50 mL). The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 16 in 64% yield; mp 276–277° C. (DMF). 1H nmr(DMSO-d6); δ 7.49 (d, J=3.6 Hz, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 8.10 (d, J=8.7 Hz, 2H). 8.14 (d, J=8.1 Hz 1H), 8.49 (dd, J=8.1, 1.5 Hz, 1H), 9.29 (d, J=1.5 Hz, 1H). 13C nmr; δ 153.0, 149.7, 146.3, 133.1, 132.8, 131.4, 130.4, 129.0, 128.5, 124.4, 118.6, 117.4, 113.2, 111.8, 110.0. Calcd. for C17H9N3O: C, 75.26; H, 3.34; N, 15.49. Found. C, 75.02; H, 3.35; N, 15.39.
Reaction SMILES: [N+:1]([N:3]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[C-:2].[C:23]1([CH2:33][C:34]([NH:36][C:37]2[CH:41]=[CH:40][S:39][C:38]=2[C:42]([OH:44])=O)=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[O:44]1[CH:2]=[N:1][N:3]=[C:42]1[C:38]1[S:39][CH:40]=[CH:41][C:37]=1[NH:36][C:34](=[O:35])[CH2:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: [C-]#[N+]N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1cccc2ccccc12)Nc1ccsc1C(=O)O
Solvent: ClCCl
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1-c1nnco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of (isocyanoimino)triphenylphosphorane (978 mg, 3.24 mmol) in anhydrous CH2Cl2 (30 mL) was added dropwise a solution of 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylic acid (340 mg, 1.09 mmol) in anhydrous CH2Cl2 (27 mL). The resulting mixture was stirred at room temperature under nitrogen overnight and evaporated under reduced pressure. Purification by flash chromatography (silica, 30:70 ethyl acetate/hexane) gave N-(2-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (45 mg, 12%). Method [7] m/z 357.9 (M+Na); retention time=5.919. 1H-NMR (CDCl3) δ 8.18 (d, J=1.1 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.61-7.41 (m, 5H), 4.27 (s, 2H).
Reaction SMILES: [CH2:1]([S:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[F:21][Sb-:22]([F:27])([F:26])([F:25])([F:24])[F:23].[Na+]>CC(C)=O>[F:21][Sb-:22]([F:27])([F:26])([F:25])([F:24])[F:23].[CH3:10][S+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCCCCCSC
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCC[S+](C)CC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
Into a 100 mL round bottom flask equipped with a magnetic stirrer and reflux condenser were placed 16.0 g (0.1 mol) methyl octyl sulfide (obtained from the Aldrich Chemical Co.), 19.9 g (0.1 mol) phenacyl bromide, 25.87 g (0.1 mol) sodium hexafluoroantimonate and 40 mL acetone. The reaction mixture was brought to reflux and held at this temperature for 15 minutes. The mixture was filtered through a plug of glass wool (to remove the sodium bromide which was formed during the reaction) and the solvent was removed on a rotary evaporator, leaving 43.1 g (83.6% yield) of the desired methyl octylphenacylsulfonium hexafluoroantimonate as a tan colored solid. The product was further purified by recrystallization, first from a 1:3 mixture of water and ethanol, then, isopropanol. The pure, colorless, crystalline initiator had a melting point of 75-76° C. The initiator was soluble in a wide variety of common solvents such as acetone, methyl ethyl ketone, chloroform and methylene chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[CH3:16])=[O:4].O1CCCC1.C([Li])CCC.[CH3:29][N:30]=[CH:31][C:32]1[S:33][CH:34]=[CH:35][C:36]=1[CH3:37]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[CH2:16][CH:31]([NH:30][CH3:29])[C:32]1[S:33][CH:34]=[CH:35][C:36]=1[CH3:37])=[O:4]
Reactant: CN=Cc1sccc1C
Reactant: Cc1cc(C(F)(F)F)ccc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(Cc1cc(C(F)(F)F)ccc1NC(=O)C(C)(C)C)c1sccc1C

Procedure:
To a chilled (10° C.) solution of 12.81 g of 2,2-dimethyl-N-(2-methyl-4-trifluoromethylphenyl)propanamide and 200 ml of anhydrous tetrahydrofuran, was added dropwise over 20 min, 48 ml of a 2.5M solution of n-butyllithium in hexanes, with stirring. The solution was stirred, with cooling, for 1 hr, and 10.65 g of an 85% solution of 3-methyl-2-thiophenecarboxaldehyde methylimine in toluene, and 20 ml of tetrahydrofuran was added, dropwise over 10 min, with stirring. After stirring and cooling for 1.5 hr, 60 ml of water was added, and the mixture was evaporated. The residue was diluted with water and extracted with dichloromethane. The combined, organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by HPLC (Waters Associates Prep LC/System 500, silica gel, 200 ml/min flow rate; the residue was dissolved in sufficient ethyl acetate-hexane (1:1) to give 50 ml of solution, and the solution was applied in 25 ml portions to the columns, Gow Mac UV detector). The appropriate fractions were combined and concentrated. The residue was purified again by preparative HPLC under similar conditions, and finally, using a single recycle (elution with ethyl acetate-hexane (1:1)) to afford 9.53 g of product, mp 64°-69° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:12])[CH3:9]>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:8]([O:10][C:11](=[O:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH3:9]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Brc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(-c2cccnc2)cc1

