Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+].Cl>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
0.65 g (1.3 mmol) of methyl 3-{3′-[(tert-butoxycarbonylmethylamino)-methyl]biphenyl-4-yl}-2-ethoxypropionate is placed in 10 ml of tetrahydrofuran, 0.5 ml of methanol and 1.9 ml (1.9 mmol) of aqueous 1M lithium hydroxide solution. After stirring at room temperature for 2 hours, the reaction medium is diluted with ethyl acetate, acidified to pH 6 with aqueous 1N hydrochloric acid solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. 0.54 g of 3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxypropionic acid is obtained in a yield of 92%.
Reaction SMILES: CN(C)[C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)C(=O)C[O:35]CCN1CCN(C(C2C=CC=CC=2)C2C=CC([Cl:51])=CC=2)CC1)C>O1CCOCC1>[ClH:21].[ClH:51].[C:22]1([CH:14]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]([OH:28])=[O:35])[CH2:9][CH2:10]2)[C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: CCN(CC)C(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Solvent: C1COCCO1
Product: Cl
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reaction time: 4 h
Yield: 74.9 %

Procedure:
The procedure described in Example 14 is followed with the difference that, instead of the (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide, 104.4 g (0.2 moles) of (RS)-N,N-diethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide are used, 100 ml of dioxane are employed as cosolvent, and, during the alkaline hydrolysis, the reaction mixture is boiled for 4 hours. Thus, 69.1 g (74.9%) of the title compound are obtained, m.p.: 225-228° C. The purity of the product corresponds to the quality requirements given in Eur. Pharm., 3, 1997, 1084.
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:20]1([NH:26][CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH:20]1([N:26]([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNC1CCCCC1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)N(C)C1CCCCC1
Yield: 28.5 %

Procedure:
Diethyl bromomalonate (17.0 g), triethylamine (9.1 g), and dry toluene (10 ml) were mixed, and with stirring, the mixture was heated under reflux. Then, N-cyclohexyl-N-methylamine (8.1 g) diluted with dry toluene (5 ml) was added dropwise, and the mixture was heated under reflux for 2.5 hours with stirring. The reaction mixture was washed with water three times, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give 5.5 g (29%) of diethyl (N-cyclohexyl-N-methylamino)malonate having the following properties.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:20][OH:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH2:46]1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:20][O:21][CH3:46])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.3 g, 0.5 mmol), methyl iodide (0.04 g, 0.02 ml, 0.3 mmol), sodium hydride (0.04 g, 1.6 mmol) and 18-crown-6 (0.3 g, 1 mmol) in N,N-dimethylformamide (3 ml) was heated at 60° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 30% ethyl acetate/hexane. The title compound was isolated as a white crystalline solid (285 mg, 97%).
Reaction SMILES: [C:1]12[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][NH:2]2.[H-].[Na+].[CH:14]([P:16]([O:30][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35])([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17])=[CH2:15]>CN(C)C=O>[O:11]=[C:8]1[C:9](=[O:10])[C:1]2[N:2]([CH2:15][CH2:14][P:16]([O:30][C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[C:34]([O:36][CH2:37][CH3:38])=[O:35])([O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1=2
Reactant: C=CP(=O)(Oc1cccc(C(=O)OCC)c1)Oc1cccc(C(=O)OCC)c1
Reactant: O=c1c2c(c1=O)NCCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OP(=O)(CCN2CCCNc3c2c(=O)c3=O)Oc2cccc(C(=O)OCC)c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A suspension of 2.6-diaza-bicyclo[5.2.0]non-1(7)-ene-8,9-dione (2) (4 mmol, 608 mg) in N,N-dimethylformamide (60 mL) was treated under dry nitrogen and under stirring with 60% sodium hydride in oil (4.1 mmol, 164 mg). After 30 minutes at ambient temperature the yellow reaction mixture was cooled to 0° C. and a solution of diethyl 3,3′-[(vinylphosphoryl)bis(oxy)]dibenzoate (3) (4 mmol, 1.618 g) in N,N-dimethylformamide (30 mL) was added at once under vigorous stirring. The reaction mixture was then stirred at ambient temperature overnight, concentrated in vacuo and the residue partitioned between 5% aqueous ammonium chloride solution and ethyl acetate (2×60 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue (>1.5 g) was flash chromatographed on silica gel (60 g). Elution with 2% methanol in chloroform afforded 600 mg (27%) of the desired title compound as a white powder; mp 116-7° C. MS (ES+): m/e 557.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].F[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:24][N:21]1[CH2:22][CH2:23][C@H:19]([O:18][C:16]2[CH:15]=[C:4]([CH:3]=[C:2]([O:1][C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:17]=2)[C:5]([NH:7][C:8]2[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:6])[C:20]1=[O:25]
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (136 mg, 0.4 mmol), 1-fluoro-4-methylsulfonyl-benzene (105 mg, 0.6 mmol) and potassium carbonate (111 mg, 0.8 mmol) in DMA (5 mL) was stirred at 120° C. for 2 hours. The solution was evaporated under reduced pressure, the residue dissolved in ethyl acetate (40 mL), washed with water (2×20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0-4% methanol in DCM to afford product (135 mg, 68%). 1H NMR δ (300 MHz, CDCl3) 2.15-2.30 (m, 1H), 2.53-2.69 (m, 4H), 2.94 (s, 3H), 3.08 (s, 3H), 3.36-3.58 (m, 2H), 4.96 (t, 1H), 7.02 (s, 1H), 7.15 (d, 2H), 7.25 (s, 1H), 7.50 (s, 1H), 7.93 (d, 2H), 8.15 (s, 1H), 8.55 (s, 1H), 9.53 (s, 1H); m/z 497 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30]>>[CH3:26][O:27][CH2:28][C:29]([NH:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:14]3[CH:13]=[N:12][CH:11]=[C:10]([NH:9][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[N:15]=3)[C:20]=2[CH:21]=1)=[O:30]
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc2ncn(-c3cncc(N[C@@H](C)c4ccccc4)n3)c2c1
Yield: 24.8 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and methoxyacetyl chloride (20 mg, 0.11 mmol) furnished the product (10 mg, 25%) after chromatography.
