Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[Br-].[Na+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([OH:11])[CH3:10].ClCl>O1CCCC1>[CH3:10][C:9]1[O:11][CH:8]=[CH:7][C:6](=[O:1])[C:5]=1[OH:4]
Reactant: O
Reactant: CC(O)c1ccco1
Agent: ClCl
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1occc(=O)c1O
Yield: 55 %

Procedure:
In a 3-neck round bottom flask equipped with a stirring bar, a gas inlet tube and an addition funnel was added 20 ml of tetrahydrofuran, 50 ml of water and sodium bromide (0.20 mole). The solution was cooled to a temperature of 0° to 20° C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.18 mole) in 20 ml of tetrahydrofuran and this was added dropwise to the rapidly stirred reaction flask while gaseous chlorine (0.40 mole) is added via the gaseous inlet tube. The rate of the alcohol addition was such that a yellow orange color was maintained. The reaction temperature was kept below 20° C. with ice bath cooling. After the alcohol and chlorine had both been added to the reaction flask, the temperature was raised to reflux to distill off the tetrahydrofuran. The isolation procedure of Example 1 was used to isolate 12.47 g of pure maltol (55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[Br:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:11]1[CH2:12][CH:13]([CH:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[CH3:15])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10]1)=[O:37]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 84.5 %

Procedure:
To a stirred solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (XV-B-1) 0.25 g (0.62 mmol) in CH2Cl2 (30 mL) at RT, 0.10 ml (0.74 mmol) of Et3N and 0.062 mL (0.74 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 0.275 g (85%) as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:23])[CH2:16][CH2:15]3)[CH:12]=[N:13][C:9]=2[CH:8]=1)(=[O:6])=[O:5]>C(O)C>[CH3:3][S:4]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[OH:23])[CH2:16][CH2:15]3)[CH:12]=[N:13][C:9]=2[CH:8]=1)(=[O:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(=O)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium borohydride (189 mg) was added to a solution of 3-{4-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]piperidin-1-yl}-1-phenylpropan-1-one (2.07 g) in ethanol (40 ml) at 0° C., the mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was evaporated to dryness, the residue was redissolved in dichloromethane and washed with water (15 ml) and brine (15 ml) and dried. Removal of the solvent gave 3-{4-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]piperidin-1-yl}-1-phenylpropan-1-ol, 2.1 g, M+H 414.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-(trifluoromethyl)benzoyl chloride (179 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the title compound (171 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.BrC1C=C([C@H](CC2C=CC=CC=2)C(C)(S(N)=O)C)C=CC=1.[CH3:43][PH:44]([O-])([O-:48])[O:45][CH2:46][CH3:47].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@@:10]([NH:9][C@@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:3]=[C:2]([P:44]([CH3:43])(=[O:48])[O:45][CH2:46][CH3:47])[CH:7]=[CH:6][CH:5]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1)c1cccc(Br)c1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)([C@@H](Cc1ccccc1)c1cccc(Br)c1)S(N)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1cccc([C@@H](N[S@@](=O)C(C)(C)C)c2ccccc2)c1
Reaction time: 8 h

Procedure:
To (S)—N—((S)-(3-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 25-b, (17.8 g, 48.7 mmol), ethyl methylphosphite (7.9 g, 730 mmol) and Et3N (14.75 g, 146 mmol) in THF (150 ml) was added PdCl2(dppf) (3.55 g, 4.87 mmol). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum to provide the crude product, 25-c, (25 g). The crude product was used to the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].CI.[C:28](O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:28])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CI
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Reaction time: 1 h

