Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[O:23][C:16]3=[C:17]([NH2:22])[N:18]=[CH:19][C:20](Br)=[C:15]3[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)[CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][C:17]1[N:18]=[CH:19][C:20]([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)[CH:38]=2)=[C:15]2[CH:14]=[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)[O:23][C:16]=12
Reactant: Nc1ncc(Br)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-4-bromo-furo[2,3-c]pyridin-7-ylamine (0.449 g, 1.06 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.419 g, 1.11 mmol) in 1,4-dioxane (60 mL) and water (12 mL) was stirred for 10 min and degassed with nitrogen for 15 min. To this stirred mixture was added Pd(PPh3)2Cl2 (100 mg, 0.14 mmol) and the solution was degassed with nitrogen for an additional 5 min. Na2CO3 (168 mg, 1.59 mmol) was added and resulting mixture was stirred at 95° C. for 4 h. The reaction mixture was cooled to RT and the solvent was removed on a rotary evaporator to give the crude compound, which was purified by flash chromatography (2% MeOH:DCM) to afford 229 mg (36%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.45 (s, 9H), 2.10 (m, 2H), 2.22 (m, 2H), 2.97 (t, J=13.2 Hz, 2H), 4.35 (m, 3H), 5.59 (br, 2H), 7.34 (s, 1H), 7.71 (s, 1H), 7.81 (s, 1H), 7.92 (d, J=5.1 Hz, 2H), 8.32 (s, 2H). MS (ESI): 596 [M+H]+.
Reaction SMILES: CC(CC(O)CO)C.[F-:9].[K+].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C1(C)C(C)=CC=CC=1>>[Cl:18][C:17]1[C:12]([F:9])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: CC(C)CC(O)CO
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 150 °C
Reaction time: 6 h

Procedure:
In a 1-liter flange flask fitted with a distillation bridge and stirrer, 29 g (0.06 mol) of polyethylene glycol dimethyl ether 500 and 139 g (2.4 mol) of potassium fluoride were introduced at 120° C. into the melt of 576 g (3.0 mol) of 2,3-dichloronitrobenzene. Subsequently, 20 g (0.19 mol) of xylene were added and the reaction suspension was azeotropically dried by application of a vacuum of 60 mbar and heating to 150° C. After the xylene had been distilled off, the distillation bridge was replaced by a reflux condenser, the reaction suspension was heated to 190° C. and stirred for 6 hours at this temperature. Amount of 3-chloro-2-fluoronitrobenzene formed: 11 GC area-% after 6 hours.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2c(c1)CCO2
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 14.2 g. of N-isopropyl-2,3-dihydro-5-benzofuranamine in 300 ml. of glacial acetic acid, cooled to 15°±5°C. is added 4.9 g. of sodium isocyanate. The mixture is stirred at room temperature for 18 hours and then concentrated in vacuo. The residue is treated with 200 ml. of 2N sodium hydroxide solution and then extracted twice with chloroform. The combined chloroform extracts are dried with anhydrous magnesium fulfate, filtered and concentrated in vacuo to obtain an oil of 1-isopropyl-1-(2,3-dihydro-5-benzofuranyl)urea.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 224 (0.500 g, 0.00102 mol) was taken in THF (8 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (0.213 g, 0.0051 mol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1.[N:25]1[CH:30]=[CH:29][C:28]([Li])=[CH:27][CH:26]=1>>[OH:1][C:2]1([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:23][CH2:24]1
Reactant: O=C1CCCCC1N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: [Li]c1ccncc1
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCCC1(O)c1ccncc1)CC2

