Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C@H:21]([OH:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([OH:24])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.[C:25](=O)([O-])[O-].[K+].[K+].O>CO.CI>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C@H:21]([OH:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: C[C@]12C[C@H](O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC1OCCOC12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C3OCCOC3C[C@@H]12

Procedure:
A mixture of 15 g of 17-ethylenedioxyestra-1,3,5(10) trien-3,11β-diol and 30 g of anhydrous potassium carbonate in 75 ml of methanol and 60 ml of methyl iodide is stirred and heated under reflux for 3 hours. The mixture is then cooled and diluted by the addition of 200 ml of water. The methanol and methyl iodide are removed by distillation under reduced pressure and the aqueous residue is extracted twice with methylene chloride. The combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. Removal of the solvent gives a residue which is crystallized from ether to yield 17-ethylenedioxy-11β-hydroxy-3-methoxyestra-1,3,5(10)-triene, m.p. 125° - 126° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[C:7]([CH2:13]Br)[CH:6]=1)(=[O:3])[CH3:2].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:15]([O:18][CH2:13][C:7]1[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:10]=[C:9]([CH3:11])[C:8]=1[Br:12])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: CC(=O)Oc1cc(C)c(Br)c(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(OC(C)=O)cc(C)c1Br
Temperature: 70 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a solution of 4-bromo-3-(bromomethyl)-5-methylphenyl acetate (11.7 g, 36.3 mmol) in N,N-dimethylformamide (60 mL) was added sodium acetate (5.96 g, 72.6 mmol), and the mixture was stirred at 70° C. for 4 hr under nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75) to give the title compound (7.29 g, yield 67%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[N:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[N:19]([CH3:20])[NH:18][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(C2CC(=O)NN2C)cc1OC1CCCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)[nH]n2C)cc1OC1CCCC1
Yield: 32.7 %

Procedure:
To a magnetically-stirred solution of 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (68.88 mmol, 20.0 g) in dry tetrahydrofuran (300 mL) at 0° C. is added, via cannula, a suspension of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 68.88 mmol, 15.64 g) in 200 mL dry tetrahydrofuran. The resulting heterogeneous mixture is allowed to warm slowly from 0° C. to room temperature overnight. The solvent is removed in vacuo and the reddish-brown residue is triturated with methylene chloride. The undissolved yellow solid is removed via suction and discarded. The filtrate is concentrated in vacuo to produce a brownish foam which is purified by flash chromatography (SiO2 : gradient ranging from 15% ethyl acetate/methylene chloride to 30% ethyl acetate/methylene chloride). Concentration in vacuo affords a light tan solid which is dried overnight in vacuo at 50° C. to give the title compound (22.54 mmol, 6.50 g., 32.7%). 1H NMR (DMSO-d6, 400 MHz) δ9.58 (s, 1H); 6.98 (m, 3H); 5.53 (s, 1H); 4.83 (m, 1H); 3.77 (s, 3H); 3.60 (s, 3H); 1.90 (m, 2H); 1.70 (m, 4H); 1.55 (m, 2H). IR (KBr, cm-1) 3440, 2950, 2830, 1950, 1600, 1517, 1483, 1310, 1252, 1235, 1165, 1135, 1020, 770.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[Mg+2].[Cl-].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])=[O:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1F
Reaction time: 16 h

Procedure:
To a solution of 2-(2-fluorophenyl)-2-methylpropanoic acid (3.98 g, 22 mmol), IPAc (31 mL) and DMF (0.017 mL), was slowly added oxalyl chloride (2.0 mL, 23 mmol) over 10 minutes. The resulting solution was stirred for 16 hours and then concentrated in vacuo to afford an oil. In a separate flask, IPAc (30.0 mL) and diethyl malonate (4.2 mL, 27 mmol) were combined. To this mixture was added anhydrous MgCl2 (2.6 g, 27 mmol). The resulting white slurry was stirred at room temperature for 30 minutes, and then TEA (10 mL, 73 mmol) was added. After stirring for an additional 2.5 hours, the reaction was chilled in an ice water bath for 10 minutes, and then the crude acid chloride (previously prepared above) was added to the white mixture via syringe over 10 minutes. The ice bath was removed, and the reaction was stirred for 1.5 hours at room temperature. The mixture was acidified with 5N HCl and added IPAc (50 mL) was added. The aqueous layer was separated and set aside. The organic layer was sequentially washed with saturated NaHCO3 solution and then water. The separated organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. MS (m/z)=325 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]1[NH:14][CH:15]=[C:16]([C:21]2[CH:22]=[N:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[C:17]=1[C:18]([NH2:20])=[O:19]>O1CCCC1.C(OCC)(=O)C>[C:8]([NH:12][C:13]1[NH:14][CH:15]=[C:16]([C:21]2[CH:22]=[N:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[C:17]=1[C:18]([NH2:20])=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])nc2)c[nH]c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])nc2)c1C(N)=O
Reaction time: 3 h
Yield: 64.1 %

