Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43](O)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30].[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1>C(Cl)Cl>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51]2)[C:43]([NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1S(C)(=O)=O
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (105 mg, 0.59 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 79, 200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (110 mg, 1.18 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (117 mg, 49%) as a pale yellow foam: mp 107-110° C.; EI-HRMS m/e calcd for C21H26N2O5S2 (M+) 450.1283, found 450.1282.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=3)[CH:7]=[CH:8]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: FC(F)(F)c1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-(trifluoromethyl)-1H-indole and iodobenzene: ESMS m/e: 262.0 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[NH:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: OCC1CCN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: OCC1CCNCCN1
Yield: 100.1 %

Procedure:
To a solution of (1,4-dibenzyl-1,4-diazepan-5-yl)methanol (500 mg) (prepared as described in Chin. Chem. Lett., 2001, 12, 951) in methanol (10 mL) was added 5% wt. palladium on charcoal (171 mg) and the mixture stirred under a 5 bar hydrogen atmosphere for 16 hours. The reaction mixture was filtered through celite and the liquors concentrated to dryness to give the sub-title compound (210 mg) as a colourless oil.
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:12]([CH2:24][CH3:25])([CH2:22][CH3:23])[O:11]1)(=O)C(C)(C)C.C(OCC[C@H]1[C@H](CC2C=CC=CC=2)OC(CC)(CC)O1)(=O)C(C)(C)C>>[CH2:15]([C@H:14]1[O:13][C:12]([CH2:22][CH3:23])([CH2:24][CH3:25])[O:11][C@@H:10]1[CH2:9][CH2:8][OH:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC1(CC)O[C@H](CCOC(=O)C(C)(C)C)[C@@H](Cc2ccccc2)O1
Agent: CCC1(CC)O[C@@H](CCOC(=O)C(C)(C)C)[C@H](Cc2ccccc2)O1
Product: CCC1(CC)O[C@H](CCO)[C@@H](Cc2ccccc2)O1
Yield: 80 %

Procedure:
The substantially same method as described in Example 247 was conducted, except that (2-((4R,5R)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 249) was used instead of (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 246), to obtain the title compound (0.9 g, 80˜95%)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.4 %

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 44) (350 mg, 1.04 mmol) was treated with trifluoroacetic acid (3 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. The solvent was removed under reduced pressure and the residue azeotroped from toluene then dichioromethane to afford the title compound (185 mg).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1.[N:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]=[N:10][C:11]([N:18]3[CH2:19][CH2:20][N:15]([C:21](=[O:22])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:30])[F:31])[CH2:16][CH2:17]3)=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid cyclopropylmethylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (31% yield). 1H NMR (500 MHz, CDCl3) δ 8.16-7.88, 7.75, 7.68-7.46, 7.18, 7.00, 4.17-3.64, 3.21-3.12, 1.07-1.00, 0.61-0.44, 0.26-0.20.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[N:11](OCCC(C)C)=O>O1CCOCC1>[Cl:1][C:2]1[C:3]2[NH:10][N:11]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(N)c(Cl)n1
Reactant: CC(C)CCON=O
Solvent: C1COCCO1
Product: Nc1nc(Cl)c2[nH]nnc2n1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A solution of 6-chloro-2,4,5-pyrimidinetriamine (10.94 g, 0.0686 mol) and isoamyl nitrite (9.20 ml, 0.0686 mol)in dioxane (500 ml, freshly purified by passage through basic alumina) was heated under nitrogen with stirring for 2 hours at 90°. The reaction mixture was cooled, treated with activated carbon, filtered, and concentrated to 150 ml. Petroleum ether (250 ml, bp 35-60°) was added. The precipitate was filtered, washed the petroleum ether (50 ml) and dried in vacuo over P2O5 at 40° for 16 hours to give 9.23 g of crude desired product which was then used in the next step.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl[CH2:16][C:17]([O:19]CC)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]([OH:19])=[O:18])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)O)ccc(C(C)=O)c1O

Procedure:
A mixture of 24.25 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 16.0 ml of ethyl chloroacetate and 26 g of anhydrous potassium carbonate in 375 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was crystallized from ethanol to give 27.2 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid, the titled compound, mp 61°-64°, (78% yield) in two crops.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)#[N:4].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15](F)[N:14]=1>CN(C)C=O>[N:14]1[C:15]([O:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]#[N:4])=[CH:16][CH:17]=[CH:18][C:13]=1[O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]#[N:4]
Reactant: N#Cc1cccc(O)c1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2cccc(Oc3cccc(C#N)c3)n2)c1
Temperature: 100 °C

