Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]([O:27]CC)=[O:26])[N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>C(O)C.C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]([OH:27])=[O:26])[N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(=O)OCC)c2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(=O)O)c2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 2-(5-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-1H-indazol-1-yl)acetate (Intermediate 39, 106 mg; 0.24 mmol) in ethanol (10 ml) was treated with 10% NaOH solution (5 ml). After stirring at RT for 2 hours the solvent was reduced in vacuo to one quarter of its original volume and water (20 ml) added. The mixture was acidified with dilute HCl and DCM (50 ml) added. After stirring at RT for 30 minutes the mixture was filtered through a hydrophobic frit and the solvent removed in vacuo. The solid formed was washed with water and dried to give the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1.CCN(CC)CC.[NH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:41]([O:40][C:39]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[NH:32][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1)=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (165.0 mg, 0.451 mmol), Et3N (0.15 mL, 1.076 mmol), and tert-butyl (1S,2R)-2-aminocyclopentylcarbamate (142.0 mg, 0.709 mmol) in DMF (6 mL) was stirred at 60° C. for 12 h. Saturated aq NaHCO3 (20 mL) was added to the mixture, which was subsequently extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered (DM1020). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc=1/1) and then triturated with IPE to provide the title compound (147 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:19][C:20]([CH3:24])=[CH:21][CH2:22]Br.[H-].[Na+]>C1COCC1>[CH3:19][C:20]([CH3:24])=[CH:21][CH2:22][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCn1c(-c2c(F)cccc2F)nc2c(C)cccc21
Reaction time: 4 h
Yield: 62.4 %

Procedure:
To 2-(2,6-difluorophenyl)-4-methylbenzimidazole (Example 13) (0.50 g, 2.05 mmol) and 3,3-dimethylallyl bromide (0.50 mL, 4.34 mmol, 210 M %) dissolved in THF (10 mL) was added NaH (60% dispersion in mineral oil) (0.17 g, 4.25 mmol, 200 M %). After 4 h, the reaction was quenched with MeOH and concentrated. The residue was redissolved in dichloromethane, washed with water and NaCl (sat. aq.), dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallized from hexane to yield white powders of 1-(3,3-dimethylallyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (0.40 g, 1.28 mmol, 63% yield). M.p. 78-79° C. 1H-NMR (200 MHz, CD2Cl2): 7.52 (m, 1H, H4″), 7.26-7.02 (m, 5H, H5,6,7,3″,5″), 5.18 (t, J=6.8 Hz, 1H, H2′), 4.62 (d, J=6.8 Hz, 2H, H1′), 2.64 (s, 3H, CH3), 1.64 (s, 3H, CH3), 1.57 (s, 3H, CH3).
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.[C:25]([NH:28][C:29]1[CH:34]=[CH:33][N:32]([CH2:35][C@@H:36]([C@H:39]([OH:41])[CH3:40])[CH2:37][OH:38])[C:31](=[O:42])[N:30]=1)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:7][O:6][C:5]1[CH:8]=[CH:9][C:2]([C:1]([C:10]2[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:38][CH2:37][C@@H:36]([CH2:35][N:32]2[CH:33]=[CH:34][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[N:30][C:31]2=[O:42])[C@H:39]([OH:41])[CH3:40])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(=O)Nc1ccn(C[C@H](CO)[C@@H](C)O)c(=O)n1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
DMTCl (0.9 g, 2.66 mmol) was added to a stirred solution of 21 (0.6 g, 2.35 mmol) in 25 ml of anhydrous pyridine. After being stirred at room temperature for 4 hrs the reaction was quenched with MeOH (2 ml) and concentrated to an oil. The oil was partition between dichloromethane and 10% citric acid. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The resulting material was chromatographed on silica eluting with a gradient of methanol (5-7.5%) in ethyl acetate. Concentration of the pure product fractions afforded 1.2 g (91%) of 22 as a white amorphous solid. 1H NMR (DMSO-d6): δ 10.78 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.27 (m, 5H), 6.97 (d, J=7.2 Hz, 1H), 6.84 (m, 4H), 4.66 (d, J=4.8 Hz, 1H), 4.01 (m, 1H), 3.78 (m, 2H), 3.73 (s, 6H), 3.73 (m, 1H), 3.09 (m, 2.89 (m, 1H), 2.12 (m, 1H), 2.09 (s, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[NH:9][C:10]([C:12]3[C:16]([NH:17][C:18](=[O:27])[C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])=[CH:15][NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].O.Cl>[OH-].[Na+].CO>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:18]([NH:17][C:16]1[C:12]([C:10]2[NH:9][C:8]3[CH:28]=[CH:29][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[N:13][NH:14][CH:15]=1)=[O:27]
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.2 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid methyl ester (12.0 mg, 0.03 mmol) in 2 M aqueous NaOH/MeOH (1:1, 4 ml) was stirred at ambient temperature for 14 h. The mixture was reduced in vacuo, water (5 ml) added and the mixture taken to pH 4 using 1 M aqueous HCl. The precipitate formed was collected by filtration and dried under vacuum to give 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid as a pale coloured solid (6 mg, 52%). (LC/MS: Rt 2.88, [M+H]+ 383.97).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]([OH:30])([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:20](=O)[CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]1[O:4][C:21]([CH2:20][C:19]([OH:30])([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[Cl:10])([CH3:22])[O:3][CH2:2]1
Reactant: OCCO
Reactant: CCC(=O)C(O)(Cc1ccc(Cl)cc1Cl)c1cccnc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(CC(O)(Cc2ccc(Cl)cc2Cl)c2cccnc2)OCCO1
Temperature: 25 °C

