Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[C:9]([NH-:13])([CH3:12])([CH3:11])[CH3:10].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:9]([NH:13][C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[NH-]
Reactant: C/C=C/C=C/C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C/C=C/C=C/C(=O)NC(C)(C)C

Procedure:
Sorbic acid (5.01 g, 44.7 mmol) and t-butylamide (3.59 g, 49 mmol) were dissolved in dimethylformamide (150 ml) and the solution was stirred under ice-cooling. To the solution was added diphenylphosphoryl azide (14.8 g, 53.8 mmol) and triethylamine (9.95 g, 98.3 mmol) was added thereto. The mixture was stirred for 18 hours while allowing to rise the temperature to room temperature. The reaction mixture was diluted with ethyl acetate and the dilution was washed with an aqueous saturated sodium chloride solution. The ethyl acetate layer was washed with an aqueous saturated sodium carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1-5:1) to obtain sorbic acid N-t-butylamide as (2.82 g, 37.6%) pale yellow solid. This compound has the following NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH2:14]Cl.[I-:16].[Na+]>CC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH2:14][I:16]
Reactant: Fc1c(C(F)(F)F)cc(Cl)c(CCl)c1F
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1c(C(F)(F)F)cc(Cl)c(CI)c1F
Yield: 99.7 %

Procedure:
Treat a solution of 1-chloro-2-chloromethyl-3,4-difluoro-5-trifluoromethyl-benzene (1.0 g, 3.8 mmol) in acetone (10 mL) with sodium iodide (2.8 g, 19 mmol) and stir the reaction 1 hr at room temperature. Dilute the reaction in EtOAc (50 mL) and filter. Concentrate the filtrate to afford 1.35 g (100%) of product. 1H NMR (d6-CDCl3) δ 7.39 (d, 1H, J=5.7 Hz), 4.46 (d, 2H, J=2.2 Hz).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][N:12]1[C:29](=[O:30])[C:28](=[O:31])[N:15]2[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[CH2:18][N:19]3[CH:23]=[CH:22][CH:21]=[C:20]3[CH:14]2[CH2:13]1.C([O-])(=O)C.[Na+]>C(Cl)Cl.O>[CH:8]([C:23]1[N:19]2[C:20]([CH:14]3[CH2:13][N:12]([CH3:11])[C:29](=[O:30])[C:28](=[O:31])[N:15]3[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[CH2:18]2)=[CH:21][CH:22]=1)=[O:9]
Reactant: CN1CC2c3cccn3Cc3ccccc3N2C(=O)C1=O
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1CC2c3ccc(C=O)n3Cc3ccccc3N2C(=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 170 mg of phosphorus oxychloride and 100 ml of dimethylformamide is stirred at room temperature for 30 minutes, whereupon the solution of 281 mg of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added dropwise. After 30 minutes, the mixture is refluxed for another 30 minutes and cooled to room temperature. It is combined with 1.5 g of sodium acetate in 5 ml of water, stirred for 30 minutes and the organic layer separated. It is washed with water, 5% aqueous sodium bicarbonate, dried, evaporated and the residue triturated with diethyl ether, to yield the 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 300°-302°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[CH:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C:13]2[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=2[NH:11]1>CCOC(C)=O>[Br:1][C:26]1[CH:27]=[CH:28][C:12]2[NH:11][C:10](=[O:9])[CH:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:15][CH2:14][C:13]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccccc2NC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2NC1=O
Yield: 203.3 %

