Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[CH2:34][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1CCCCC1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (0.44 mL, 3.1 mmol) in THF (5 mL) at 0° C. was added n-butyllithium (1.6 M in hexane, 1.94 mL, 3.1 mmol) dropwise and the solution is stirred for 20 min. After cooling the solution to −78° C., a solution of cyclohexanone (0.32 ml., 3.1 mmol) in THF (2 mL) is added dropwise. The solution is stirred at −78° C. for 1 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (1.0 g, 3.1 mmol) in THF (3 mL) is added dropwise. The solution was warmed to RT and stirred for 18 h. Saturated NaHCO3 is added and the mixture is extracted with EtOAc. The organic layer is washed with water then brine and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 20-33% EtOAc/hexane as eluent to give the title compound as a yellow liquid. NMR (CDCl3): δ 7.79-7.77 (d, J=8.33 Hz, 1H), 7.46-7.31 (m, 5H), 6.93 (d, J=1.51 Hz, 1H), 6.81-6.79 (dd, J=1.52 Hz, 8.34 Hz, 1 H), 5.22 (s, 2H), 3.20-3.16 (m, 1H), 2.53-2.39 (m, 2H), 2.33-2.25 (m, 1H), 2.11-2.05 (m, 1H), 1.96-1.90 (m, 1H), 1.85-1.79 (m, 1H), 1.66-1.55 (m, 2H), 1.35-1.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1.4 g (0.0046 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-100) in 30 mL of dimethylformamide was added 2.27 g (0.0069 mole) of cesium carbonate, followed by 0.87 mL (0.014 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water was added to the residue to give a precipitate. The solid was collected by filtration, washed with water and dried under vacuum to give 1.37 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-100) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CS(C)=O.CCOC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: ClCCCn1nnc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of benzotriazole (303 mg, 2.54 mmol) and powdered NaOH (101 mg, 2.52 mmol) in DMSO was added 1-bromo-3-chloro propane (437 mg, 2.77 mmol). The reaction mixture was stirred for 16 h at 20° C. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O (100 mL) and saturated NaCl (100 mL), dried over MgSO4 and concentrated in vacuo. Column purification (hexanes:EtOAc 4:1) yielded 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (167 mg, 34%). The title compound was prepared according to Example 286, Step C as a yellow oil (21 mg, 42%) from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b]l[1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.88-1.98 (m, 3H), 1.99-2.18 (m, 2H), 2.20-2.41 (m, 5H), 2.51-2.60 (m, 1H), 2.64-2.71 (m, 1H), 2.89-3.00 (m, 1H), 3.03-3.13 (m, 2H), 3.21-3.27 (m, 1H), 3.47-3.60 (m, 1H), 3.76-3.88 (m, 1H), 4.73 (t, 2H, J=6.6 Hz), 6.61 (t, 1H, J=7.4 Hz), 6.84 (d, 1H, J=6.6 Hz), 6.94 (dd, 1H, J=1.1, 8.1 Hz), 7.37 (td, 1H, J=1.1, 7.4 Hz), 7.49 (td, 1H, J=1.1, 7.8 Hz), 7.57 (d, 1H, J=8.0 Hz), 8.07 (d, 1H, J=8.4 Hz) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12](C)[CH3:13]>CCO>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CN(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 40 °C
Yield: 89.6 %

Procedure:
A mechanically stirred mixture of 2-chloro-5-nitropyridine (56.25 g, 0.355 mol) and absolute EtOH (960 ml), under nitrogen was treated, during 15 minutes with 25% aqueous trimethylamine (217 g). The mixture warmed to 40° C. and a thick yellow precipitate formed; it was warmed to 80° C. during 1 hour, cooled to ambient temperature and filtered. The solid was washed with cold 20% H2O-EtOH and dried to give 53.2 g of the titled product, m.p. 151°-152° C.
Reaction SMILES: [H][H].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH3:10])[CH:5]1[OH:11]>[Pt]>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: CC1CCCC(C)C1O
Reactant: [H][H]
Agent: [Pt]
Product: Cc1cccc(C)c1O
Yield: 95 %

