Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)C.[ClH:18]>O>[ClH:18].[N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:17])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
The 4-pyridin-4-yl-benzoic acid ethyl ester (430 mg, 1.89 mmol) was heated to 100° C. in 6.5 mL of 3M HCl solution overnight to completion. The mixture was cooled to room temperature and diluted with water (dissolves precipitate). The solution was filtered and concentrated in vacuo to afford the 4-pyridin-4-yl-benzoic acid hydrochloride salt as a pale yellow solid (380 mg, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 8.93 (d, J=5.6 Hz, 2H), 8.27 (d, J=5.6 Hz, 2H), 8.13 (d, J=8.0 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), —CO2H or —NH+ not observed. LCMS (APCI+) m/z 200 [M+H]+; Rt=1.05 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@@H:18]3[CH2:22][CH2:21][N:20]([N:23]4[CH2:28][CH2:27][CH:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]4)[C:19]3=[O:40])=[C:13]([Cl:41])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1>[Cl:41][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[CH:15][C:14]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][Si:30]([CH:31]([CH3:32])[CH3:33])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:25][CH2:24]2)[C:19]1=[O:40]
Reactant: COC(=O)c1ccc(-c2ccc(C[C@@H]3CCN(N4CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 98.4 %

Procedure:
Treat a solution of 3′-Chloro-4′-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (0.76 g) in THF (15 mL) with 2N LiOH (15 mL) at room temperature for 5 hours. Partition the mixture between ethyl acetate (25 mL) and 1 N HCl (10 mL). Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford 0.73 g (98%) of the title compound. MS (m/z): 585 (M+).
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 0.046 mol) prepared as described in example P5a, in dichloromethane (120 ml) was added triethylamine (7.7 ml, 0.055 mol) followed by dropwise addition of a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (9.1 g, 0.046 mol) in dichloromethane (10 ml) at 0° C. After complete addition of acid chloride the mixture was stirred 5 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was washed with 1N HCl (100 ml), followed by 1N NaOH (100 ml), then with water (2×100 ml) and finally with brine solution (50 ml) before drying over sodium sulfate and evaporation of the solvent. The resulting crude mass 20.5 g of a sticky dark brown oil was purified by column chromatography using 60-120μ mesh silica gel and product collected at 40% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (7.9 g, 41%) as off white solid. m.p: 110-112° C. 1H NMR (400 MHz, CDCl3): δ1.38-1.39 (d, 3H), 3.20-3.26 (dd, 1H), 3.32-3.37 (dd, 1H), 3.70 (s, 3H), 3.97 (s, 3H), 4.88-4.93 (m, 1H), 7.02-7.29 (t, 1H), 7.27 (s, 2H), 7.81 (s, 1H) MS [M+H]+ 426/428/430
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([C:10]([N:29]2[CH2:30][CH2:31][CH:27]([O:26][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:33][CH:32]=3)[CH2:28]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(OC2CCNC2)cc1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)C2)c1
Yield: 20 %

Procedure:
Prepared in analogy to Example 1 from 5-methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example A4) and 3-(4-trifluoromethyl-phenoxy)-pyrrolidine. The crude material was purified by chromatography (methanol/dichloromethane) to yield the title compound as a white solid (yield 20%). MS (m/e): 499.4 (M+H+, 100%).
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH2:3].CC(C)([O-])C.[K+].CS(C)=O>O>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:2][CH3:3]
Reactant: C=CCn1c2ccccc2c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC=Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Into a 100 mL round bottom flask fitted with a magnetic stirrer, reflux condenser and nitrogen inlet were placed 2.07 g (0.01 mole) of 9-allyl carbazole, 1.12 g (0.01 mole) of potassium t-butoxide and 10 mL of DMSO. The reaction mixture was stirred for 20 minutes at room temperature and then was heated to 120° C. and kept at that temperature for two hours. TLC on silica gel was used to monitor the reaction. After cooling to room temperature, the reaction mixture was poured into 20 mL of distilled water and extracted with ethyl ether. The organic layer was washed with distilled water to remove DMSO, then anhydrous sodium sulfate was added and the mixture stirred for an hour. Thereafter, the sodium sulfate was removed by filtration and a rotary evaporator was used to remove the solvent. 9-(1-Propenyl)carbazole was isolated in 63% yield (1.3 g) as a pale yellow viscous liquid. 1H NMR (300 MHz, CDCl3) showed that the product was consisted of approximately a 1:2 ratio of cis and trans 9-(1-propenyl)carbazole isomers.
Reaction SMILES: [OH:1][C@H:2]([CH2:16][OH:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15].C(NCCCCC1C=CC=CC=1OC[C@@H](O)CO)(OCC1C=CC=CC=1)=O>>[OH:1][C@@H:2]([CH2:16][OH:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: NCCCCc1ccccc1OC[C@H](O)CO
Agent: O=C(NCCCCc1ccccc1OC[C@@H](O)CO)OCc1ccccc1
Product: NCCCCc1ccccc1OC[C@@H](O)CO
Yield: 99 %