Procedure:
The title compound was prepared from rac-8-(2-oxo-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 4-pyridyl-lithium in analogy of the procedure described for the synthesis of (rac,cis)-8-(2-hydroxy-2-phenyl-cyclohexyl)-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 73e). (rac,cis) 8-(2-Hydroxy-2-pyridin-4-yl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as colorless solid, MS (ISP): 407.4 MH+.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])=[C:13]3[C:14](=[O:37])[C:15]4[C:20]([C:7]([C:8]=23)=[N:6]1)=[C:19]([O:21]CC1C=CC=CC=1)[CH:18]=[CH:17][C:16]=4[O:29]CC1C=CC=CC=1.ClCCl.B(Cl)(Cl)Cl>CO>[OH:29][C:16]1[CH:17]=[CH:18][C:19]([OH:21])=[C:20]2[C:15]=1[C:14](=[O:37])[C:13]1[C:8]3[C:7]2=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:44])[CH3:1])[C:9]=3[CH:10]=[CH:11][C:12]=1[NH:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]
Reactant: CN(C)CCNc1ccc2c3c(nn2CCN(C)C)-c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2C(=O)c13
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCNc1ccc2c3c(nn2CCN(C)C)-c2c(O)ccc(O)c2C(=O)c13
Temperature: 25 °C
Yield: 47.6 %

Procedure:
0.35 g (0.59 mmol) of 2-[2-(dimethylamino)-ethyl]-5-[[2-(dimethylamino)ethyl]amino]-7,10-bis(phenylmethoxy)-anthra[1,9-cd]pyrazol-6(2H)-one is dissolved in cold, dry dichloromethane (4 ml) and boron trichloride (4 ml, 1M solution in dichloromethane) is added dropwise over 30 minutes under argon. The reaction mixture is maintained at 0°-5° C. for 1 hour and then treated dropwise with cold methanol under argon. The mixture is then maintained at room temperature for 2 hours and then evaporated to dryness in vacuo. The resulting crude hydrochloride salt is dissolved in a minimum volume of methanol and then chromatographed on a column of silica gel (60A) using an eluting solvent of dichloromethane:methanol (80:20 v/v) and then dichloromethane:methanol:triethylamine (80:20:1 v/v). The major red band is collected and evaporated in vacuo to yield 0.115 g of the title compound as a red solid, m.p. 101 C; λmax (methanol) (E/cm/M) 580 nm (11200), 334 nm (7463), 290 nm (5667).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=O)=[C:15]([CH3:20])[N:14]=[C:13]3[CH2:21][CH2:22][CH3:23])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32].[CH3:38][NH2:39]>>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([NH:39][CH3:38])=[O:19])=[C:15]([CH3:20])[N:14]=[C:13]3[CH2:21][CH2:22][CH3:23])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32]
Reactant: CCCc1nc(C)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Reactant: CN
Product: CCCc1nc(C)c(C(=O)NC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1

Procedure:
From the product of Example 91 and methylamine according to the method of Example 103.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:30]=[CH:29][C:13]([C:14]([NH:16][C@H:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[CH3:18])=[O:15])=[CH:12][C:11]=1[Cl:31])=[O:9].[C:32](OC(=O)C)(=[O:34])[CH3:33].ClCCl.C(O)C.ClCl>C(O)(=O)C>[C:32]([NH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:30]=[CH:29][C:13]([C:14]([NH:16][C@H:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[CH3:18])=[O:15])=[CH:12][C:11]=1[Cl:31])=[O:9])(=[O:34])[CH3:33]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: ClCl
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 78 %

Procedure:
Prepared analogously to Example 124 from 4-((2R)-2-aminomethylpyrrolidin-1-ylcarbonyl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and acetic anhydride in glacial acetic acid. Yield: 78%; Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C24H25Cl2N5O3 (502.40); mass spectrum: (M+H)+=502/504/506 (chlorine isotope) and (M−H)−=500/502/504 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNCCCC
Reactant: O=C1CCc2cccc(Cl)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)C1CCc2cccc(Cl)c2C1
Yield: 28.7 %