Procedure:
27 ml of ethylene glycol and 0.8 ml of concentrated sulphuric acid are added to a solution of 5 g of 5-(2,4-dichlorophenyl)-4-hydroxy-4-(3-pyridyl)-3-pentanone (see Example 1, 3rd end product) in 90 ml of toluene and the reaction mixture is heated at reflux temperature for 24 hours on a water separator. After cooling to room temperature the mixture is neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, the solvent is removed by evaporation under reduced pressure and the residue is recrystallized from methylene chloride/n-hexane. In this manner there are obtained 5.3 g of 5-(2,4-dichlorophenyl)-4-hydroxy-4-(3-pyridyl)-2-pentanone ethylene ketal as colorless crystals, m.p. 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:8]1
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Yield: 190.1 %

Procedure:
To a mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.203 g) and aminoguanidine hydrochloride (80 mg) were added ethanol (6 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 1.5 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 131) (0.25 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (45.8 mg) with purity >90%. MS (pos) m/z 395.2, 397.2.
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[O:10]1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]>O>[F:38][C:20]([F:19])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[C:26]([C:27]([O:29][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[O:28])=[CH:30][CH:31]=[CH:32][N:33]=1
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OC(OC(=O)c2cccnc2Nc2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 50 °C
Yield: 49.5 %

Procedure:
Triethylamine (20 ml) and 3-bromophthalide (21.3 g) were added to a suspension of 2(3'-trifluormethylanilino)-nicotinic acid (28,2 g in 500 ml of acetone). The mixture was refluxed during 4 hours. The obtained greenish yellow suspension was poured into 6000 ml of water, which was previously heated at 50° C. The stirred reaction mixture was cooled to 5° C., and the formed precipitate was filtered and washed with cool water. Yield: 52% (20.5 g) of phthalidyl 2-(3'-trifluormethylanilino)-pyridin-3-carboxylate, m.p: 162°-164° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C=O)C>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:1][C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH:7]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 557.3 %

Procedure:
To benzyl 4-oxopiperidine-1-carboxylate (152 g, 650 mmol) in DMF (650 mL) was added TMS-Cl (148 mL, 117 mmol) followed by triethylamine (326 mL, 234 mmol). The slurry was warmed to 80° C. for 16 hours, diluted with hexanes (1 L), washed 3 times with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to obtain benzyl 4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate, (199 g, 652 mmol) as a orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)CCC>O1CCCC1>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1CCOC1
Product: O=C(c1ccco1)c1cc([N+](=O)[O-])ccc1Cl
Yield: 78.7 %