Procedure:
Compound 73 was prepared in a similar fashion to the synthesis of compound 70 starting from compound 72 (1.67 g, 4.5 mmol). Amine 73 (1.06 g, 99%) was isolated as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m, 2H), 1.54 (m, 2H) 2.55 (m, 2H), 3.45 (m, 2H), 3.75 (m, 3H), 3.94 (m, 2H), 6.83 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(C(O)c2ccccc2)nc2cnc3ccccc3c21
Temperature: -78 °C

Procedure:
1-(2-Methylpropyl)-1H -imidazo[4,5-c]quinoline (4 g; 0.017 mol) was dissolved in tetrahydrofuran (50 mL) then cooled to −78° C. A 7.75 mL portion of n-butyl lithium (2.5 M in hexanes) was added dropwise to the cooled solution. At 15 minutes post addition, benzaldehyde (2.7 mL; 0.027 mol) was added and the reaction mixture was allowed to warm slightly. The reaction was quenched with water then diluted with ethyl ether. The ether was separated, dried with magnesium sulfate then concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 5% methanol in methylene chloride as the eluent to give an oily yellow solid. This material was recrystallized from methylene chloride/hexane to provide a white crystalline solid, m.p. 160-166° C. Analysis: Calculated: C, 76.1; H, 6.4; N, 12.7; Found: C, 75.9; H, 6.3; N, 12.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](OB(O)O)=[CH:9][CH:8]=1)[CH3:2].Br[C:19]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]2[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(OB(O)O)cc1
Reactant: O=C1C=C(Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)CSc1ccc(C2=CC(=O)CC2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
{4-[(2-Ethoxy-2-oxoethyl)thio]phenyl}boric acid 2.80 g (11.7 mmol) and 3-bromo-2-cyclopenten-1-one 1.88 g (11.7 mmol) synthesized according to the method of C. M. Marson et al. were dissolved in 25 mL of 1,2-dimethoxyethane, followed by addition of 12 mL of 3N aqueous sodium carbonate solution and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) methylene chloride complex 0.48 g (0.59 mmol), and the mixture was stirred for 4 hours at 90° C. The temperature of the reaction solution was adjusted to room temperature, followed by concentration. Then, water was added to the residue, followed by extraction with methylene chloride and drying over anhydrous magnesium sulfate. The solvent was concentrated, and the crude product obtained was purified by silica gel column chromatography (Biotage, solvent for elution; hexane/ethyl acetate) to give the title compound 2.43 g (yield 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10](I)[C:3]=12.[CH3:13][N:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][C:15]1=2.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10]([C:22]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][CH2:19][N:14]([CH3:13])[C:15]=4[CH:23]=3)[C:3]=12
Reactant: CN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Cn1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCl
Product: CN1CCOc2ccc(-c3cn(C)c4nccc(Br)c34)cc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a suspension of 4-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (D7) (300 mg, 0.890 mmol) and 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (353 mg, 1.283 mmol) in ACN (2.5 mL) was added 2M sodium carbonate aqueous solution (4.72 mL, 9.43 mmol). DMF (4 mL) and DCM (3 mL) were added to aid the solubility. Then, bis(triphenylphosphine)palladium(II)chloride (81 mg, 0.116 mmol) was added and the reaction was stirred at 55° C. for 30 mins. Volatiles were removed by evaporation before partitioning between DCM and water. The organic layer was separated, dried and concentrated. The crude material was purified on silica eluting with gradient of 0-40% ethyl acetate in cyclohexane to afford the title compound (130 mg). LCMS (A): m/z (M+H)+ 358/360, C17H16BrN3O requires 357/359 (acidic).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([NH2:11])[CH2:10][CH2:9]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.Cl>ClC(Cl)C.O>[CH:8]1([NH:11][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:9]1
Reactant: O=C1CCCCC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: C1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To cyclohexanone (1.0 mL, 10 mmol) in dichloroethane (30 mL) was added cyclopropylamine (0.70 mL, 10 mmol), NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.57 mL, 10 mmol). The reaction was stirred at room temperature for 10 h. The reaction mixture was poured into water (60 mL) and acidified to pH 2 with 5 N HCl followed by removal of the organic portion. The aqueous portion was brought to pH>12 with 5 N NaOH and extracted with CH2Cl2 (3×30 mL). The collected organic extracts were dried with Na2SO4 and the volatile organics were removed in vacuo to afford the desired intermediate.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:26]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:25][C:24]=2[C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[C:29]([C:28]1[CH:27]=[C:26]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:23]=1[O:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:41])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])([CH3:31])([CH3:32])[CH3:30]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C(C)(C)C)c1

