Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO/[CH:3]=[C:4](\[C:11]([O:13][CH3:14])=[O:12])/[CH:5]=[CH:6]/[C:7]([O:9]C)=O.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[CH:15]1([N:21]2[C:7](=[O:9])[CH:6]=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CO/C=C(/C=C/C(=O)OC)C(=O)OC
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(=O)n(C2CCCCC2)c1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (1.23 g) in DMF (30 mL) was added cyclohexanamine (670 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min under a nitrogen atmosphere. The reaction mixture was heated to reflux for 5 hr. The mixture was cooled with an ice-water bath and poured into water (100 mL). The resulted mixture was extracted with EtOAc (100 mL×2), and the organic phases were combined, washed with brine two times, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc-hexane (1:2-1:1) to give methyl 1-cyclohexyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (520 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](C3C=CC=CC=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH-].[K+].Br[CH2:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36]>CO>[C:1]1([N:8]2[C:9]([CH2:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCC#CCBr
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCC#CCc1c(-c2ccccc2)nc(-c2ccccc2)n1-c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 2,4,5-triphenylimidazole (1.07 g) in dimethyl-formimide (20 ml) was treated with sodium hydride 50% in oil (0.17 g) and methyl 7-bromohept-5-ynoate (0.95 g). The solution was stirred for 18 hours when the solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform hexane to give a clear oil which was dissolved in methanol (20 ml) and treated with 10% potassium hydroxide solution (10 ml) for 2 hours. The methanol was removed under reduced pressure and the remaining aqueous was acidified (pH 3) and filtered. The filtrate was extracted with chloroform (3×50 ml). The chloroform extracts were dried over magnesium sulphate, filtered and the solvent removed to give a solid which was recrystallised from acetonitrile to give 7-(1,2,4-triphenyl-imidazolyl)-hept-5-ynoic acid as white prisms, m.p. 144°-145° C.; Found: C, 79.99; H, 5.81; N, 6.40% (C28H24N2O2);Requires: C, 79.97; H, 5.75; N, 6.66%
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[CH2:37]([O:40][C:41]([NH:43][C@@H:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42])[CH:38]=[CH2:39]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:45](=[O:46])[C@@H:44]([NH:43][C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH:48]([CH3:50])[CH3:49])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: C=CCOC(=O)N[C@H](C(=O)O)C(C)C
Product: C=CCOC(=O)N[C@H](C(=O)OC(C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1)C(C)C
Yield: 91 %

Procedure:
In analogy to Example 5, 400 mg (0.78 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-2-allyloxycarbonylamino-3-methylbutyric acid and, after workup and purification, 495 mg (91%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CS(Cl)(=O)=O.[Br-:39].[Li+].[Cl-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:39][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2cccc(CO)c2)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2cccc(CBr)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.3 g of N-[3-(hydroxymethyl)phenyl]-3-(tetradecyloxy)benzeneacetamide in 60 ml of tetrahydrofuran is added 1.11 g of methanesulfonyl chloride and 978.95 mg of triethylamine followed by stirring at ambient temperature for 2 hours. Added 6.32 g of lithium bromide and stirred for an additional 2.5 hours. The reaction is poured into a mixture of saturated sodium chloride and saturated sodium bicarbonate then extracted with ether. The organic layer is dried and evaporated to give the desired product as a white solid, m.p. 104°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:33][C:31]2[CH:30]=[CH:29][C:26]3[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=3[N:32]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(-c3ccc(CCN)cn3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(-c3ccc(CCNCc4ccc5c(n4)NC(=O)CS5)cn3)c2n1
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a stirred solution of 2-[6-(6-methoxy[1,5]naphthyridin-4-yl)pyridin-3-yl]ethylamine (0.94 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (0.18 g, 0.94 mmole) and Na2SO4 (500 mg). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (36 mg, 0.94 mmole). After 24 h, the reaction solution was concentrated under vacuum and to the residue was added 1M HCl (5 mL) and EtOAc (50 mL). After stirring for 1 h, 6M NaOH (1 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated. Purification on reverse-phase HPLC (CH3CN/H2O, 10-90%) afforded the title compound (0.13 g, 30%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.89 (br s, 1H), 9.15 (m, 1H), 8.90 (m, 1H), 8.57 (d, J=9.1 Hz, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.20 (m, 2H), 7.51 (m, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.24 (m, 2H), 4.02 (s, 3H), 3.55 (m, 2H), 3.41 (m, 2H), 3.30 (s, 2H). LC-MS (ES) m/e 459 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Br:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([NH:12][S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Product: Cc1cc(Br)cc(C(=O)O)c1NS(=O)(=O)c1ccc(F)cc1
Yield: 36 %