Procedure:
To sodium hydride (0.38 g, 9.5 mmol) in N,N-dimethylformamide (3 mL) was added 3-cyanophenol (1.1 g, 8.9 mmol) and 2,6-difluoropyridine (0.4 mL, 4.4 mmol). After heating in an oil bath at 100° C. for 15 hours the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica gel (50 g) with methylene chloride/hexane (3/1) to give 3,3′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile). Recrystallization from ethyl acetate/hexane gave pure 3,3′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl3) 7.79 (t,1), 7.45 (m,4), 7.32 (m,4), 6.72 (d,2) ppm.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:19])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>[Cl-].[Na+].C(O)C.O1CCCC1>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][S:19][C:10]2[CH2:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:28][CH2:29]1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CN1CCN(CCCl)CC1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(CCSC2=Nc3ccc(Cl)cc3C(c3ccccc3)=NC2)CC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
To a solution of 5.7 g of 1,3-dihydro-5-phenyl-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 57 ml of a 10% aqueous potassium hydroxide solution and 6 ml of tetrahydrofuran is added at room temperature with stirring 7.0 g of 1-chloro-2-(4-methyl-1-piperazinyl)ethane dihydrochloride, and the resulting mixture is stirred at 40° C. for 4 hours. The reaction mixture is diluted with an aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure. An oily product obtained as the residue is dissolved in ethyl alcohol and added with 3.8 g of fumaric acid, and the solvent is distilled off under reduced pressure to obtain a crystalline product. Recrystallization from tetrahydrofuran to obtain 5.4 g of 2-[2-(4-methyl-1-piperazinyl)ethylthio]-5-phenyl-7-chloro-3H-1,4-benzodiazepine difumarate, m.p. 193°-194° C. (decomposition), yield 42%.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-2].[Ca+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ca+2]
Product: Cc1ccc(-c2ccccc2)cc1

Procedure:
3.56 g (20 mmol) of sodium p-toluenesulfinate, 3.14 g (20 mmol) of bromobenzene, 0.0225 g (0.1 mmol) of palladium acetate, 0.0478 g (0.12 mmol) of 1,2-bis(diphenylphosphino)-ethane, 11.2 g (200 mmol) of calcium oxide and 60 ml of each solvent indicated in Table 1 were placed in a 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 6 hours, respectively. After the completion of the reaction, the amount of 4-methyl-biphenyl formed was analyzed by means of high performance liquid chromatography. The results are shown in Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O-:27])=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][N+:14]([O-:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C(N(C)C)=N.[CH2:43]=[O:44]>C(#N)C.C([O-])(O)=O.[Na+]>[C:31]([O:30][C:28]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]([N+:14]([O-:16])=[O:15])[CH2:43][OH:44])[C:25]([O:27][CH2:12][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:26])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)[O-]
Reactant: C=O
Agent: CN(C)C(=N)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(CO)[N+](=O)[O-])C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5S)—N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate (2.30 g, 3.975 mmol) and 1,1,3,3-tetramethylguanidine (46 mg, 0.40 mmol) in acetonitrile (20 mL) was added formaldehyde (0.15 mL, 37% aqueous solution). After stirring for 60 min, more formaldehyde (0.050 mL, 37% aqueous solution) was added. After stirring for an additional 60 min the mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (25%→75% ethyl acetate/hexanes) to give the title compound (1.44 g). MS 409.1 (M+1-2Boc).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33]>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH:15]=[CH2:16]
Reactant: C=CC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@H](Oc1cccc(Cl)c1C)[C@H]1CCNC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (31 mg, 130 μmmol) was dissolved in DMF (470 μL, 6.1 mmol). 60% Sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 10.1 mg, 169 μmmol) was carefully added, and the mixture allowed to stand for 15 minutes. 2-Chloro-6-fluorotoluene (47.0 μL, 390 μmmol) was added. The mixture was stirred at 70° C. for 3 hours. The reaction was quenched with MeOH, and the solvent was removed. 1.2M HCl in EtOH (630 μL, 760 μmmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1 mg, 100% purity). MS m/z: [M+H]+ calcd for C15H20ClNO, 266.12; found 266.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].[CH3:17][O:18][CH2:19][C:20]([NH:22][NH2:23])=O.C[O-].[Na+]>C(OCCO)C>[CH3:17][O:18][CH2:19][C:20]1[N:2]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=3)[CH:8]=2)[NH:23][N:22]=1
Reactant: CCOC(=O)c1cnc2ccc(C#N)cn12
Reactant: COCC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCCO
Product: COCc1n[nH]c(-c2ccc3ncc(C(=O)O)n3c2)n1
Temperature: 110 °C

Procedure:
To a solution of ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (24q) (265 mg, 1.23 mmol) and 2-methoxyacetohydrazide (193 mg, 1.85 mmol) in 2-ethoxyethanol (5 mL) was added NaOMe (0.5 M in MeOH, 3.7 mL). The mixture was heated at 110° C. in a sealed vial overnight. The reaction mixture was purified by HPLC to give 6-(3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (99). MS m/z 274.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[Na+].[Na+].N#N>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CO>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:16]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)c2ccccc12
Reactant: COC(=O)c1cccc(C(=O)OC)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccc(C(=O)OC)c1-c1ccc(C)c2ccccc12

