Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[OH:16])=[CH:5][CH:4]=1.[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:16][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[C:13]([CH3:14])[C:8]=1[CH2:7][C:6]1[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(Cc2c(C)cc(C)cc2O)cc1
Solvent: ClCCl
Product: COc1ccc(Cc2c(C)cc(C)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 2-(4-methoxybenzyl)-3,5-dimethylphenol (4.0 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroaceto-imidoyl-α-D-glucopyranose (8.9 g) in dichloromethane (100 mL) was added boron trifluoride diethyl-ether complex (2.5 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: dichloromethane). The solvent was removed under reduced pressure, ethanol was added to the residue, and the resulting crystals were collected by filtration. The obtained crystals were dried under reduced pressure to give 2-(4-methoxybenzyl)-3,5-dimethylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].OS(O)(=O)=O.[CH2:15](OC(OCC)OCC)[CH3:16]>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH:5]=[C:6]([O:7][CH2:15][CH3:16])[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C=C(C)OCC
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a solution of ethylacetoacetate (2.7 kg, 20.74 mol) in ethanol (4 L) was added conc.H2SO4 (4 ml) at 25° C. under a nitrogen atmosphere. The mixture was heated to 50° C. before adding triethylorthoformate (3073.6 g, 20.74 mol) drop wise. The mixture was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure to give the title compound (2.8 kg, 85%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.9 (s, 1H), 4.1 (m, 2H), 3.7 (m, 2H), 2.2 (s, 3H), 1.2 (m, 3H), 1.1 (m, 3H).
Reaction SMILES: [CH2:1]([CH2:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[CH2:1]([CH2:8][CH:9]([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCc1ccccc1)C(=O)O
Yield: 83.3 %

Procedure:
The diethyl benzylmethylmalonate (75 g) was combined with 300 ml of ethanol and a solution of 100 g potassium hydroxide in 300 ml of water and heated to a gentle reflux for 5 hours. After cooling, the mixture was extracted with diethyl ether (2×300 ml). The aqueous phase was then acidified with 120 ml concentrated hydrochloric acid, and extracted with diethyl ether (3×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to yield 49.2 g of benzylmethylmalonic acid as a yellow solid (83% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:25]([O-])(O)=O.[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:25])=[O:12]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccnc1Nc1ccc(-c2cccc(O)c2)cc1F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cccnc1Nc1ccc(-c2cccc(O)c2)cc1F
Yield: 38.4 %