Procedure:
0.226 cm3 (1.62 mmol) of triethylamine and 0.058 cm3 (0.809 mmol) of acetyl chloride are added, at a temperature close to 20° C. under an argon atmosphere, to a solution of 0.20 g (0.809 mmol) of 2-amino-4-(6-nitropyridin-3-yl)-1H-pyrrole-3-carboxamide in 40 cm3 of tetrahydrofuran. After stirring for 3 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is diluted in 200 cm3 of ethyl acetate and then washed with 50 cm3 of water and 50 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.15 g of 2-acetylamino-4-(6-nitropyridin-3-yl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 2.11 (s, 3H); 6.90 (broad m, 2H); 6.95 (d, J=3.0 Hz, 1H); 8.13 (dd, J=2.5 and 8.5 Hz, 1H); 8.27 (d, J=8.5 Hz, 1H); 8.65 (d, J=2.5 Hz, 1H); 10.2 (s, 1H); 11.7 (broad m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19][C:20](O)=O.[OH-].[Na+]>O>[CH3:17][O:18][CH2:19][C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: COCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 200 °C
Reaction time: 0.12 h

Procedure:
3-Amino-4-(2-methylpropylamino)quinoline (5.0 g; 0.023 mol) and methoxyacetic acid (20 mL) were mixed and heated at about 200° C. until all bubbling had stopped. Heating was continued for 5-10 min longer and the dark solution was allowed to cool to room temperature. The solution was diluted with water, made strongly basic with 50% sodium hydroxide and extracted with ether. The combined extracts were dried over magnesium sulfate and evaporated to dryness to yield 5.2 g of crude product. The crude product was used as such for further reactions. A small sample was recrystallized from ether to yield nearly colorless crystals, m.p. 96-99° C. Analysis:. Calculated: C, 71.4; H, 7.1; N, 15.6. Found: C, 71.1; H, 7.0; N, 15.6.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].ON1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]O)=[O:36])[CH:30]=1>C(Cl)Cl.CCOCC>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=1)[C:35]([OH:37])=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In an alternative synthesis of (10), N-hydroxysuccinimide (558 mg, 4.8 mmol) was added to a solution of compound (6) (500 mg, 2.4 mmol) in CH2Cl2 (10 mL) and the reaction mixture cooled to 0° C. m-Chloroperbenzoic acid (1.62 g, 7.2 mmol, commercial grade: 77% in water) was added over a period of 10 min and the mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10) together with m-chlorobenzoic acid. The crude product mixture was purified by column chromatography on silica gel, eluting with 4:6 EtOAc:hexane. Residual m-chlorobenzoic acid was removed by repeated crystallizations from a mixture of tert-butyl methyl ether and hexane, resulting in analytically pure product (66 mg, 10%).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([O:19]CC)=[O:18])=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[OH-].[Na+]>C(O)C>[CH2:1]([NH:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNc1ncc(C(=O)OCC)c(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCNc1ncc(C(=O)O)c(O)n1