Procedure:
500 ml of catalyst were introduced into a fluidized-bed reactor having a capacity of 0.7 liter. The catalyst contained 0.25% by weight of platinum on a magnesium aluminum spinel carrier and had a particle size of from 0.2 to 0.6 mm and a BET specific surface area of 125 m2 /g. The temperature of the reactor was brought to 275° C., and the mixture which was preheated to this temperature and consisted of 200 liters/hour of nitrogen and 20 liters/hour of hydrogen was passed in. 60 g/hour of gaseous 2,6-dimethylcyclohexanol were passed continuously through the fluidized catalyst bed produced in this manner. The reaction product was obtained by cooling the exit gases, and was distilled. 100 g of 2,6-dimethylcyclohexanol were converted to 90.5 g (yield: 95% of theory) of 2,6-dimethylphenol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].Cl>CN(C=O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)([O-:21])=[O:20]
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a stirred solution of 4-(2-hydroxyethyl)morpholine (1.7 g, 12.96 mmol) in DMF (2 mL) was added NaH (0.52 g, 60% dispersion in oil, 12.96 mmol). The reaction mixture was stirred at r.t. for 10 minutes, then cooled to 0° C. A solution of 2-fluoronitrobenzene (1.5 g, 10.63 mmol) in DMF (2 mL) was added over 5 min. The reaction mixture was allowed to warm to r.t., then was stirred for 2 h before the addition of 2M aqueous HCl (50 mL). The aqueous fraction was separated, neutralised with aqueous sat. NaHCO3 and extracted with EtOAc (2×50 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.4 g, 90%) as a yellow oil that was used without further purification. LCMS (ES+) 253.0 (M+H)+, RT 2.06 minutes (Method 5).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1(C)C=CC=CC=1.O>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: NCCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 90 %

Procedure:
A solution of 3-bromopropylamine hydrobromide (547.5 g, 2.5 mol) in 500 mL of toluene and 600 mL of water was cooled to 6° C. and then aqueous potassium carbonate (1L, 5M, 5 mol) and benzyl chloroformate (1L, 2.63 mol) were added simultaneously at a rate such that the reaction temperature remained below 16° C. The mixture was allowed to warm to room temperature and then stirred for 80 minutes and 1.3L of additional water was added. The aqueous later was separated and extracted with toluene (1×300 mL). The combined organic layers were washed with 1N hydrochloric acid (2×300 mL), saturated sodium bicarbonate (1×300 mL) and saturated aqueous sodium chloride (1×300 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was extracted with hexanes (3×1L). The extract was concentrated under reduced pressure at 50° C. to give benzyl (3-bromopropyl)aminoformate (612.9 g, 2.25 mol) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)c1

Procedure:
Example 75 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.44 (s, 1H), 7.40–7.37 (m, 2H), 7.32–7.25 (m, 4H), 6.96 (d, 1H, J=7.2 Hz), 6.81 (br s, 1H), 3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.94 (d, 2H, J=12.4 Hz), 2.49 (m, 1H), 2.34 (t, 4H, J=6.4 Hz), 2.20 (s, 3H), 1.99–1.81 (m, 6H), 1.72–1.55 (m, 10H); ESMS m/e: 496.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>CCO.C1COCC1.[Pd]>[OH:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2ccc(C(=O)O)c(O)c2)cc1
Reaction time: 0.42 h
Yield: 35 %