Procedure:
8-Chloro-2-tetralone (3 gm, 16.6 mMol) in toluene (25 mL) was reacted with dibutylamine (5.6 mL, 33.2 mMol) and sodium borohydride (2.0 gm) as described in Example 2 to give the title compound as a colorless oil (1.4 gm, 29%). The tosylate salt was formed and recrystallization (ethyl acetate) gave a colorless, crystalline solid (m.p.=73°-74° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:17]5[CH2:18][CH2:9][CH2:10][CH2:11][CH2:16]5)=[CH:14][CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Reactant: C1CCNCC1
Product: O=C(CCN1CCCCC1)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCCC4)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (400 mg, 1.0 mmol) was treated with piperidine (3 mL) according to the general aminolysis procedure to give the desired product BR-ACO-17 (300 mg, 61%) as a dark yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.BrCC1C=CC([F:44])=CC=1Cl.C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C>>[Cl:1][C:2]1[CH:35]=[C:34]([F:44])[CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccc(F)cc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-chloro-4-fluoro-benzene and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [Na].[CH3:2][C:3]([CH3:8])([CH3:7])[C:4](=O)[CH3:5].[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=O)[CH3:10].C(O)(=O)C.O.[NH2:24][NH2:25]>>[C:3]([C:4]1[CH:5]=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:18])[NH:25][N:24]=1)([CH3:8])([CH3:7])[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NN
Reactant: CC(=O)C(C)(C)C
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Sodium metal (13.8 g, 0.5 mol) was added portionwise to ice-cold anhydrous EtOH (700 mL). After complete dissolution of the Na, a mixture of 3,3-dimethylbutan-2-one (50 g, 0.5 mol) and oxalic acid diethyl ester (77 ml, 0.5 mol) was added drop-wise. The reaction mixture was stirred in ice-salt bath until TLC indicated completion of the reaction. Acetic acid (38.1 ml, 0.5 mol) was added and the mixture was stirred at RT for 30 min. The reaction mixture was cooled in an ice-salt bath and treated with hydrazine hydrate (29.4 g, 0.5 mol). After complete addition, the mixture was warmed to RT and stirred until judged complete by TLC. The reaction mixture was concentrated under reduced pressure and re-dissolved in EtOAc. The EtOAc solution was washed with NaHCO3, brine and water, dried (MgSO4) and concentrated in vacuo. The resultant solid was washed with cold petroleum ether to give ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (49 g, 50% yield over two steps) as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.65 (s, 1 H), 4.38 (q, J=6.8 Hz, 2 H), 11.39 (t, J=6.8 Hz, 3 H), 1.35 (s, 1 H); MS (ESI) m/z 197.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:38]I>CN(C=O)C.O>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:38])[C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:11][CH2:12]1)=[O:5])[CH3:35]
Reactant: CI
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(=O)N(C)c1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Reaction time: 0.17 h
Yield: 50.3 %