Reaction SMILES: N1([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)CCCC1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH2:20]>O1CCOCC1>[C:13]1([CH2:12][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]2=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCC(N2CCCC2)CC1
Reactant: O
Reactant: ClCc1ccccc1
Solvent: C1COCCO1
Product: O=C1CCCCC1Cc1ccccc1

Procedure:
A mixture of 1-(1-pyrrolidinyl)cyclohexane (85.4 g) and benzyl chloride (100 ml) in dioxane (400 ml) was heated under reflux for 23 hours under nitrogen. Water (100 ml) was then added and the brown oil was distilled to give (2RS)-2-phenylmethylcyclohexanone (47.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:27][C:23]2[CH:24]=[CH:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][N:17]=3)[N:22]=2)[C:9](=[O:11])[N:10]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1cccc(Cl)c1CNC1=NC(=O)C(=Cc2ccc3ncccc3n2)S1
Temperature: 130 °C
Yield: 52.1 %

Procedure:
To a suspension of 2-(2-chloro-6-methyl-benzylamino)-thiazol-4-one (40.8 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 15 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-(2-chloro-6-methyl-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (32.9 mg, 52.1%). HR-ES (+) m/e calcd. for C20H15ClN4OS: (M+H)+ 395.0728. Found: 395.0728.
Reaction SMILES: [C:1]([OH:10])(=O)[C@H:2]([C@@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=C(C)C=1>O>[CH2:11]([N:18]1[C:6](=[O:7])[C@@H:4]([OH:5])[C@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: NCc1ccccc1
Solvent: Cc1cccc(C)c1
Solvent: O
Product: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of D(-)-tartaric acid (4.5 g, 30 mmol), benzylamine (3.3 ml, 30,2 mmol) and m-xylene (50 ml) was heated at reflux temperature for 4 hours with simultaneous capture of water. The mixture was cooled to room temperature, filtered and washed with m-xylene twice (2×2 ml) and acetone (10 ml) to give (3S,4S)-1-benzyl-3,4-dihydroxy-2,5-dioxopyrrolidine (5.0 g, yield: 76%) as light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.[CH3:19][C@H:20]1[CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:19][CH:20]1[CH2:25][CH:24]([O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:4](=[O:18])[CH:3]=2)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32]
Reactant: C[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 10.4 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridine-2(1H)-one (173 mg, 0.652 mmol), cis-tert-butyl 2-methyl-4-(methylsulfonyloxy)piperidine-1-carboxylate (191 mg, 0.652 mmol) and potassium carbonate (180 mg, 1.304 mmol) in DMF (3.0 mL) was heated at 140° C. for 6 hrs and 100° C. overnight. To the above mixture additional potassium carbonate (90 mg, 1 equiv.) was added and the reaction was heated at 120° C. for 3 hrs and then cooled to room temperature. The mixture was diluted with EtOAc and water and the aqueous layer was extracted further with EtOAc (4×). The combined organic layers were washed with brine/water (1:1, 2×), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield trans-isomer of tert-butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (31.4 mg, 10.4%) as an off-white solid. 1H NMR (500 MHz, CDCl3). δ 8.07 (d, J=8.25 Hz, 2H), 7.61 (d, J=8.25 Hz, 2H), 7.22 (d, J=7.70 Hz, 1H), 6.02 (dd, J=7.70, 2.20 Hz, 1H), 5.97 (d, J=2.20 Hz, 1H), 4.50-4.66 (m, 2H), 4.09-4.13 (m, 1H), 3.09 (s, 3H), 2.91-3.05 (m, 1H), 2.10-2.22 (m, 1H), 1.96-2.07 (m, 1H), 1.69-1.85 (m, 1H), 1.51-1.64 (m, 1H), 1.48 (s, 9H), 1.23 (d, J=7.15 Hz, 3H). MS (ESI) 463 (M+H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:15][C:16]([F:44])([F:43])[C:17]1[CH:41]=[C:40]([NH2:42])[C:20]2[NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)=[N:23][C:19]=2[CH:18]=1.[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([F:55])[C:53]=1[F:54])[CH:49]=O>C(Cl)(Cl)Cl>[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([F:55])[C:53]=1[F:54])[CH2:49][NH:42][C:40]1[C:20]2[NH:21][C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[C:35]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:28][CH2:29]3)=[N:23][C:19]=2[CH:18]=[C:17]([C:16]([F:15])([F:43])[F:44])[CH:41]=1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Nc1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(CNc2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaBH(OAc)3 (211 mg, 1 mmol, Aldrich) was added to a mixture of 5-(trifluoromethyl)-2-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-benzimidazol-7-amine (215 mg, 0.5 mmol, Example 58) and 3,4,5-trifluoro-benzaldehyde (88 mg, 0.55 mmol, Aldrich) in chloroform (2 mL) in one portion. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (30 mL), and washed successively with 1 N NaOH (15 mL) and brine (15 mL), dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with 25% EtOAc/hexane to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 575 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCOCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)CC2CCOCC2)c1C