Procedure:
472 mg of N-bromosuccinimide (2.65 mmol) are introduced at AT into a 100 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 40 ml of EtOAc and 0.5 g of 2 (1.8 mmol). The medium is left stirring overnight, and is washed with 40 ml of HCl (1N), 40 ml of saturated aqueous solution of NaHCO3 and 40 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 1.3 g of an oil are obtained, which oil is crystallized from 10 ml of isopropyl ether. After filter-drying, 450 mg of product 10 (white solid) are obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37]C(OC(C)(C)C)=O)[CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[I:54][C:55]1[CH:60]=[CH:59][C:58]([S:61](Cl)(=[O:63])=[O:62])=[CH:57][CH:56]=1>O1CCOCC1.C(OCC)(=O)C>[CH2:2]([O:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37][S:61]([C:58]3[CH:59]=[CH:60][C:55]([I:54])=[CH:56][CH:57]=3)(=[O:63])=[O:62])[CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cccc(C#N)c1)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccc(I)cc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
25 ml of 4 N solution of hydrogen chloride in dioxane and 12.5 ml of dioxane were added to 2.54 g (4.34 mmol) of 3-[(2S)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]-2-(t-butoxycarbonylamino)propoxy]benzonitrile. After stirring at room temperature for 24 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of DMF. 1.77 ml (13.0 mmol) of diisopropylethylamine and 1.97 g (6.51 mmol)) of 4-iodobenzenesulfonyl chloride were added to the solution at 0° C. 30 minutes after, the temperature was elevated to room temperature, and the reaction mixture was stirred for 19 hours. Ater the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[N:14])=[C:11]([CH2:15][CH3:16])[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.O.IC.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]#[N:14])=[C:11]([CH2:15][CH3:16])[N:10]([CH3:25])[C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c(CC)c(C#N)c1-c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(CC)n1C
Temperature: 30 °C
Reaction time: 14 h
Yield: 97.9 %

Procedure:
Step DI: Suspend ethyl 3-(4-bromophenyl)-4-cyano-5-ethylpyrrole-2-carboxylate (7.0 kg, 20.17 mol, 1 eq, prepared in step C above) in acetone (70 L) in a 100-L reactor. Add water (0.7 L), iodomethane (3.153 kg, 1.38 L, 22.21 mol, 1.1 eq), and potassium carbonate (5.58 kg, 40.37 mol, 2 eq). Stir the mixture at 30° C. for 14 h. Concentrate the reaction mixture by removing 41 L of solvent by distillation at 50° C. under reduced pressure. Add water (55 L) slowly over 45 min at 20-22° C. Cool the suspension to 0° C. within 1 h and stir for an additional h at this temperature. Collect the precipitate by filtration and wash with a cold (0-5° C.) mixture of acetone/water (1.2+3 L.) and then with water (4.2 L). Dry the product in 100-L rotary evaporator under reduced pressure at 60° C. for 66 h to obtain 7.133 kg of title compound as a beige powder (98% yield). 1H NMR (CDCl3, 500.0 MHz): δ 1.08 (t, J=7.1 Hz, 3H), 1.34 (t, J=7.1 Hz, 3H), 2.88 (q, J 2 0=7.1 Hz, 2H), 3.92 (s, 3H), 4.13 (q, J=7.1 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H); 13C NMR DMSO-d6, 125.7 MHz): δ 12.96, 13.44, 18.79, 60.16, 92.04, 115.22, 119.96, 121.12, 130.73, 131.58, 131.86, 132.05, 147.87, 159.82; Anal. Calcd for C17H17BrN2O2: C, 56.52; H, 4.74; Br, 22.12; N, 7.75; 0, 8.86. Found: C, 56.32; H, 4.72; N, 7.73; IR (KBr): 3347, 2979, 2938, 2216, 1698, 1441, 1510, 1476, 1400, 1379, 1258, 1212, 1110, 771 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.69 (s, 3H), 6.68 (d, 2H, J=8.8 Hz), 7.36-7.47 (m, 4H), 7.46, 7.55-7.69 (m, 5H), 9.65 (s, 1H). MS: m/z 448.3 (M++1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[CH2:19]([O:18][C:16]([NH:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a stirred solution of valinol (13.96 g, 0.14 mol) and triethylamine (18.87 mL, 0.14 mol) in 250 mL of dry methylene chloride cooled to 0° C. under a nitrogen atmosphere was added 19.3 mL (0.14 mol) of benzyl chloroformate dropwise over 20 min. After warming to RT overnight, the mixture was diluted with methylene chloride (100 mL) and washed with 1N HCl (2X), brine and dried with anhydrous magnesium sulfate. The resulting mixture was filtered and evaporated to give 30.70 g (95.6%) of N-benzyloxycarbonyl-valinol as a white solid: Rf =0.27 (silica gel; 1:1 hexane:ethyl acetate). Used without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[N:4]([CH3:15])[CH:3]=1
Reactant: CI
Reactant: COc1nccc2c(I)c[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c(I)cn(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
3-Iodo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.75 g, 2.74 mmol) in dimethylformamide (10 mL) was treated with 60% sodium hydride in mineral oil (0.219 g, 5.47 mmol) at room temperature for 20 minutes. To this solution was added methyl iodide (0.505 g, 3.56 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 10% ethyl acetate/hexanes to give 0.75 g (95%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[Cl:39])[C@@H:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1.Cl.[O:43]1CCOCC1>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:43])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[Cl:39])[C@@H:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1
Reactant: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c2c(=O)[nH]c(N)nc21
Temperature: 135 °C

