Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:11].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:11])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)CN2CCN(Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium carbonate (18.84 g) and water (41.4 ml) was added to a stirring suspension at 0° to 5° C. of 2-bromo-1-(3,4-dimethoxyphenyl)-1-ethanone (32.03 g, described in Example 4) and 1-benzylpiperazine (24 ml) in acetonitrile (90 ml). The suspension was stirred at room temperature for 2.5 hr and evaporated. The residue was dissolved in a mixture of water and chloroform, and the chloroform layer was dried and evaporated. Chromatographic purification on silica gel (700 g) using ethyl acetate-hexane (60:1 to 100:1) gave 32 g of 2-(4-benzyl-1-piperazinyl)-1-(3,4-dimethoxyphenyl)-1-ethanone, nmr(CDCl3) δ2.65, 3.57, 3.74, 3.89, 3.91, 6.81, 7.37 and 7.53.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](SCC)[C:16]([C:19]([N:21]([CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[O:20])=[N:17][CH:18]=1.C(=O)(O)[O-].[Na+].[S:42]([O-:46])([O-])(=[O:44])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([S:42]([CH2:2][CH3:3])(=[O:46])=[O:44])[C:16]([C:19]([N:21]([CH3:33])[C:22]2[CH:23]=[CH:24][C:25]([S:28][C:29]([F:31])([F:30])[F:32])=[CH:26][CH:27]=2)=[O:20])=[N:17][CH:18]=1
Reactant: CCSc1cc(Cl)cnc1C(=O)N(C)c1ccc(SC(F)(F)F)cc1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(Cl)cnc1C(=O)N(C)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.2 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 9.07 g of 5-chloro-3-ethylsulfanyl-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide (Compound of Present Invention 158) and 223 ml of chloroform under ice cooling, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 7.0 g of 5-chloro-3-ethylsulfonyl-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 118) and 2.04 g of 5-chloro-3-ethylsulfonyl-N-methyl-N-(4-trifluoromethylsulfinylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 117).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)Cl.CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:16](=[O:17])[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cc2ccccc2)cc1
Reaction time: 2 h

Procedure:
To 10.8 g (0.10 mole) methoxybenzene and 13.9 g. (0.09 mole) phenylacetyl chloride in 1.0 1. methylene chloride there are added, by small amounts, 13.3 g. (0.10 mole) aluminium chloride at room temperature and with strong agitation. The reaction mixture is agitated for a further 2 hours and then is poured onto ice and 50 ml. hydrochloric acid are added. After separation of the organic phase, the aqueous solution is shaken out twice with 500 ml. methylene chloride each time, the combined organic phases are washed with water and the solvent is removed in vacuo. The smeary residue is freed of the volatile components by steam distillation and the remaining solid is crystallized from ethanol after filtration and washing with water. Obtained are colorless crystals having a melting point of 75° C.; Rf 0.7 [CHCl3 /CH3OH (9/1)]; yield: 18.3 g. (90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:12]([N:14]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:13].O.NN>CO>[NH2:14][CH:12]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:7][C:2]=1[F:1])[CH3:13]
Reactant: CC(c1ccc(C(C)(C)O)cc1F)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC(N)c1ccc(C(C)(C)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
A mixture of 158 mg (0.48 mmol) (±)-2-[1-[2-fluoro-4-[1-hydroxy-1-methyl-ethyl]-phenyl]-ethyl]-isoindole-1,3-dione and 0.08 ml (2.4 mmol) hydrazine hydrate in 10 ml methanol was stirred at room temperature overnight. The resulting precipitate was filtered and the filtrate concentrated to give a solid. The solid was triturated with chloroform, filtered and the filtrate was then concentrated to give 110 mg (100%) oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1>C(Cl)Cl.CO>[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][N:46]([C:11]([NH:5][C:4]4[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=4[O:2][CH3:1])=[O:12])[CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1
Reactant: COc1ccccc1N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1NC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, 2-methoxyaniline, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(piperazin-1-yl)quinoline are reacted to afford the product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](N3CCCCC3)[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1.Cl.C[OH:31]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][C:11](=[O:31])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CO
Reactant: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1
Agent: Cl
Solvent: O
Product: CN1CCC(=C2c3ccccc3CC(=O)c3ccccc32)CC1

Procedure:
1-Methyl-4-(10-[1-piperidyl]-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, 2.4 g., is refluxed for 4 hours with 100 ml. of 10% HCl in water and 50 ml. of methanol. The methanol is evaporated and the remaining oil and water is made basic with solid NaHCO3 until no more CO2 is evolved. It is then extracted three times with 50 ml. each of toluene, combined extracts dried over MgSO4, filtered and the toluene evaporated on a rotary evaporator leaving a residual product which crystallizes on standing. Three recrystallizations of this product from hexane give 1-methyl-4-(10,11-dihydro-10-oxo-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, m.p. 142°-143°C.
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CSc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.6 %

