Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][C:29]1([C:33](O)=[O:34])[CH2:32][O:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([C:29]5([CH3:28])[CH2:32][O:31][CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC1(C(=O)O)COC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC1(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)COC1

Procedure:
The title compound, white solid (19 mg, 52%), MS (ISP) m/z=430.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 3-methyloxetane-3-carboxylic acid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)=[O:5])C.[OH-].[Li+]>>[Cl:31][C:26]1[CH:25]=[C:24]([N:7]2[CH2:8][CH:9]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:22])([F:21])[F:23])(=[O:12])=[O:13])[CH2:10][CH:6]2[C:4]([OH:5])=[O:3])[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccc(F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccc(F)c(Cl)c1

Procedure:
In analogy to the procedure described in example 253e, 1-(3-chloro-4-fluoro-phenyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].[CH:18]([N-:21][CH:22](C)C)(C)[CH3:19].[Li+].CCCCCCC.C1COCC1.O>O1CCCC1>[CH3:22][N:21]1[CH2:18][CH2:19][C@@H:9]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[OH:17])[C@@H:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@@H](c2cc(Cl)ccc2O)[C@@H]1c1ccccc1Br
Yield: 79 %

Procedure:
To a solution of trans-2-bromo-5′-chloro-2′-hydroxystilbene (81 g, 261 mmol) in tetrahydrofuran (570 ml) trimethylamine-N-oxide.dihydrate (43.4 g, 390 mmol) was added at ambient temperature. Lithium diisopropylamide in heptane/THF (2M, 1070 ml, 2140 mmol) was then added during the course of 1 hour while maintaining the temperature below 40° C. After completion of the reaction water (120 ml) was added. Solvent was evaporated to a small volume after which ethyl acetate (250 ml) was added. The pH was adjusted to pH 8 with 18 % hydrochloric acid (˜250 ml) and ethyl acetate (250 ml) was added. The organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2×120 ml). The combined organic layers were washed with water (325 ml) and with brine, dried (MgSO4) and then evaporated in vacuo. The resulting oil was crystallised from ethanol/water (1/1, v/v) to give the title pyrrolidine (62.0 g, 79%). Purity according to HPLC is 99% a/a.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]>[Pd](Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:6]2[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([F:1])[CH:7]=2)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Product: COc1ccc(-c2ccc(OC)c(F)c2)cc1F