Procedure:
A solution of 50.2 g of ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 300 ml of absolute 1,2-dimethoxyethane is added dropwise while stirring at 20° C. during 10 minutes to a suspension of 3.6 g of sodium hydride in 100 ml of absolute 1,2-dimethoxyethane. The reaction mixture is stirred for 1 hour, treated with 21.3 g of methyl iodide and stirred for a further 2 hours. The mixture is subsequently rendered neutral with 0.5 ml of acetic acid and evaporated to dryness under reduced pressure. The residue is dissolved in 500 ml of ethyl acetate, the solution shaken three times with 250 ml of water, and the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of hot methylene chloride, seeded, and treated with diethyl ether. There is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin- 3-yl)-benzoate, m.p. 141°-143° C.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N[C@@H](CC)CO)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](CO)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.8 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-1-hydroxymethyl-propylamino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (40 mg) is dissolved in a mixed solvent of methanol (0.3 ml) and tetrahydrofuran (1 ml) and thereto is added a 1M-aqueous sodium hydroxide solution (0.5 ml), and the mixture is stirred at room temperature for 30 minutes. To reaction mixture are added a 10% aqueous citric acid solution and a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-1-hydroxymethyl-propylamino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (41 mg). MS (m/z): 669 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.Cl.[NH2:31][C:32]1([CH2:35][OH:36])[CH2:34][CH2:33]1.C(N(C(C)C)C(C)C)C>ClCCl>[OH:36][CH2:35][C:32]1([NH:31][C:14]([C:12]2[CH:11]=[N:10][C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH2:34][CH2:33]1
Reactant: COCCOc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1
Reactant: NC1(CO)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOc1ncc(C(=O)NC2(CO)CC2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a suspension of 0.05 g (0.00016 mol) of 6-(4-chloro-phenyl)-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid in 2.0 ml dichloromethane was added 0.024 g 1-chloro-N,N,2-trimethyl-1-propenylamine and the mixture was stirred at room temperature for 30 min. To the resulting slightly brown solution was added 0.040 g of (1-amino-cyclopropyl)-methanol hydrochloride and dropwise 0.1 ml N-ethyldiisopropyl-amine. The mixture was stirred at ambient temperature for 30 min. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate to yield 0.035 g (55% yield) of the title compound as off white solid. MS (ISP) (M+H+)=378.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C:23]=3[N:24]2[CH3:27])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C:23]=5[N:24]4[CH3:27])=[CH:20][CH:19]=3)[C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 25.5 %

Procedure:
4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (259 mg, 1.09 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (400 mg, 1.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (145 mg, 25%) as a yellow solid: ESI MS m/z 521 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.C[O:16]B(OC)OC.C(OO)(=O)C>CCOCC.CCCCCC>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([OH:16])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(O)cn1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M hexane solution of n-butyllithium (23 mL, 58 mmol) was added over 30 minutes to a −78° C. solution of 5-bromo-2-methoxypyridine (10 g, 53 mmol) in ether (120 mL), keeping the temperature below −65° C. The slurry was stirred for 30 minutes, and then trimethylborate (6.1 mL) was added quickly to the reaction solution. Again the temperature was maintained below −65° C. The solution was stirred for 10 minutes, warmed to 15° C. and then cooled to −78° C. Peracetic acid (56 mmol) was added dropwise, while the temperature was kept at or below −65° C. After addition, the reaction was warmed briefly to −50° C., cooled back to −65° C., then stirred at approximately 25° C. overnight. The reaction was quenched with water (100 mL), and then extracted with ether (3×150 mL). The organic portions were combined and washed with aqueous NaHSO3 solution and brine. The organic portions were extracted two times with 2N aqueous NaOH solution. The pooled basic aqueous fractions were washed with Et2O and then acidified with NaHSO4. The product precipitated out as oil; the aqueous mixture was extracted three times with Et2O, the pooled ether fractions were dried with Na2SO4, and stripped of solvent in vacuo. Yielded 3.6 g of a brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:30][CH2:31][C:32]([O:34][CH3:35])=O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(#N)C.O>[CH3:35][O:34][C:32]1[O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:9]=[C:10]([O:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=4)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:36])[CH2:3][O:2][CH3:1])[CH:7]=3)=[CH:24][CH:25]=2)=[N:30][CH:31]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(=O)OC)[nH]2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncc(OC)o3)[nH]2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
Methyl N-[(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)carbonyl]glycinate (270 mg, 0.523 mmol) synthesized in Example (24a) was dissolved in acetonitrile (10 mL), and triphenylphosphine (410 mg, 1.56 mmol), triethylamine (0.22 mL, 1.58 mmol) and carbon tetrachloride (0.33 mL, 3.42 mmol) were added, followed by stirring at room temperature for 15 hours under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with ethyl acetate (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-40%) to afford the desired product (162 mg, yield 62%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1B(O)O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.O1CCOCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]=[O:9])=[CH:7][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Reactant: Clc1ccc(I)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: O=Cc1ccc(-c2ccc(Cl)cc2)c(F)c1
Yield: 89.5 %