Procedure:
2-n-Octylamino-5-ethoxycarbonyl-4-hydroxypyrimidine (400 mg, 1.4 mmol) was hydrolysed in boiling water (10 ml): ethanol (3 ml) with NaOH (5 mmol, 200 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:46][CH:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1>CN(C)C=O>[CH3:46][CH:47]1[CH2:52][CH2:51][CH2:50][N:49]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[N:13]=[C:12]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:48]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Reactant: CC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCCN(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and (RS) 3-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: C1(N[C:8]2([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[OH-].[NH4+:33]>[Pd].CO>[C:16]1([NH:33][CH:10]2[CH2:9][CH:8]([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(CCc2ccccc2)C(Nc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 60 parts of phenylmethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate and 320 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. Upon the addition of a concentrated ammonium hydroxide solution, the precipitate, which is formed during the hydrogenation, is dissolved. The catalyst is filtered off and the filtrate is concentrated. Methanol is added and the whole is concentrated again. After cooling to room temperature the product is filtered off and dried in vacuo at 120° C., yielding 43.7 parts of 4-(phenylamino-1-(2-phenylethyl)-4-piperidinecarboxylic acid; mp. 268° C.
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:34])[C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([CH3:28])[C:22]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]>C(O)(=O)C.C(Cl)(Cl)Cl.ClCCl>[CH2:9]([O:11][C:12](=[O:34])[C@H:13]([CH2:20][C:21]1[C:22]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[C:23]2[C:24](=[CH:25][CH:26]=1)[NH:27][N:1]=[CH:28]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C[C@@H](Cc1ccc2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Isoamyl nitrite (170 μL, 1.3 mmol) was added dropwise to a cooled (water ice bath) solution of 2-(R)-(2-acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester in 5% acetic acid-chloroform (5 mL). Mixture was stirred at 0° C. for 1.5 hours. Mixture was diluted with dichloromethane (20 mL) and then washed with saturated aqueous sodium bicarbonate (2×20 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as amber oil in 99% yield. MS m/e (M+H)+=377.1.
Reaction SMILES: [NH:1]([C:8](=O)[CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][C:11]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:19]1[C:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[N:10]([CH2:9][CH2:8][NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]=2[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(NCCn2c3c(c4ccccc42)CCNCC3)cc1
Yield: 21.8 %

Procedure:
tert-Butyl 6-(2-anilino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.059 g, 0.14 mmol) was dissolved in THF (5 mL) and LAH (0.0080 g, 0.21 mmol, 1.5 equiv.) was added. The reaction mixture was refluxed for 6 h under N2. The reaction mixture was quenched with water and extracted with EtOAc. The extracts were treated with TFA, and the resulting mixture was concentrated. THF and excess LAH were added and the reaction mixture was refluxed for 2 h. The reaction mixture was quenched by the addition of acetone, methanol, and water. The resulting mixture was extracted with EtOAc (4×) and the reaction mixture was concentrated. The crude product was purified by PTLC (1 mm×20 cm×20 cm plate, developed with 10% MeOH:CH2Cl2, eluted with MeOH) to yield N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]aniline (0.0093 g) in 22% yield. 1H NMR (400 MHz, CDCl3) δ 2.87-2.89, 2.93-2.96, 3.03, 3.09, 3.49-3.53, 4.31, 6.57, 6.74, 7.07-7.28, 7.50.
Reaction SMILES: C([Li])CCC.[C:6]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:7][C:8]([O:10][Si](C)(C)C)=O.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[C:26]([NH:30][C:31]2[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=2[Cl:39])=[CH:25][C:21]=1C(Cl)=O>CCCCCC.C(OCC)C.C(COC)OC.C(OCC)(=O)C>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[C:26]([NH:30][C:31]2[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=2[Cl:39])=[CH:25][C:21]=1[C:8](=[O:10])[CH2:7][C:6]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)O[Si](C)(C)C
Reactant: O=C(Cl)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
1.4 ml of a 1.6 M solution of butyllithium in hexane was added to a solution of 3.47 g (17.0 mmol) of ethyl trimethylsilyl malonate in 45 ml of diethyl ether at −75° C. in such a way that the temperature did not rise above −60° C. The mixture was then stirred at −75° C. for 30 minutes. The 2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino)benzoyl chloride was dissolved in 45 ml of dimethoxyethane and added dropwise in 40 minutes. The mixture was slowly warmed to 10° C. and stirred at this temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed twice each with 250 ml portions of water and saturated sodium bicarbonate solution. The organic phase was dried and concentrated. 3.88 g of the crude mixture were obtained and were reacted without further purification in the next stage.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](I)[CH3:22].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:21]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH3:22]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 2.33 g of ethyl iodide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation, the product is obtained in the form of a solid. Melting point 175°-179°. Rf (ethyl acetate/hexane 4:1)=0.52.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](C2C=CC(C(OC(C)(C)C)=O)=CC=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:40]([OH:46])(C(F)(F)F)=[O:41]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:39])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[C:22]([C:40]([OH:46])=[O:41])[CH:23]=[CH:24][C:25]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1cc(C(=O)O)ccc1-c1ccccc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of tert-butyl 4′-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)-1,1′-biphenyl-4-carboxylate (1.37 g) in DCM (15 mL) was added TFA (15 mL). The resulting mixture was stirred for 30 min. Evaporation of the solvents gave the title compound as a colorless oil (1.10 g, 67%). M+(LC/MS(ESI)): 486.1; M−(LC/MS(ESI)): 484.6. HPLC (Condition A), Rt: 4.13 min (HPLC purity: 91.7%) 1H NMR (DMSO, 300 MHz) δ 7.94 (d, 2H, J=7.9 Hz), 7.72-7.61 (m, 6H), 7.42 (d, 1H, J=7.9 Hz), 7.33 (t, 2H, J=7.5 Hz), 7.25 (d, 1H, J=8.3 Hz), 4.49 (m, 4H), 4.20 (m, 2H), 1.10 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[C:15]([CH3:17])[C:8]([CH2:9][NH:10]C(=O)CCl)=[C:7]([OH:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(O)C>[NH2:10][CH2:9][C:8]1[C:15]([CH3:17])=[CH:16][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=1[OH:18]
Reactant: Cc1cc(C(C)(C)C)cc(O)c1CNC(=O)CCl
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(C)(C)C)cc(O)c1CN

