Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1>C(O)C.[Pd].C(O)(=O)C>[CH3:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: OCc1ccc2cc[nH]c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc2cc[nH]c2c1
Reaction time: 20 h

Procedure:
6-hydroxymethyl indole (6.135 g, 41.69 mmol) was dissolved in ethanol (70 ml). 10% Palladium on charcoal (0.610 g) was suspended in acetic acid (70 ml) and added to the ethanol (70 ml) solution. The mixture was placed on the high pressure hydrogenator at 60 psi. After 20 hours, the mixture was filtered through Celite and the resulting solution concentrated in vacuo. The mixture was purified by flash chromatography using chloroform as solvent to yield a colourless oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1([C:22]([C:24]2[C:32]3[CH:31]=[CH:30][C:29]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][C:27]=3[N:26](COCC[Si](C)(C)C)[N:25]=2)=[O:23])[CH2:21][CH2:20]1.O>O1CCCC1>[N:19]1([C:22]([C:24]2[C:32]3[CH:31]=[CH:30][C:29]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:28][C:27]=3[NH:26][N:25]=2)=[O:23])[CH2:21][CH2:20]1
Reactant: C[Si](C)(C)CCOCn1nc(C(=O)N2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)N1CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 470.3 %

Procedure:
6 cm3 of a commercial 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of 0.235 g of aziridin-1-yl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone in 2.5 cm3 of tetrahydrofuran cooled to a temperature in the region of 0° C. After stirring for about 48 hours at a temperature in the region of 20° C., the mixture is poured into 30 cm3 of an ice plus water mixture and extracted with three times 50 cm3 of diethyl ether. The combined organic phases are washed with three times 25 cm3 of water and 25 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (90/10 by volume)], 0.80 g of aziridin-1-yl(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)methanone is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]=2[C:6]([CH3:16])=[C:5]2[CH:17]=[N:18][CH:19]=[CH:20][C:4]=12.CC(C)=O.[CH3:25][N:26]=[C:27]=[O:28]>N1C=CC=CC=1>[CH3:25][NH:26][C:27](=[O:1])[OH:28].[OH:1][CH2:2][C:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]=2[C:6]([CH3:16])=[C:5]2[CH:17]=[N:18][CH:19]=[CH:20][C:4]=12
Reactant: CN=C=O
Agent: Cc1c2cnccc2c(CO)c2[nH]c3ccccc3c12
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)O