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoate (0.80 g, 2.71 mmol) in acetonitrile (20 mL), cesium carbonate (1.75 g, 5.42 mmol) and methyl iodide (1.93 g, 13.6 mmol) were added. The resulting reaction mass was heated at 80° C. for 8 h. On completion, the mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give crude material which was purified by column chromatography to give the title compound (0.70 g, 84%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29].O>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH2:25]/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)/C=C/CBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1cc(SC/C=C/C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-di-tert-butyl-4-mercaptophenol (II) (590 mg; 2.48 mmol) in dry ether (10 ml), triethylamine (303 mg; 3 mmol) was added, and a solution of ethyl 4-bromocrotonate (580 mg; 3 mmol) in dry ether (5 ml) was added while cooling with ice, followed by stirring at room temperature for 2 hours. The reaction mixture was combined with water (50 ml) and extracted with ether (50 ml). The extract was washed with water (50 ml) two times and concentrated under reduced pressure. The crude intermediate product as pale yellow oil was dissolved in ethanol (30 ml), 10 % sodium hydroxide solution (3 ml) was added thereto, and the resultant mixture was stirred at room temperature for 2 hours. To the reaction mixture, acetic acid (2 ml) was added, and the resulting mixture was concentrated under reduced pressure to make a volume of about 10 ml, which was extracted with ethyl acetate (50 ml). The extract was washed with water (50 ml) two times, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on silica gel and eluted with ethyl acetate. The collected fractions were concentrated under reduced pressure, and the crystalline residue was recrystallized from n-pentane to give the objective compound (Ih) (270 mg). m.p., 104°-106° C. Yield, 34 %.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])[C:34](=[O:54])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][C:51](O)=[O:52])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:51](=[O:52])[CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:54])[CH:33]([OH:32])[CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])=[CH:18][CH:17]=1
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Reactant: O=C(O)COCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCC(=O)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
31 is prepared similarly to 18 starting from 68 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (15), 76 mg of [2 ({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)-ethoxy]acetic acid (27), 62 μl of diisopropylcarbodiimide and 44 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 31: C43H55F2N3O14 (875.93) MS (ESI) 876 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.OC1C(C#N)=CNC(=O)C=1.CS(O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)(=O)=O.C(C1C=NC(N2CCC(CS([O-])(=O)=O)CC2)=NC=1)CC>>[Cl:1][C:2]1[C:3]([O:18][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Agent: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Agent: N#Cc1c[nH]c(=O)cc1O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
The intermediate was prepared according to the procedures described in Example 221 substituting 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile for 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate for 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate in Step B. MS (ESI) 392 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C([Li])CCC.[CH3:12][C:13]1[S:17][C:16]([C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27](F)(F)F)[CH3:19])=[CH:15][CH:14]=1>CCOCC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:27]1[C:22]2[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=[C:18]([C:16]2[S:17][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:19]=1
Reactant: CC(=Nc1ccccc1C(F)(F)F)c1ccc(C)s1
Reactant: CN(C)CCN
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(-c2cc(NCCN(C)C)c3ccccc3n2)s1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
A solution of N,N-dimethylethylenediamine (0.66 ml, 6.0 mmol) in ether (15 mL) was treated with a commercial solution of n-butyllithium (6.0 mmol) in hexanes at -10° C., and the resultant mixture was stirred at -10° C. for 20 minutes before treatment with a solution of ketimine 12q (0.42 g, 1.5 mmol) in ether (5 mL). The mixture was stirred at -10° C. for an additional 45 minutes, and then quenched with water (0.5 mL). The organic layer was concentrated on a rotary evaporator to give a crystalline residue. Removal of colored polymeric materials on a short silica gel column by eluting quinoline 9g with hexanes/Et3N/EtOH (7:2:1) was followed by crystallization of the purified 9g from hexanes; yield 82%, mp 103°-105° C.