Procedure:
To a mixture of 2-(3-fluoro-3′-hydroxybiphenyl-4-ylamino)nicotinic acid (1 g, 3.08 mmol) and NaHCO3 (0.5 g, 6.17 mmol) in acetone (20 ml) was added dropwise dimethyl sulphate (0.47 g, 3.70 mmol). The mixture was heated to reflux overnight and then concentrated. Ethyl acetate was added to the crude and washed twice with 4% solution of NaHCO3 and brine. The organic phase was then dried over MgSO4 and concentrated in vacuo to afford 0.4 g of solid beige pure enough for the next synthetic step. Yield=36%
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21]O)[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(Cl)Cl>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:14](=[O:17])[N:13]([CH3:18])[C:12]4[N:11]([CH2:24][C:20]([CH3:23])([CH3:21])[N:19]=4)[C:10]3=[N:9]2)=[CH:5][CH:6]=1
Reactant: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)c2cn(Cc3ccc(-c4ccccc4)cc3)nc2N2CC(C)(C)N=C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 2-(biphenyl-4-ylmethyl)-6-(1-hydroxy-2-methylpropan-2-ylamino)-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (17 mg, 0.042 mmol) in methylene chloride (1 mL), is added 2.0 M CH2Cl2 solution of thionyl chloride (63 μL, 0.126 mmol) under argon. The reaction mixture is stirred at r.t. overnight. The reaction is quenched with 5% NaHCO3, and the resulting mixture is purified by chromatography to give 11 mg of the final product as white solids (Yield: 68%). 1H NMR (400 MHz, DMSO-d6+CDCl3) δ 1.36 (s, 6H), 3.30 (s, 3H), 3.69 (s, 2H), 5.30 (s, 2H), 7.36 (m, 3H), 7.43 (m, 2H), 7.58 (m, 4H), 8.10 (s, 1H). MS (FAB) m/z 386.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.CCCCCC.[O:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21]1>C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([C:23]2([OH:26])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1ccocc1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cccc(Br)c2)CCOCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred −78° C. solution of 1,3-dibromobenzene (19.71 g, 81.05 mmol) in THF (150 mL) is added 1.6 M butyl lithium in hexane (50.66 mL, 81.05 mmol) and the reaction is stirred 10 minutes. 4H-Pyran-4-one, tetrahydro- (5.41 g, 54.04 mmol) is added dropwise and the reaction is stirred at −78° C. for 2 h. The reaction is quenched by addition of saturated aqueous ammonium chloride (25 mL) and is then diluted with minimal water and extracted with EtOAc. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure to afford a residue that is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (11.18 g, 76%). GC-MS (m/e): (79Br/81Br) 256, 258 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([O:11]C)=[N:10][C:5]2=[CH:4][CH:3]=1.O1CCOCC1.Cl>O>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: COc1nc2ccc(Cl)nc2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(Cl)nc2s1
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
To round bottom flask was added give 5-chloro-2-methoxy[1,3]thiazolo[5,4-b]pyridine (1-3) (5.76 g, 28.7 mmol), 1,4-dioxane (90 mL), and a 6N solution of HCl in water (23.9 mL, 144 mmol). The reaction mixture was then heated to 95° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 20 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted methanol and concentrated to give 5-chloro[1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-4) as a tan solid. HRMS (M+H)+: observed=186.9731, calculated=186.9727.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C@@H:7]([C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])[CH2:8][CH2:9][CH2:10][CH:11]=O)=[CH:4][C:3]=1[CH3:26].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][C:29]=1[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([O:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[C:3]([CH3:26])[CH:4]=2)[C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])=[CH:30][C:29]=1[CH3:36]
Reactant: Cc1cc(CN)ccc1F
Reactant: Cc1cc(O[C@H](CCCC=O)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(CNCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-5-(4-fluoro-3-methylphenoxy)-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-6-oxohexanal (70 mg, 0.19 mmol) in 3 mL DCE was added 4-Fluoro-3-methyl-benzylamine (32 mg, 0.23 mmol) followed by NaBH(OAc)3 (56 mg, 0.26 mmol) and AcOH (13.8 mg, 0.23 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[C:12]2[C:13](=[O:23])[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[C:12]2[C:13](=[O:23])[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COc1cc(OCc2ccccc2)cc2oc3ccccc3c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(O)cc2oc3ccccc3c(=O)c12