Procedure:
Racemic 3-{4-[1-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester (0.333 g, 0.500 mmol) is dissolved in tetrahydrofuran (3.0 mL) and sodium hydroxide (3.0 mL, 5N) is added. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with hydrochloric acid (3.0 mL, 5N) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound is used without further purification. MS (ES): 652.2 [M−H]−.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1.[Cl:14][C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>[OH-].[Na+]>[ClH:14].[CH3:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:15](=[O:16])[O:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[CH:13][C:8]=2[N:9]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1nc2cc(N)ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-methylbenzothiazole dihydrochloride (530 mg, 2.23 mmol) was dissolved in 1 N NaOH (10 mL) and was extracted with EtOAc (3×20 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in CH2Cl2 (10 mL), p-nitrophenyl chloroformate (586 mg, 2.91 mmol) was added, and the reaction mixture was stirred at rt overnight. The resulting solid was collected by filtration, was washed with CH2Cl2, and was dried under vacuum. This gave 853 mg of the title compound contaminated with some 5-amino-2-methylbenzothiazole. LC-MS: RT=8.49 min, [M+H]+=330.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[Br:22])[NH:15][C:14]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[Br:22])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc(Br)c2C12CCN(Cc1ccccc1)CC2
Solvent: C1CCOC1
Product: Brc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A solution of 1′-benzyl-4-bromospiro[indoline-3,4′-piperidin]-2-one (12.0 g, 32.3 mmol) in THF (300 mL) was carefully treated with the addition of BH3-THF complex (97 mL, 97 mmol). The reaction was then heated at 80° C. for 24 hours. The reaction mixture was quenched by the addition of 1N HCl. The aqueous layer was extracted with EtOAc (3×100 mL). The aqueous layer was basified to a pH of 12 with NaOH pellets and extracted with EtOAc (3×200 mL). The organic layers were dried with MgSO4 and concentrated under reduced pressure to give 1′-benzyl-4-bromospiro[indoline-3,4′-piperidine] (7.3 g, 63%) as an oil. LCMS (APCI+) m/z 357/359 [M+H]+; Rt=3.07 min.
Reaction SMILES: [F:1][CH2:2][CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH:29]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][N:39]=1)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH:29]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:3][CH2:2][F:1])=[CH:40][N:39]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: FCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 54 mg 1-fluoro-2-iodoethane (0.31 mmol) in N,N-dimethylformamide (10 mL) was subsequently added 101 mg potassium carbonate (0.73 mmol), followed by 100 mg of di-tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(5-hydroxypyridin-2-yl)methyl]hexanedioate (0.21 mmol), and the resulting mixture was stirred for 20 h at room temperature. The mixture was then partitioned between water and ethyl acetate, the aqueous layer was then extracted with ethyl acetate again. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC, method A to give 56 mg (approx. 90% purity, 46% purity adjusted yield) of the target compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH3:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12].CC/C=C/CC>CN(C=O)C>[CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC/C=C\CC
Agent: CC/C=C/CC
Solvent: CN(C)C=O
Solvent: CCC=CCC
Product: C=CCCCC