Procedure:
A mixture of the product from Step B (200 mg, 0.3 mmol) in 1,4-dioxane (15 mL) and aqueous NaOH (2N, 15 mL) in a pressure bottle was heated overnight at 135° C. The mixture was then cooled to 0° C., neutralized with 2N aqueous HCl and evaporated to dryness. The crude product was suspended in MeOH, filtered, and the solid thoroughly washed with MeOH. The combined filtrate was concentrated, and the residue purified on a silica gel column (5×5 cm) using CH2Cl2/MeOH (40/1, 30/1 and 20/1) as eluent to give the desired compound (150 mg) as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: C1=CCCCC1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)C1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
To a fluorobenzene (5 mL) solution of cyclohexene (82 mg, 1 mmol) at RT was added acetyl chloride (86 mg, 1.1 mmol) and then the reaction was cooled in an ice bath. Aluminum chloride (150 mg, 1.1 mmol) was slowly added to the solution, then the reaction was slowly allowed to warm to room temperature, was stirred at room temperature for 24 h and was then heated to 80° C. for 1 h. The reaction mixture was cooled to room temperature and was then slowly added to ice cold water. The mixture was extracted with ethyl acetate and the organic portion was dried over sodium sulfate, concentrated under vacuum, and purified on a silica gel column to afford 1-[4-(4-fluoro-phenyl)-cyclohexyl]-ethanone containing about 30% of another unidentified substance (176 mg).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:19])[CH2:3][CH2:2]2
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: C1CN2CCC(CC2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Br)cc1)N1CCN2CCC1CC2
Temperature: 0 °C

Procedure:
0.379 g (3.0 mmol) of 1,4-diazabicyclo[3.2.2]nonane and 0.84 ml (6.0 mmol) of triethylamine in 5 ml of dichloromethane are introduced into a 50-ml three-necked flask, the mixture is cooled to 0° C., 0.730 mg (3.1 mmol) of 4-bromophenyl chloroformate in solution in 3 ml of dichloromethane is added dropwise and the stirring is maintained at 0° C. for 10 min.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH2:25][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(OC(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.7 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (935 mg, 3.85 mM), 3-trifluoromethoxybenzyl bromide (1.0 g, 3.93 mM), and potassium carbonate (531 mg, 3.85 mM) in 20 mL DMF was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.6 g (100%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMSO-d6) δ 7.7 (dd, 1H, J=1 and 8 Hz), 7.45 (t, 1H, J=8 Hz), 7.3-7.1 (m, 4H), 7.05 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 1729, 1647, 1439, 1259, 1176, and 1116. MS (ES) m/e 418.
Reaction SMILES: C([O:4][C:5]([C@@H:7]1[CH2:22][C@@:15]2([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:23])[CH:13]=2)[O:8]1)=O)CC.O.[NH2:25][NH2:26]>C(O)C>[F:23][C:12]1[CH:13]=[C:14]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:22][C@@H:7]([C:5]([NH:25][NH2:26])=[O:4])[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: NN
Reactant: CCCOC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Solvent: CCO
Solvent: O
Product: NNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Yield: 46.7 %