Procedure:
The compound (120 mg) prepared in Step 2 of Example 9, Pd/C (60 mg), and anhydrous ethanol (30 mL) were added and a hydrogen gas was supplied at a pressure of 50 psi, followed by hydrogen reduction reaction for 12 hours. The reaction mixture was filtered through celite and washed with 20 mL of DMF. The filtrate was combined, and the solvent was removed under reduced pressure. The resulting residue was directly used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[Cl:39][CH2:40][C:41]1[C:42]([CH3:47])=[N:43][O:44][C:45]=1[CH3:46].Cl>CN(C=O)C.CCOCC>[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:40][C:41]3[C:42]([CH3:47])=[N:43][O:44][C:45]=3[CH3:46])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1noc(C)c1CCl
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2c(C)noc2C)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 24 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (1.00 g, 2.281 mmol) in DMF (10 mL) is added K2CO3 (1.580 g, 0.011 moles). After stirring for 15 minutes 4-chloromethyl-3,5-dimethylisoxazole (0.35 g, 2.39 mmol) is added. The mixture is stirred for 24 hours. The solvents were removed under high vacuum. After diluting with ethyl acetate and washing with water and brine the solution is dried over MgSO4. Evaporation in vacuo affords a viscous oil which is dissolved in ether and treated with ethereal HCl to afford a foamy solid upon evaporation in vacuo. This solid is crystallized from ethyl acetate/hexane.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(O)(=O)C>[Br:27][CH:1]([C:3]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2]
Reactant: CCc1nc2cccc(C)c2c(=O)n1-c1ccc(F)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2nc(C(C)Br)n(-c3ccc(F)cc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a mixture of 1.969 g 2-ethyl-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (IX) (6.974 mmol, 1.000 equiv) and 0.687 g sodium acetate (8.37 mmol, 1.20 equiv) in 28 mL glacial acetic acid at 40° C. (external temperature, oil bath) was added a solution of 0.372 mL bromine (7.32 mmol, 1.05 equiv) dissolved in 5 mL glacial acetic acid dropwise by addition funnel over 30 min. After 2 h the reaction solution was poured into 250 mL water. The resulting mixture was stirred vigorously at room temperature for 1 h, after which time the precipitate was collected by vacuum filtration, rinsing with warm (ca. 40° C.) water (3×50 mL). The solid was dried in vacuo over phosphorous pentoxide overnight, affording 2.19 g of a white solid. m.p. decomposes upon heating. 1H NMR (CDCl3)δ2.04 (d, 3H, J=6.8 Hz), 2.82 (s, 3H), 4.51 (q, 1H, J=6.8 Hz), 7.15 (ddd, 1H, J1=2.4 Hz, J2=4.4 Hz, J3=8.4 Hz), 7.23 (dd, 1H, J1=2.8 Hz, J2=10.8 Hz), 7.25-7.31 (m, 2H), 7.56 (ddd, J1=2.8 Hz, J2 4.8 Hz, J3 8.8 Hz), 7.64 (2×d, 2×1H, J=5.2 Hz) ppm. MS (ESI+) 361.1 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Yield: 37 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (1.0 g, 3.83 mmol) in dioxane (10 ml) was added to a mixture of 2-aminonaphthalene (0.55 g, 3.83 mmol) and NaHCO3 (0.48 g, 5.71 mmol) in water (6 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (3:2, v/v) as eluent. The obtained product was crystallised from petroleum ether-ethyl acetate to give the title compound (0.52 g, 34%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.73 (3H, s); 6.67 (1H, d, J=16.0 Hz); 7.21-8.07 (11H, m); 8.16 (1H, s); 10.55 (1H, s).
Reaction SMILES: C(OC([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]([C@@H:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[CH:25]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:54].C(O)C>ClCCl>[ClH:54].[ClH:54].[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH2:8])=[CH:25][C:26]=1[C@@H:38]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:39][CH2:40][N:41]([CH:45]([CH3:46])[CH3:47])[CH:42]([CH3:44])[CH3:43])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1OCc1ccccc1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCN)ccc1OCc1ccccc1)C(C)C

Procedure:
Di-tert-butyl(7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenoxy}heptyl)imidodicarbonate (Preparation 17, 220 mg, 0.30 mmol) was dissolved in dichloromethane (6 ml) then hydrogen chloride (2M solution in diethyl ether, 6 ml, 12 mmol) was added and after 30 minutes, ethanol (1 ml) was added and left over night. The solvent was removed in vacuo to furnish the title compound as a pale brown foam, 190 mg.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>C(OCC)(=O)C.CN(C)C=O>[CH:26]1([O:17][C:15]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH:16]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(O)cc1Nc1ccc(F)cc1
Reactant: BrC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCCCC2)cc1Nc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To N,N-dimethylformamide 3.0 mL solution of methyl 2-(4-fluoroanilino)-4-hydroxybenzoate 0.30 g were added potassium carbonate 0.16 g and cyclohexyl bromide 0.42 mL at room temperature, and it was stirred at 80° C. for 8 hours. After the reaction mixture was cooled to room temperature,11.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=8:1] to give methyl 4-(cyclohexyloxy)-2-(4-fluoroanilino)benzoate 40 mg of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24][OH:25])[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33]1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.IC.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24][O:25][CH3:33])[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1csc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1
Reaction time: 0.08 h

