Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[N:6]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]3)[N:6]=2)[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: OB(O)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)sc2C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(Cl)cc(C(F)(F)F)c3)sc2C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of the compound (230 mg, 0.71 mmol) obtained in Example 80e and 3-chloro-5-trifluoromethylphenylboronic acid (210 mg, 0.92 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.71 mL, 1.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (60 mg, 0.071 mmol), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (230 mg, 76%) as colorless crystals.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C>C(O)C>[C:14]1(=[O:23])[N:13]([CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-bromomethylphthalimide (5.28 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.29 g of the desired product (69.4%, pale yellow crystals).
Reaction SMILES: C(NC(C)C)(C)C.[C:8](=[O:10])=O.C([Li])CCC.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=1.[CH:24]1([CH2:27][N:28]([CH2:31][CH:32]2[CH2:34][CH2:33]2)C=O)[CH2:26][CH2:25]1>CCOCC.CC(C)=O>[CH:24]1([CH2:27][N:28]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:17]2[C:22]([CH:8]=[O:10])=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)[CH2:26][CH2:25]1
Reactant: O=CN(CC1CC1)CC1CC1
Reactant: Fc1cccc(F)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=Cc1ccc(F)nc1N(CC1CC1)CC1CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
Diisopropylamine (1.4 mL, 9.6 mmol) was stirred in ether (10 mL). The solution is cooled −78° C. with dry ice and acetone. n-Butyllithium (4 mL, 9.6 mmol) was added and the resulting solution was allowed to stir at −78° C. for about 15 minutes. 2,6-Difluoropyridine (0.8 mL, 8.7 mmol) was added and the solution was allowed to stir at −78° C. for about 2 hours. N,N-bis-cyclopropylmethyl formamide (1.71 g, 10.9 mmol) was added and the solution was allowed to stir at −78° C. for about 1 hour. The solution was quenched with 10% potassium phosphate. The solution was extracted with ether (2×20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give an orange oily product. Purification by silica gel chromatography and eluting with 20% ethyl acetate in hexanes afforded the title compound as an orange oil (224 mg, yield: 10.3%).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[CH:29]=[CH:28][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:33])([F:34])[F:20])=[CH:27][CH:26]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)C=Cc4ccc(C(F)(F)F)cc4)ccc3o2)C1
Yield: 56.7 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.040 g, 0.154 mmol), 3-(4-trifluoromethyl-phenyl)-acrylic acid (0.050 g, 0.230 mmol), HATU (0.058 g, 0.154 mmol), polystyrene-bound diisopropylamine (0.385 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (20 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography (12 g column, eluting with 10% 2M NH3 in MeOH/CH2Cl2) to yield the product as a yellow-white solid (0.040 g, 57%). mass spectrum (m/e): 459.0 (M+1), 457.0 (M−1). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J=15.2 Hz, 1H), 7.61 (m, 4H), 7.53 (d, J=12.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.64 (d, J=15.6 Hz, 1H), 3.62-3.49 (m, 2H), 3.20 (s, 3H), 2.77-2.55 (m, 4H), 2.44-2.37 (m, 1H), 2.38 (s, 3H), 2.09-1.98 (m, 1H), 1.63-1.53 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([C:16]([NH2:18])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:5][CH:6]=1.[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](O)=[O:26].Cl.CN(C)CCCN=C=NCC>ClCCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([C:16]([NH2:18])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:5][CH:6]=1)=[O:26]
Reactant: NC(=O)n1c(-c2cc(N)cs2)cc2ccccc21