Procedure:
35 g (148 mmol) of 4-methylnaphthaleneboronic acid, 33.8 g (124 mmol) of dimethyl 2-bromoisophthalate and 220 ml of 2 M Na2CO3 solution are suspended in 1 l of toluene and 1 l of EtOH, the mixture is saturated with N2, 2.9 g (3 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is heated at the boil for 2 h. The mixture is poured into 3 l of a mixture of water/MeOH/6 M HCl 1:1:1, the beige precipitate is filtered off with suction, washed with water, EtOH and toluene and dried. The content of product according to 1H-NMR is about 95% with an overall yield of 37 g (90%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[Cl:9][C:10]1[NH:18][C:17]2[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][CH2:23]/[C:24](=[N:27]/[H])/[NH:25]O)[C:14](=[O:29])[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:12]=2[N:11]=1>CN1C(=O)CCC1>[Cl:9][C:10]1[NH:18][C:17]2[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[N:25]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[O:8][N:27]=3)[C:14](=[O:29])[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:12]=2[N:11]=1
Reactant: O=C(O)c1cccs1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCCC)c1=O)NO
Solvent: CN1CCCC1=O
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3cccs3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
2-Thiophenecarboxylic acid (14 mg, 0.11 mmol) was dissolved in NMP (0.9 ml) and treated with CDl (18 mg, 0.11 mmol). After 1 h, (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) was added and the mixture heated in the microwave at 150° C. for 15 min. The solution was directly purified by MDAP to obtain the title compound which was then freeze dried from 1,4-dioxane to give the title compound as a white solid (19 mg, 31%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C1(P(C(C)(C)C)C(C)(C)C)C=CC=CC=1.[C:22]([C:24]1[CH:25]=[C:26](Cl)[CH:27]=[CH:28][C:29]=1[C:30]([F:33])([F:32])[F:31])#[N:23].C1(C(N)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[C:22]([C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[C:30]([F:31])([F:32])[F:33])[CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])#[N:23]
Reactant: N#Cc1cc(Cl)ccc1C(F)(F)F
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C=Cc1ccc(C(F)(F)F)c(C#N)c1
Reaction time: 4 h

Procedure:
0.619 g (7.2 mmol) of methyl acrylate, 38.7 mg (120 μmol) of NBu4Br, 6.7 mg (30 μmol) of palladium acetate and 26.7 mg (120 μmol) of phenyldi(t-butyl)phosphine are weighed into a Schlenk vessel. 1.23 g (6 mmol) of 3-cyano-4-trifluoromethylchlorobenzene and 1.53 ml (7.2 mmol) of dicylohexylmethylamine and also 3.5 ml of dimethylacetamide are then added. The Schlenk vessel is placed in a heating bath at 130° C. and the contents are stirred. After 4 hours, the contents are poured into 30 ml of water and the product is extracted by shaking with t-butyl methyl ether. After drying the organic phase over MgSO4, the solvent is removed under reduced pressure and the product is isolated. Yellowish, crystalline solid, yield: 1.31 g (85.5% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:20][C:21]2[C:22]([CH3:37])=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c2c1CCCC2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 103 mg (0.41 mmol) of the above prepared 3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, 118 mg (0.41 mmol) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 4G]) and 175 mg (0.54 mmol) of cesium carbonate in 5 ml of acetonitrile was stirred at 60° C. for 2 hours. Then, the solvent was evaporated i. V. and the residue was chromatographed on SiO2 with a mixture of dichloromethane and tert.-butyl methyl ether (98:2, vol./vol.) as eluent. Thereby, 169 mg of the title compound was obtained as off white solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:11]([NH:23][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 82.8 %

Procedure:
Benzenesulfonyl chloride (353 g, 2 mol) was added dropwise to a toluene (2000 mL) solution of dodecylamine (371 g, 2 mol) and triethylamine (203 g, 2 mol) with ice bath cooling. During the one hour addition period, the temperature increased to about 40° C. After filtration of the triethylamine hydrochloride, the toluene solution was washed with dilute HCl, dilute NaOH and water. After drying over magnesium sulfate, the toluene was removed in vacuo and the precipitate slurried in hexane and filtered to give 539 g of product. Melting point 57-60° C. Calculated for C18H32NO2S 326, found 326. 1H NMR (CDCl3) δ0.88 (t, 3, CH3), 1.24 (d, 18, CH2), 1.45 (s, 2, CH2), 4.66 (sb, 1, NH), 7.49-7.84 (m, 5, arom.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[O:5][C:6]=1[CH3:7].C([O-])(=O)C.[NH4+:20]>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:20][C:6]=1[CH3:7]
Reactant: [NH4+]
Reactant: Cc1cc(C(=O)c2ccccc2)oc1C
Agent: CC(=O)[O-]
Product: Cc1cc(O)c(-c2ccccc2)nc1C
Temperature: 250 °C
Reaction time: 10 h
Yield: 16079.1 %

Procedure:
(4,5-Dimethylfuran-2-yl)-phenyl-methanone (1 g) and ammonium acetate (910 mg) were placed in a sealed tube, and the mixture was stirred at 250° C. for 10 hr. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6-dimethyl-2-phenyl-pyridin-3-ol (160 g, yield 16%).