Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:15][C:16]#[C:17][CH3:18])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28]>>[OH:28][NH:27][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:15][C:16]#[C:17][CH3:18]
Reactant: NO
Reactant: CC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: CC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 45 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.15 g of the product was isolated. Yield 45%; white solid; mp 190° C.; MS: 377.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, J=13.8 Hz, 1H), 3.74 (d, J=13.8 Hz, 1H), 7.50-7.58 (m, 2H), 7.80-7.95 (m, 3H), 8.35-8.40(m, 1H), 8.74-8.79 (m, 2H), 11.1 (brs, 1H), IR (KBr, cm−1): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s; Anal. Calc'd for C18H17FN2O4S.HCl.0.5H2O: C, 51.24; H, 4.54; N, 6.64. Found: C, 51.21; H, 4.35; N, 6.46.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:14][CH:13]2[O:15][CH:9]([CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:12]2)[CH2:8]1.[CH3:27][C:28]1[C:32]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1.C(N(CC)CC)C>C(Cl)Cl>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:11]2[CH2:10][CH:9]3[O:15][CH:13]([CH2:14][N:7]([CH2:6][CH2:5][NH:4][S:33]([C:32]4[C:28]([CH3:27])=[N:29][O:30][C:31]=4[CH3:37])(=[O:35])=[O:34])[CH2:8]3)[CH2:12]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: N#Cc1ccc(OCCN2CC3CN(CCN)CC(C2)O3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1S(=O)(=O)NCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile tri hydrochloride salt (1 g, 2.35 mmol; Prep F) and 3,5-dimethylisoxazole-4-sulfonyl chloride (0.597 g, 3 mmol) were dissolved in DCM (25 mL). Triethylamine (1.95 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature overnight under a nitrogen amosphere. The reaction mixture was concentrated and then redissolved in DCM (25 mL) and transferred to a phase separator. The DCM layer was washed with water (30 mL) and the layers were separated. The retained water was extracted with DCM (25 mL) and the layers were separated. The combined DCM fractions were concentrated under reduced pressure. Purification was performed by precipitation from a mixture of DCM, EtOAc and IPA to give a solid material (0.2 g, 17%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24]>CS(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1
Reactant: Oc1ccccc1Cl
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
142 mg (1 mmol) of 2,4-difluorobenzaldehyde were dissolved in 5 ml DMSO and taken and combined with 200 mg (1.45 mmol) of K2CO3. 128 mg (1 mmol) of 2-chlorophenol were dissolved in 10 ml DMSO and added and stirred for 2 days at ambient temperature. The reaction mixture was filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. The substance was purified by reversed-phase chromatography.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[C:11]([CH2:13][N:14]3[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[N:12]=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cccc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [OH-].[K+].[CH3:3][Si:4]([CH3:28])([CH3:27])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:11]([C:22]([O:24]CC)=[O:23])=[CH:10]2.CO.O>O1CCOCC1>[CH3:3][Si:4]([CH3:28])([CH3:27])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:11]([C:22]([OH:24])=[O:23])=[CH:10]2
Reactant: CCOC(=O)c1cc2cccc([Si](C)(C)C)c2n1Cc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: C[Si](C)(C)c1cccc2cc(C(=O)O)n(Cc3cccc(F)c3)c12
Yield: 80.3 %

Procedure:
0.23 g (4.06 mmol) of potassium hydroxide is added to a solution of 0.5 g (1.35 mmol) of ethyl 7-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained according to the protocol described in stage 5.2, in 30 ml of a mixture (v/v/v) of methanol, water and dioxane. After stirring at reflux for three hours, the reaction mixture is one-third concentrated under reduced pressure and then taken up in 10 ml of water. The medium is acidified at pH 1 by successive additions of 1N hydrochloric acid. The precipitate is recovered by filtration, washed with water and then dried under reduced pressure. 0.37 g of the expected product is thus isolated, which product is used as it is in the subsequent stage.
Reaction SMILES: [Na].[CH3:2][CH2:3][OH:4].[F:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1>CCOC(C)=O>[CH2:3]([O:4][CH2:14][CH:12]([OH:13])[CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([F:5])=[CH:7][CH:8]=1)[CH3:2]
Reactant: Fc1ccc(OCC2CO2)cc1
Reactant: CCO
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCOCC(O)COc1ccc(F)cc1
Yield: 86.3 %

