Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][OH:12].[C:13]([O-])(=O)C.[Na+].C([O-])([O-])OCC>C(O)(=O)C>[CH2:9]([C:7]1[CH:6]=[CH:5][C:4]2[N:3]([N:2]=[CH:13][C:11]=2[OH:12])[CH:8]=1)[CH3:10]
Reactant: CCc1ccc(CO)[n+](N)c1
Reactant: CC(=O)[O-]
Agent: CCOC([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1ccc2c(O)cnn2c1
Temperature: 140 °C
Yield: 42 %

Procedure:
A mixture of 3.8 g of 1-amino-5-ethyl-2-hydroxy methylpyridinium chloride, 2.5 g of sodium acetate, 25 ml of acetic acid and 8.9 g of ethyl orthoformate was refluxed for 4 hours in an oil bath at 140° C. After evaporated under vacuum, to the residue was added water. The mixture was brought to pH 11 by the addition of potassium carbonate and extracted with ethyl acetate. Ethyl acetate extract was then dried over anhydrous sodium sulfate, decolorized with charcoal and concentrated to dryness. After purification of the oily residue by silica gel column chromatography, eluted with chloroform, the light brown viscous oil that had a yellowish green fluorescence by irradiating of the long wave ultraviolet rays (3650 Å) was obtained. By recrystallization from chloroform-methanol, 1.36 g of the desired product, pale yellow needles, were obtained. Yield: 42.0%, mp 78°-79° C. The result of elemental analysis was illustrated in Table 3.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:32]=[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:14]([CH2:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:32]=[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[C:14]([CH2:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CC(C)C(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
In 3 ml of ethanol is dissolved 0.55 g of ethyl 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-2-methylpropanoate, to which is added 1.5 ml of 5 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for two hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain 0.45 g of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-2-methylpropanoic acid as a white solid product.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>O1CCOCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:14][C:9]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[N:6]=[C:11]([CH3:13])[CH:10]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(O)c2cc(I)ccc2n1
Yield: 30.7 %

Procedure:
4-Iodoaniline (25 g), ethyl acetoacetate (17.8 g) and polyphosphoric acid (112.5 g) in dioxane (500 mL) were refluxed for 20 hours. The reaction was diluted with water (2 L) and solid sodium carbonate added until the solution reached pH 10.0. The resulting precipitate was isolated by filtration, washed with water and dried under vacuum. Trituration with ether gave the sub-title compound (10 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[CH3:23][O:24][C:25](=[O:29])[CH:26](Br)[CH3:27]>>[CH3:23][O:24][C:25](=[O:29])[CH:26]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2)[CH3:27]
Reactant: COC(=O)C(C)Br
Reactant: Cc1c(Cc2ccc(Cl)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Product: COC(=O)C(C)Oc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 34d using 8-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1H-quinolin-2-one and 2-bromopropionic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([F:14])([F:13])[C:8](OCC)=[O:9])=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[F:14][C:7]([F:13])([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: CCOC(=O)C(F)(F)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a solution of ethyl pyridin-4-yl-difluoroacetate (0.59 g) prepared in (1) in ethanol (10 mL) was added NaBH4 (0.11 g) at 0° C. The reaction mixture was stirred at RT for 2 hr. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, and then dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: ethyl acetate) to give the title compound (0.082 g, 1%).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:5][N:4]=1>CO>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=1
Reactant: COc1ncc(-c2ccccc2C)c(OC)n1
Solvent: CO
Product: Cc1ccccc1-c1c[nH]c(=O)[nH]c1=O
Yield: 90.2 %

Procedure:
To a solution of 2,4-dimethoxy-5-o-tolyl-pyrimidine (Prep52, 400 mg, 1.7 mmol) in MeOH (10 mL) 2N HClaq (3 mL) was added. After refluxing for 48 hours, the solvents were evaporated. The crude was triturated with ethyl acetate to give 310 mg of the desired product (90% yield) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH:9]([CH3:11])[CH3:10])=[CH:3][C:4](OCC)=[O:5].S(Cl)([Cl:14])=O.Cl>C1C=CC=CC=1>[CH3:1][C:2]([CH:9]([CH3:11])[CH3:10])=[CH:3][C:4]([Cl:14])=[O:5]
Reactant: CCOC(=O)C=C(C)C(C)C
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CC(=CC(=O)Cl)C(C)C

