Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>[OH-].[Na+]>[C:1]1([S:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.5 %

Procedure:
Benzenesulphonyl chloride (7 mmol) was added to a solution of 7-aminoheptanoic acid (7 mmol) in 10% sodium hydroxide solution (10 ml). The mixture was stirred at room temperature for 3 hours. The pH was adjusted to 1 with 2NHCl and the solution was extracted with chloroform (3×100 ml). The chloroform extracts were dried over magnesium sulphate, the solvent was removed and the residue was recrystallised from methanol-water to give 7-(benzenesulphonamido)heptanoic acid (0.75 g, 38%); m.p. 75°-77° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)CCC>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Reactant: C1COCCN1
Solvent: CCCCO
Product: CS(=O)(=O)c1ccc(Nc2cc(N3CCOCC3)nc(-c3ccccc3)n2)cc1

Procedure:
A sample of (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.18 g, 0.48 mmol) was treated with morpholine (0.08 g, 0.97 mmol) in n-butanol at refluxing temperature for 12 hour to give the desired product.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C@@H:6]([OH:19])[CH2:7][NH:8]C(=O)OCC1C=CC=CC=1.[Cl-].[NH4+].S(I)(C1C=CC(C)=CC=1)(=O)=O.N.[OH-].[NH4+]>O.CC(O)C.O1CCCC1.[Zn]>[NH2:8][CH2:7][C@@H:6]([C@@H:2]1[CH:3]=[CH:4][CH2:5][O:1]1)[OH:19]
Reactant: O=C(NC[C@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)I)cc1
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: NC[C@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Alternative Preparation of Benzyl (S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17); Zinc and ‘One-Pot’ Procedure. A solution of ammonium chloride (140 mg, 2.62 mmol) in water (1.5 mL) was added to a solution of iodotosylate (38) (800 g, 1.95 mmol) in propan-2-ol (3 mL) and tetrahydrofuran (6 mL) under argon. Zinc dust (140 mg, 2.15 mmol) was then added in portions over 5 minutes then the suspension stirred for 16 hours before filtering through celite in vacuo. The filter cake was washed with diethyl ether (15 mL). Hydrochloric acid (1M, 15 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (15 mL) then the combined organic phase was washed with brine (15 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue (0.54 g) was dissolved in ammonium hydroxide (4.5 mL) and a solution of ammonia in 2-propanol (3 mL, 2.0M, 6 mmol) then heated in a sealed tube at 75° C. for 16 hours. The solvents were removed in vacuo (transfer assisted with methanol) then the residue azeotroped with diethyl ether (5 mL) before adding ammonium hydroxide (4.5 mL) and ammonia in 2-propanol (3 mL, 2.0M, 6 mmol). The suspension was heated in a sealed tube at 75° C. for 16 hours. The solvents were removed in vacuo (transfer assisted with methanol) then the residue azeotroped with diethyl ether (3×5 mL) to obtain (S)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH:18]=[C:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.[CH2:31]([O:33][CH2:34]Cl)[CH3:32].C(N(C(C)C)CC)(C)C.ClCCCl>C(OCC)(=O)C.CO>[CH2:31]([O:33][CH2:34][O:25][C@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C:19](=[CH:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][C@@H:8]3[O:9][C@@:5]4([O:29][CH2:30][C@H:2]([CH3:1])[CH2:3][CH2:4]4)[C@@H:6]([CH3:28])[C@@H:7]32)[CH2:24]1)[CH3:32]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: CCOCCl
Solvent: CO
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4C[C@@H]5O[C@]6(CC[C@@H](C)CO6)[C@@H](C)[C@@H]5[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
A mixture of diosgenin (2.5 g, 6.0 mmol), chloromethyl ethyl ether (1.14 g, 12.0 mmol), diisopropylethylamine (3.90 g, 30.0 mmol) and 1,2-dichloroethane (75 mL) was stirred under nitrogen atmosphere at ambient temperature for 4 hours. Methanol (<1 mL) was added to quench the reaction. The mixture was diluted with ethyl acetate and washed with water (2x), brine (1x), dried over sodium sulfate, filtered and concentrated in vacuo to give 2.17 g (76.5%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([NH:21][CH2:22][CH3:23])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([N:21]([CH2:22][CH3:23])[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:29][CH:30]=3)=[O:36])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and borane complex (1.9 g; 5.2 mmol) dissolved in CH2Cl2 (15 mL) is added 4-trifluoromethoxyphenyl isocyanate (1.6 g; 7.8 mmol) and the reaction was stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to provide 1.66 g (58%) of 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:21](=[O:34])[CH2:22][O:23][NH:24][C:25](=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:21](=[O:34])[CH2:22][O:23][NH:24][C:25](=[O:33])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(=O)CONC(=O)Cc1ccccc1
Solvent: CC#N
Product: O=C(O)CC(NC(=O)OCc1ccccc1)C(=O)CONC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 33.7 %

