Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4].C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:1])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1OCC(=O)OCC
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(C(=O)CBr)cc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Bromine (4.25 ml; 85 mmol) in AcOH: CHCl3 (1:1; 10 ml) was added to a vigorously stirred solution of the compound of example 20b (25.92 g; 80 mmol) in AcOH:CHCl3 (1:1; 110 ml) at 55-60° C. for 15 min. The mixture was stirred at room temperature for 5 min. and poured over crushed ice and NaHCO3 and extracted with EtOAc. The EtOAc layer was washed with water, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound. Yield, 19.34 g, (60%); mp, 84-85° C. (EtOAc-PE 60-80° C.); analysis: C16H19O7Br: requires C, 47.66; H, 4.75; Br, 19.82; found: C, 48.08; H, 4.82; Br, 19.40%.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH:20]=1>>[S:23]1[C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]1=2
Reactant: Brc1cc2ccccc2s1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cc3ccccc3s1)O2

Procedure:
Reaction of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromobenzo[b]-thiophene under the conditions described in example 16 gave after chromatographic isolation and crystallization from ether/hexane colorless crystals with m.p. 120°-123° C.
Reaction SMILES: [F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[C:4]=1[C:16]([O:18]C(C)(C)C)=[O:17].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[C:4]=1[C:16]([OH:18])=[O:17]
Reactant: COc1ccccc1-c1noc(CF)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1noc(CF)c1C(=O)O

Procedure:
Treating tert-butyl 5-(fluoromethyl)-3-(2-methoxyphenyl)isoxazole-4-carboxylate with TFA/DCM (1:1) at room temperature for one hour followed by evaporation of DCM/TFA in vacuo provided the title compound. 1H-NMR (CD3OD, 400 MHz): δ 7.53-7.44 (1H, m), 7.42-7.35 (1H, m), 7.13-6.98 (2H, m), 5.74 (2H, d, J=47.2 Hz), 3.78 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)[CH3:33].Cl.C(N)C>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:27][CH:26]=1)[CH3:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (122 mg, 0.29 mmol) was taken up in DMF (2.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (152 ul, 0.87 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (165 mg, 0.434 mmol), and ethanamine hydrochloride (26.0 mg, 0.318 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 135 mg (85%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.82 (s, 1H), 9.83 (br. s., 1H), 8.25 (t, J=5.6 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 6.94-7.12 (m, 3H), 4.59 (d, J=13.1 Hz, 1H), 4.27 (br. s., 2H), 3.85-4.10 (m, 3H), 3.43 (d, J=10.4 Hz, 2H), 3.21-3.30 (m, 2H), 2.95-3.19 (m, 4H), 2.61-2.72 (m, 1H), 2.05 (d, J=11.8 Hz, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.1 Hz, 1H), 1.31-1.62 (m, 3H), 1.09 (t, J=7.2 Hz, 3H). [M+H] calc'd for C23H27N5O3, 449; found, 449. MP: 232.6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[CH3:1])[CH2:6][OH:7]
Reactant: [H][H]
Reactant: Cc1ccc(CO)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CO)cc1N
Yield: 94.8 %

Procedure:
4-Methyl-3-nitro benzylalcohol (9.7 g, 58 mmol) in ethanol (200 mL) was reduced under 4 atmospheres of hydrogen gas for 4 hours in the presence of 10% Pd/C (0.5 g) to yield after a standard workup 7.54 g (93%) of the title compound.
Reaction SMILES: [ClH:1].[N:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:22]=[C:21]([NH2:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1)=[N+]=[N-].[Sn](Cl)[Cl:25]>CO>[ClH:25].[ClH:1].[NH2:2][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:22]=[C:21]([NH2:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1
Reactant: Cl[Sn]Cl
Reactant: [N-]=[N+]=NCCc1ccccc1C1N=C(N)c2ccccc2N1
Agent: Cl
Solvent: CO
Product: NCCc1ccccc1C1N=C(N)c2ccccc2N1
Reaction time: 2 h