Procedure:
3,4-Dimethyl-2-pentenoic acid (XI, 4.1 g) was heated to a gentle boil with thionyl chloride (50 g) in benzene (50 mL) until the generation of hydrochloric acid gas ceased. Removal of the excess thionyl chloride and benzene by evaporation in vacuo followed by a distillation of the reaction product gave pure 3,4-dimethyl-2-pentenoylchloride (IX, 64° C. (9.5 mm)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C@@H:10]([C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([C@@H](N)C)C=CC=CC=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C@H:10]([C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: C[C@H](N)c1ccccc1
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 14.9 %

Procedure:
A mixture of (3R*,5S*)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (6.16 g), (S)-(−)-1-phenylethylamine (2.60 g) and ethanol (24 ml) was dissolved by heating to 70° C. and recrystallization was conducted. The precipitated crystals were collected by filtration, dissolved again in ethanol (7 ml) and recrystallization was carried out. The precipitated crystals were collected by filtration, and suspended in water. The suspension was acidified with saturated aqueous potassium hydrogen sulfate solution, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (915 mg) as a powder.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([F:30])[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([F:30])[CH2:28][CH2:29]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H](N)C[C@H]1CC[C@H](F)CC1)C(=O)OCc1ccccc1

Procedure:
A solution of benzyl (S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)-propyl(methyl)carbamate (200 mg, 0.47 mmol) in TFA/CH2Cl2 (15 mL, v/v 20%) was stirred for 1 h at rt, then quenched by addition of sat'd aq NaHCO3 solution until gas evolution ceased. The mixture was extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to obtain benzyl (S)-2-amino-3-(trans-4-fluorocyclohexyl)propyl(methyl)carbamate (140 mg, yield 93%). 1HNMR (CDCl3, 400 MHz): δ 1.42 (m, 4H), 1.64 (m, 4H), 2.98 (d, 3H), 3.21 (m, 1H), 3.50 (m, 1H), 3.90 (m, 1H), 5.13 (d, 2H), 7.33 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:21]1[CH:25]=[CH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 50 ml of pyridine were dissolved 2.5 g of 5-fluorouracil and 0.4 g of p-toluenesulfonic acid. To this solution were added 1.5 ml of 2,3-dihydrofuran and the mixture was reacted for 6 hours at 120° C. in an oil bath. Further, 3 ml of 2,3-dihydrofuran in 4 portions were added and the mixture was reacted for 15 hours. After completion of the reaction, pyridine was removed from the reaction liquid by distillation and the residue was dissolved in 100 ml of chloroform and filtered to separate insoluble matters. The filtrate was washed with water, dried and concentrated by removing chloroform by distillation. The precipitated crystals were collected by filtration, washed with a small amount of ether and dried to obtain 2.0 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The crystals had a melting point of 167°-168° C. and were identical in IR-absorption spectra with the standard sample.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: OCc1ccc2c(n1)OCCO2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc2c(n1)OCCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
To a stirred solution of (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)methanol (24 g, 0.14 mol) in anhydrous CH2Cl2 (500 mL) was added activated MnO2 (25.0 g, 0.28 mol) at 0° C. in portions. The mixture was stirred at room temperature for 5 hours and another batch of activated MnO2 (25.0 g, 0.28 mol) was added in identical fashion. The mixture was stirred at room temperature overnight. The mixture was filtered through a Celite® pad and the filtrate was concentrated. The residue was purified via column chromatography (silica gel, EtOAc/petroleum ether 1:15 to 1:10) to yield 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-6-carbaldehyde (16.0 g, 67%) as a yellow solid. MS (ES+) 166.2 (M+H)+. 1H NMR δ (CDCl3) 4.40 (s, 2H), 4.91 (s, 2H), 7.37 (d, 1H), 7.61 (d, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1>C1COCC1.O=[Mn]=O>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc(CO)cc2s1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Cc1nc2ccc(C=O)cc2s1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A solution of (2-methylbenzo[d]thiazol-6-yl)methanol (300 mg; 1.67 mmol) in anh. THF (15 ml) was treated with MnO2 (2.269 g; 26.11 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 6.5 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with THF. The filtrate was concentrated to dryness under reduced pressure giving 2-methylbenzo[d]thiazole-6-carbaldehyde as a yellow solid. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 178.15 g/mol.
Reaction SMILES: Br[C:2]1[C:7]2[C@H:8]3[C@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=[CH:4][CH:3]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:11][CH2:10][CH2:9]3.C[Si]([N:27]=[C:28]=[O:29])(C)C>O1CCCC1.CCCCC>[NH2:27][C:28]([C:2]1[C:7]2[C@H:8]3[C@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=[CH:4][CH:3]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:11][CH2:10][CH2:9]3)=[O:29]
Reactant: Cc1ccccc1N1CCC[C@H]2c3c(Br)cccc3CC[C@@H]21
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccccc1N1CCC[C@H]2c3c(cccc3C(N)=O)CC[C@@H]21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of the (-)-trans-1,2,3,4,4a,5,6,10b-octahydro-10-bromo-4-(methylphenyl)benzo[f]quinoline (B-8, 6.60 g, 18.5 mmol) in dry tetrahydrofuran (50 mls) under nitrogen was cooled to -78° C., and t-bulyllithium (1.7M in pentane, 22.3 mls, 38.1 mmol) was added in about 10 seconds. The mixture was stirred at -78° C. for 5 minutes, and trimethylsilylisocyanate (46.5 mmol) was added via a syringe in one shot. The cold bath was removed, and the mixture was stiffed at ambient temperature for 1.5 hours. Water (30 mls) was added, and the mixture was stiffed for 10 minutes. Hydrochloiric acid (10%, 10 mls) was added, and file mixture was stiffed for 30 minutes. The mixture was bascified with 15% NaOH and extracted 3 times with methylene chloride. The extracts were dried (MgSO4), and the solvent was removed under vacuum to leave a white solid containing solvent (10.76 g). A sample (0.52 g) was crystallized from acetonitrile (20 mls) to yield the title compound (-) B-9 as white crystals (0.21 g, m.p. 189°-190° C., [α]D =-183.7° (25° C., THF, C=0.705)).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[S:18](Cl)(=[O:20])=[O:19])([O:11][CH3:12])=[O:10]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:17]1[CH:16]=[CH:15][S:14][C:13]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:19])=[O:20]
Reactant: Cc1noc(N)c1Br
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 73 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide was prepared in the same manner as described in Example 10 from 5-amino-4-bromo-3-methylisoxazole and 2-(carbomethoxy)thiophene-3-sulfonyl chloride in 73% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 198-200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:16]1([N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:27][C:24]3[N:25]=[CH:26][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:23]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Nc1ncn(-c2ccccc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-phenyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a brownish solid (Yield=64%). MS ISP (m/e): 340.4 (100) [(M+H)+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.[CH3:21][N:22]([CH3:36])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](N(OC)C)=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([N:22]([CH3:36])[CH3:21])=[CH:24][CH:25]=2)[C:17]([F:20])=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CON(C)C(=O)Cc1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc(CC(=O)c2cc(Br)cnc2F)cc1
Temperature: -20 °C
Yield: 42.5 %