Procedure:
3-Benzyloxycarbonylamino-4-oxo-5-phenylacetylaminooxy-pentanoic acid, 1,1 dimethylethyl ester (208 mg, 0.365 mmol) was taken up in 3 mL of 1:1 trifluoroacetic acid (TFA)CH2Cl2 and allowed to stir for 2 hours. Reaction was diluted with acetonitrile (MeCN) (10 mL) and concentrated. The residue was stripped down from MeCN five times. Purification by chromatography (SiO2, 90:9:1 CH2Cl2 -acetone-formic acid) afforded 3-benzyloxycarbonylamino-4-oxo-5-phenylacetylaminooxy-pentanoic acid (51 mg, 34%) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]Cl)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:28][CH:27]=3)[O:30][C:31]=2[CH3:36])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole (example 123 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C@H:10]1[O:15]B(C2C=CC=CC=2)[NH:13][C@@H:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C([N+]([O-])=O)=CC=C([O:38][C:39]([O:41][CH2:42][C:43]2[S:47][CH:46]=[N:45][CH:44]=2)=O)C=1>C1COCC1>[NH2:1][C@H:2]([C@@H:10]([OH:15])[CH2:11][C@@H:12]([NH:13][C:39]([O:41][CH2:42][C:43]1[S:47][CH:46]=[N:45][CH:44]=1)=[O:38])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](Cc1ccccc1)[C@@H]1C[C@H](Cc2ccccc2)NB(c2ccccc2)O1
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 40 mmol of crude (4S,6S,1S)-6-(1-amino-2-phenylethyl)-4-benzyl-2-phenyl-3-aza-2-bora-1-oxacyclohexane in 700 ml of anhydrous THF was cooled to -40° C. and treated dropwise over a period of 1 h with a solution of 7.83 g (27.9 mmol) of ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate in 300 ml of dry THF. The resulting solution was allowed to warm to 0° C. for 3 h, then to ambient temperature for 16 h. The solvent was removed in vacuo, and the residue was taken up in 700 ml of ethyl acetate, washed with three 150 ml portions of 1N aqueous NaOH and one 150 ml portion of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography using methanol/chloroform mixtures provided the desired compound mixed with its regioisomer. A second chromatography using 1-3% isopropylamine in chloroform provided 5.21 g of the desired compound which solidified upon standing.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCCN(c2ccccc2)C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-phenylazocan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 64 (5.7 mg, 0.022 mmol) to give a white solid (6.6 mg, 46% yield). Anal. Calcd. for C44H54N4O6S m/z 766.5. found: 767.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.34 (2H, m), 7.31-7.03 (14H, m), 6.84 (1H, d, J=7.7 Hz), 5.32 (1H, t, J=4.7 Hz), 5.14-5.09 (1H, m), 5.06-4.98 (1H, m), 4.97-4.90 (1H, m), 4.19 (1H, t, J=14.0 Hz), 3.67 (3H, s), 3.53 (1H, d, J=14.3 Hz), 3.07 (1H, ddd, J=14.2, 11.1, 2.7 Hz), 2.87-2.67 (5H, m), 2.43-2.26 (3H, m), 2.04-1.95 (2H, m), 1.82-1.45 (16H, m), 1.34-1.24 (1H, m).
Reaction SMILES: [CH2:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:28])([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[OH:4][CH:2]([CH2:1][O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH2:3][NH:28][C:17]([CH3:27])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: C1C2CC3CC1CC(OCC1CO1)(C2)C3
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COC23CC4CC(CC(C4)C2)C3)cc1
Yield: 53.4 %

Procedure:
Using the method of Example 16, supra, 1-adamantyl glycidyl ether (350 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 207 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 338 (M+1, 0.1), 372 (0.3), 266 (65), 163 (1), 135 (100), 121 (16); 1H-NMR (CDCl3) δ7.02 (2H, d, J=8.3), 6.74 (2H, d, J=8.6), 3.70 (3H, s), 3.64 (1H, m), 3.38 (4H, m), 2.71 (1H, dd, J=11.5 and 4.0), 2.57 (3H, m), 2.06 (3H, broad s), 1.64 (6H, broad s), 1.53 (6H, m), 1.13 (4H, apparent t, J=6.9), 0.98 (3H, s), 0.97 (3H, s); 13C-NMR (CDCl3) δ157.8, 131.2, 130.0, 113.1, 77.8, 70.5, 69.4, 54.9, 52.8, 46.3, 44.6, 32.0, 26.7, 26.6, 25.6, 23.9.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[C@:11]([F:32])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[C:33]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@:11]([F:32])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH2:10][CH2:9]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccccc1[C@]1(F)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1[C@]1(F)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reaction time: 3 h