Reactant: Cc1ccoc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1ccoc1C(=O)Nc1csc(-c2cc3ccccc3n2C(N)=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(4-amino-2-thienyl)-1H-indole-1-carboxamide (51.4 mg, 0.2 mmol, 1 eq) and 3-methyl-furan-2-carboxylic acid (25.2 mg, 1 eq) in anhydrous DCE (2 mL) was added 4-(dimethylamino)pyridine (4.9 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.1 mg, 1.2 eq). After the reaction was stirred at 60° C. for 1 hour, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:100 to 1:2) to yield 2-{4-[(3-methyl-2-furoyl)amino]-2-thienyl}-1H-indole-1-carboxamide as a yellow solid in amount of 42 mg.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=4)[O:31][CH2:32][C:33]([O-:35])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:43]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])P(=O)(OCC)OCC.[CH3:60]N(C)C=O.[H-].[Na+]>O>[CH2:57]([O:56][P:52](/[CH:43]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=4)[O:31][CH2:32][C:33]([O:35][CH3:60])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)([O:53][CH2:54][CH3:55])=[O:59])[CH3:58]
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(OCC(=O)[O-])c2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(OCC(=O)OC)c3)oc2C)c(OC)c1)OCC
Reaction time: 4 h
Yield: 68 %

Procedure:
To a mixture of methyl ((3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenoxy)acetate (0.30 g), tetraethyl methylenediphosphonate (0.16 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.025 g) at room temperature, and the mixture was stirred at the same temperature for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenoxy}acetate as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, v/v) (0.25 g, yield 68%).
Reaction SMILES: [NH2:1][C@@H:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@H:7]1[O:15][C:16](=[O:18])[CH3:17])=[O:4].[C:23]([O-])(O)=[O:24].[Na+].[CH2:28]([O:30][C:31]([C@:33]1([NH:38][C:39]([C@@H:41]2[CH2:45][C@@H:44]([OH:46])[CH2:43][NH:42]2)=[O:40])[CH2:35][C@@H:34]1[CH:36]=[CH2:37])=[O:32])[CH3:29]>C(#N)C>[CH2:28]([O:30][C:31]([C@@:33]1([NH:38][C:39]([C@@H:41]2[CH2:45][C@@H:44]([OH:46])[CH2:43][N:42]2[C:23](=[O:24])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][C@H:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C@H:7]2[O:15][C:16](=[O:18])[CH3:17])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:40])[CH2:35][C@H:34]1[CH:36]=[CH2:37])=[O:32])[CH3:29]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Reactant: CC(=O)O[C@@H]1Cc2ccccc2[C@@H]1NC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@H](C(=O)N[C@H]1c2ccccc2C[C@H]1OC(C)=O)C(C)(C)C)C(=O)OCC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of compound 89 (1.81 g) in acetonitrile at 0° C. solid NaHCO3 (800 mg) and p-nitrophenychlorocarbonate (1.2 g) was added. The slurry was taken up to ambient temperature and stirred for another 30 min. To this slurry a solution of compound 91 (1.6 g) in acetonitrile (5 mL) diisopropylethylamine (1 mL) was added. After 10 min the resulting mixture was concentrated, re-dissolved in ethyl acetate and washed with K2CO3 (aq) and then with 0.5 N HCl. Dried and concentrated which gave a >80% pure product by HPLC M+H+599.6
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[CH3:16][Sn:17]([N:20]=[N+:21]=[N-:22])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][Sn:17]([CH3:19])([CH3:18])[N:20]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[N:2][N:22]=[N:21]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Temperature: 70 °C

Procedure:
A solution of 2-cyano-4'-methylbiphenyl (1.93 g) in toluene (25 mL) was treated with trimethyltin azide (2.65 g) and heated at reflux for 24 hours. The resulting suspension was cooled to 70° C. and filtered. The collected solid was dried at reduced pressure to give the title compound. 1H-NMR (CDCl3) δ7.5 (m, 4H), 7.0 (q, 4H), 2.3 (s, 3H), 0.4 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH3:2].Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]([NH:12][OH:13])=[NH:7])[CH3:2]