Procedure:
Diisopropylamine (1.93 ml, 13.66 mmol) and tetrahydrofuran (80 ml) were combined and cooled to −20° C. with stirring. n-Butyl lithium (2.5 M in hexanes, 5.2 ml, 13.00 mmol) was slowly added and stirred at this temperature for 30 minutes. The temperature was decreased to −78° C. and neat 5-bromo-2-fluoropyridine (1.34 ml, 13.02 mmol) was added (internal temperature was not allowed to exceed −68° C.). The reaction mixture was stirred at −78° C. for 40 minutes. The reaction mixture was added to a solution of 2-(4-dimethylamino-phenyl)-N-methoxy-N-methyl-acetamide (2.76 g, 12.42 mmol) in tetrahydrofuran (10 ml). The combined reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was slowly warmed to room temperature, and quenched with saturate aqueous ammonium chloride. The reaction mixture was extracted with methylene chloride, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0 to 40% ethyl acetate in hexanes) to give 1.78 g (43%) of 1-(5-bromo-2-fluoro-pyridin-3-yl)-2-(4-dimethylamino-phenyl)-ethanone. MS m/z 337.1+339.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>O1CCOCC1.O>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: Cn1cccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Reaction time: 3 h
Yield: 33.5 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (2.56 g, 10.00 mmol)[prepared according to Example 95], 5-(5,5-dimethyl)-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (3.88 g, 20.0 mmol)[prepared according to Preparation 7], potassium carbonate (4.15 g, 30.0 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (II) dichloromethane complex (0.073 g, 0.1 mmol) in 1,4-Dioxane (12 mL) and water (3.00 mL) were heated at 80° C. in a sealed tube. After 3 hrs, another batch of 5-(5,5-dimethyl)-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.94 g, 10.0 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (II) dichloromethane complex (0.073 g, 0.1 mmol) were added. After 2 hr, the mixture was concentrated and purified by silica gel eluting with 0-35% ethyl acetate/hexane affording the title compound as a yellow solid (1.74 g, 3.35 mmol, 34%): LC-MS (ES) m/z 257 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[O:6].ClC1C=C(C=CC=1OCC)C=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:21])=[O:6]
Reactant: CCCCCOc1ccc(C=O)cc1Cl
Reactant: CCOc1ccc(C=O)cc1Cl
Product: CCCCCOc1ccc(C(=O)O)cc1Cl
Yield: 72 %

