Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=CC=1.Cl.[F:28][C:29]([F:44])([F:43])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C@H:37]2[CH2:41][CH2:40][CH2:39][C@@H:38]2[NH2:42])=[N:34][CH:35]=1.[CH2:45]([O:47][C:48]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:49]=1[C:50](O)=[O:51])[CH3:46]>>[CH2:45]([O:47][C:48]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:49]=1[C:50]([NH:42][C@H:38]1[CH2:39][CH2:40][CH2:41][C@@H:37]1[NH:36][C:33]1[CH:32]=[N:31][C:30]([C:29]([F:28])([F:43])[F:44])=[CH:35][N:34]=1)=[O:51])[CH3:46]
Reactant: CCOc1ccc(C)cc1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1Br
Product: CCOc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 3-bromo-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 28) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 2-ethoxy-5-methylbenzoic acid (CAS number 854645-34-4; 57 mg, 0.32 mmol) and was then purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[CH2:27]([O:26][C:24](=[O:25])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A biphasic mixture of 2-(4-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in example 1Ga step B, and ethyl chloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) was prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction was then diluted with H2O and extracted with EtOAc (2×). The organic phases were washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 20-40%) gave 48 mg (55%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester as an off-white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]([CH2:14][CH3:15])[S:7](=[O:13])(=[O:12])[N:8]=[C:9]([CH3:11])[N:10]=1>O1CCCC1>[CH2:14]([N:6]1[C:5]([O:2][CH3:1])=[N:10][C:9]([CH3:11])=[N:8][S:7]1(=[O:13])=[O:12])[CH3:15]
Reactant: CCN1C(Cl)=NC(C)=NS1(=O)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(OC)=NC(C)=NS1(=O)=O

Procedure:
19.8 parts of 30 percent strength sodium methylate were added to a solution of 20.95 parts of 3-chloro-2-ethyl-5-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide in 120 parts of tetrahydrofuran at 20°-25° C. in the course of 10 minutes, while stirring. The reaction mixture was stirred for three hours at 25° C. and then concentrated, the residue was taken up in ethyl acetate, and the solution was extracted twice with dilute sodium carbonate solution. The organic phase was separated off, dried and chromatographed over silica gel. The solution was then concentrated under reduced pressure, giving 14.5 parts of 2-ethyl-5-methyl-3-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 50°-53° C.
Reaction SMILES: N(C(OC)=O)=NC([O-])=O.[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:19]1[CH:24]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:20]=1.C(O)CC>C1COCC1>[C:10]([O:18][CH2:20][CH2:19][CH3:24])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: COC(=O)N=NC(=O)[O-]
Solvent: CCCO
Solvent: C1CCOC1
Product: CCCOC(=O)c1ccccc1
Reaction time: 26 h
Yield: 55 %

Procedure:
The methyl azodicarboxylate resin (4.0 g of 0.28 meq/g, ~1.1 meq) was suspended in THF (150 ml). A solution of benzoic acid (0.134 g, 1.1 mmol) in the THF (10 ml) was added. Ph3P (0.288 g, 1.1 mmol) and n-propanol (0.180 g, 0.22 ml, 3 mmol) in THF (7 ml) were added slowly at 25° C. and the mixture stirred for 26 hours. The resin was filtered and washed with CH2Cl2 (4×150 ml), and Et2O (2×100 ml). The yellow oil obtained on concentration of filtrate and washings was purified by flash chromatography (0.5% EtOAC in hexane) to yield to 55% of n-propyl benzoate. (Using dimethyl azodicarboxylate instead of the resin, a 56% yield was obtained). FT IR (neat) on the ester 1721, 1315 (m), 1276, 1111, 711cm-1 ; 1H NMR (80 MHz CDCl3) δ 0.98 (t, 3H, -CH2CH3), 1.75 (m, 2H, -CH2CH2CH3), 4.25 (t, 2H, --OCH2), 7.43 (t, 3H,) 8.30 (m, 2H) (Ph); EI--MS: 164.0836 (M+, 164.0838 calcd. for C10H12O2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16]O)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)(Cl)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])=[C:5]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of (6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methanol (1.6 g, 4.2 mmol) in toluene (30 ml) was added thionyl chloride (0.61 ml, 8.4 mmol), and the mixture was heated under reflux for 30 min. The solvent was evaporated and the residue was dissolved in N,N-dimethylformamide (30 ml). Potassium phthalimide (1.2 g, 6.3 mmol) was added and the mixture was stirred at 55° C. for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and the aqueous layer was extracted with ethyl acetate (50 ml). The extract and the organic layer were combined and the mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and then saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and toluene (20 ml)-ethyl acetate (10 ml) was added to the residue. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether to give 2-[(6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.7 g, yield 82%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].C([Li])CCC.CN(C)[CH:16]=[O:17].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:3][C:4]1[S:5][C:6]([CH:16]=[O:17])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1cccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
To a solution of 2-ethoxythiophene (355 mg, 2.77 mmol) in 14 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (1.22 mL, 2.5 M in hexanes) dropwise over 5 minutes. After stirring at −78° C. for 20 minutes, dimethylformamide (1.07 mL, 13.9 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 60 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (2×75 mL), washed with 1 N hydrochloric acid (2×40 mL), water (40 mL) and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-7% ethyl acetate in hexanes) to give 5-ethoxy-2-thiophenecarbaldehyde (216 mg, 49%). Used without further characterization.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:3]1[C:2](=[O:1])[CH:7]=[C:6]([CH3:8])[O:5][C:4]1=[O:9])[CH3:14]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-6-methyl-2-pyrone (11.50 g, 91.2 mmol) in toluene (30 mL) is added N,N-dimethylformamide dimethyl acetal (13.00 mL, 97.9 mmol). After stirring for 2 h at room temperature, the reaction mixture is evaporated under reduced pressure and co-evaporated with toluene several times. Yield: 18.5 g; ESI mass spectrum: [M+H]+=182; r.t. HPLC: 0.72 min (Z002_007).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:15]([N:19]=[C:20]=[S:21])([O:17][CH3:18])=[O:16]>C(#N)C>[C:15]([NH:19][C:20](=[S:21])[NH:6][C:5]1[CH:7]=[C:8]([S:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])([O:17][CH3:18])=[O:16]
Reactant: CCCSc1ccc([N+](=O)[O-])c(N)c1
Reactant: COC(=O)N=C=S
Solvent: CC#N
Product: CCCSc1ccc([N+](=O)[O-])c(NC(=S)NC(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a stirred mixture of 2-nitro-5-propanylthioaniline (21.2 g.; 0.10 mole) in acetonitrile (50 ml.) is added portionwise carbomethoxy isothiocyanate (11.7 g.; 0.10 mole). The reaction mixture is maintained at room temperature and is filtered to remove a small amount of dark colored insoluble material. The clear filtrate was permitted to stand at room temperature for two hours and the precipitate which forms is collected by filtration, washed with cold acetonitrile and dried to yield 1-(3-carbomethoxythioureido)-2-nitro-5-propylthiobenzene (17.6 g.), m.p. 122°-125° C.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]([NH:7][C:8]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:9]=1[CH2:10][O:11][C:12]1[C:13]([N+:18]([O-])=O)=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:6]>O.C(O)C.[Fe]>[NH2:18][C:13]1[C:12]([O:11][CH2:10][C:9]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:8]=2[NH:7][C:5]([O:4][CH3:3])=[O:6])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)Nc1cccc(C)c1COc1cccnc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)Nc1cccc(C)c1COc1cccnc1N
Reaction time: 0.5 h

Procedure:
To a mixture of iron powder (2.76 g) and ammonium chloride (0.275 g) in water (19 ml) and ethanol (63 ml) was added portionwise 3-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-nitropyridine (6.27 g) under reflux and then stirred for an additional 30 minutes. The hot mixture was filtered by suction and the filtrate was made alkaline with sodium bicarbonate and evaporated in vacuo. The residue was washed with water, dried, and recrystallized from ethyl acetate to give 2-amino-3-(2-methoxycarbonylamino-6-methylbenzyloxy)pyridine.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: Cc1ccccc1NCC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
1.12 ml of bromoacetyl bromide (12.9 mmol) was added to a solution of 2.4 g of [1,1-dimethyl-2-(2-methylphenylamino)ethyl]carbamic acid t-butyl ester obtained in Example (51a) (8.62 mmol) in N,N-dimethylacetamide (85 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 3.21 g of the title compound (yield: 93%).