Procedure:
The procedure for synthesis is briefly explained below. First, 2-fluoroanisole [1] is reacted with bromine to give 2-fluoro-4-bromoanisole [2], which is subsequently reacted with magnesium to give a compound [3] of Grignard reagent type. This compound is condensed with 2-fluoro-4-bromoanisole [2] in the presence of a palladium chloride catalyst to give 3,3'-difluoro-4,4'-dimethoxybiphenyl [4]. In this way, the biphenyl skeleton is formed. Then, the both terminals of 3,3'-difluoro- 4,4,-dimethoxybiphenyl [4] are demethylated by boron tribromide to give 3,3'-difluoro-4,4'-dimethoxybiphenyl [4]. One of the two hydroxyl groups in the compound [5] is blocked by acylation with acetic acid chloride to give a compound [6]. The remaining hydroxyl group in the compound [6] is alkylated with a halogenated alkyl having a specific chain length (p=6 to 15) to give a compound [7]. Finally, the compound [7] undergoes hydrolysis by an alkali catalyst (sodium hydroxide) to remove the acyl group. Thus there is obtained an unblocked compound [8], which is ready for coupling with a cyclohexane ring through an ester linkage.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (6.48 g, 19.6 mmol) and Pd(OH)2/C (20% Pd, 1 g) in 50 mL of methanol was stirred under a hydrogen atmosphere (balloon) for 18 h. The reaction mixture was then filtered through a celite plug, and the filtrate was concentrated to give tert-butyl 4-[3-(ethoxycarbonyl)phenyl]piperidine-1-carboxylate which did not require further purification. 1HNMR (CDCl3, 500 MHz): δ 7.91 (m, 2H), 7.40 (m, 2H), 4.40 (q, J=7.0 Hz, 2H), 4.28 (br s, 2H), 2.83 (m, 2H), 2.73 (tt, J=12.5, 4.0 Hz, 1H), 1.85 (br d, J=13.0 Hz), 1.67 (dq, J=4.0, 12.5 Hz, 2H), 1.51 (s, 9H), 1.42 (t, J=7.0 Hz).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][N:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:9])C.[OH-].[Na+]>C1COCC1>[CH:10]1([N:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]([OH:16])=[O:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCCN(C)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CCCC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10 g of 4-bromobutyric acid ethyl ester and 15 g of N-cyclohexyl-N-methylamine were added to 40 mL of ethanol, and the mixture was heated to reflux for 2 hours. After air-cooling, the mixture was concentrated under reduced pressure and extracted with 200 mL of ethyl acetate. The extracted material was washed with purified water, dried with magnesium sulfate, and then concentrated. The obtained residue was distilled under reduced pressure to give 10.5 g of N-cyclohexyl-N-methyl-gamma-aminobutyric acid ethyl ester. The obtained N-cyclohexyl-N-methyl-gamma-aminobutyric acid ethyl ester was added to a sodium hydroxide solution (2.4 g of sodium hydroxide/100 mL of purified water), and THF was added thereto until the mixture became homogeneous. After stirring at room temperature for 3 hours, the mixture was neutralized with DOWEX50W [H+ form] and concentrated under reduced pressure. The obtained residue was recrystallized to give 5.2 g of the desired product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2([C:12]3[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=3[O:14][CH2:15][CH2:16][N:17](C)[C:18](=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)[C:5](=[O:33])[N:4]([C:34]2[CH:39]=[C:38]([C:40](=[O:45])[NH:41][CH:42]3[CH2:44][CH2:43]3)[CH:37]=[C:36]([F:46])[C:35]=2[CH3:47])[CH:3]=1.C([O-])=O.[NH4+]>C(O)(C)C.[Pd]>[CH:42]1([NH:41][C:40](=[O:45])[C:38]2[CH:39]=[C:34]([N:4]3[CH:3]=[CH:2][N:7]=[C:6]([NH:8][C:9]4([C:12]5[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=5[O:14][CH2:15][CH2:16][NH:17][CH3:18])[CH2:11][CH2:10]4)[C:5]3=[O:33])[C:35]([CH3:47])=[C:36]([F:46])[CH:37]=2)[CH2:44][CH2:43]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC2(c3ccccc3OCCN(C)C(=O)OCc3ccccc3)CC2)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)cc(F)c3C)c2=O)CC1
Temperature: 80 °C
Yield: 81.9 %

Procedure:
10% Pd/C (87 L paste ex. Johnson Matthey, 110 mg) was washed with isopropanol (10 mL) and then suspended in further isopropanol (10 mL). A sample of this suspension (291 μL, ˜3.2 mg Pd/C) was added to a solution of benzyl [2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate (Preparation 4e, 10.5 mg, 14.9 μmol) and ammonium formate (33.3 mg, 512 μmol) in isopropanol (0.1 mL). The reaction vessel was sealed and the suspension heated to 80° C. (jacket temperature) for 10 min. The reaction mixture was then filtered through Celite and the cake washed with ethyl acetate. The filtrates were combined and washed with brine that had been basified to pH 12 with KOH. The solution was filtered through a short pad of sodium sulfate and concentrated to dryness in vacuo to afford N-cyclopropyl-3-fluoro-4-methyl-5-[3-[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropylamino]-2-oxo-1(2H)-pyrazinyl]benzamide (6.0 mg) as a colourless solid.
Reaction SMILES: [CH3:1][Mg]Br.[Si:4]([O:11][CH2:12][C:13]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14]1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[Cl-].[NH4+]>O1CCCC1>[Si:4]([O:11][CH2:12][C:13]1([CH:17]([OH:18])[CH3:1])[CH2:14][CH2:15][CH2:16]1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCC1(C=O)CCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C1(CO[Si](C)(C)C(C)(C)C)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (21 mL, 1.0 M tetrahydrofuran solution) was cooled to 0° C., a solution of 1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutanecarbaldehyde (4.0 g) in tetrahydrofuran (40 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 hr. Methylmagnesium bromide (10 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at 0° C. for 30 min. The reaction mixture was added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as an oily compound (2.5 g, 58%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:9]([C:10]([O:12]C)=[O:11])=[CH:8][S:7][CH:6]=1)(=[O:3])[CH3:2]>[OH-].[K+]>[C:1]([NH:4][C:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][S:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cscc1NC(C)=O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Nc1cscc1C(=O)O
Yield: 93.1 %