Procedure:
By following the procedure of Example 134 the product of Example 133 and 4-flurobenzenesulfonyl chloride provides 5-bromo-2-(4-fluoro-benzenesulfonylamino)-3methyl-benzoic acid as a yellow solid in 36% yield. Electrospray Mass Spec: 386.0 (M-H)-
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
2-Nitrobenzenesulfonyl chloride (4.43 g, 20 mmol) in methylene chloride (20 mL) was added dropwise to the ice-cooled solution of pyrrolidine (8.4 mL, 100 mmol) in methylene chloride (100 mL). The reaction mixture was stirred at room temperature for 2 hours and washed with 3N HCl (2×60 mL) and brine (60 mL). The organic layer was dried (Na2SO4) and concentrated to yield the intermediate nitrobenzene derivative (5.12 g, 100%). 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, 1H), 7.70 (m, 2H), 7.60 (d, 1H), 3.40 (t, 4H), 1.92 (t, 4H), 1.80 (t, 4H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH:9]=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCCCC1CCCC1
Reaction time: 72 h
Yield: 62.7 %

Procedure:
4-Cyclopentyl-butyraldehyde (4.9 g, 35 mmol) was taken up in ethanol (100 mL) and treated slowly with sodium borohydride (1.72 g, 4.54 mmol). The reaction was stirred for three days and quenched with water (10 mL). The reaction was diluted with dichloromethane (200 mL) and washed with water (2×100 mL). The organic phase was dried (MgSO4), filtered, and concentrated to yield an oil. The product was passed through a pad of silica to yield 4-cyclopentyl-butan-1-ol as a colorless oil (3.12 g, 63%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([O:21][CH3:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:23])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([O:21][CH3:22])[C:17]([F:18])([F:19])[F:20])=[CH:12][NH:11][C:10]=1[CH3:23]
Reactant: COC(c1c[nH]c(C)c(OCc2ccccc2)c1=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COC(c1c[nH]c(C)c(O)c1=O)C(F)(F)F
Reaction time: 0.92 h
Yield: 61 %

Procedure:
A clear solution of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-methoxy-ethyl)-1H-pyridin-4-one (609 mg, 1.86 mmol) in methanol (32 mL) was debenzylated using Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 154 mg) as catalyst under a hydrogen atmosphere at 50 psi of pressure. The reaction was completed in 55 min. The mixture was diluted with methanol (50 mL), sonicated for 10 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was collected and concentrated in vacuo to give 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-methoxy-ethyl)-1H-pyridin-4-one as a solid product (0.27 g, 61% yield, HPLC Method 1 (Example 24), RT=9.7 min, purity (peak percent area): 99.3% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 7.42 (s, 1H), 5.19 (q, J=7.0 Hz, 1H), 3.32 (s, 3H), 2.20 (s, 3H); MS-ESI (m/z) 238.1 [M+1]+, 206.2 (100%), 186.1, 178.2, 158.2.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[C:7]([CH2:10][C:11](=O)[CH3:12])(=O)[CH3:8].C([O-])([O-])=O.[K+].[K+]>O>[CH3:12][C:11]1[CH:10]=[C:7]([CH3:8])[NH:6][C:4](=[O:5])[C:3]=1[C:1]#[N:2]
Reactant: CC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)c(C#N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.1 %

