Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C@@H:43]([CH2:62][C:63]1[N:64]=[CH:65][NH:66][CH:67]=1)[C:44]([NH:46][C@@H:47]([CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:53][CH2:52]1)[OH:50])=[O:45].[CH:68]1([CH2:71][O:72][C:73]([C:75]([S:78]([CH2:81][CH:82]([CH2:86][C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[C:83](O)=[O:84])(=[O:80])=[O:79])([CH3:77])[CH3:76])=[O:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:56]1([CH2:55][C@H:47]([NH:46][C:44]([C@@H:43]([NH:42][C:83]([C@@H:82]([CH2:86][C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)[CH2:81][S:78]([C:75]([CH3:76])([CH3:77])[C:73]([O:72][CH2:71][CH:68]2[CH2:70][CH2:69]2)=[O:74])(=[O:80])=[O:79])=[O:84])[CH2:62][C:63]2[N:64]=[CH:65][NH:66][CH:67]=2)=[O:45])[C@@H:48]([OH:54])[C@H:49]([CH:51]2[CH2:52][CH2:53]2)[OH:50])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C(=O)OCC1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)OCC1CC1)S(=O)(=O)C[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
77 mg (0.76mmol) of triethylamine, 118 mg (0.76mmol) of HOBT and 289 mg (0.76 mmol) of HBTU were added in sequence at room temperature under nitrogen to a solution of 250 mg (0.69mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4propionamide and 281 mg (0.76 mmol) of rac-α-[[[1-[(cyclopropylmethoxy)carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamic acid in 20 ml of dimethylformamide. The yellow reaction solution was stirred at room temperature overnight. For the working-up, the reaction solution was evaporated in a high vacuum. The residue was taken up in 40 ml of ethyl acetate and extracted twice with in each case 10 ml of saturated sodium hydrogen carbonate solution and 10 ml of saturated sodium chloride solution. The organic extracts were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue (560 mg) was chromatographed on 50 g of silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and pyridine as the eluent. After lyophilization from dioxan/water there were obtained 110 mg of the less polar cyclopropylmethyl 2-[[(R)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulfonyl]-2-methylpropionate, MS: 715 (M+H)+, and 142 mg of the more polar epimeric cyclopropylmethyl 2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1 -(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulfonyl]-2-methylpropionate, MS: 715 (M+H)+, each as a colourless powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13]S(O)(=O)=O.O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:10]([O:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: C1=CN(Cc2ccccc2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Temperature: 0 °C
Yield: 77 %

Procedure:
To an ice-cooled solution of 1-benzyl pyrroline (0.01 mol), 98% H2SO4 (0.012 mol), water (1.5 g), and acetone (10 mL) in a round bottom flask was added 77% m-CPBA (0.013 mol) with stirring, and allowed to react for about 50 h at room temperature. After completion of the reaction (TLC monitor), acetone was evaporated under reduced pressure, and the mixture was neutralized by 1M NaOH, and extracted with toluene (30 mL×3). The precipitates that appeared were filtered, and the filtrate was repeatedly washed with water (30 mL×2). After the solvent was evaporated under reduced pressure, pure product was obtained in 77% yield via column chromatography (silica gel, CH2Cl2:EtOAc:MeOH, 7.5:2.00:0.5).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:19][CH:20]([CH3:22])[CH2:21][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[OH:16]
Reactant: CC(C)C[Mg]Br
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a solution of 4′-(trifluoromethyl)biphenyl-4-carbaldehyde (7.0 g, 28 mmol) in tetrahydrofuran (280 mL) was added isobutylmagnesium bromide (21 mL, 2M in THF, 42 mmol) dropwise at −15° C. The reaction was stirred at −10° C. for 2 hours. The reaction was quenched with 1N HCl (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (3.9 g, 45%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 7.62 (s, 4H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 2H), 4.77-4.73 (m, 1H), 1.75-1.67 (m, 1H), 1.50-1.46 (m, 2H), 0.92-0.90 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>>[CH3:15][O:14][C:12]([C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:1][C:24]([NH:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=1)=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:13]
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2cn1