Procedure:
To a solution of 400 mg (1.53 mmol) of the carbinol 25 in 25 mL of dry pyridine and 20 mL of reagent grade acetone there was added 900 uL of MeNCO. The solution was magnetically stirred at room temperature in a stoppered flask until all the starting alcohol had disappeared as judged by TLC (ca. 3 days). The solvents were removed in vacuo, and the residue was crystallized from EtOAc-CH2Cl2 -MeOH to give 152 mg of the desired carbamate, mp 213°-214.5° C. The filtrate was concentrated to dryness and the remaining solid was flash chromatographed to give an additional 145 mg of material of similar purity: wt 307 mg (61%); NMR (Me2SO-d6) 11.62 (s, 1 H), 9.71 (s, 1 H), 8.46 (d, 1 H), 839 (d, 1 H), 7.97 (d, 1 H), 7.61-7.54 (m, 2 H), 7.32-7.29 (m, 1 H), 7.04 (d, 1 H), 5.77 (s, 2 H), 3.34 (s, 3 H), 2.60 (s, 3 H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[N:32]1([C:38]2([CH2:44][NH2:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:45][CH2:44][C:38]5([N:32]6[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]6)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: NCC1(N2CCCCC2)CCCCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCC5(N6CCCCC6)CCCCC5)c4)cc23)CC1
Yield: 34.7 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), 1-[1-(1-piperidinyl)cyclohexyl]methanamine (17 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (18.7 mg, 27%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:28][N:29]([CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:42]([C:43]([OH:45])=O)=[CH:41][CH:40]=2)=[CH:32][CH:31]=1.Cl.C[O:51][C:52](=[O:55])[CH2:53][NH2:54].C(=O)([O-])O.[Na+].[OH-].[Li+].Cl>C(O)C>[CH3:48][N:29]([CH3:28])[C:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]([NH:54][CH2:53][C:52]([OH:55])=[O:51])=[O:45])=[CH:46][CH:47]=2)=[CH:34][CH:35]=1
Reactant: CN(C)c1ccc(CCOc2ccc(C(=O)O)cc2)cc1
Reactant: COC(=O)CN
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
N-Ethyl-N,N-diisopropylamine (388 μL, 2.23 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (615 mg, 2.22 mmol) were added to a solution of ethanol (10 mL) containing 4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoic acid (567 mg, 1.99 mmol) prepared in Example 23 (23a) and glycine methyl ester hydrochloride (280 mg, 2.23 mmol). The mixture was stirred at room temperature for 18 hours, and a saturated sodium hydrogen carbonate aqueous solution was added thereto to terminate the reaction. The mixture was extracted with ethyl acetate twice, and the organic layers were dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1 to 2:5, v/v) to give an oily compound. To a solution of ethanol (6 mL) containing the resulting compound, a 2 M lithium hydroxide aqueous solution (1.60 mL, 3.20 mmol) was added. The mixture was stirred at 60° C. for 40 minutes, and then 10% hydrochloric acid (3.5 mL) was added thereto under ice-cooling. The mixture was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 395 mg of the title compound (white powder, yield: 58%)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([O:31]C(=O)C)([CH3:30])[C:26]([F:29])([F:28])[F:27]>O.CC(C)=O>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:22])[CH2:20][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: CC(=O)O[C@](C)(C(=O)Nc1ccc(Sc2ccc(NC(=O)CCl)cc2)cc1Cl)C(F)(F)F
Reactant: CNC
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CC(=O)Nc1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1

Procedure:
Dimethylamine (0.17 ml of a 40% solution in water) was added to a solution of (R)-N-{2-chloro-4-[4-(2-chloroacetylamino)phenylsulphanyl]phenyl}-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (Method 19) (0.25 g) in acetone (1.5 ml). After 24 hours volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water, and the organic layer was poured onto a Varian Chem Elut column. Elution with ethyl acetate gave the title compound (0.25 g) as a foam. NMR: 1.6 (s, 3H), 3.1 (s, 2H), 3.3 (s, 6H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 (d, 2H), 7.7 (m, 3H), 7.9 (d, 1H), 9.7 (s, 1H) 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:16]=2)[C:12](OC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:13][CH2:12][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=1
Reactant: COC(=O)c1cncc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cncc(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of methyl 5-phenylnicotinate (640 mg) in THF (20 mL) at 0° C. was added LiAlH4 (3 mL of a 1M solution). After 1 h, H2O (0.12 mL), 15% sodium hydroxide (0.12 mL) and H2O (0.36 mL) were added successively. The mixture was filtered, washing with EtOAc. The filtrate was concentrated and chromatographed (silica gel; EtOAc/hexane (4:1-5:1)) to provide the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])/[C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[C:17](\[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)/[CH2:18][CH3:19])/[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C(=C(\CC)c1ccccc1)c1ccc(OCOC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
To a solution of 2 (3.4 g, 9.99 mmol) in MeOH (85 ml) was added 2N NaOH (50 ml), and the mixture was stirred at 80° C. for 15 h. After cooling, 2 N HCl (50 ml) was added drop wise under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with brine, dried over Na2SO4, then concentrated. The residual solid was triturated with hexanes to give 3 (88%). 3: colorless powder; 1H-NMR (CDCl3) δ 1.03 (3H, t, J=7.4 Hz), 2.81 (2H, q, J=7.4 Hz), 3.42 (3H, s), 5.08 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=8.8 Hz), 7.02 (2H, m), 7.11-7.19 (3H, m).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[C:18]=2[CH2:27][CH2:28][CH3:29])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5](=[O:30])[C:4]([OH:31])=[O:3])=[CH:7][CH:8]=2)=[C:18]([CH2:27][CH2:28][CH3:29])[C:19]=1[OH:26])(=[O:25])[CH3:24]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A solution of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.7 g) in methanol (50 mL) was treated with sodium carbonate (0.38 g) in water (2.5 mL), and the reaction was stirred at room temperature for 2 hours. After the solvents were removed in vacuo, dichloromethane (40 mL) and water (40 mL) were added and the mixture was acidified with 3N hydrochloric acid. The dried (Na2SO4) organic layer was evaporated, and the residue was crystallized from dichloromethane-hexane to yield in two crops, 0.435 g of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid, mp 129°-130° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)n1
Yield: 22.4 %