Procedure:
To a solution of 2-(2-(2-azidoethyl)phenyl)-1,2-dihydro-4-quinazolinamine hydrochloride (Example 50, 0.38 g, 1.16 mmol) in methanol (10 ml) was added tin dichloride (0.33 g, 1.73 mmol) and the mixture stirred for 2 h (effervescence). Evaporation and purification by RPHPLC eluting with trifluoroacetic acid/water/methanol (1:90:10, increasing the gradient to 1:5:95) gave the product, MS (+FAB) 266 ([M+H]+), 1H NMR (d6 -DMSO) 10.07 (1H, s), 9.29 (1H, s), 8.51 (1H, s), 7.98 (2H, s), 7.91 (1H, s), 7.69 (1H, d), 7.33-7.55 (4H, m), 6.7-7.0 (2H, m), 6.17 (1H, s), 2.9-3.1 (4H, m).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:28][O:27][C:25]([C:21]1[CH2:22][CH2:23][N:24]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[F:30])[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=1)=[O:26]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-fluorobenzaldehyde (471 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl-7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (382 mg) as yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([O:32]C)=[O:31])[CH2:8][CH2:7]1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=[O:31])[CH2:8][CH2:7]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of methyl 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (376 mg) in a mixture of THF-methanol (5-10 ml) was added 1N sodium hydroxide solution (3.0 ml) at room temperature, and the mixture was stirred at 50° C. for 24 hours. After concentration under reduced pressure, 1N hydrochloric acid was added to pH 3-4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether and hexane to give 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (346 mg) as yellow crystals.
Reaction SMILES: O.O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Na+].[C:14](#[N:17])[CH:15]=[CH2:16].C(O)(=O)C>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:16][CH2:15][C:14]#[N:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: C=CC#N
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a suspension of sodium 4-bromophenylsulfinate dihydrate (130 g, 0.53 mol) in water (600 mL) was added acrylonitrile (70 mL, 1.07 mol) and acetic acid (62 mL, 1.07 mol). The reaction was stirred for 1.5 h at 100° C. then cooled to room temperature. The solid was filtered off, washed thoroughly with water and dried over P2O5 to give 3-[(4-bromophenyl)sulfonyl]propanenitrile (125 g). δH (400 MHz, CDCl3): 7.27–7.22 (4H, m), 2.85 (2H, t, J 7.6), 2.30 (2H, t, J 7.6).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:25]
Reactant: CCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: CCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 83 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using ethylamine instead of methylamine, to the title compound (90 mg, 83%) which was obtained as a white solid. MS: m/e=338.4 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=O)=O.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K].O>CN(C)C=O>[C:26]1(=[O:36])[N:30]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCOS(C)(=O)=O)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[3-(3-methanesulfonyloxypropyl)phenoxy]-2-methylpropionate (1.93 g, 5.18 mmol) was dissolved in dimethylformamide (10.0 mL). Subsequently, potassium phthalimide (1.15 g, 6.22 mmol) was added thereto, and the mixture was stirred overnight at 80° C. Water was added thereto, and the resultant mixture was extracted with diethyl ether. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=5/1), thereby the target compound was obtained (1.8 g, 82%).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.Cl.C(OCC)(=O)C>C1COCC1>[OH:15][C:9]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=CCCC1
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.96 g (10 mmol) of 2-cyclohexen-1-one in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.61 g of the desired product (yield 94%).
Reaction SMILES: [H][H].[C:3]1([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH:15]([OH:20])[CH2:16][N:17]=[N+]=[N-])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[C:3]1([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH:15]([OH:20])[CH2:16][NH2:17])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(O)COc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: NCC(O)COc1ccc(-c2ccccc2)cc1
Yield: 106.9 %

Procedure:
Hydrogen was introduced into a mixture of 2.94 g of 3-(4-phenylphenoxy)-2-hydroxypropylazide (prepared as described in Preparation 83), 0.3 g of 10% w/w palladium-on-carbon and 60 ml of ethanol for 3 hours. At the end of this time, insolubles were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give 2.84 g of the title compound, melting at 137.7° to 146.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N-:16]=[N+]=[N-].[Na+]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[NH:16][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: O=C1CCCCC(Cc2ccc(Cl)cc2)N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To an ice-cold solution of 4.47 g of 2-(4-chlorobenzyl)cyclohexanone in 100g of polyphosphoric acid add 2.6 g of sodium azide while stirring. Stir the mixture for another 1.5 hours at 0° and for a further 8 hours at room temperature, pour it into ice water and then extract it with methylene chloride. After drying the organic phase over sodium sulfate distill off the solvent to obtain 2.85 g of the title compound as a light brown oil.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10](=[O:12])[CH3:11].C(O)(=O)C(O)=O>O>[OH:12][CH:10]([C:4]1([CH3:9])[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1)[CH3:11]
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: CC=O
Agent: O=C(O)C(=O)O
Solvent: O
Product: CC1=C(O)C(=O)C(C)(C(C)O)O1
Yield: 54.6 %