Reactant: CCc1cccc(C#N)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc(C(=N)NO)c1
Yield: 46 %

Procedure:
3-Ethyl-benzonitrile (400 mg, 3.05 mmol) with 5 M hydroxylamine hydrochloride (0.61 mL) and 1 M sodium hydroxide (3.05 mL) in ethanol (3 mL) were stirred at room temperature for 60 h. Work up as in example 4 afforded 230 mg (46%) of 3-ethyl-N-hydroxy-benzamidine.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.[C:8](Cl)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1.CCCCCC>[C:8]([NH:1][C:2]1[C:6]([NH:7][C:8](=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][S:4][CH:3]=1)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1cscc1N
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)Nc1cscc1NC(=O)CCCCCCCCCCCCCCC
Yield: 70 %

Procedure:
This compound was prepared in a yield of 70% of theory starting from 3,4-diaminothiophene and palmitoyl chloride (boiling point 141° C. at 1.4 mbar) in a similar manner to above. The melting point was 107-109° C. (from toluene-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[F:27][C:28]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([CH3:39])[C:29]=1[C:30](Cl)=[O:31].Cl>C1COCC1>[F:27][C:28]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([CH3:39])[C:29]=1[C:30]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:31]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)Cl
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
A solution of 8.0 g (60.5 mmol) of malonic acid monoethylester, bipyridyl (catalytic) and 200 ml of dry THF was cooled to -35° C. under argon, treated with 32 ml of 1.9M n-butyllithium (60.8 mmol), and warmed to -5° C. To this suspension was added another 32 ml of 1.9M n-butyllithium until a pale pink color persisted for 10 minutes. The mixture was cooled to -78° C. To this mixture was added a solution of 6.3 g (30.2 mmol) of 2,4,5-trifluoro-6-methylbenzoyl chloride in 75 ml of dry THF, and the reaction mixture was stirred at -78° C. for one hour. The solution was then warmed to -35° C., poured onto a mixture of ice and 1N hydrochloric acid (70 ml), and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, 3M hydrochloric acid, and water, and was stirred over magnesium sulfate. Concentration gave an orange oil which was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate, to give 7.2 g of the title compound.
Reaction SMILES: ClC1N=C(OC)N=C(OC)N=1.[F:12][C:13]([F:38])([F:37])[C:14]1[CH:36]=[CH:35][CH:34]=[CH:33][C:15]=1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[N:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].CN1CCOCC1.[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>C1COCC1.C(OCC)(=O)C>[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:30]([C:27]2[N:28]=[N:29][C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16](=[O:17])[C:15]4[CH:33]=[CH:34][CH:35]=[CH:36][C:14]=4[C:13]([F:37])([F:12])[F:38])[CH2:23][CH2:22]3)=[CH:25][CH:26]=2)=[O:32])=[CH:49][CH:48]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.105 g, 0.60 mmol) was added to a cooled (0° C.) solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (0.190 g, 0.50 mmol) and methylmorpholine (0.07 mL, 0.63 mmol) in THF (10 mL). The reaction mixture was stirred at 0° C. for 15 min, and then at ambient temperature for 1 h. 4-Chloroaniline (0.0765 g, 0.60 mmol) was then added. After stirring at ambient temperature for 20 h, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography and recrystallization from ethyl acetate/hexanes afforded the title compound in 67% yield (0.164 g). 1H NMR (300 MHz, CDCl3) δ 9.79, 8.08, 7.82-7.55, 7.36-7.28, 7.02, 4.10-4.00, 3.93-3.68, 3.35. 13C NMR (75 MHz, CDCl3) δ 167.6, 160.7, 160.0, 144.8, 136.2, 134.2, 132.4, 129.5, 129.2, 129.1, 127.2, 126.9, 126.8, 126.7, 125.4, 121.8, 120.7, 112.6, 46.3, 44.5, 44.3, 41.2. MS (ES+) m/z 490.1 (M+1).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[O:22]>C1COCC1>[CH3:14][N:13]1[C:9]([CH:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[OH:22])=[CH:10][N:11]=[CH:12]1