Procedure:
The title compound was prepared from methyl 6-(2-(7-phenylheptanoyl)oxazol-5-yl)picolinate (9 mg, 0.059 mmol) following General Procedure E. Preparative thin layer chromatography (2% AcOH/EtOAc) yielded the title compound as a white solid (5 mg, 57%): 1H NMR (THF-d8, 500 MHz) δ 8.11-8.04 (m, 4H), 7.22-7.08 (m, 5H), 3.08 (t, 2H, J=7.5 Hz), 2.61 (t, 2H, J=7.5 Hz), 1.76-1.68 (m, 2H), 1.68-1.62 (m, 2H), 1.45-1.41 (m, 4H); 13C NMR (THF-d8, 125 MHz) δ 185.6, 163.1, 156.4, 151.4, 147.6, 144.7, 141.0, 137.1, 126.7, 126.5, 126.1, 123.9, 122.8, 121.1, 37.1, 34.3, 30.0, 27.6, 27.5, 22.2; MALDI-FTMS m/z 379.1645 (M+H+, C22H23N2O4, requires 379.1652).
Reaction SMILES: N[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[NH:6]2.N(OCCC(C)C)=O.C(Br)(Br)[Br:36]>>[Br:36][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[NH:6]2
Reactant: BrC(Br)Br
Reactant: CCOC(=O)Nc1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]1
Agent: CC(C)CCON=O
Product: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1

Procedure:
The product of example 5, step (d) (1 g) was dissolved in bromoform (14 ml) and iso-amyl nitrite (0.1 ml) and heated at 40° C. for 5 hr. The reaction mixture was then evaporated to dryness and purified by flash chromatography on silica gel with 20% ethyl acetate in dichloromethane, yielding the subtitled compound as a yellow solid (208 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>CCOCCO>[CH2:16]([NH:20][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:17][CH2:18][CH3:19]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Reactant: CCCCN
Solvent: CCOCCO
Product: CCCCNc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Yield: 34 %

Procedure:
A mixture of 2,4-dichloro-5-methylsulfonylbenzoic acid (6.0 g.; 0.0224 mole), butylamine (9 ml.) and ethyl cellosolve (20 ml.) is heated at reflux in a nitrogen atmosphere for 5 hours. The solvent is distilled at reduced pressure and the residue is dissolved in water (75 ml.) then treated with dilute hydrochloric acid which causes the product to precipitate. After recrystallization from butyl chloride there is collected 2.3 g. (34% yield) of 2-butylamino-4-chloro-5-methylsulfonylbenzoic acid, m.p. 187°-9° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:21])[CH:9]=[CH:10][CH:11]=1.Cl.O>O1CCCC1>[CH3:21][C:13]1[N:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[CH:2]=[O:1])[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: Cc1cc2ccccc2n1-c1cccc(C2OCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ccccc2n1-c1cccc(C=O)c1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 5.4 %