Procedure:
A solution of 6.3N hydrochloric acid in 20 cm3 of dioxane is added to a solution of 2.07 g of (3aS,4S,7aS)-7,7-diphenyl-4-fluoro-4-(2-methoxyphenyl)-2-tert-butoxycarbonyl-perhydroisoindole in 20 cm3 of dioxane at room temperature. The reaction mixture is stirred at this temperature for 3 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in 40 cm3 of absolute ethanol and the crystals are filtered off and then dried. 1 g of (3aS,4S,7aS)-7,7-diphenyl-4-fluoro-4-(2-methoxyphenyl)-perhydroisoindole hydrochloride is obtained in the form of white crystals which melt at 270° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:20]=[N:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24][CH2:25][CH:26](Br)[CH2:27][CH3:28]>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:20]=[N:19][N:18]([CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])[C:17](=[O:21])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cn[nH]c(=O)c2)cc1OC1CCCC1
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1ncc(-c2ccc(OC)c(OC3CCCC3)c2)cc1=O
Reaction time: 1 h

Procedure:
To 5-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridazin-3-one prepared in Working Example 5, sodium hydride was added and stirred for 1 hour. Then, 3-pentylbromide dissolved in dimethylformamide was added dropwise and stirred for 18 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The residue that had been filtered and concentrated was purified by flash chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>CC(=O)CC>[F:14][C:2]([F:13])([F:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:12][C:24]([CH3:28])([CH3:27])[CH:25]=[CH:26][C:10]=2[CH:11]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(c1ccc(O)cc1)C(F)(F)F
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)C=Cc2cc(S(=O)(=O)C(F)(F)F)ccc2O1
Temperature: 180 °C
Reaction time: 20 h
Yield: 38.9 %

Procedure:
1 g (4.4 mmol) of 4-trifluoromethylsulphonylphenol are stirred under argon at 80°-90° C. for 20 hours together with 0.66 g of potassium carbonate, 80 mg of potassium iodide and 2 g of 3-chloro-3-methyl-1-butyne in 13 ml of dry butanone. 0.33 g of potassium carbonate, 40 mg of potassium iodide and 1 g of 3-chloro-3-methyl-1-butyne are then added once again and the mixture is stirred at 80°-90° C. for a further 20 hours. It is then allowed to cool and is filtered, and the filtrate is evaporated. The residue is taken up in 20 ml of methylene chloride, washed with water (2×20 ml), dried and evaporated. The oil which remains (1.3 g) is heated under argon to 180° C. for 3 hours in o-dichlorobenzene (3 ml). After distilling off the solvent, the residue is chromatographed on silica gel. 0.5 g of colorless oil are obtained (50 % of theory). M+ =292 (5).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][C:3]([C:4]=23)=[CH:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:29])C=1Cl>C1COCC1.O>[O:29]=[C:13]1[C:3]2=[CH:2][NH:1][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:4]=32)[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12]1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]c3cccc(c23)C1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)c2c[nH]c3cccc(c23)C1

Procedure:
tert-butyl 1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 12 (100 mg, 0.37 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (167 mg, 0.73 mmol) in THF/water 9/1 (8 ml) was stirred under N2 over night at room temperature. The compound was purified on a Biotage preparative flash column eluting with 15-100% EtOAc in petroleum ether 40-65° C. Obtained 58 mg of the title compound. MS (ESI+) m/z 231 [M+H-isobutene]+.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([O:35]C)=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[C:28]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([OH:35])=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ncccc4C(F)(F)F)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ncccc4C(F)(F)F)CC3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(3-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)quinoxaline-6-carboxylate (236.2 mg, 0.46 mmol, 1.00 equiv, 95%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (91.2 mg, 5.00 equiv) in water (2 mL), which was added dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 105.4 mg (48%) of 2-phenyl-3-(4-(3-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]([OH:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCC[N+](CCCC)(CCCC)CCCC.OS([O-])(=O)=O>[CH2:3]([O:22][CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCC=Cc1ccccc1
Reactant: OCC=Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: C(=Cc1ccccc1)COCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a four-neck 1000 ml round bottom flask, equipped with a mechanical stirrer, thermometer, and condenser, were added 50% w/w aqueous NaOH (250 ml), cinnamyl bromide (80.44 g, 400 mmol), and TBAHS (5.2 g, 14.9 mmol). The mixture was stirred at room temperature for a period of time of about 20 minutes. To the mixture was added cinnamyl alcohol (50 g, 365 mmol), drop-wise over a period of time of about 60 minutes. The reaction was maintaned at a temperature below about 30° C. with an ice water bath, and allowed to stir overnight. Once the reaction was complete, the mixture was cooled and ice cold water (500 ml) was slowly added. The quenched reaction was allowed to stir for a period of time of about 30 minutes and then twice extracted with dichloromethane (250 ml). The organic portion was separated and twice washed with brine (250 ml), dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness in vacuo. Crude di-CE (96.0 g) was obtained as an amber liquid that was distilled in vacuo (175-180° C. at 775 mTorr) to provide distilled di-CE (75.0 g, mmol) as a clear yellow liquid. G.C. 87.1% (retention time 11.95 min.). 1H NMR (CDCl3) δ7.2-7.4 (br m, 10, C6H5), 6.65 (d, 2, CH), 6.35 (m, 2, CH), 4.2 (d, 4, CH2). FT-IR (neat) 3081, 3058, 3026, 2928, 2845, 1677, 1495, 1448, 1360, 1124, 1072, 969, 742, 693.