Procedure:
When the product of Step A was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A the identical process afforded the title compound in 72% yield. 1H-NMR (CDCl3) 0.92 (tr, 3H); 1.42-1.65 (m, 4H); 1.76-1.9 (m, 2H); 4.08 (tr, 2H, J=6.51 Hz); 6.92 (d, 1H, J=8.7 Hz); 7.95 (dd, 1H, J=2.1, 8.61 Hz); 8.1 (d, 1H, J=2.07 Hz).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br.C(OCC)C>CS(C)=O.O.C(O)(C)C>[C:13]([C:12]1([C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:14]
Reactant: BrCCCCBr
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To 79.2 g (1.65 m) of 50% sodium hydride suspended in 750 ml DMSO was added dropwise a mixture of 121.6 g (0.75 mole) p-nitrophenylacetonitrile and 161.7 ml (0.75 mole) 1,4 dibromobutane in 750 ml of a 50:50 mixture of DMSO, diethyl ether. The temperature was held between 25°-30° C. The reaction mixture was stirred at room temperature overnight then cooled to 10° C. Thirty-eight ml of isopropanol was added followed by the cautious addition of 2.8 l of water. Air was bubbled through the black reaction mixture to remove most of the ether. Black solid was filtered and taken up in diethyl ether. The ether solution was washed two times with 2 N HCl and two times with brine, dried over MgSO4, and concentrated in vacuo. The resulting dark solid was extracted six times with boiling hexane. The hexane solution was concentrated to a small volume to yield 127.5 g of product, melting point 76°-77° C.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C@:10]([C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([NH:26][C@@H:27]([CH2:41][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:28][N:29](C)[C:30](=O)OCC4C=CC=CC=4)=[O:25])[CH2:19]3)([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>CCOC(C)=O.Cl[Pd]Cl>[CH:42]1([CH2:41][C@H:27]([NH:26][C:24]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([C@@:10]([C:6]3[C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=[CH:8][CH:7]=3)([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:19]2)=[O:25])[CH2:28][NH:29][CH3:30])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: COCCCC[C@@](O)(c1cccc2ccoc12)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCC2)CN(C)C(=O)OCc2ccccc2)C1
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Product: CNC[C@H](CC1CCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc3c2OCC3)C1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a solution of benzyl (S)-2-((R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclopentylpropylmethylcarbamate (98.5 mg, 0.156 mmol) in EtOAc (10 mL) was added PdCl2 (30 mg) and the mixture was stirred under a hydrogen balloon at rt for 3˜5 hrs. After filtration, the filtrate was evaporated and the residue, was purified by prep HPLC to afford (3R)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide (36.2 mg, 46.5%). 1H NMR (CD3OD, 400 MHz) δ 0.89 (m, 1 H), 1.12-2.15 (m, H), 2.58 (m, 2 H), 2.71 (s, 3 H), 2.93 (m, 1 H), 3.15 (m, 3 H), 3.23 (s, 3 H), 3.98 (m, 2 H), 4.26 (m, 1 H), 4.48 (m, 2 H), 6.83 (m, 1 H), 7.12 (m, 1 H), 7.21 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15].OS(O)(=O)=O>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(N(C)C)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(N(C)C)cc1[N+](=O)[O-]

Procedure:
N-[4-(dimethylamino)phenyl]acetamide obtained in step I above was nitrated using nitric acid (1.2 eq)+H2SO4 (1.0 eq) at 0 to 5° C. for 2 hrs. After the completion of the reaction, reaction mixture was added to ice and pH was adjusted to 8, extracted with dichloromethane, which was evaporated to dryness to obtain N-[4-(dimethylamino)-2-nitrophenyl]acetamide.