Procedure:
Prepared from methyl 5-aminoisoquinoline-3-carboxylate (Description 107) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 404 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[C:32]([CH2:34]Cl)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[S:30][CH:31]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-thiazole (example 4 a]) in acetonitrile in the presence of cesium carbonate to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11]([CH2:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=1)([OH:13])=[O:12].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:22]([CH2:21][C:17]1[CH:16]=[C:15]([CH2:14][C:11]([OH:13])=[O:12])[CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: COc1ccccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNC(=O)Cc1cccc(CC(=O)O)c1
Yield: 31 %

Procedure:
Prepared from 2-methoxy-benzylamine (1.4 g), (3-carboxymethyl-phenyl)-acetic acid (2 g), 1-hydroxybenzotriazole (1.4 g), Hunigs base (1.8 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.0 g), using the method of Example 44 (step a), to give 990 mg of the sub-titled compound as a white solid.
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:12][NH2:13]>C(O)C>[CH:1]1([C:6]2[CH:7]=[C:8]([NH2:9])[NH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CCCC2)n[nH]1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
To a solution of 3-cyclopentyl-3-oxo-propionitrile (1.0 g, 7.3 mmol, 1 eq) in ethanol (10 mL) was added a 64 wt.-% solution of hydrazine hydrate (1.1 mL, 14.6 mmol, 2 eq). The mixture was heated at 80° C. for 16 h and was evaporated to dryness. The residue was purified by flash chromatography using dichloromethane and methanol (100/0 to 90/10) to afford 5-cyclopentyl-2H-pyrazol-3-ylamine as yellow oil (510 mg, 46% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26]O)=[CH:24][CH:23]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[N:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][C:25]3[C:20]([CH3:19])=[N:21][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[CH:23][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To an ice cold solution of (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (70 mg, 0.28 mmol), [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (76 mg, 0.28 mmol) and tributylphosphine (110 μl, 0.42 mmol) in tetrahydrofuran (4 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (73 mg, 0.42 mmol) under an argon atmosphere. The cooling bath was removed and stirring continued for 14 h. Filtration over celite and evaporation of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 105 mg (0.21 mmol, 75%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12]N=CC=1)=[O:7].[C:19]([C:21]1C=CC=CN=1)#[N:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:21]=[CH:19][N:20]=1)=[O:7]
Reactant: N#Cc1ccccn1
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Product: COc1ccc(C(=O)c2ccccn2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)pyridine was prepared analogously to 4-(3,4-dimethoxybenzoyl)pyridine using 2-cyanopyridine. The crude mixture was purified by flash column chromatography (silica gel, 1% methanol/methylene chloride) to afford after drying in vacuo (60° C., 1 mm) 1.67 g (34%) of the product: mp 91.5-93° C.; 1H NMR (CDCl3) δ 8.76-8.70 (m, 1H), 8.05-7.71 (m, 4H), 7.55-7.45 (m, 1H), 7.00-6.89 (m, 1H), 3.96 (s, 3H), 3.96 (s, 3H); 13C NMR (CDCl3) δ 192.1, 155.7, 153.3, 148.7, 148.2, 136.9, 128.9, 126.7, 125.7, 124.4, 112.6, 109.8, 56.0, 55.9; Anal. Calcd for C14H13NO3. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.96; H, 5.47; N, 5.66.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:19]1([C:25]#[C:26][C:27]([O:29]CC)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:26][C:27](=[O:29])[C:10]=2[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CCC(=Nc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(Cl)c(Cl)c2)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Reaction time: 96 h
Yield: 21.3 %