Procedure:
In a round-bottomed flask equipped with a stirrer and a condensor, 12.8 g (0.1 mole) of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone and 44 g (1.0 mole) of acetaldehyde were introduced into a solution of 3.0 g of oxalic acid in 100 ml of water. The mixture was stirred and refluxed for 1 hour. After cooling, the mixture was extracted 5 times with 25 ml portions of chloroform and the organic solvent was evaporated off. The residue was purified by chromatography on 50 g of polyamide. After elution by means of a 50/50 mixture of ether and petroleum ether, 9.4 g of the title compound was obtained (which corresponds to a yield of 54%). Recrystallization from ether gave the pure product with m.p. 112-114°C).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[NH2:14])([O-:3])=[O:2].[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]([NH2:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: Nc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
2-Nitro-6-trifluoromethyl-phenylamine (10.0 g, 48.5 mmol) was placed in a 200 mL round-bottom flask equipped with a magnetic stir bar. Glacial acetic acid (100 mL) and bromine (3.24 mL, 63.1 mmol) were added, and the mixture was stirred at RT for 18 h. The mixture was poured into ice (200 mL), and the excess bromine was quenched with 10% aq Na2S2O3 (25 mL). The precipitate was isolated by filtration and washed with water. The solid was air-dried and then dried under vacuum to yield 13.8 g (100%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.49 (d, J=2.3 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:2].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[Br:15][CH:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:2]
Reactant: CCc1nc2ccc(F)cc2[nH]c1=O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nc2ccc(F)cc2[nH]c1=O
Temperature: 80 °C
Reaction time: 20 h
Yield: 133 %

Procedure:
3-Ethyl-7-fluoroquinoxalin-2(1H)-one (20.61 g, 107.2 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (18.77 g, 64.34 mmol) suspended in carbon tetrachloride (1072 ml, 107.2 mmol). To the heterogeneous mixture was added benzoyl peroxide (3.463 g, 10.72 mmol) and the mixture was heated at reflux with stirring (oil bath temperature: 80° C.) for 20 h. After 20 h, the mixture was cooled to rt. After cooling, the mixture was poured into saturated aqueous sodium bicarbonate solution (1 L) with stirring. The precipitate was collected by filtration and washed with water (1 L) to give 3-(1-bromoethyl)-7-fluoroquinoxalin-2(1H)-one (23.19 g, 79.8% yield) as a tan solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]=1)[C:5](O)=[O:6].B>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:8]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Br)cc(CO)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 3-bromo-5-[(tert-butoxycarbonyl)amino]benzoic acid (13.6 g, 43.1 mol) in tetrahydrofuran (44 mL) at 0° C. was treated with 1 M borane in THF (64.6 mL, 64.6 mmol) dropwise and stirred at 20° C. for 1 h. The reaction mixture was concentrated, diluted with ethyl acetate (200 mL), and washed with 1 M HCl (100 mL) and brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a colorless oil that was used without further purification. LCMS for C12H16BrNO3Na (M+Na)+: m/z=323.9, 325.9.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:43])[CH2:29][CH2:30][C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[O:32])[CH2:24][CH:23]1[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:51].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:51].[F:50][C:46]1[CH:45]=[C:44]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28](=[O:43])[CH2:29][CH2:30][C:31]([NH:33][C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=3)=[O:32])[CH2:24]2)[CH:49]=[CH:48][CH:47]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CCC(=O)Nc2ccc(C(=O)O)cc2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(C(=O)CCC(=O)Nc2ccc(C(=O)O)cc2)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 107 mg of 4-({4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoyl}amino)benzoic acid in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. Diisopropylether was added thereto, and the resulting precipitate was collected by filtration, and dried under reduced pressure to obtain 28 mg of 4-({4-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-4-oxobutanoyl}amino)benzoic acid hydrochloride as a pale yellow solid.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH3:35])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].O1CCOCC1>Cl.C(Cl)Cl>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([CH3:35])[N:26]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of tert-butyl [(1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (200 mg, 1.65 mmol) dissolved in 4 M of HCl in 1,4-dioxane (10 mL, 40 mmol) was stirred at room temperature for 1 h. The reaction was diluted with methylene chloride, washed with saturated NaHCO3 solution, dried with sodium sulfate, filtered, and concentrated in vacuo to provide the desired product (0.15 g, 94%). LCMS calculated for C20H30F3N4O: (M+1) 399.2; found 399.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([CH2:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:7])=[O:6].[H-].[Na+].CN(C)C(=O)C>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:12]2[CH:22]=[CH:23][C:9]([CH:8]3[CH2:2][CH2:3][CH2:4][S:5]3(=[O:7])=[O:6])=[CH:10][CH:11]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS(=O)(=O)CCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(C2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-(3-bromopropyl)sulfonylmethyl-4'-chlorobenzophenone (2.5 g) and 60% sodium hydride (0.3 g) were added to N,N-dimethylacetamide (70 ml), and the mixture was stirred for 16 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product as a slightly yellow viscous substance 1.0 g, yield: 50%).