Procedure:
To a solution of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic acid n-propyl ester (30.0 g, 93.1 mmol) in 600 ml of ethanol was added hydrazine hydrate (46.6 g, 0.931 mol). After refluxing the mixture under an argon atmosphere for 2 hours, the reaction mixture was evaporated in vacuo to dryness. To the residue was added 100 ml of saturated aqueous sodium chloride and the aqueous layer was extracted with ethyl acetate (300 ml×5). The combined ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 17.3 g (Yield: 63.1%) of crude crystals. The crystals were recrystallized from ethanol to give colorless needles of the desired compound (12.8 g, 46.7%).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([CH2:8][OH:9])[CH2:6][C@H:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]1)[CH3:2].I([O-])(=O)(=O)=[O:17].[Na+]>CC#N.O.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:5]1[CH2:6][C@H:7]([C:8]([OH:17])=[O:9])[C@H:3]([CH2:1][CH3:2])[CH2:4]1)[CH3:15]
Reactant: CCOC(=O)C[C@@H]1C[C@@H](CC)[C@@H](CO)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C[C@@H]1C[C@@H](CC)[C@@H](C(=O)O)C1
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of ethyl 2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate (0.140 g, 0.653 mmol) in MeCN (2 mL), water (4 mL) and EtOAc (2 mL) was added sodium periodate (0.349 g, 1.633 mmol) followed by ruthenium(III) chloride hydrate (0.0015 g, 0.0065 mmol). After about 2 h, the reaction mixture was diluted with EtOAc (20 mL) and water (10 mL). The organic layer was separated and extracted with aqueous NaOH (1 N, 10 mL). The pH of the aqueous layer was adjusted to about 1 with concd HCl and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd in vacuo to provide (1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylic acid (0.150 g, 101%) as an oil which was used without further purification. 1H NMR (600 MHz, CDCl3) δ 10.68 (bs, 1H), 4.13 (q, J=7.1 hz, 2H), 2.99-2.95 (m, 1H), 2.76-2.64 (m, 1H), 2.31 (d, J=7.6 Hz, 2H), 2.24 (ddd, J=13.5, 8.7, 4.8 Hz, 1H), 2.18-2.11 (m, 1H), 1.81 (dt, J=13.0, 8.4 Hz, 1H), 1.55-1.45 (m, 3H), 1.31-1.27 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:31][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([F:27])=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
2-Benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (400 mg) was dissolved in DMF (4 ml) and methyl iodide (0.14 ml) and potassium carbonate (300 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (200 mg).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:1]([OH:24])=[O:23]
Reactant: Cc1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1C
Yield: 82 %

Procedure:
Five-hundred grams molten erucic acid were slowly added to a mixture of 679 gms toluene and 723 gms concentrated sulfuric acid while maintaining the temperature below 10° C. Tolyldocosanoic acid (acid value 123) was obtained in 82% yield. Distilled tolyldocosanoic acid (108 gms), 400 mls acetic acid 9.8 gms Co(OAc)2.4H2O and 1.3 gms ZrO(OAc)2 were then heated at 105° C. and 350 psi O2 for six hours during which time the acid value increased from 127 to 207. The selectivity to the desired carboxyphenyldocosanoic acid was 64.4% at a tolyldocosanoic conversion of 53.7%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.CCN(CC)CC.[O:26](S(C(F)(F)F)(=O)=O)[S:27]([C:30]([F:33])([F:32])[F:31])(=O)=[O:28]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[S:27]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2)(=[O:28])=[O:26]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1,1-dimethylethyl 6-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.146 g; 0.586 mmol) and Et3N (0.17 mL; 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added Tf2O (0.11 mL; 0.67 mmol(, dropwise over 2 min. The mixture was stirred overnight, gradually warming to room temperature, diluted with CH2Cl2, washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum which slowly solidified. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.87 (t, J=5.7 Hz, 2H), 3.66 (br. t, J=5.5 Hz, 2H), 4.59 (s, 2H), 7.04-7.12 (m, 2H), 7.18 (d, J=8.4 Hz, 1H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][CH2:4]2)=[O:17]
Reactant: O=C(Cl)CCCCCl
Reactant: c1ccc2c(c1)CCCO2
Product: O=C(CCCCCl)c1ccc2c(c1)CCCO2

Procedure:
Using chroman (5.40 g) and 5-chlorovaleryl chloride (6.82 g) according to the same method as that of Reference Example 1, the title compound was obtained as a fine yellow oil (7.9 g).