Procedure:
120 mg (0.286 mmol) of compound from Example 100 above, 3-(4-fluorophenyl)-6-(4-hydroxymethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of DMF. 17 mg (0.429 mmol) of 60% NaH and a spatula of dibenzo-18-crown-6 are added. After stirring for 5 minutes, 27 μl (0.429 mmol) of iodomethane are added. The mixture is allowed to stir for 4 h at ambient temperature. A saturated NaHCO3 solution is added, the mixture is extracted with EtOAc and then with CH2Cl2 and the organic phase is concentrated to dryness without drying. The residue is taken up in MeOH, and the white precipitate is filtered off and washed with MeOH and then with a minimum amount of Et2O.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:14])/[CH:15]=[CH:4]/[C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Br:1]
Reactant: O=Cc1ccc(Cl)cc1Br
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(Cl)cc1Br
Yield: 60.7 %

Procedure:
2-Bromo-4-chlorobenzaldehyde (Boegesoe, Klaus P. et al., J. Med. Chem. (1983), 26(7), 93547) (6.3g, 28.7 mmol) and methoxycarbonylmethylenetriphenylphosphor-ane (10.5 g, 31.6 mmol) were refluxed in toluene (143 ml) for 1 hour. The reaction mixture was cooled and purified via chromatography (SiO2, acetone/hexanes 5/95) to yield the title compound as colorless crystals (4.8 g, 61%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CO[C:11](OC)([CH3:13])[CH3:12].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>O>[CH3:12][C:11]1([CH3:13])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: COC(C)(C)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC[C@H]2CCC(=O)N21
Temperature: 75 °C
Yield: 1198.3 %

Procedure:
To a mixture consisting of (R)-5-hydroxymethyl-2-pyrrolidinone (20 g, 174 mmol) in 2,2-dimethoxypropane (1.4 L, 11.400 mmol) was added camphorsulfonic acid (1.0 g, 4.3 mmol). The stirring mixture was heated to 75° C. for 20 hours. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate, diluted with water, and extracted with ethyl acetate. The combined organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography. Elution with methanol-dichloromethane (1:70 v/v) afforded the title compound as a white solid (21.2 g, 78%); TLC Rf 0.6 (solvent system: 25:75 v/v ethyl acetate-hexane); MS (ESI+) m/z 156.1 (M+H)+, 178.1 (M+Na)+; 1H-NMR (CDCl3) δ 4.3-4.2 (m, 1H), 4.1 (dd, 1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.2-2.1 (m, 1H), 1.9-1.7 (m, 1H), 1.7 (s, 3H), 1.5 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=O)[CH2:13][CH2:12][C:11]2=O)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:6][C:5]=1[C:17]([F:20])([F:18])[F:19])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCCC2)cc1C(F)(F)F
Yield: 99.5 %

Procedure:
To a solution of 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2,5-dione (400 mg, 1.39 mmol) in THF (10 mL) was added BH3 (1.39 mL of 1 M in THF, 1.39 mmol) dropwise. The reaction mixture was then refluxed under N2 atmosphere for 16 h. The reaction was cooled, quenched with methanol, and concentrated in vacuo to provide 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine as a yellow solid (360 mg, quantitative yield). M+H m/z 261.1.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](=[O:29])N(OC)C)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:7]=2[CH:8]=1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: Brc1cccc2occc12
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2c(Br)cccc2o1

Procedure:
The title compound (1.45 g) was prepared from 4-bromo-benzofuran (3.65 g, WO0109111) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (5.17 g) according to a procedure similar to that for Description 2.