Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH3:25][OH:26]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([O:26][CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reactant: CO
Product: COC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 5 mL of methanol. The reaction vessel was sealed and then subjected to microwave irradiation for 15 minutes at 125° C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (16 mg, 0.043, 43%). ESI-MS m/z calc. 372.1, found 373.2 (M+1)+ Retention time 3.43 minutes. 1H NMR (400 MHz, CD3CN) δ 3.42 (s, 3H), 4.23 (s, 2H), 4.94 (s, 1H), 7.21-7.53 (m, 10H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CC(N(C)C)=O.CO>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([N:35]3[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]3)[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN(C)C1CCN(c2nc(-c3cc(Cl)ccc3OC(F)F)c(NC(=O)c3cnn4cccnc34)s2)CC1
Temperature: 160 °C
Yield: 39.2 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (100 mg, 0.2 mmol) and 4-dimethylaminopiperidine (128 mg, 1 mmol) were dissolved in DMA (1 ml) and heated in a microwave at 160° C. for 1 hour. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by MDAP (Method 1). Appropriate fractions were combined and evaporated to afford a yellow solid. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a yellow-orange solid (43 mg, 39%). LCMS (Method 5) [M+H]+=548.1, RT=3.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.23 (s, 1H), 9.36 (dd, 1H, J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.63 (dd, 1H, J=1.6, 4.2 Hz), 7.66 (d, 1H, J=2.7 Hz), 7.59 (dd, 1H, J=2.6, 8.8 Hz), 7.41 (d, 1H, J=9.0 Hz), 7.31 (dd, 1H, J=4.2, 6.7 Hz), 7.18 (t, 1H, J=73.5 Hz), 3.93 (d, 2H, J=12.7 Hz), 3.02 (dd, 2H, J=10.3, 12.3 Hz), 3.05-2.95 (m, 1H), 2.40-2.26 (m, 6H), 1.92-1.89 (m, 2H), 1.58-1.47 (m, 2H).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.O>[CH:23]1([O:22][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[CH2:13][C:12]2[O:28][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=3[N:11]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(CC(=O)Nc2cccc([N+](=O)[O-])c2O)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(Cc2nc3cccc([N+](=O)[O-])c3o2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A solution of N-(2-hydroxy-3-nitrophenyl)-3-cyclopentyloxy-4-methoxyphenylacetamide (2.0 g) and pyridinium p-toluene-sulphonate (500 mg) in xylene (140 ml) was refluxed, under nitrogen, overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml), dried (CaSO4) and evaporated in-vacuo to yield an orange oil. The oil was purified by flash chromatography (SiO2 ;dichloromethane;ethanol;ammonia (50:1:0.1)) to yield the title compound (1.107 g, 58%) as an orange solid (top 95°-98.5° C.). δH (250 MHz;d6DMSO) 1.45-1.95 (8H,m,4×CH2), 3.70 (3H,s,OMe), 4.36 (2H, s,CH2), 4.74 (1H,m,CH), 6.89 (2H,bs,ArH), 7.02 (1H,bs,ArH), 7.56 (1H,t,ArH), 8.15 (1H,dd,ArH), 8.17 (1H,dd,ArH). m/z 368 (M+), 338 (M--NO), 300 (M--C5H8), 285, 270, 253, 149, 137, 123, 100.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([O:16][CH3:17])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](NC(=O)C1C=CC(N)=C(OC)C=1)(C)(C)C>>[C:1]([NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([O:16][CH3:17])[CH:8]=1)([CH2:4][CH3:19])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1N
Product: CCC(C)(C)NC(=O)c1ccc(N)c(OC)c1