Procedure:
2-Fluoro-4-formylphenyl boronic acid (263 mg, 1.57 mmol) was added to the mixture of 1-chloro-4-iodobenzene (250 mg, 1.05 mmol), PdCl2(PPh3)2 (36 mg, 0.5 mmol), and disodium carbonate (332 mg, 3.13 mmol) in a solution of water (1 mL) and dioxane (2 mL). The mixture was reacted at 130° C. for 22 min in a microwave reactor. After cooling, water was added, and the mixture was extracted with ethylacetate. The organic solvent was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in heptane to give the title compound (220 mg, 0.94 mmol, 90%) as a white solid. 1H NMR (D2O) δ 10.02 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.67 (d, J=10.4 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([C:15](=[O:24])[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:7][CH2:6]2.O.O.[Sn](Cl)Cl.Cl>C(O)C.CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([C:15](=[O:24])[CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN1CCOCC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: COc1cc2c(cc1N)N(C(=O)CCN1CCOCC1)CC2
Reaction time: 8 h

Procedure:
To a solution of 5-(methyloxy)-1-[3-(4-morpholinyl)propanoyl]-6-nitro-2,3-dihydro-1H-indole (0.44 g, 1.31 mmols) in absolute ethanol (150 mL) and DMA (20 mL) was added tin(II)chloride dihydrate (1.77 g, 7.84 mmols) and 1M HCl (3.0 mL). After overnight stirring, reaction was quenched with excess saturated Na HCO3 solution, stirred for one hr. and filtered through celite which was rinsed with methanol. After organic solvent removal, the aqueous layer was extracted with dichloromethane (2×200 mL), the organic layers were combined, adsorbed to silica gel and purified by column chromatography (DCM to 5% MeOH/DCM+0.1% NH4OH) to afford 5-(methyloxy)-1-[3-(4-morpholinyl)propanoyl]-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=306.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[NH:15]([C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([CH3:32])[C:26]([CH3:34])([CH3:33])[CH2:25]2)=[O:22])=[CH:19][CH:18]=1)[NH2:16].C(O)(=O)C>C(O)C>[O:6]=[C:4]1[N:15]([C:17]2[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]3[CH2:25][C:26]([CH3:33])([CH3:34])[N:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH2:29]3)=[O:22])=[CH:19][CH:18]=2)[NH:16][C:2]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:3]1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Reactant: CCOC(=O)CC(=O)c1cnccn1
Solvent: CCO
Solvent: CC(=O)O
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-n3[nH]c(-c4cnccn4)cc3=O)cc2)CC1(C)C

Procedure:
3-Oxo-3-pyrazin-2-yl-propionic acid, ethyl ester (78 mg) and 4-hydrazino-N-(1,2, 2,6,6-pentamethyl-piperidin-4-yl)-benzamide (141 mg) were dissolved in ethanol (3.5 ml) and acetic acid (0.5 ml) and the solution stirred at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product. LC/MS: main peak is product (m/z: 434)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6]2)#[N:2].C1C(=O)N([Br:28])C(=O)C1>CC#N>[Br:28][C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C#N)ccc2c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2cc(C#N)ccc2c1Br
Yield: 91 %