Procedure:
Methyl 3-acetamidothiophene-4-carboxylate (10.0 g, 50.25 mmol) was added to a 5% methanolic potassium hydroxide solution (100 mL). The mixture was refluxed 2 hours, cooled, and concentrated. The residue was dissolved in water and the acidity was adjusted to pH 1 by addition of 1 N hydrochloric acid (HCl). The precipitate was collected, washed with water, and air dried to afford 8.66 g (93%) of 3-acetamidothiophene-4-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH2:13])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:13][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(N)c1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(N)(CO)c1cccc(Br)c1
Temperature: -7 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A solution of the (RS)-2-amino-2-(3-bromo-phenyl)-propionic acid methyl ester (9.39 g, mmol) in tetrahydrofuran (360 ml) was treated portionwise at −5° C. with lithiumaluminiumhydride (1.41 g, 36 mmol; 282 mg/2 min). After complete addition, stirring was continued at 0-5° C. for 30 minutes. For the workup, the reaction mixture was cooled to −7° C., and water (9 ml) was added dropwise. Thereafter, 2 N sodium hydroxy solution (9 ml) was added and stirring continued for 15 minutes at room temperature. They grey suspension was filtrated through Dicalite® which was washed with tetrahydrofuran (200 ml). The filtrate was evaporated at reduced pressure. 8.67 g of crude (RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol were obtained as a colorless oil. The purity of the product allowed using it in the next step without further purification. Mass (calculated) C9H12BrNO [230.106]; (found) [M+H]+=230, 232.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][C:11]([O:13]CC)=O)[CH2:3][C:4]([O:6]CC)=O.C[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:25]C)[CH:24]=1)[NH2:21]>>[OH:17][C:18]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:20]2[C:19]=1[C:4](=[O:6])[CH2:3][CH:2]1[CH2:9][CH2:10][C:11](=[O:13])[N:21]12
Reactant: COc1cc(N)cc(OC)c1
Reactant: CCOC(=O)CCC(=O)CC(=O)OCC
Product: O=C1CC2CCC(=O)N2c2cc(O)cc(O)c21
Yield: 77 %

Procedure:
By the procedures of Examples 2 and 3, diethyl 3-oxohexanedioate [Tetrahedron 23, p. 897 (1967)] and 3,5-dimethoxyaniline were converted to title product, recrystallized from ethyl acetate/cyclohexane, in 77% yield, m.p. 254°-256° C.; m/e 233 (m+); ir (KBr) 3448, 2857, 1680, 1639 cm-1.
Reaction SMILES: [CH3:1][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([N:6]1[CH2:11][CH2:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[C:3]([O-:5])=[O:4].[OH:22][S:23]([OH:26])(=[O:25])=[O:24]>CC(C)=O>[S:23](=[O:24])(=[O:22])([OH:26])[OH:25].[CH3:1][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([N:6]1[CH2:11][CH2:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)[O-])(c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C(=O)O)(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 27.5 °C
Reaction time: 0.08 h