Procedure:
A slurry of 2-hydroxy-4-(4-nitro-phenoxy)benzoic acid (950 mg; 3.5 mmol) in 99% EtOH (30 mL) and THF (0.5 mL) was added 5% Pd/C (100 mg) and stirred under H2 atmosphere (1 atm.) for 25 minutes. The black solution was filtered through celite and evaporated to dryness yielding 300 mg (35%) of a brown powder. Mp. 187-188° C.; MS (ESI+): 246 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26]>ClCCl>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:15])[C:23]2[CH:22]=[CH:21][C:20]([O:25][CH3:26])=[C:19]([F:18])[CH:24]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 17.2 %

Procedure:
To an ice-cooled slurry of AlCl3 (2.01 g, 15.1 mmol) in dichloromethane (10 mL) was slowly added 4-chlorocarbonyl-benzoic acid methyl ester (2 g, 10.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 20 min in the ice bath then 2-fluoroanisole (1.4 mL, 12.1 mmol) in dichloromethane (5 mL) was added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into ice cold 1 N HCl (10 mL) and the mixture was stirred for 15 min. The reaction mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude solid was triturated with hot hexanes, filtered and washed with hexanes to give 0.5 g (17%) of compound 173 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 3.89 (s, 3H), 3.94 (s, 3H), 7.32 (t, J=8.5 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.59-7.63 (m, 1H), 7.81 (d, J=8.2 Hz, 2H), 8.04 (s, 1H), 8.10 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:37]([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=1[F:28])(=[O:39])=[O:38]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(F)c2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (3.0 g, 12 mmol) in tetrahydrofuran (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 15.5 mL, 15.5 mmol). The reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was cooled to −78° C. and 2,3,4-trifluorobenzene-1-sulfonyl chloride (1.8 mL, 12 mmol) was added. After 2 further lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 2.4 mL, 2.4 mmol) and 2,3,4-trifluorobenzene-1-sulfonyl chloride (0.3 mL, 2.4 mmol) were added. After 1 h, the reaction mixture was allowed to warm to ambient temperature, diluted with ethyl acetate (150 mL), washed with saturated ammonium chloride (2×125 mL) and brine (2×125 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with methanol to afford N-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a pale yellow solid in 67% yield (3.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][OH:45]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH2:43][CH2:44][OH:45])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCCO
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCO

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-amino-1-propanol (18 ul) according to Method A to give material was re-purified by reversed phase HPLC in absence of trifluoroacetic acid to give the title compound (11 mg). 1H-NMR (400 MHz, CD3OD) d 7.84 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.27-7.17 (m, 5H), 7.04 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 4.51 (m, 1H), 4.23 (dd, J=5.2 Hz, J=9.3 Hz, 1H), 3.25 (m, 1H), 3.15 (m, 1H), 2.75 (m, 1H), 1.62 (m, 2H), 1.36 (s, 9H); HRMS m/z 587.2493 (calc. of monoisotopic mass for C29H37N3O10 gives 587.2479).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:34])[CH:4]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.ClCCl>[ClH:1].[CH3:2][CH:3]([CH3:34])[CH:4]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)C(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A saturated solution of HCl gas in anhydrous diethyl ether was added portion wise to a solution of tert-butyl 4-(3-(2-methyl-1-phenylpropylamino)-4-nitrophenyl)piperazine-1-carboxylate (145 mg, 0.32 mmol) in anhydrous dichloromethane (0.5 mL). The resulting mixture was allowed to stand at room temperature for 30 min, and conversion was monitored by LCMS. The solvent was concentrated down in vacuo and co-evaporated with diethyl ether to yield 60 mg (53%) of the title compound: 1H NMR (400 MHz, CD3OD): δ 8.04 (dd, 1H), 7.36-7.32 (m, 4H), 7.28-7.24 (m, 1H), 6.34 (br d, 1H), 5.89 (br s, 1H), 4.45 (br d, 1H), 3.50-3.20 (m, 8H), 2.18 (m, 1H), 1.09 (d, 3H), 0.98 (d, 3H). MS (ESI) m/z: Calculated: 354.26; Observed: 355.6 (M++1) [corresponding to the free base].
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: 0 °C
Yield: 90.4 %