Procedure:
Slowly add sodium (1 g, 43.5 mmol) to absolute EtOH (80 mL) and stir the mixture at ambient temperature for 2 hours. Add 2-[(4-fluorophenoxy)methyl]oxirane (2.0 g, 11.89 mmol) in a single portion and stir for 16 hours at ambient temperature. Add 30 mL EtOAc; wash with H2O (10 mL) three times; then dry the organic layer over Na2SO4; filter; and concentrate the filtrate under reduced pressure to give the title compound (2.55 g, 86.3%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO) δ 7.15 (m, 2H), 6.95 (m, 2H), 5.05 (m, 1H), 3.95 (m, 3H), 3.49 (m, 4H), 1.05 (t, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(Cl)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (63 mg, 69%), MS (ISP) m/z=363.5 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8]([O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]([O:15]C)=O)=[O:9]>II.C1COCC1>[CH2:28]([C:7]1[C:8](=[O:9])[O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]=1[OH:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a 1-L, 3-necked, round-bottomed flask fitted with a Claisen adapter with N2 inlet, a West condenser and a thermocouple-J-KEM controller and a rubber septum was added 13.9 g (0.572 g-atom, 3.2 equiv.) of magnesium (from Chromasco) was added. A small flake of I2 (about 45 mg) was added and the mixture was heated to about 80° C. 1,2-Dibromoethane (3.4 g, 18 mmol) and 350 mL of THF were added to the hot Mg/I2 mixture to activate the metal surface. Methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate (82.9 g, 179 mmol) from Example 2, 1,2-dibromoethane (33.6 g, 179 mmol) and 400 mL of THF were added to the addition funnel. This mixture was slowly added to the Mg/THF mixture at reflux over about 1 h. The reaction mixture was stirred overnight (14 h) at about 60° C. The resulting yellow solution was decanted away from the metal into a 1-L, round-bottomed flask. The residual Mg metal was rinsed twice with 60 mL of THF. The combined THF solution was concentrated on a rotary evaporator. The syrupy mixture was taken up in 1750 mL of methylene chloride and added to a mixture of 500 mL of water, 200 mL of ice and 98 mL of 10% HCl in a separatory funnel. The aqueous layer was removed, the organic layer washed once with 200 mL of saturated sodium chloride, dried (NaSO4), filtered, and the solvent removed on a rotary evaporator. The crude white solid (66.7 g) was slurried in 100 mL of hexane, cooled to 0° C., filtered, and rinsed twice with 50 mL of cold hexane. The isolated white solid was dried in an oven at 40° C. under reduced pressure (10 mm Hg) overnight resulting in 28.4 g of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one (45-50% yield based on methyl (R)-3-hydroxytetradecanoate).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([C:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=2)[C:14]([CH2:30][O:31][C:32]2[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=2[CH3:41])=[C:13]([CH3:42])[N:12]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:12]=[C:13]([CH3:42])[C:14]([CH2:30][O:31][C:32]2[CH:37]=[C:36]([CH:38]([CH3:39])[CH3:40])[CH:35]=[CH:34][C:33]=2[CH3:41])=[C:15]([C:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=2)[N:16]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2=CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2=CCNCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidin-4-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (741 mg, 1.3 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. is added TFA (2 mL). The mixture is then stirred a room temperature for 16 h. After removal of the solvent and excess of TFA under reduced pressure, the residue is neutralized with sat. NaHCO3, and extracted with CH2Cl2. The extracts are dried over anhydrous MgSO4, concentrated and purified by silica gel column chromatography to provide the desired product. [mass expected (469.7); mass found (M+1: 470.6)].
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2=[O:19].C([Sn]([C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:20])=[C:3]([F:21])[C:2]=2[C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:7](=[O:19])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9]1)[CH3:13]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(CC)c2c(Br)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Yield: 80 %

Procedure:
5.4 g of ethyl 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example Z22), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 100 ml of hexane, and the resulting solid is filtered off with suction and dried. 4.53 g of ethyl 1-ethyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (80% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[C:11]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:31][CH3:32])[CH2:26]2)[CH:10]=1.C(=O)(O)[O-].[Na+].[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[C@@H:27]([CH2:31][CH3:32])[CH2:26]2)[CH:10]=1
Reactant: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
To a vigorously stirred solution/suspension of the product from example 69 part f) (0.393 g) and solid sodium bicarbonate (0.342 g) in DCM (3 ml) and water (3 ml) was added benzenesulfonyl chloride (0.21 ml) dropwise. The mixture was stirred for 16 h. The organic layer and 1 further DCM extract were combined and purified by passage through SCX resin eluting with MeCN, MeOH followed by 7M NH3 in MeOH. The basic fractions were concentrated in vacuo, dissolved in DCM (3 ml) and treated with TFA (20 ml) for 16 h. Concentration in vacuo and purification by RPHPLC gave the title product as a white foam (45 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14]([Cl:19])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Product: CCOC(=O)c1nc(Cl)c2ccccc2n1
Yield: 90 %