Procedure:
1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.1 g, 0.1 mmol) was added to a stirred and degassed solution of 3-bromopyridine (1.5 ml, 15.6 mmol) and 4-[2-ethoxycarbonylethyl]phenylboronic acid (P20) (3.5 g, 15.8 mmol) in dimethyl formamide (30 mL) and 2N sodium carbonate solution in water (15 mL). The reaction mixture was stirred at 100° C. for 18 hours, then allowed to cool. The solution was filtered through celite, then ethyl acetate (100 mL) was added and the organic phase was washed three times with brine (100 mL). The organic layer was dried (anhydrous magnesium sulfate), concentrated and purified by chromatography on silica gel (30% v/v ethyl acetate in petroleum ether) to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Product: O=C1CCC(c2ccc(NC(=O)CCl)cc2)=NN1
Yield: 81.4 %

Procedure:
30.2 g (0.16 mole) of 6-(p-aminophenyl)-4,5-dihydropyridaz-3-one, 18.1 g (0.16 mole) of chloroacetyl chloride and 150 ml of absolute benzene are refluxed for 2 hours. The product is filtered off at room temperature, washed first with benzene and then with water, and dried under reduced pressure at 80° C. 34.6 g (81% of theory) of 6-(p-chloroacetylaminophenyl)-4,5-dihydropyridaz-3-one are obtained as a beige solid which, after recrystallization from dimethylformamide/water, melts, with decomposition, at 233° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[F:15])=[N:5][N:6]=1.[CH3:16][NH:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].O>[F:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:4]1[S:3][C:2]([N:17]([CH3:16])[CH:18]2[CH2:19][C:20]([CH3:26])([CH3:27])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)=[N:6][N:5]=1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: COc1cccc(F)c1-c1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cccc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Yield: 27.6 %

Procedure:
A stirred solution of 2-bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole (335 mg, 1.159 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (197 mg, 1.159 mmol) in NMP (2.5 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was diluted with saturated NaHCO3(aq) (30 mL), water (20 mL), and extracted with DCM (75 mL). The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 298 nm. The product containing fractions were combined and loaded onto a 5 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an orange oil (121 mg, 28% yield). LC-MS: Rt 0.88 min; MS m/z 379.4 [M+H]+; [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (td, J=8.34, 6.57 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 6.97 (t, J=9.09 Hz, 1H), 4.26-4.36 (m, 1H), 3.86 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.62, 2.53 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH:10]=2)[CH:8]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: CNC(=O)/C=C/c1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: CNC(=O)/C=C/c1cc(O)cc(-c2ccc3cc(O)ccc3c2)c1
Yield: 13 %

Procedure:
The compound is prepared by reaction of (E)-3-[3-methoxy-5-(6-methoxy-naphthalene-2-yl)phenyl]-N-methylacrylamide (200 mg, 0.58 mmol, 1 eq) with boron tribromide solution (5 eq) according to method G. Purification by preparative thin-layer chromatography with dichloromethane/methanol 90/10 yielded the desired product in a yield of 13%, 25 mg.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.CN(C)CCCN=C=NCC.[C:22]([OH:28])(=O)[CH2:23][CH2:24][C:25]#[CH:26]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:22](=[O:28])[CH2:23][CH2:24][C:25]#[CH:26]
Reactant: CNC
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethylamine (2 M solution in tetrahydrofuran, 8.53 ml), triethylamine (2.59 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3221 mg), were added to a solution of 4-pentynoic acid (552 mg) in methylene chloride (150 ml) and this reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed successively with 1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to give the title compound (129 mg). The obtained compound was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:27]
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 1.0 g (2.985 mmol) of the product of Example 3 in 10 mL of DMF was added 0.149 g (3.731 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 minutes at room temperature and then 0.28 mL (4.478 mmol) of iodomethane was added. The reaction was then stirred for 18 h, and next diluted with ether. The organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid. The solid was washed with ether/hexanes (1:1) to give 0.788 g (76%) of the desired product as a white solid. Electrospray Mass Spec: 350.1 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[O:16][CH:17]=[CH:18][C:19]=1[CH3:20].Cl>C(=S)=S>[CH3:20][C:19]1[CH:18]=[C:17]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[O:16][C:15]=1[CH3:14]
Reactant: Cc1ccoc1C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C(=O)c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
Carbon disulfide (35 ml) was added to benzoyl chloride (7.3 g) and anhydrous aluminum chloride (7.0 g) under an argon atmosphere, and a solution of 2,3-dimethylfuran (5.0 g) in carbon disulfide (35 ml) was added dropwise thereto at 10° C. The mixture was then stirred for 30 min while raising the temperature to room temperature. 10% Hydrochloric acid (200 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane. The dichloromethane layer was then washed with water and a 5% aqueous sodium bicarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-phenyl-methanone (2.5 g, yield 25%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 2-ethoxybenzoic acid (0.75 g, 4.5 mmol) in 23 mL of methylene chloride at 0° C. was treated with oxalyl chloride (0.44 mL, 4.9 mmol) followed by 2 drops of dimethylformamide. The solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure to provide 0.83 g of 2-ethoxybenzoyl chloride. To a solution of 4-trifluoromethylthiazol-2-ylamine (0.50 g, 3.0 mmol) in 10 mL THF at 0° C. was added a solution of the fleshly prepared acid chloride in 5 mL of THF and 2 mL of methylene chloride, followed by triethylamine (1.0 mL, 6.6 mmol). The reaction mixture was warmed to 65° C. and stirred 8 hours. The mixture was diluted with ethyl acetate and washed twice with water, then brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 30-50% ethyl acetate/hexanes gradient) afforded 0.47 g (50%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.66 (t, J=6.95 Hz, 3H), 4.38 (q, J=6.89 Hz, 2H), 7.03-7.10 (m, 2H), 7.17 (d, J=7.80 Hz, 1H), 7.42 (s, 1H), 8.29 (dd, J=7.97, 1.86 Hz, 1H) MS (DCI/NH3) m/z 317 (M+H)+.