Procedure:
To a solution of 2-cyanoacetamide (8.40 g, 100 mmol) and acetylacetone (10.0 g, 100 mmol) in H2O (200 mL) was added K2CO3 (4.00 g, 28.9 mmol). The mixture was stirred at RT for 22 hours. Then the precipitated solid was filtered with Buchner funnel, washed with ice cold H2O, and dried under vacuum pressure to give 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (13.5 g, 91% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.[ClH:14].O1CCOCC1>C(O)C.C(OCC)C>[ClH:14].[N:9]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: c1cn[nH]c1
Reactant: Nc1cc(I)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCO
Product: Nc1cc(-n2cccn2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 20 mL reaction vessel was charged with 4-iodopyridin-2-amine (1.5 g, 6.8 mmol) and 1H-pyrazole (4.0 g, 58.9 mmol). Concentrated hydrochloric acid (1.5 ml) and 1,4-dioxane (1.5 mL) were added, and the reaction vessel was sealed. The mixture was irradiated in a microwave oven at 120° C. for 45 min and then at 130° C. for 60 min. The mixture was cooled to rt and then diethyl ether (6 ml) and ethanol (3 ml) were added. The mixture was sonicated for 10 min, and the solid was collected by filtration and washed with diethyl ether and n-hexane to give 4-(1H-pyrazol-1-yl)pyridin-2-amine hydrochloride (1.2 g, 90%) as a white solid. LCMS (ESI) m/z 161 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[O-]S([O-])(=O)=O.[Mg+2].[CH:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1.[C:18](O)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([O:16][C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)C1CC1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC1
Reaction time: 0.33 h
Yield: 48.7 %

Procedure:
The esterification was performed following conditions described in Wright, Stephen W.; Hageman, David L.; Wright, Ann S.; Mc Clure, Lester D., Tetrahedron Letters 1997, 38(42), 7345-7348. 8.04 ml (150 mmol) concentrated sulfuric acid was added to a vigorously stirred suspension of 72.22 g (600 mmol) MgSO4 in 450 ml CH2Cl2. The mixture was stirred for 20 min, after which 11.90 ml (150 mmol) of cyclopropanecarboxylic acid was added. 55.59 ml (750 mmol) of tert-butanol was added last. The mixture was sealed tightly and stirred for 18 h at room temperature. The reaction was quenched with aqueous saturated NaHCO3 and stirred until all MgSO4 had dissolved. The aqueous phase was extracted with ether (two times). The organic phases were washed with water (5×), aqueous saturated NaCl solution and dried (Na2SO4) to give 10.38 g of the title compound as volatile, light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(C)C)(C)C>>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: CNCc1ccccc1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Solvent: CC(C)OC(C)C
Product: CN(Cc1ccccc1)C(=O)/C=C/c1cc(Cl)cnc1N

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and N-methyl benzylamine as a yellow solid following crystallisation from diisopropyl ether:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[N+]=[N-].[FH:11]>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[NH2:8]
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: F
Solvent: C1CCCCC1
Product: Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4.11g. (0.03 mole) of 2-fluorophenylazide in 81 ml. of cyclohexane was treated with 20 ml. of hydrogen fluoride. The reaction mixture was then shaken at room temperature for 24 hours, then cooled, vented, and rinsed from the bomb with two successive applications of 100 ml. of dichloromethane and then 100 ml. of water. The reaction mixture was then blown down under nitrogen, quenched in 75g. of ice, and rendered basic with KOH pellets. The reaction mixture was extracted with dichloromethane to yield 2.2g. (57%) of a brown-red fluid after drying over MgSO4. The 2,4-difluoroaniline structure of the final product was confirmed by IR, and the product had a b.p. of 90°-92° C. at 40 mm. Hg.
Reaction SMILES: C([O:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:16])[CH3:15])(=O)C.P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[K+].[K+].Cl>C1(C)C=CC=CC=1>[C:14]([NH:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[C@H:5]([OH:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(Cl)cc1C(OC(C)=O)c1ccccc1Cl
Agent: Cl
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Cl)cc1[C@H](O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 144 h
Yield: 22.7 %