Procedure:
To a mixture of 2-chloro-5-nitrobenzoyl chloride(5.50 g, 0.0250 mol) and tetrahydrofuran is added 2-tributylstannylfuran (10.1 g, 0.0275 mol) followed by dichloro-bis-triphenylphosphine palladium (0.540 g, 0.00075 mol). The resultant mixture is stirred overnight at room temperature and concentrated in vacuo. The resultant oil is chromatographed on silica gel with methylene chloride-hexanes to afford the title compound as a bright yellow solid (4.95 g, 78.7%, mp 93-96° C.) which is identified by IR and NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:18]1([C@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClC(Cl)Cl
Product: C[C@H](c1ccccc1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 65.1 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 121 mg of (R)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene k chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 210 mg of the desired product as colorless needles. Yield: 65%. m.p. 95.5-96° C.; [α]20 D=41.5° (C=0.348 AcOEt); MS(EI+) 323 (M)+
Reaction SMILES: [C:1]([O:16]CC1C=CC=CC=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:46][CH2:47][C@@H:48]([C@H:50]([C@@H:52]([C@@H:54]([CH2:56][OH:57])[OH:55])[OH:53])[OH:51])[OH:49]>CN(C=O)C.O>[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:46][CH2:47][C@@H:48]([C@H:50]([C@@H:52]([C@@H:54]([CH2:56][OH:57])[OH:55])[OH:53])[OH:51])[OH:49])=[O:16])([OH:14])=[O:13]
Reactant: O=C([O-])CCCCCCCCCCC(=O)OCc1ccccc1
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCC(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Monobenzyl dodecanedioate (530 mg, 1.7 mmol) was dissolved in 10 mL of DMF, to which EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) (325 mg, 1.7 mmol) and HOBt (1-hydroxybenzotriazole) (230 mg, 1.7 mmol) were added. The mixture was stirred at room temperature for one hour and then D-glucamine (380 mg, 1.9 mmol) was added. The mixture was stirred at room temperature overnight, poured into 50 mL water, agitated and filtered to give the desired amide, of formula IIa in 95% yield. NMR (DMSO-D-6)7.70(brm, 1H), 7.30(m, 5H), 5.07(s, 2H), 4.73(d, 1H, J=4.5 Hz), 4.44(d, 1H, J=5.4 Hz), 4.36(d, 1H, J=6.0 Hz), 4.32 (t, 1H, J=5.7 Hz), 4.24(d, 1H, J=6.6 Hz), 3.58–3.52(m, 3H), 3.50–3.40(m, 3H), 3.21(m, 1H), 3.00(m, 1H), 2.33(t, 2H, J=7.2 Hz), 2.05(t, 2H, J=7.2 Hz), 1.50(m, 4H), 1.22(m, 12H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](O)=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:8]1[C:7]2[C:12](=[N:13][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2nc(OCC)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2nc(OCC)ccc2c1Cl

Procedure:
In a similar manner to Example B1, ethyl 7-ethoxy-4-hydroxy-1,8-naphthyridine-3-carboxylate (8.8 g) and phosphorus oxychloride (50 ml) were heated at 80° C. for 25 minutes to give ethyl 4-chloro-7-ethoxy-1,8-naphthyridine-3-carboxylate, m.p. 72°-75° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=CC(C)=CN=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[C:5]([CH3:25])=[CH:4][CH:3]=[CH:2][N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: Cc1ccc(Br)nc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ncccc1C