Procedure:
A solution of N-{4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-fluoro-phenyl}-2-ethyl-butyramide (48 mg, 0.10 mmol) in DMF (2 mL) was treated with NaH (60% in mineral oil; 5 mg, 0.12 mmol). After 10 min, MeI (7 μL, 0.12 mmol) was added. After 3 h, the mixture was diluted with water and extracted with DCM. The organic layer was concentrated to give an oil, which was purified by PTLC to give an off white solid (25 mg, 50%). MS (ESI): mass calcd. for C29H41FN4O2, 496.96. m/z found, 497.5 [M+H]+. 1H NMR (CDCl3): 7.49-7.46 (m, 2H), 7.40-7.32 (m, 3H), 6.93-6.89 (m, 1H), 6.87-6.81 (m, 2H), 4.37 (s, 1H), 3.51-3.47 (m, 1H), 3.45-3.40 (m, 1H), 3.33-3.25 (m, 1H), 3.24 (s, 3H), 3.19-3.16 (m, 5H), 2.75-2.70 (m, 4H), 2.23-2.19 (m, 1H), 1.63-1.56 (m, 2H), 1.41-1.33 (m, 2H), 1.12-1.05 (m, 6H), 0.81 (t, J=7.4, 6H).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:15]1([CH2:21][O:22][C@@H:23]([C@@H:27]([C@@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)O)[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]([OH:26])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1>[CH2:9]([O:8][P:7]([O:11][CH2:12][CH3:13])([CH2:6][C:24]1([O:26][C@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:23]1[O:22][CH2:21][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:25])=[O:14])[CH3:10]
Reactant: O=C(O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(CC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 15.6 ml of 1.6M n-butyllithium in hexane and 20 ml of tetrahydrofuran at -78° C., was added a solution of 3.80 g of diethyl methylphosphonate in 10 ml of tetrahydrofuran during 10 minutes. After 15 minutes at -78° C., a solution of 4.18 g of 2,3,5-tris-O-(phenylmethyl)-D-arabinonic acid, qamma-lactone [Y. Rabinsohn & H. G. Fletcher, J. Org. Chem., 32, 3452-3457 (1967)] in 15 ml of tetrahydrofuran was added during 5 minutes. After 30 minutes at -78° C. the solution was warmed to 0° C. during 5 minutes, stirred at 0° C. for 2 minutes, recooled to -78° C. and quenched with 3.0 ml of glacial acetic acid. The mixture was partitioned with dichloromethane-water. The organic layer was washed successively with water, sodium bicarbonate solution, water and brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (ethyl acetate-heptane) giving the desired compound as an oil, CMR δ 101.2 and 104.3 (doublets, corresponding to anomeric carbon of minor and major anomer, respectively).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33].O>O1CCCC1.C(OCC)(=O)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([N:9]1[C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:10]1=[O:12])(=[O:33])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-naphthalenesulfonyl chloride (471 mg) was added at 0° C., and the mixture was stirred at room temperature overnight. After water was added carefully, ethyl acetate (100 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=3:1 to 2:1) afforded 320 mg of white powder.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].Br[CH2:8][CH2:9][F:10].CC(=CC)C.[OH-:16].[Na+].OO>O1CCCC1>[F:10][CH2:9][CH2:8][C:1]1[CH2:5][CH:4]([OH:16])[CH2:3][CH:2]=1
Reactant: FCCBr
Reactant: [OH-]
Reactant: c1cc[cH-]c1
Agent: CC=C(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1CC=C(CCF)C1
Reaction time: 2 h
Yield: 16 %

Procedure:
To 25 ml of 2 M tetrahydrofuran solution of sodium cyclopentadienylide was added under ice-cooling and under nitrogen stream 6.3 g of 1-bromo-2-fluoroethane and stirred for 2 hours. The resulting reaction liquid was filtered with cerite, and the filtrate was added under ice-cooling and under nitrogen stream to a tetrahydrofuran solution of disiamylborane prepared by using 75 ml of 1 M borane-tetrahydrofuran complex and 18.5 ml of 2-methyl-2-butene and the resulting mixture was stirred for 8 hours. Then 3 N aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide were successively added under ice-cooling to the reaction liquid obtained above, and the resulting mixture was stirred for 1 hour. The reaction liquid thus obtained was extracted two times with diethyl ether. The combined ether layer was washed with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel column chromatography to obtain 1.1 g of (RS)-3-(2-fluoroethyl)-3-cyclopenten-1-ol. Yield 16%
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>COCCOC.C(OCC)(=O)C.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>[CH:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2ccc(F)cc2)cc1C=O
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-isopropoxy-benzaldehyde (504 mg, 2.07 mmol) in 1,2-dimethoxyethane (5 mL) were added tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol), 2M aqueous sodium carbonate (2.5 mL), and 4-fluorobenzeneboronic acid (396 mg, 2.83 mmol). The reaction mixture was stirred for 2 hours at reflux temperature, cooled, diluted with ethyl acetate, washed with water, saturated brine solution, dried (Na2SO4), and evaporated. The title compound was purified by flash chromatography eluting with 4% diethyl ether in hexane; yield 347 mg.