Procedure:
To 0.2 g of N-(4-tert-butyl-2-hydroxy-6-methylbenzyl)-2-chloroacetamide from Step A in 10 mL of 95% ethanol was added 1 mL HCl. The resulting mixture was refluxed for 4 h then aged overnight at 50° C. The reaction mixture was concentrated to remove the ethanol and then partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]2[CH:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1>CC(C)=O.C(O)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1
Reactant: O=C(NC1C2CCN(CC2)C1Cc1cccnc1)c1cc2ccccc2o1
Agent: O=C(O)c1ccc(Cl)cc1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C(N[C@@H]1C2CCN(CC2)[C@@H]1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Yield: 94 %

Procedure:
Solid p-chlorobenzoic acid (46.8 mg, 0.299 mmol) was added in one portion to a solution of the earlier eluting isomer of N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl]benzofuran-2-carboxamide from Example 15 (108 mg, 0.299 mmol) in acetone (10 mL). This mixture was warmed to near reflux for 30 min and cooled to ambient temperature. No precipitate formed, so the solution was concentrated to about 20% of its former volume (hot plate), at which point crystals began to form. The mixture was cooled and diluted with isopropanol (2 mL). This mixture was concentrated by slow evaporation of solvent at ambient temperature, and the resulting solids were collected and dried. This produced 145 mg (94% yield) of light yellow crystals, mp 150-152° C. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.38 (d, 1H), 7.93 (d, 2H, p-chlorobenzoic acid), 7.67 (m, 2H), 7.57 (d, 1H), 7.45 (m, 1H), 7.36 (d, 2H, p-chlorobenzoic acid), 7.30 (m, 1H), 7.27 (s, 1H), 7.16 (m, 1H), 7.00 (d, 1H, amide), 6.90 (broad s, quaternary ammonium), 4.62 (m, 1H), 3.85 (dd, 1H), 3.36 (m, 1H), 2.95-3.25 (m, 5H), 2.16 (s, 1H), 1.70-2.10 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.FC(F)(F)S(O[CH2:15][C:16]([F:19])([F:18])[F:17])(=O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=c1ccc(Br)c[nH]1
Product: O=c1ccc(Br)cn1CC(F)(F)F

Procedure:
5-bromo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one was prepared from 5-bromopyridin-2(1H)-one and 2,2,2-trifluoroethyl trifluoromethanesulfonate following a procedure analogous to that described in Example 59 Step 1.