Procedure:
In the same way, from the compound N-tert-butyl-3-methoxy-4-nitrobenzamide, N-tert-butyl-3-methoxy-4-aminobenzamide is prepared; M.p.=160° C.
Reaction SMILES: [H-].[Na+].[CH:3]([NH:5][CH2:6][C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])=[O:4].CI.Cl[CH2:20]Cl>CN(C=O)C>[CH:3]([NH:5][CH:6]([CH3:20])[C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])=[O:4]
Reactant: ClCCl
Reactant: O=CNCC(=O)c1ncn2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(NC=O)C(=O)c1ncn2ccsc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (31 mg) was added to a solution of 0.24 g of 7-formylaminoacetylimidazo[5,1-b]thiazole in 4 ml of DMF. The mixture was stirred at 60° C. for 30 min, and cooled to room temperature. Thereafter, 176 mg of methyl iodide was added thereto. The mixture was stirred for one hr. Dichloromethane was added to the reaction mixture. The mixture was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 0.12 g of 7-(2-formylaminopropionyl)imidazo[5,1-b]thiazole.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5].[H][H].O.N>[Pd].O1CCOCC1>[NH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:2]=[CH:19][CH:18]=[C:17]([NH2:20])[CH:16]=1)=[O:5]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 30 °C

Procedure:
In a closed glass vessel with a thermometer and a stirrer, there are charged 102.3 g (0.3 moles) of 2,4'-dichloro-5,3'-dinitro benzophenone, 5 g of 5% palladium/active carbon catalyst (from Nihon-Engelhardt Co.) and 300 ml of dioxane. At 70°-80° C., hydrogen is introduced into the vessel while the mixture being stirred, so that 42 l (1.88 moles) of hydrogen is absorbed in the mixture during ten hours. After being cooled to 30° C., the mixture is added with 55 g (0.9 moles) of 28% ammonia water and then introduced with hydrogen while being stirred at 30°-40° C. so as to absorb 13.2 l (0.59 moles) of hydrogen during 5 hours. The reaction mixture is subject to filtering at 30°-40° C. to remove the catalyst. On cooling, there is obtained 3,3'-diamino benzophenone as yellow crystals. The crystals are filtered, washed with 30 ml of 50% aqueous solution of dioxane and dried. Yield 56.5 g (89%). M.P. 149°-150.5° C. Recrystallization from ethanol gives yellow needle-like pure crystals of said benzophenone. M.P. 150°-151° C.
Reaction SMILES: [Na].CN(C)C=O.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].Cl.[CH2:18]([OH:22])[CH2:19][CH2:20][CH3:21]>[Cu]Cl>[CH2:18]([O:22][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCO
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: Cl[Cu]
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
2.16 g (93.9 mmol) of sodium are dissolved in 15 ml of n-butanol at 110° C. for 3 hours. 20 ml of dimethylformamide are added at ambient temperature and then the medium is degassed several times. 3.4 g (34.1 mmol) of copper(I) chloride are added at ambient temperature and then the reaction medium is stirred for 10 minutes. 6.2 g (31 mmol) of 3-bromo-4-hydroxybenzaldehyde are added and then the reaction medium is stirred at 120° C. for 2 hours. The reaction mixture is cooled to ambient temperature and then the reaction is halted by the addition of 50 ml of a 2M hydrochloric acid solution. The medium is extracted with 250 ml of ethyl acetate. The solvents are evaporated and then the residue is filtered through a silica gel patch (2 cm): eluent heptane/ethyl acetate 8/2. After evaporation of the solvents, 5.55 g of orange oil are obtained. This oil is crystallized from pentane. 4.8 g of 3-butoxy-4-hydroxybenzaldehyde are obtained in the form of a brown solid after filtration.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]([CH:23]=[CH2:24])=[O:22].C(N(CC)CC)C>C(O)C>[CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[N:12]([CH2:24][CH2:23][C:21](=[O:22])[CH3:20])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(C)=O
Reactant: CCCCn1c(=S)c2[nH]cnc2n(CCCC)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCn1c(=S)c2c(ncn2CCC(C)=O)n(CCCC)c1=O
Reaction time: 1 h