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (150 mg, 0.43 mmol) was reacted with 2-bromo-5-methylpyridine (73 mg, 0.43 mmol) to afford the desired 2-[3-methoxy-4-(3-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.60–8.58 (d, 1H), 7.96–7.90 (m, 3H), 7.80–7.79 (m, 1H), 7.70 (s, 1H), 7.62–7.60 (m, 1H), 7.39–7.36 (m, 2H), 7.10–7.08 (m, 1H), 4.01(s, 3H), 2.43 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][N:11]([CH2:14][CH:15](Cl)[CH3:16])[CH:12]=[O:13]>>[CH3:10][N:11]([CH2:14][CH:15]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:16])[CH:12]=[O:13]
Reactant: CC(Cl)CN(C)C=O
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1NC(C)CN(C)C=O
Yield: 22 %

Procedure:
One proceeds as described in Method C) of Example 14 with the difference that 2,6-dimethyl-aniline and 1-(N-methylformamido)-2-chloro-propane are applied as starting substances. The title compound is obtained with a yield of 22%; b.p.: 155°-165° C./80 Pa, m.p.: 69.5°-72° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH:38]([C:42](=[O:45])[NH:43][CH3:44])[CH2:37]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C>CN(C)C=O.Cl>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:38]([C:42](=[O:45])[NH:43][CH3:44])[CH2:37]1)(=[O:34])=[O:35])[CH:27]=[CH:26]2
Reactant: CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (100 ml), lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxylate (616 mg), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine trifluoroacetate (1.12 g), 1-hydroxybenzotriazole monohydrate (36 mg) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (579 mg) were dissolved and the resulting solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Dichloromethane was then added to the residue, followed by washing with water. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column [Φ3.0×(1.5+8) cm, ethyl acetate:methanol=100:4], whereby a colorless foam was obtained. The resulting foam was dissolved in 1N HCl (20 ml), followed by concentration under reduced pressure, whereby the title compound (845 mg) was obtained as a pale yellow foam.
Reaction SMILES: [Cu][C:2]#[N:3].[CH2:4]1[O:22][C:7]2([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)[O:6][CH2:5]1>CN(C=O)C.O>[CH2:4]1[O:22][C:7]2([CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]([C:2]#[N:3])=[CH:19][CH:20]=3)=[O:14])[CH2:11][CH2:12]2)[O:6][CH2:5]1
Reactant: N#C[Cu]
Reactant: O=C(c1ccc(Br)nc1)N1CCC2(CC1)OCCO2
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cn1
Temperature: 150 °C
Yield: 52.4 %

Procedure:
A stirred suspension of copper (I) cyanide (0.66 g, 7.4 mmol) and 1-(6-bromo-3-pyridyl)carbonyl-4-piperidone ethylene ketal (2.2 g, 6.7 mmol, prepared as in Example V from 6-bromo-3-pyridinecarboxylic acid) in DMF (30 ml) was heated at 150° C. for 3 h. The mixture was cooled, diluted with water, extracted with ethyl acetate, dried over sodium sulphate and evaporated. Purification by flash chromatography on silica, eluting with 20% ethyl acetate/hexane, gave a white crystalline solid (0.96 g, 52%), m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[CH:13]=[O:14].[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:18].[K+]>O.ClCCl>[Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:10])([F:12])[F:11])[C:3]=1[C:13]([OH:18])=[O:14]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A mixture of 29.5 g (131 mmol) of 5-chloro-1-ethyl-3-(trifluoromethyl)-pyrazole-4-carboxaldehyde in 350 mL of distilled water was prepared and 0.733 g (131 mmol) of potassium hydroxide and 20.6 g (131 mmol) of potassium permanganate were added to it. The mixture was heated to 60° C. with stirring for 2 hours. The color turned from purple to dark brown. An aliquot was taken, filtered to remove the solids, acidified, and analyzed by gas chromatography to determine that the reaction was complete. The reaction mixture was then filtered to remove the solids and the filtrate was acidified to pH 2. The precipitate that formed was recovered by filtration and washed with water to obtain a white solid. This solid was partially dissolved in hot dichloromethane and the insoluble portion removed by gravity fIltration. The filtrate was concentrated by evaporation under reduced pressure to obtain 23.4 g of the title compound as a white solid melting at 164°-166° C.