Procedure:
To 500 ml of toluene were added 6.2 g (0.022 mole) of 1-(3,4-dichlorophenyl)-N-phenylpropaneimine and 3.9 g (0.022 mole) of ethyl phenylpropiolate, followed by addition of 3.6 g (0.023 mole) of aluminum chloride. After heating the reaction mixture with stirring at 60°-70° C. for 4 days under a nitrogen atmosphere, the reaction mixture was poured into 400 ml of 2N sulfuric acid which had been ice-cooled, followed by extraction with dichloromethane. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). The resulting crystals were recrystallized from a 2:1 mixed solvent of acetone and hexane to afford 1.9 g of 2-(3,4-dichlorophenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone having a melting point of 188°-191° C.
Reaction SMILES: O[C:2]1([C:12]2[C:20]([OH:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([SiH](CC)CC)C.CCCCCCC>COC(C)(C)C>[OH:21][C:20]1[C:12]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])=[CH:13][C:14]2[O:18][CH2:17][O:16][C:15]=2[CH:19]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Product: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCO2
Temperature: 10.5 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A 1600 L reactor was charged with 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (113.1 kg, 396 mol), evacuated and filled with nitrogen. Trifluoroacetic acid (679 kg) was added in two portions over 20 minutes and the internal temperature was lowered to 10° C. over 1 h. Triethylsilane (69.2 kg, 595 mol) was added over 2 h 05 min at 10-11° C. and the mixture was stirred for a further 0.5 h at 10-11° C. A 1000 L reactor was charged with heptane (524 kg) and tert-butyl methyl ether (63 kg). The contents of the 1000 L reactor were transferred to the 1600 L reactor over 13 minutes at an internal temperature of 10-11° C. The resultant yellow-orange suspension was allowed to warm to 23° C. over 1 h. The solid was collected by filtration, washed with heptane (464 kg) followed by tert-butyl methyl ether (57 kg) and dried at 50° C. under a reduced pressure of 58 to 7 mbar over a period of 25 h to afford 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (82.8 kg, 75%) as an off-white solid: purity (HPLC-UV at 300 nm) 98.0% a/a; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.25 (s, 1H), 7.17-7.10 (m, 1H), 6.95-6.81 (m, 3H), 6.55 (s, 1H), 6.43 (s, 1H), 5.92-5.85 (m, 2H), 4.66 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.9, 150.1, 146.6, 142.7, 139.6, 130.9, 127.4, 123.8, 121.2, 115.9, 109.5, 109.0, 100.7, 97.8, 55.0.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27](=[O:48])[C:28]1[CH:33]=[C:32]([C:34]#[C:35][Si](C)(C)C)[CH:31]=[CH:30][C:29]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CCOCC>[CH2:19]([O:26][C:27](=[O:48])[C:28]1[CH:33]=[C:32]([C:34]#[CH:35])[CH:31]=[CH:30][C:29]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Tetra-butyl ammonium fluoride (2.97 mL of a 1 M solution in THF, 2.97 mmol) was added to a solution of 2-benzyloxy-5-(2-trimethylsilyl-ethynyl)-benzoic acid benzyl ester (1.07 g, 2.58 mmol) in THF (10 mL) at room temperature. After 30 minutes, the mixture was diluted with ether (20 mL) and washed with water (3×30 mL) and brine (1×30 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes) to afford 687 mg (78%) product as a light orange oil. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H, J=2 Hz); 7.52 (dd, 1H, J=9.1, 1 Hz); 7.38 (m, 10H); 6.95 (d, 1H, J=9.1 Hz); 5.35 (s, 2H); 5.19 (s, 2H); 3.0 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([CH2:19][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][NH:6][C:7]3=[O:12])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: O=C1NCCc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a mixture of 2.4 g (14.7 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone and 2.5 g of cesium carbonate in 30 ml of ethanol was added 2.5 g (15.0 mmol) of benzyl bromide. The mixture was stirred for 18 hours at room temperature. Then an additional 2.5 g of cesium carbonate and 2.5 g of benzyl bromide was added and the mixture was heated under reflux conditions for four hours. The reaction was partitioned between water and ether, the ether layer was filtered (to remove solid), dried (MgSO4), and concentrated. The residue was dissolved in hexane, filtered, concentrated, and the residue was crystallized from ethanol to give 3.01 g (81%) of the desired product; mp 171°-173°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[OH-].[K+].Cl>O>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCc2ccccc2)cc1

Procedure:
A mixture of 6.0 g. of ethyl p-benzylaminobenzoate (prepared as described in Example 9), 100 ml. of ethanol-water (9:1) and 6.0 g. of potassium hydroxide are refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water, chilled, filtered and the solid washed with water to give pale cream crystals, m.p. 165°-168° C. Recrystallization from ethanol gives tan crystals, m.p. 167°-169° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[S:16][C:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[S:16][C:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)s2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)s2)n1
Yield: 85.6 %