Procedure:
1-[3-(1,3-Dioxolan-2-yl)phenyl]-2-methyl-1H-indole (1.1 g, 3.94 mmol) synthesized according to the method described in J. Am. Chem. Soc., 2002, vol. 124, pp. 11684-11688 was dissolved in tetrahydrofuran (40 mL), 5 N hydrochloric acid (10 mL) was added to the solution, and the mixture was stirred at 50° C. for 40 min. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:6) to give the title compound (50 mg, yield 5%) as a pale-yellow oil. MS: m/z 236 (MH+).
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][O:29][CH2:30][C:31](O)=[O:32]>>[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:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (10.3 mg, 47%), MS (ISP) m/z=404.5 [(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) (20 mg, 0.0543 mmol) and 2-methoxyacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:3]=1[F:27].[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:3]=1[F:27]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(Cl)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
Trans-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (178 mg, 0.44 mmol) (from example 65, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (18.51 mg, 0.46 mmol) dissolved in water (0.200 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.028 mL, 0.46 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (2.278 mL, 13.67 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. Crude trans-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-oxo-2,3-dihydro-isoxazol-5-yl)piperidine-1-carboxylate (158 mg, 96%) was isolated as a light yellow oil. MS m/z 273 (M+H)+
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1.C(O)(C(F)(F)F)=[O:28].N>C(Cl)Cl.C(Cl)(Cl)Cl>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N+:17]([O-:28])=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5][O:4][CH3:3])[CH3:26])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: O=C(O)C(F)(F)F
Reactant: COCCN(C)CCCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCCN(C)CCCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 4.7 %

Procedure:
H2O2 (70%, 3.0 mL, ca. 60.4 mmol) was added dropwise to a stirred solution of TFM (8.4 mL, 60.4 mmol) in DCM (80 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., and added to a solution of 1-oxide 52 (2.0 g, 6.04 mmol) and TFA (1.0 mL, 13.0 mmol) in CHCl3 (80 mL) at 0° C. and the solution stirred at 20° C. for 18 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-18%) of MeOH/DCM, to give 1,4-dioxide 53 (99 mg, 5%) as a red solid: mp 77-79° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.26 (br s, 1H, NH), 3.66 (t, J=6.3 Hz, 2H, CH2), 3.59 (t, J=5.6 Hz, 2H, CH2), 3.36 (s, 3H, OCH3), 3.03-3.12 (m, 4H, H-6, H-8), 2.66-2.71 (m, 4H, 2×CH2), 2.39 (s, 3H, NCH3), 2.19 (p, J=7.4 Hz, 2H, H-7), 1.91 (p, J=6.6 Hz, 2H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.5, 58.9, 56.8, 55.9, 42.5, 40.5, 33.4, 32.4, 25.9, 25.6; HRMS (FAB+) calcd for C17H26N5O3 (MH+) m/z 348.2036, found 348.2032.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)[C:4]([O:6]CC)=[O:5].[OH-].[K+].CCCCCC.C(O)CC>C(O)C.O>[ClH:1].[NH2:2][CH:3]([CH:9]1[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(N)C1c2ccccc2C=Cc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCCO
Product: NC(C(=O)O)C1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
Ethyl α-amino-5H-dibenzo[a,d]cycloheptene-5-acetate, hydrochloride (0.21 g, 0.6 mmol) dissolved in 10 mL of absolute ethanol is stirred with 3 mL of 1.25 M ethanolic potassium hydroxide solution until TLC (SiO2, hexane:2 propanol/3:1) shows no starting material (2 hours). The solvent is stripped and a residual solid is taken up in water and extracted with dichloromethane. The aqueous layer is acidified with 6 N hydrochloric acid to pH 1 and stripped to dryness. The residue is treated with 5 mL of boiling water, cooled to room temperature, then refrigerated overnight. A solid is collected, washed with diethyl ether (0.05 g); mp 225° C. (dec).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])[CH3:3].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>>[CH3:4][C:2]([Si:5]([CH3:29])([CH3:30])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:9]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(=O)C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of 66.30A (0.500 g, 1.2 mmol) in THF (15.00 mL, 183 mmol) at 0° C. was added LAH in THF (2.3 mL, 2.3 mmol, 1.0M). The reaction was stirred for two hours. 1N NaOH(aq) was added to quench the reaction mixture, and the reaction was then extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.30B as a colorless oil (0.400 g, 80% yield).