Procedure:
While stirring, D-leucine (76.6 g, 584 mmol, 1.0 eq) was dissolved into 920 mL of aq. 3.0 M HBr (2.8 mol, 4.7 eq) and cooled to 0° C. A solution of NaNO2 (64.5 g, 934 mmol, 1.6 eq) in 200 mL water was slowly added over 20 minutes and the mixture was stirred at 0° C. for 3 hours. The mixture was extracted 2× with 500 mL EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure, to yield (R)-2-bromo-4-methylpentanoic acid as a yellow oil (103 g). 1H-NMR (DMSO) δ (ppm): 0.9 (m, 6H), 1.6-1.7 (m, 1H), 1.7-1.9 (m, 2H), 4.3 (t, 1H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1(O)[CH2:31][CH2:30][C:25]2([O:29][CH2:28][CH2:27][O:26]2)[CH2:24][CH2:23]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1[CH2:31][CH2:30][C:25]2([O:26][CH2:27][CH2:28][O:29]2)[CH2:24][CH:23]=1
Reactant: OC1(c2cc(F)c(F)cc2F)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc(F)c(C2=CCC3(CC2)OCCO3)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask (3 L) under nitrogen atmosphere equipped with a Dean-Stark trap, toluene (350 mL), para-toluenesulphonic acid monohydrate (p-TSA) (1 g) and 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (94.2 g) were added and the mixture was refluxed overnight. Additional p-TSA (1 g) was added. Refluxing was continued overnight and then the reaction was stirred at room temperature for two more days. The reaction mixture was treated with 0.1N aqueous sodium hydroxide solution (500 mL) and extracted with heptanes (500 mL). The organic layer was washed with water (3×500 mL), dried over anhydrous sodium sulfate, filtered and evaporated to yield crude product which was purified by column chromatography (silica gel, gradient 2% to 40% ethyl acetate in heptanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Br:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Br:25])[CH:27]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc(Br)c1
Product: CC(NC(=O)c1coc(Oc2cccc(Br)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 56.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-bromophenol (45 mg, 0.26 mmol) to give the title compound (38 mg, 56%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH3:14].CO.[OH-].[Na+].Cl>O>[CH3:14][C:5]1[CH:6]=[C:7]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1ccc(C2(C)CC2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2(C)CC2)ccc1C(=O)O
Temperature: 80 °C
Yield: 85.1 %

Procedure:
2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid methyl ester (2.75 g, 13.46 mmol) was treated with methanol and 5 M aqueous sodium hydroxide solution (20.46 ml, 102.32 mmol). This solution was heated to 80° C. for 4 hours. The reaction mixture was concentrated until methanol was evaporated. A white solid was obtained. The solid was dissolved in 50 ml water under heating then cooled with an ice bath; acidified with 10 ml conc. hydrochloric acid. A white precipitate was formed; filtered; washed with water; dried under high vacuum over night to yield 2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid (2.18 g, 11.46 mmol) MS (ESI) 189.1 (M-H)−
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=O)[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:43]([NH:49][CH3:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:49]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH3:50])=[O:42])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCNC
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Product: CCCCCCN(C)C(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Yield: 71 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]pentanoic acid (0.12 g, 0.21 mmol) prepared in Example 128 and N-hexyl-N-methylamine (0.3 ml), the same procedure as shown in Example 129 was repeated to give the titled compound (0.10 g, yield: 71%) as a white powder (cis:trans=3:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH2:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](O)=[O:30])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:29]([C:28]1[C:32]([CH3:36])=[CH:33][CH:34]=[CH:35][C:27]=1[CH2:25][CH3:26])=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: CCc1cccc(C)c1C(=O)O
Product: CCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)OC
Yield: 46 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-ethyl-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 46% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-ethyl-6-methylbenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 513.1359. Calcd. mass, 513.1348 (M+H).