Procedure:
A solution of 140 (4.48 g, 18 mmol) and NBS (3.85 g, 21.6 mmol) in MeCN (80 mL) was stirred at reflux for 1 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2, washed with 10% aqueous Na2SO3, water, dried, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give tert-butyl 1-bromo-6-cyano-2-naphthylcarbamate (141) (5.69 g, 91%): mp (iPr2O/hexane) 164-166° C.; 1H NMR [(CD3)2SO] δ 9.01 (s, 1H), 8.63 (d, J=1.5 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.93 (dd, J=8.9, 1.8 Hz, 1H), 1.50 (s, 9H). Anal. (C16H15BrN2O2) C, H, N, Br.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17](Br)[CH3:18])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(O)C>[OH:25][CH2:24][CH2:26][NH:27][CH2:18][CH2:17][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:21]=[CH:22][CH:23]=[C:8]([CH:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:7])[CH:9]=1)=[O:20]
Reactant: CC(Br)C(=O)NCCCOc1cccc(C(C)N2CCCC2)c1
Reactant: NCCO
Solvent: CCO
Product: CC(c1cccc(OCCCNC(=O)CCNCCO)c1)N1CCCC1

Procedure:
500 mg of the amide compound obtained in step (A) was heated under reflux for 2 hours in 1 ml of ethanolamine and 1 ml of ethanol. The solvent was distilled off under reduced pressure, and potassium carbonate was added. The mixture was extracted with chloroform. The solvent was distilled off, and the residue was purified by TLC (developing solvent: chloroform/diethylamine=10:1) to afford 355 mg of N-[3-(2-hydroxyethylamino)propionyl]-3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine.
Reaction SMILES: C(S([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])(=O)=O)C1C=CC=CC=1.CC(OC(N[C@H](C(O)=O)CCCCNC(OCC1C(Cl)=CC=CC=1)=O)=O)(C)C.C(N)(C)(C)C.F.C1(OC)C=CC=CC=1>>[NH2:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: N[C@@H](CCCCNS(=O)(=O)Cc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Agent: F
Solvent: CC(C)(C)N
Solvent: COc1ccccc1
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Boc-Lys(Xys)-OH (124.4 mg, 0.3 m.mol), Nε -benzylsulfonyllysine (90 mg., 0.3 m.mol) and Boc-Lys-(2-Cl-Z)-OH.t-butylamine salt (146.4 mg, 0.3 m.mol) are each treated with hydrogen fluoride (2 ml) in the presence of anisole (0.1 ml) at -20° C. for one hour. After the hydrogen fluoride is distilled off, the residue is dissolved in water (50 ml). An aliquot of the solution is taken and the lysine content of the sample is determined by an amino acid analyzer. The % yields of lysine are calculated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[C:4](=[O:15])[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:37][CH2:36][CH2:35]1>>[C:36]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[C:4](=[O:15])[N:3]=1)(=[O:37])[CH3:35]
Reactant: C[C@@H](O)[C@H](CO)Cn1ccc(N)nc1=O
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(=O)Nc1ccn(C[C@@H](CO)[C@@H](C)O)c(=O)n1
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 45 (1.3 g, 2.7 mmol) in 38 ml of THF was added 2.3 ml of 1M TBAF in THF. The reaction was stirred for 24 hrs, concentrated and chromatographed on silica eluting with, first, 10% MeOH in dichloromethane and, second, with 15% MeOH in dichloromethane. Concentration of the pure product fractions afforded 0.5 g (72%) of 46 as white amorphous solid. 1H NMR (DMSO-d6): δ10.81 (s, 1H), 7.98 (d, J=7 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 4.58 (d, J=5 Hz, 1H), 4.48 (t, J=5 Hz, 1H), 3.82 (d, J=7 Hz, 2H), 3.67 (m, 1H), 3.46 (m, 1H), 3.38 (m, 1H), 2.09 (s, 3H), 1.89 (m, 1H), 1.09 (d, J=6 Hz, 3H).