Procedure:
1,3-di-n-butyl-6-thioxanthine (8,3 g), methylvinylketone (2,9 ml) and triethylamine (1 ml) were dissolved in ethanol (10 ml) and the mixture was slowly heated with stirring at 40°-50° C. for one hour. After cooling of the clear solution, the 1,3-di-n-butyl-7-(3-oxobutyl)-6-thioxanthine precipitated in the form of yellow needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[N:17]([CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c3n2-c2ccccc2Cl)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (107 mg) was dissolved in N,N-dimethylformamide (2 ml), and methyl bromoacetate (0.025 ml) and potassium carbonate (50 mg) were added to the solution. Then, the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic layer was concentrated to give 139 mg of the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)=[O:37])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), N-(tert-butoxycarbonyl)glycylglycine (0.232 g, 1.0 mmol), N,N-dicylohexylcarbodiimide (0.206 g, 1.0 mmol) and DMAP (0.122 g, 1.0 mmol) in 10 mL of CH2Cl2 was stirred overnight at ambient temperature. The reaction mixture was diluted with CH2Cl2 and filtered through a plug of silica gel. The gel was rinsed with additional CH2Cl2. The combined filtrates were concentrated in vacuo to give 0.35 g to the title compound as a white solid, mp 103–104° C.;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:11])[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1cnccc1C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1ccncc1CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
A solution of 0.6 g (3.4. mmoles) of (4-trifluoromethylpyridin-3-yl)-methanol dissolved in 50 ml of diethyl ether was cooed to −30° C. Thereto was added 1.4 g (5.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 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, to obtain 0.61 g (yield: 75.3%) of 3-bromomethyl-4-trifluoromethylpyridine as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-])=O)[C:11]=2[N:10]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:9]1=[O:27])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[Pd]>[NH2:17][C:16]1[C:11]2[N:10]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:9](=[O:27])[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CCCn1c(=O)n(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCCn1c(=O)n(CC(=O)OC(C)(C)C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
A mixture of methyl 4-[3-(2-tert-butoxy-2-oxoethyl)-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate from Step B (129 mg, 0.33 mmol) and 10% Pd/C (40 mg) in EtOH (30 mL) and EtOAc (15 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 1 h, the reaction was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: 71/z=364 (M+1).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])=O>>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[Cl:1]
Reactant: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Reactant: [Cl-]
Agent: [Al+3]
Product: Cc1cc(C)c(Cl)c(C)c1
Temperature: 180 °C
Yield: 72 %

Procedure:
0.5 g of anhydrous aluminium chloride was added to 50 g of 2,4,6-trimethylphenyl chloroformate and the mixture was heated at 180° C. for 1.5 hours at normal pressure. The reaction mixture was then cooled and worked up as described in Example 1. 2,4,6-Trimethylchlorobenzene was obtained in a yield of 72%.
Reaction SMILES: [OH:1][CH:2]([CH3:40])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH3:40])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:41]2[CH:45]=[CH:44][N:43]=[CH:42]2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1c(OCCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCCCn2ccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of trans-2-[-3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(4-bromobutoxy)phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (64 mg, 0.10 mmol)(Example 19C), imidazole (27 mg, 0.40 mmol) and potassium carbonate (55 mg, 0.40 mmol) in acetone (3 mL) was heated with stirring at 60° C. under nitrogen for 24 h. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried, and evaporated to a residue. Purification by preparative TLC (CH2Cl2 -MeOH; 92.8, v/v) gave the title compound: Rf 0.5; MS, m/z 632 M+. ; NMR (CDCl3) δ 1.28 (bd, CH2CHOHCH3), 6.94 & 7.08 (bs, NCH=CHN).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2.[H-].[Na+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:25][CH:27]1[O:29][CH2:28]1)[CH:9]=2
Reactant: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1OC
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc1OC