Procedure:
To a mixture of 2-acetylamino-5-chloro-α-(2-chlorophenyl)benzyl acetate (2.0 g), toluene (30 ml), 0.1M potassium dihydrogen phosphate (aq. sol., 20 ml) and 0.1M potassium monohydrogen phosphate (aq. sol., 20 ml) was added Lipase AP6 (Amano Pharmaceutical) (0.8 g) and the whole mixture was stirred vigorously at room temperature for 6 days. To this reaction mixture was added 1N-hydrochloric acid (50 ml) to stop the reaction, followed by extraction with ethyl-acetate (50 ml). The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:methylene chloride:ethyl acetate=4:1:1-1:1:1). The unreacted 2-acetylamino-5-chloro-α-(2-chlorophenyl)benzyl acetate (1.28 g) was recovered from the first fraction. Then, (S)-2-acetylamino-5-chloro-α-(2-chlorophenyl)benzyl alcohol (0.40 g) was obtained as oil from the second fraction. The optical purity of this product as determined by high performance liquid column chromatography using a chiral column [ULTRON ES-OVM (Shinwa Chemical Industries, Ltd.)] was 85% ee. This (S)-2-acetylamino-5-chloro-α-(2-chlorophenyl)benzyl alcohol of 86 (85)% ee was dissolved in hexane-diethyl ether and the crystals (47 mg) that had separated out were separated. The mother liquor was distilled under reduced pressure to provide (S)-2-acetylamino-5-chloro-α-(2-chlorophenyl)benzyl alcohol of higher purity as oil (0.31 g). Optical purity 96.4% ee.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(O[C:17](=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=2)[NH:26][C:25]1=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C>CN(C=O)C>[N:1]1([CH2:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11]/[C:17](=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:9][CH:8]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CC=CC2)cc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CC=CC2)cc1)c1ccccc1

Procedure:
Prepared from 4-(2,5-dihydro-pyrrol-1-ylmethyl)aniline and 3-(1-ethoxy-1-phenylmethylidene)-5-nitro-2-indolinone in DMF.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([CH:21]3[CH2:23][CH2:22]3)[CH:16]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: Cn1nc(C2CC2)cc1N
Reactant: CCOC(=O)c1nc(C)ccc1Br
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 5-Amino-3-cyclopropyl-1-methylpyrazole was performed in accordance with the general method of Example 78, step 3 to yield the title compound as an orange solid, MS (ISP): m/e 301.4 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41]([N:19]([CH2:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH3:17])[CH:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]1)=[O:42]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CCOc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 39 (613 mg, 1.32 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (366 mg, 1.58 mmol) using Method D to give the title compound.
Reaction SMILES: [I-].[CH3:2][C:3]1[N:10]2[C:6](=[NH+:7][C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=32)[S:5][CH:4]=1.C([O-])(O)=O.[Na+]>>[CH3:2][C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:9]=32)[S:5][CH:4]=1
Reactant: Cc1csc2[nH+]c3ccc(C(F)(F)F)cc3n12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Product: Cc1csc2nc3ccc(C(F)(F)F)cc3n12
Yield: 84.7 %

Procedure:
1.4 g (3.64 mmol) of 3-methyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide 4a were poured in a NaHCO3 saturated aqueous solution (60 mL). The mixture was extracted 3×60 mL of CH2Cl2; the organic layer was dried with MgSO4 and evaporated under reduced pressure to yield 3-methyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a]benzimidazole 5a (790 mg, yellow powder, 85%). Mp=127° C.; 1H NMR (300 MHz, CDCl3) δ=2.79 (3H, d, J=1.3, CH3), 6.46 (1H, q, J=1.3, H5), 7.60-8.08 (3H, m, Ar); 13C NMR (75 MHz, CDCl3) δ=14.44, 105.89, 108.10 (q, J=4), 119.39, 120.29 (q, J=4), 122.73 (q, J=32), 124.74 (q, J=272), 129.49, 129.87, 150.41, 159.70; HRMS m/z C11H7F3N2S [M+H]+ calcd: 257.0355, found: 257.0353. Same result as for (4a) 3-methyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:9][O-].[Na+].CI>CO>[CH3:9][S:3][C:2]1[NH:1][CH:8]=[CH:7][C:5](=[O:6])[N:4]=1
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(=O)cc[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20 g (153 mmol) 2-thiouracil are suspended in 250 mL MeOH and then 8.7 g (152.9 mmol, 1 eq) sodium methoxide are added. The solution is stirred for 5 min at RT and then 12.4 mL (198.8 mmol, 1.3 eq) methyl iodide are added dropwise. The reaction mixture is stirred overnight, then poured onto water and extracted 3× with approx. 150 mL chloroform. The combined organic phases are dried on MgSO4, the solvent is eliminated in vacuo and 16 g E-1 are obtained.