Reactant: Cn1cncc1Br
Reactant: O=Cc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of isopropylmagnesium chloride/lithium chloride complex (1.3 M in THF, 19.5 mL, 25.35 mmol) was added dropwise by syringe to a solution of 5-bromo-1-methyl-1H-imidazole (4.12 g, 25.58 mmol) in dry THF (130 mL) at 0° C. After 15 minutes, the Grignard solution was added via cannulation to a solution of picolinaldehyde (2.0 mL, 20.93 mmol) in dry THF (55 mL) at 0° C. The reaction mixture was stirred for 5 minutes at 0° C., then warmed to room temperature for 1 hour. The reaction mixture was then cooled in an ice bath and quenched with saturated aqueous ammonium chloride. The mixture was partitioned between brine and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([OH:14])=[C:10]([CH3:13])[CH:11]=2)[O:6][C:5](=[O:16])[CH:4]=1.[OH-:17].[Na+].Cl>>[OH:14][C:9]1[C:10]([CH3:13])=[CH:11][C:12]2[C:3]([CH2:4][C:5]([OH:16])=[O:17])=[CH:2][O:6][C:7]=2[C:8]=1[CH3:15]
Reactant: Cc1cc2c(CCl)cc(=O)oc2c(C)c1O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc2c(CC(=O)O)coc2c(C)c1O
Yield: 75 %

Procedure:
4.8 g (20.1 mmol) of 4-(Chloromethyl)-7-hydroxy-6,8-dimethyl-2H-chromen-2-one are heated at reflux for 3 h in 11 of 0.2 N NaOH. The reaction solution is adjusted to pH 3 with HCl and extracted 4 times with ethyl acetate. The combined organic phases are washed with a saturated solution of NaCl, dried over sodium sulfate and concentrated. 3.3 g (75%) of 2-(6-hydroxy-5,7-dimethyl-1-benzofuran-3-yl) acetic acid are obtained.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@H](O)CN
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](O)Cn1ccc2c1-c1cc(Cl)ccc1C2
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
A solution of 2.5 g of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone and 100 mg of p-toluenesulfonic acid in 120 ml in anhydrous toluene was heated on a water separator. A solution of 3.6 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.56 g (53%) of (S)-1-(7-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH:10]=O)=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH2:10][NH:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:4][N:3]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: CNc1nc(Cl)ncc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CNc1nc(Cl)ncc1CNc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A solution of 2-chloro-4-methylamino-pyrimidine-5-carbaldehyde (1.08 g, 6.3 mmol) and N-(3-amino-4-methyl-phenyl)-3-trifluoromethylbenzamide (2.04 g, 6.9 mmol) in MeOH (70 mL) is stirred for 2 hours at 45° C. and then treated with sodium cyanoborohydride (1.19 g, 18.9 mmol) and acetic acid (1 mL) sequentially. After stirring for 2 hours at room temperature, the reaction mixture is diluted with CHCl3 and washed with saturated NaHCO3 The organic layer is dried over MgSO4 and concentrated under reduced pressure. The residue is purified by flash column chromatography (SiO2, EtOAc/hexane=1/2) to give N-{3-[(2-chloro-4-methylaminopyrimidin-5-ylmethyl)amino]-4-methylphenyl}-3-trifluoromethylbenzamide (1.80 g, 64%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14]O.OS(O)(=O)=O>O>[CH3:14][O:12][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:13]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A mixture of 1-adamantanecarboxylic acid (572 gm.), methanol (2.2 liters), and H2SO4 (90 ml.) was refluxed 5 hours and then cooled to room temperature overnight. The reaction mixture was poured into 28 liters of water and extracted with chloroform (2 × 150 ml. for each 3.5 liters of solution). The chloroform extracts were combined, washed with water, dried, and concentrated. The residual oil was distilled to give 476 gm. product (77.5% yield) b17 approx. 143°.