Procedure:
The title compound was prepared from 11f (6.8 mg, 0.016 mmol) following general procedure A. Flash chromatography (SiO2, 0.5×6 cm, 0-2% AcOH-EtOAc) afforded the title compound (5.4 mg, 86%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 10.51 (s, 1H(—OH)), 8.46 (s, 1H), 8.23 (dd, 1H, J=0.9, 7.6 Hz), 8.07 (t, 1H, J=7.8 Hz), 8.00 (dd, 1H, J=0.9, 7.9 Hz), 7.27 (m, 2H), 7.17 (m, 3H), 3.16 (t, 2H, J=7.4 Hz), 2.61 (t, 2H, J=7.7 Hz), 1.79 (m, 2H), 1.65 (m, 2H), 1.42 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 194.3, 175.8, 168.6, 149.0, 146.7, 144.1, 142.8, 142.6, 139.9, 128.5, 128.4, 125.8, 124.7, 123.8, 38.4, 36.0, 31.4, 29.23, 29.17, 24.1; HRMS-ESI-TOF m/z 395.1436 ([M+H]+, C22H22N2O3S requires 395.1424). 1,3,4-Thiadiazoles (5a-5c, 12a-12, 25):
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]2[O:10][C:11](=[O:13])[N:12]=[C:8]2[CH:7]=[C:6]([N:14]2[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]2)[N:5]=1.[CH3:20][O:21][C:22](N1C2C=CC=CC=2N=C1)=[O:23].C(O)(=O)C>CN(C)C=O>[N:14]1([C:6]2[N:5]=[C:4]([NH:3][C:22]([O:21][CH3:20])=[O:23])[N:9]3[O:10][C:11](=[O:13])[N:12]=[C:8]3[CH:7]=2)[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]1
Reactant: Nc1nc(N2CC=CCC2)cc2nc(=O)on12
Reactant: COC(=O)n1cnc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc(N2CC=CCC2)cc2nc(=O)on12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.2 g of sodium hydride are added portionwise to a solution, cooled to 15°, of 4.66 g of 5-amino-7-[3,6-dihydro-1(2H)-pyridyl]-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidin-2-one in 200 ml of dimethylformamide. The mixture is stirred vigorously at room temperature for 30 minutes. Thereafter, 5.28 g of 1-methoxycarbonylbenzimidazole in 50 ml of dimethylformamide are added thereto. After 2 hours, the mixture is treated with ice-cold water and adjusted to pH 5 with glacial acetic acid. The precipitate which results is recrystallized from methylene chloride/methanol, and there is obtained methyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, m.p. 212°-214°
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc2c(c1)CCCC2
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-2-naphthol (2.50 g, 16.9 mmol) in DMF (5 mL), is added dropswise NBS (3.0 g, 16.9 mmol). The solution is stirred at room temperature for 18 h. The mixture is washed with water, extracted with CH2Cl2, dried over MgSO4 and concentrated. The crude material is purified via Biotage, eluting with 5-40% EtOAc/hexanes to afford 1-bromo-5,6,7,8-tetrahydronaphthalen-2-ol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:23])[NH:21][C:20]([NH2:22])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][C:17]1([CH3:23])[CH2:18][N:19]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:22]=[C:20]2[NH:21]1
Reactant: CC1(C)CN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)Cn2c(nc(-c3ccncn3)cc2=O)N1

Procedure:
A mixture containing 2.09 (10.3 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, 2.0 g (10.3 mmol) of 5,5-dimethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide and 2.85 g (20.6 mmol) of potassium carbonate in 15 ml of methanol were heated at reflux temperature during 18 h.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Br:12]Br.O>C(Cl)(Cl)Cl>[Br:12][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
2-trichloroacetyl pyrrole 6 (5.00 g, 23.3 mmol) was dissolved in anhydrous chloroform (20 mL). The solution was cooled to −10° C. before the drop-wise addition of bromine (1.20 mL, 23.3 mmol) to the flask. Once addition was complete the reaction was allowed to warm to room temperature on its own accord while stirring for an additional 30 minutes. The reaction was poured into water (40 mL) and extracted with chloroform (3×20 mL). The combined organic layers were washed with sat. NaHCO3 (2×30 mL), brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification of the residue by column chromatography (Hexanes/Diethyl Ether 95:5) yielded the title compound 7 (6.37 g, 93%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.54 (s, 1H), 7.32 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 171.67, 129.06, 122.01, 121.54, 97.60, 94.56; HRMS (FAB) calcd for C6H3BrCl3NO (M+) 288.8464, found 288.8479.