Procedure:
2.18 g (10 mmol) of 2-ethoxycarbonylquinazolin-4-one was suspended in 20 ml of phosphorus oxychloride. The mixture was refluxed for one hour, and the solvent was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate, and the obtained solution was washed with saturated sodium bicarbonate solution three times, dried over anhydrous sodium sulfate, filtered, and evaporated to give 2.13 g (90% mmol) of 2-ethoxycarbonyl-4-chloroquinazoline as a pale-yellow solid. LC/MS (m/z) 237 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:13]1[CH:26]=[CH:25][C:16]([CH:17]=[C:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>Cl>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:13]1[CH:26]=[CH:25][C:16]([CH:17]=[C:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1)C(=O)O
Yield: 85.6 %

Procedure:
Ethyl 4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl-(3-pyridyl)methyl]-α-methylcinnamate, 1.2 g (2.8 mmol), was dissolved in 20 ml of concentrated hydrochloric acid, and refluxed by heating for 2 hours. After cooling, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and the resulting substance was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column chromatography (ethyl acetate-ethanol(9:1)), and recrystallized from ethyl acetate, to give 0.96 g (85.6%) of 4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl(3-pyridyl)methyl]-α-methylcinnamic acid. The physical data are shown in Table 1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.[Cl:21]C1C=C2C(C=CC(COC3C=CC(CO)=CC=3)=N2)=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:21]
Reactant: OCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 72 %

Procedure:
The procedure from Example 6, part B was used except 3-(quinolin-2-ylmethoxy)benzyl alcohol was substituted for 4-(7-chloroquinolin-2-ylmethoxy)benzyl alcohol. The intermediate was obtained in 72% yield: mp 39°-43° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C)CCN(C)C.CCCCCC.C([Li])CCC.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>C(OCC)C>[CH2:36]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ncccc1NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1nccc(Cc2ccccc2)c1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of tert-butyl (2-methoxypyridin-3-yl)carbamate (25.1 g) and N,N,N′,N′-tetramethylethane-1,2-diamine (40.6 mL) in diethyl ether (374 mL) was added 1.6M n-butyllithium hexane solution (168 mL) at −78° C., and the mixture was stirred under argon atmosphere at 0° C. for 1 hr. To the reaction mixture was added benzyl bromide (24.9 g) at −78° C., and the mixture was stirred under argon atmosphere at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give the title compound (25.4 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:22]1([CH3:66])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:24]([C@@H:42]([CH:62]2[CH2:64][CH2:63]2)[CH2:43][O:44][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]1=[O:65])[CH:20]=[CH2:21]>C1COCC1.C(OCC)(=O)C>[CH2:19]([C@@:22]1([CH3:66])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:24]([C@@H:42]([CH:62]2[CH2:63][CH2:64]2)[CH2:43][OH:44])[C:23]1=[O:65])[CH:20]=[CH2:21]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tetrabutylammonium fluoride in THF (1M, 2.10 mL, 2.10 mmol) was added to a solution of diastereomers (5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 251, Step D, 488 mg, 0.700 mmol) in THF (10 ml).The reaction was stirred at ambient temperature for 2 hours. The mixture was diluted in ethyl acetate and washed with water and sat. aq. NaCl solution. The organic layer was dried over sodium sulfate. Silica gel chromatography eluting with ethyl acetate/hexane gave the title compound as a single diastereomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH:16]=O)=[CH:12][C:11]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:16][CH2:15][CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=2)[CH2:31][CH2:30]1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(OC)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(OC)cc2)n1

Procedure:
308 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methoxyphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (251 mg, 0.876 mmol), 1-(2-fluorophenyl)piperazine (208 mL, 1.314 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][C:28]3[N:33]=[CH:32][N:31]=[C:30]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=4[OH:44])[CH:29]=3)[CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.O>[N:5]1([CH2:4][CH2:3][O:44][C:35]2[CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=[CH:39][C:34]=2[C:30]2[N:31]=[CH:32][N:33]=[C:28]([O:27][C:24]3[CH:25]=[C:26]4[C:21]([CH:20]=[CH:19][CH:18]=[N:17]4)=[CH:22][CH:23]=3)[CH:29]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCOCC1
Reactant: Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(OCCN2CCOCC2)c1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
A solution of 4-(2-chloroethyl)morpholine hydrochloride (58 mg, 0.31 mmol, Aldrich) in DMF (1.0 mL) was stirred at room temperature and treated with K2CO3 (86 mg, 0.62 mmol). After stirring for 5 min, the resulting solution was added to a mixture of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethylphenol, (Example 191), (100 mg, 0.26 mmol) and NaH (13 mg, 0.52 mmol, 95%, Aldrich) in DMF (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h and then heated at 70° C. for 20 h. The resulting mixture was allowed to cool to room temperature and diluted with water. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (gradient 0% to 4.0% MeOH/CH2Cl2) afforded the title compound as a white solid. MP: 132–133° C. MS (ESI, pos. ion) m/z: 497 (M+1).