Procedure:
The 3-hexene feedstock was assumed to have a composition of 33 wt % cis-3-hexene and 67 wt % trans-3-hexene. The normal boiling points for 1-, 2-, and 3-hexene are listed in Example 2. The normal boiling for DMF, the extraction solvent in this example, is 152° C. (305° F.). The isomerization reaction was assumed to occur at the bottom of the column. The column was assumed to have 150 theoretical stages, a kettle reboiler, and a total condenser. The operating conditions for the column consisted of a pressure of 7 atm, condenser temperature of 140° C. (283° F.), and reboiler temperature of 232° C. (450° F.). In addition, 100 lb/hr of DMF was added to the 10th theoretical stage of the column (near the top). This resulted in a column with a diameter of 11.8 ft and a reflux ratio of 518. For this case, the 1000 lb/hr 3-hexene feed resulted in 980 lb/hr of 99 wt % 1-hexene product. The column bottoms contained 91 wt % DMF, which can be recycled back to the column. A detailed material balance is shown in the following table. RXFEED is the distillation column feed stream, SOLVENT is the DMF extractive distillation solvent stream, BOTTOMS is the distillation column bottoms stream, and 1-HEXENE is the product stream, which is obtained from the top of the column.
Reaction SMILES: C([N:5]1[CH:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[C:6]1=[O:19])(C)(C)C.C(O)(=O)C.O.[NH2:25]N>O>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:19])[NH:25][N:5]=[CH:13]2)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
In a 250 mL round-bottomed flask, 2,5-di-tert-butyl-3-hydroxyisoindolin-1-one (4.9 g, 18.7 mmol, Eq: 1.00) was combined with acetic acid (60 ml) to give a colorless solution. The reaction was heated to 90° C. Hydrazine monohydrate (1.61 g, 1.57 ml, 20.6 mmol, Eq: 1.1) was added dropwise. The reaction was stirred at 90° C. for 1 h. The reaction mixture was diluted with 24 mL H2O and slowly cooled to 25° C. over 3 h. The reaction mixture was concentrated but not quite to dryness. The reaction mixture was taken up in dichloromethane. The reaction mixture was poured into 75 mL sat NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. to give pure product as a white solid, which was purified by flash chromatography (silica gel, 80 g, 1% to 4% MeOH in DCM) to afford the desired product (3.7 g) as a white solid. (M+H)+=203 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.32 (s, 9 H) 6.58 (d, J=1.89 Hz, 1 H) 6.76 (dd, J=8.31, 1.89 Hz, 1 H) 7.06 (s, 1 H) 7.26 (d, J=8.31 Hz, 1 H) 9.19 (br. s., 1 H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([C:23]([OH:25])=O)[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH:35][CH3:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([C:23](=[O:25])[N:35]([CH3:36])[CH3:34])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)O)ccc2c1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)N(C)C)ccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a stirred solution of (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7-methylquinoline-2-carboxylic acid (14 mg, 0.032 mmol), dimethylamine HCl salt (13 mg, 0.16 mmol) and DIPEA (0.056 mL, 0.32 mmol) in DMF (1 mL) was added HATU (61 mg, 0.16 mmol) at 0° C. The mixture was stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with water and brine, then dried over Na2SO4. Concentration and purification by column chromatography provided the product (7 mg, 45%). LCMS-ESI+ (m/z): 483.2, 485.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:6]([OH:7])[C:5]=1[OH:14])([O-:3])=[O:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:17]=1[C:18](Cl)=[O:19]>>[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:17]=1[C:18]([O:7][C:6]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:14])=[O:19]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Product: Cc1cccc(C)c1C(=O)Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Temperature: 100 °C

Procedure:
A mixture containing 2.0 g of 3,5-dinitrocatechol in 5 ml of 2,6-dimethylbenzoylchloride was heated for 20 hours in 100° C. The excess 2,6-dimethylbenzoylchloride was removed in high vacuum. The residue was purified in silicagel column. Yield 1.5 g (45%), yellow viscous oil, which was crystallized from petroleum ether, m.p. 163°-165° C.