Procedure:
Reaction of 3′,4′-dimethoxy-7-hydroxy-flavone, 27 (6 g, 20 mol), 50% sodium hydride (2.4 g, 100 mmol) and epichlorohydrin (3.9 mL, 50 mmol) in dry dimethyl formamide (200 mL) using identical procedure as described for 28 furnished 33. Yield 5.3 g (74%); mp 148-149° C.; MS (FAB) 355 (M++1); IR (KBr) 1632; 1H NMR (200 MHz, CDCl3) δ 8.13 (d, J=9.5 Hz, 1H), 7.73 (dd, J=8.5 Hz, 2.0 Hz, 1H), 7.35 (d, J=1.9 Hz, 1H), 7.00 (dd, J=7.1 Hz, 2.3 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.68 (s, 1H), 4.39 (dd, J=11.1 Hz, 2.9 Hz, 1H), 4.05 (dd, J=11.1 Hz, 5.8 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.44-3.40 (m, 1H), 2.96 (t, J=4.5 Hz, 4.5 Hz, 1H), 2.81 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>O1CCCC1>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:19](=[O:22])[CH:20]=[CH2:21])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(F)ccc1N
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCc1cc(F)ccc1NC(=O)C=C
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A round-bottom flask containing the product from Step 1 (10.6 g, 70.1 mmol) was fitted with a stirbar and septa. Tetrahydrofuran (200 mL) and triethylamine (15.0 mL, 108 mmol) were added, giving a solution that was cooled to −10° C. Acryloyl chloride (6.0 mL, 73.6 mmol) was then added, and the resulting mixture was allowed to gradually warm to room temperature. After 16 hours, the reaction was concentrated to remove most of the tetrahydrofuran, then diluted with ethyl acetate (200 mL) and washed with 1:1 H2O:saturated aqueous NaCl solution (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give an oil which was purified via flash chromatography on silica gel (15% to 40% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[NH:7][C:8](=[O:30])[C:9]2[C:10]3[N:19]([CH3:20])[C:18]([NH:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17][C:11]=3[CH:12]=[CH:13][C:14]=2[C:15]=1[CH3:16]>CCO.CC(O)=O.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[NH:7][C:8](=[O:30])[C:9]2[C:10]3[N:19]([CH3:20])[C:18]([NH:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17][C:11]=3[CH:12]=[CH:13][C:14]=2[C:15]=1[CH3:16]
Reactant: COC(=O)C=Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CCc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
To a solution of the product of Example 12 (30 mg, 0.06 mmol) in EtOH (3 mL) and AcOH (4 mL) in a Parr reactor was added PtO2 (2 mg, 0.007 mmol). The Parr reactor was charged with 50 psi of H2 and shaken for 12 h. The crude reaction was filtered through diatomaceous earth with EtOH and concentrated in vacuo. Column chromatography (2% MeOH—CH2Cl2) provided the title compound (9 mg, 30%), mp 268° C.(dec); MS(ES) 459, 461 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:42])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=3[C:30]([O:32][CH3:33])=[O:31])=[O:25])=[CH:22][C:21]([C:38]([F:41])([F:40])[F:39])=[N:20]2)[CH:15]=1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:42])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=3[C:30]([O:32][CH3:33])=[O:31])=[O:25])=[CH:22][C:21]([C:38]([F:39])([F:41])[F:40])=[N:20]2)[CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)N)c1
Yield: 99 %

Procedure:
Compound 15f (108 mg, 0.177 mmol) was shaken in a solution of DCM (0.7 mL) and TFA (0.3 mL) for 1 hour. The reaction was then diluted with DCM and concentrated under reduced pressure. More DCM was added to the residue and then removed again by reduced pressure. The residue was then dissolved in ethyl acetate and washed with saturated NaHCO3 (3×). The aqueous phases were combined and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give the compound 9 h (89.3 mg, 99% yield) as a white crust. 1H NMR (CD3OD) δ(ppm): 7.97 (d, J=8.0 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 7.46-7.44 (m, 2H), 7.41 (t, J=7.6 Hz, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 4.82 (s, 2H), 4.51 (d, J=15.6 Hz, 1H), 4.98 (d, J=15.6 Hz, 1H), 3.89 (s, 3H), 3.42 (q, 1H), 1.27 (d, J=6.8 Hz, 3H). LRMS (ESI): calc 509.1; found 510.1 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.[C:18](#[N:20])C>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:18]#[N:20])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1
Reactant: CC#N
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Product: N#Cc1ccc2[nH]c(-c3cccnc3)c(C#N)c2c1

Procedure:
2-Pyridin-3-yl-1H-indole-5-carbonitrile (Example 8) is processed according to the method described in Example 140, using acetonitrile instead of dichloromethane, to give 2-pyridin-3-yl-1H-indole-3,5-dicarbonitrile. 1H NMR (400 MHz, MeOD) δ ppm 7.68 (dd, J=8.6 Hz, 1H), 7.72 (dd, J=8.1, 4.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 8.47 (dt, J=8.1, 1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 9.19 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 245.0823 [(M+H)+calcd for C15H9N4: 245.0827].