Procedure:
To 2 g (+)-Methyl(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate was added 5 mL of acetone and stirred at 25-30° C. The temperature of the reaction mixture was raised from 25 to 65° C. and then kept at 65° C. for 5 min. At temperature 50-52° C. 0.676 g of concentrated H2SO4 was added. The reaction mixture was cooled from 52° C. to 5° C., and additional acetone was added and stirred for 5 min. Later the reaction mixture was stirred at 25-30° C. for 12 hrs, the thick precipitate obtained was filtered, washed with 5 mL of acetone and the residue was dried in a vacuum oven. The yield of titled product obtained was 1.27 g (47%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:17])[NH:9][C@H:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH3:11])([CH3:6])([CH3:5])[CH3:4]>CO.C(O)(C)C>[C:3]([O:7][C:8](=[O:17])[NH:9][C@H:10]([CH:12]([OH:16])[CH2:13][CH2:14][CH3:15])[CH3:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CCCC(O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Sodium borohydride (3.7 g) was added in divided portions to a methanol/isopropanol (30 ml/30 ml) solution containing (S)-tert-butyl(3-oxohexan-2-yl)carbamate (17.5 g) at room temperature, followed by stirring for 1 hour. The solvent was distilled away under reduced pressure, and water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a white solid of tert-butyl((2S)-3-hydroxyhexan-2-yl)carbamate (17 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][OH:40])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C.O>C(Cl)Cl>[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][O:40][S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)(=[O:11])=[O:12])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](COS(=O)(=O)c4cccc([N+](=O)[O-])c4)OC3=O)cc2F)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Nitrobenzenesulfonyl chloride (1.70 g, 7.67 mmol) was added to an ice cooled solution of (R)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-hydroxymethyl-2-oxo-3-oxazolidinyl]-pheny]azetidine (Example 81, Step 5, 2.79 g, 6.97 mmol) and triethylamine (1.41 g, 14.0 mmol) in methylene chloride (40 mL). After 16 hr, water (50 mL) and methylene chloride (100 mL) were added. The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed over silica gel (150 g, 40-60 μm) eluting with 25-100% ethyl acetate-hexane to give the title compound as a sticky foam. FAB-HRMS: theory 586.1290 (M+1); meas 586.1295.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(F)c1F
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
To a solution of 2,3-difluorobenzaldehyde (2.9 g, 20.41 mmol) in conc. sulfuric acid (18 mL, 324 mmol) at 0° C., was added nitric acid (70%) (3.6 mL, 56.4 mmol) dropwise. The reaction mixture was removed from the ice bath and was stirred at rt for 3 h. The reaction mixture was poured onto ice, then was diluted to ˜350 mL with H2O. The aqueous was extracted with EtOAc (3×). The combined organic phase was washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was dissolved in EtOAc (10 mL), then was diluted with hexanes (40 mL). The solution was filtered though a 1″ pad of SiO2, then the pad was rinsed with 20% EtOAc/hexanes. The filtrate was concentrated. The resultant oil was dissolved in chloroform and hexanes, loaded onto a 150 g column and eluted with a gradient from 0 to 15% EtOAc/hexanes to give 11A (1.345 g, 7.19 mmol, 35.2% yield) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[N+:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1)([O-:32])=[O:31]
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cc2s1)C1CC1
Temperature: 150 °C
Reaction time: 14 h
Yield: 36.2 %

Procedure:
To a suspension of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.53 g, 6.53 mmol) and potassium carbonate (3.72 g, 26.9 mmol) in N,N-dimethylformamide (50 mL) were added 1-fluoro-3-nitrobenzene (1.08 g, 7.65 mmol) and 18-crown-6 (1.07 g, 4.05 mmol), and the mixture was stirred at 150° C. for 14 hr. The reaction mixture was cooled to room temperature, and added to a mixed solvent (1:1, 300 mL) of ethyl acetate and hexane. The mixture was washed with water (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was collected by filtration, and the residue was subjected to silica gel column chromatography using ethyl acetate and hexane (1:1) as an eluent to give the title compound (840 mg, 36%) as a pale-yellow solid.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:35])[N:20]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:21]3=[O:26])=[O:15])=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:35])[N:20]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:6]([NH2:5])=[O:7])[CH2:31][CH2:30]2)[C:21]3=[O:26])=[O:15])=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: NC(=O)N1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At room temperature, 0.18 ml of trimethylsilyl isocyanate are added dropwise to a suspension of 50 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide in 2.5 ml of absolute dichloromethane. The mixture is stirred at room temperature for 48 h and then, after concentration, chromatographed on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[CH:29]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccn(C[C@@H](C)NC(=O)c3cc(-c4ccco4)n[nH]3)n2)ccc(C#N)c1Cl
Yield: 73.9 %

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.077 g, 0.280 mmol), 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.055 g, 0.308 mmol), DIPEA (0.073 ml, 0.420 mmol), HOBt (0.057 g, 0.420 mmol) and EDCI (0.081 g, 0.420 mmol) using the method of Example 34(d) affording 0.090 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.15-1.17 (m, 3H), 2.52 (s, 3H), 4.32-4.35 (m, 2H), 4.44-4.51 (m, 1H), 6.61 (d, 2H), 7.65-7.67 (m, 1H), 7.75-7.79 (m, 1H), 7.82 (d, 1H), 7.84 (d, 1H), 8.30 (m, 2H), 8.35 (m, 2H), 13.69 (m, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Nicotinic acid (4.025 g, 0.0327 mol) and N-hydroxysuccinimide (3.763 g, 0.0327 mol) were dissolved in 130 ml of dioxane. Dicyclohexylcarbodiimide (6.75 g, 0.032 mol in 20 ml of dioxane was added. The reaction mixture was then stirred at room temperature for 3 hours. The dicyclohexylurea which precipitated was removed by filtration and the solvent was removed by rotary evaporation. The crude product was recrystallized from ethyl acetate to give light yellow crystals which were then washed with anhydrous ether. The product, obtained in 72% yield (5.2 g) and melting at 129°-131° C., has the formula: ##STR1549##