Reaction SMILES: C(O)C.Cl.Cl.[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:38](=[O:37])[CH2:39][OH:40])[CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CO)CC1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)-quinazoline dihydrochloride ethanol solvate (91.8 g), 4-(dimethylamino)pyridine (73.3 g) and acetonitrile (330 ml) were stirred at 20° C. to 25° C., under nitrogen. Acetoxyacetyl chloride (28 ml) was added maintaining the temperature at less than 30° C., followed by an acetonitrile line wash (37 ml). The reaction mixture was stirred at ambient for 60 minutes before water (250 ml) and 47% w/w sodium hydroxide solution (77.2 ml) were added followed by a water line wash (25 ml), keeping the temperature at less than 30° C. The reaction mixture was stirred at ambient for 120 minutes before the lower aqueous layer was separated. Water (735 ml) was added to the organic layer and mixture stirred at ambient until a solid crystallised. The solid was filtered, washed with a 50% aqueous acetonitrile (2×90 ml), and then dried in a vacuum oven between 50° C. and 55° C. to give the title product (65.8 g; 83.9% yield); melting point 195.5–196.5° C.; NMR Spectrum: (DMSO d6) 1.64–1.83 (m, 2H); 1.98–2.14 (m 2H); 3.28–3.48 (m, 1H); (m, 2H); 3.57–3.67 (m, 1H); 3.81–3.92 (m, 1H); 4.00 (s 3H); 4.14 (s, 2H); 4.81 (m 1H); 7.27 (s 1H); 7.36 (t 1H); 7.54–7.64 (m 2H); 8.00 (s 1H); 8.66 (s 1H); Mass Spectrum: (M+H)30 460.9.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6](Cl)(Cl)[C:7]([F:10])([F:9])[F:8].[CH2:13]([C:15]1[CH:30]=[C:29]([O:31][CH2:32][CH:33]=[C:34]([Cl:36])[Cl:35])[CH:28]=[C:27]([CH2:37][CH3:38])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH:25]=O)[CH3:14].C(OC(=O)C)(=O)C>[Zn].CN(C)C=O>[CH2:13]([C:15]1[CH:30]=[C:29]([O:31][CH2:32][CH:33]=[C:34]([Cl:35])[Cl:36])[CH:28]=[C:27]([CH2:37][CH3:38])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24]/[CH:25]=[C:6](\[Cl:5])/[C:7]([F:10])([F:9])[F:8])[CH3:14]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCCOCC=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCCOC/C=C(\Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.5 %

Procedure:
To a mixture of 0.12 g of aluminum chloride and 50 ml of N,N-dimethylformamide was added 3.04 g of 1,1,1-trichlorotrifluoroethane. After stirring at room temperature for 1 hour, 1.21 g of 5-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde was added, and the reaction mixture was further stirred at room temperature for 4 hours, to which 1.38 g of acetic anhydride was added. After stirring at room temperature for 1 hour, 0.88 g of zinc dust was added, and the reaction mixture was stirred at room temperature for 12 hours and filtered. The filtrate was poured into 50 ml of diluted hydrochloric acid and extracted twice with 100 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.91 g of (Z)-3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(5-(3-chloro-4,4,4-trifluoro-2-butenyloxy)pentyloxy)benzene (yield, 72%), nD26.0 1.4958.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][OH:23])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>CO.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][O:23][CH2:26][CH2:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: C=CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)CCOCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
A mixture of (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methanol (50 mg, 0.161 mmol), tert-butyl acrylate (0.059 mL, 0.403 mmol), and Triton B (40% in MeOH) (7 μL, 0.016 mmol) in toluene (1 mL) was stirred at rt for 5 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-30% EtOAc:hexanes) to afford the title compound (61 mg, 85% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.28 (dd, J=9.1, 6.7 Hz, 1H), 7.19-7.13 (m, 2H), 7.12-7.07 (m, 1H), 7.01 (ddd, J=4.4, 3.3, 1.8 Hz, 2H), 6.86 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 3.92 (s, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.17 (s, 2H), 2.48 (t, J=6.3 Hz, 2H), 2.10-1.95 (m, 4H), 1.86-1.73 (m, 2H), 1.70-1.58 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CC(N(C)C)=O.[Br:19][CH2:20][CH2:21][CH2:22]Br>O>[Br:19][CH2:20][CH2:21][CH2:22][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCBr
Yield: 77 %

Procedure:
90 g of potassium phthalimide was mixed with 300 ml of dimethylacetamide and stirred. 74 ml of 1,3-dibromopropane was added to the system. The system was then allowed to undergo reaction at a temperature of 120° C. over 4 hours. The reaction solution was poured into 1 l of water. The resulting crystals were filtered off with suction. The crude crystals were recrystallized from ethanol to obtain 100 g of N-(3-bromopropyl)-phthalimide (7). (Yield: 77%; m.p. 65° C.)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15]>C(Cl)Cl>[C:14]([C:13]([NH:12][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])([CH3:19])[CH:16]([CH3:18])[CH3:17])#[N:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)C(C)(N)C#N
Solvent: ClCCl
Product: CC(C)C(C)(C#N)NC(=O)c1ccccc1C(=O)O
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a stirred boiling mixture of 28.1 g (0.189 mole) of phthalic anhydride in 28 ml methylene chloride is added dropwise 23.6 g (0.21 mole) of 2-amino-2,3-dimethylbutyronitrile in 57 ml methylene chloride. After the addition, heating is constinued for 3 hours. The mixture is cooled and the precipitate removed by filtration, washed with methylene chloride and air-dried to give 44.2 g (90%) of N-(cyano-1,2-dimethylpropyl)phthalamic acid, melting point 154-155° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].Cl.[CH3:9][NH:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:9][N:10]([CH3:11])[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)CCCCl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 21.77 gm (180.5 mMol) 5-chloro-2-pentanone, 13.40 gm (164.3 mMol) dimethylamine hydrochloride and 50.0 gm (361.8 mMol) potassium carbonate in 150 mL acetonitrile was stirred at room temperature for 2 days and then at reflux for 2 hours. The reaction mixture was then cooled to room temperature and partitioned between water and dichloromethane. The phases were separated and the aqueous phase again extracted with dichloromethane. All organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The desired product was then isolated by distillation.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)cc12

Procedure:
(±)-tert-Butyl 4-((1-(3-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (62 mg, 0.12 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 42 mg (77%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.82 (s, 1H), 7.37-7.40 (m, 2H), 7.29-7.32 (m, 3H), 7.19 (m, 1H), 4.55 (q, J=6.7 Hz, 1H), 3.41 (q, J=8.9 Hz, 1H), 3.30 (d, J=8.9 Hz, 1H), 2.87-2.93 (m, 2H), 2.68-2.84 (m, 2H), 2.55 (s, 3H), 2.10-2.25 (m, 2H), 1.81-1.93 (m, 2H), 1.42 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.8, 143.6, 139.2, 128.7, 127.3, 127.1, 126.7, 124.9 (q, J=272 Hz), 122.9, 122.4 (q, J=32.6 Hz), 119.8, 117.4, 78.3, 50.5, 42.6, 41.5, 33.5, 22.0, 11.9. Mass spec.: 418.19 (MH)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]2[N:12]=[C:13]([CH3:15])[S:14][C:10]=2[CH:9]=[C:8]([F:16])[CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:11]2[N:12]=[C:13]([CH3:15])[S:14][C:10]=2[C:9]([N+:1]([O-:4])=[O:2])=[C:8]([F:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2c(Cl)cc(F)cc2s1
Agent: O=S(=O)(O)O
Product: Cc1nc2c(Cl)cc(F)c([N+](=O)[O-])c2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 7 ml of concentrated nitric acid in 6 ml of concentrated sulfuric acid was added to a solution of 10 g (50 mmol) of 4-chloro-6-fluoro-2-methylbenzothiazole in 35 ml of concentrated sulfuric acid. Stirring was carried out for 10 minutes, after which the mixture was poured into ice water. Thereafter, the suspended desired product was separated off and, for purification, was dissolved in 100 ml of 3:1 cyclohexane/ethyl acetate. After filtration over a bed of silica gel, 8 g of desired product was obtained from the remaining solution; mp.: 130° to 132° C.