Procedure:
2.0 mol/L Sodium hydroxide aqueous solution 2.0 mL was added to a mixed solution of methanol 2.4 mL and tetrahydrofuran 2.4 mL of methyl 2-(4-fluoroanilino)-4-((phenylthio)methyl)benzoate 0.48 g, and it was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure, ethyl acetate and water were added to it, and it was adjusted to pH4.0 with 1.0 mol/L hydrochloric acid. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-((phenylthio)methyl)benzoic acid 0.40 g of pale yellow solid.
Reaction SMILES: [OH-].[NH4+:2].Cl[C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1>CS(C)=O.[Cl-].[Na+].O>[I:10][C:9]1[C:4]([NH2:2])=[CH:5][C:6]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1
Reactant: FC(F)(F)c1cc(Cl)c(I)cn1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(C(F)(F)F)ncc1I
Temperature: 110 °C

Procedure:
Concentrated aqueous ammonium hydroxide (10 mL) was added to a solution of 4-chloro-5-iodo-2-(trifluoromethyl)pyridine (4.11 g, 13.3 mmol) in DMSO in a glass pressure tube. The tube was sealed and placed in an oil bath pre-heated to 110° C. for 48 h. The resulting solution was diluted with brine, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give 5-iodo-2-(trifluoromethyl)pyridin-4-amine. Retention time (min)=1.584, method [1], MS(ESI) 289.0 (M+H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[ClH:10].C([O:14][CH2:15][CH3:16])(=O)C>>[Cl-:10].[OH:14][C:15]1[CH:16]=[CH:1][C:2]([C:3]2[CH:5]=[CH:1][C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[O+:4]=2)=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cl
Reactant: O=Cc1ccccc1O
Product: Oc1ccc(-c2ccc3ccccc3[o+]2)cc1
Product: [Cl-]
Reaction time: 24 h

Procedure:
122 g of Salicylaldehyde and 136 g of 4-hydroxy-acetophenone were dissolved in a four-necked one-liter flask equipped with a mechanical stirrer and containing 400 ml of anhydrous ethyl acetate. Under agitation and at room temperature, a stream of dry hydrochloric acid was passed into the solution in such manner that saturation was completed in the course of one hour. The mixture was left under agitation for 24 hours, during which precipitation of the reaction product began. Filtration was carried out, the product dried at 40° C. in the presence of KOH and recrystallisation carried out twice from methanol. There were obtained 179 g of 4'-hydroxyflavylium chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(Cl)(=O)OCC.Cl.[CH2:41]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH2:46])[CH3:42]>O1CCCC1>[CH2:41]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH:46][C:24](=[O:26])[C@H:12]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:42]
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
3.49 g (10 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine and 1.21 g (12 mmole) of N-methylmorpholine were dissolved in 30 ml of anhydrous tetrahydrofuran, and then, whilst cooling the solution at -5° C., 1.30 g (12 mmole) of ethyl chlorocarbonate was added dropwise, with stirring, over a period of 15 minutes. 2.35 g (12 mmole) of L-leucine ethyl ester hydrochloride [which had been suspended in 10 ml of methylene chloride and neutralized with 1.21 g (12 mmole) of N-methylmorpholine] were added. The mixture was stirred for 2 hours with ice cooling, and then left standing overnight at room temperature. It was then condensed by evaporation under reduced pressure. Water was added to the residue, and the precipitating oily substance was extracted with ethyl acetate. The organic extract was washed with 1N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-leucine ethyl ester thus obtained in a syrupy form was dissolved in 30 ml of dimethylformamide, and 5.06 g (100 mmole) of hydrazine hydrate were added to the solution. The mixture was stirred for 36 hours at room temperature. The reaction product was then condensed by evaporation under reduced pressure, and water was added to the residue. The colorless crystals produced were collected by filtration, thoroughly washed with water and dried in a desiccator to yield 4.23 g of the title compound melting at 200°-204° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C(C)=CC=CC=1.CCCCCC>[N:11]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C(O)c1ccc(N2CCCCCC2)nc1
Temperature: 140 °C
Reaction time: 30 h

Procedure:
A suspension of 6-chloronicotinic acid (5.0 g) and perhydroazepine (7.16 mL) in xylene (20 mL) was stirred at 140° C. for 30 hours under an atmosphere of argon. The reaction mixture was cooled to room temperature, diluted with hexane and filtrated. The insoluble material was dissolved in ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to give the title compound (3.19 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].NCC1CCN(CC2C=CC(Cl)=C(Cl)C=2)C1.[NH2:29][CH2:30][C@@H:31]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[Cl:44])[CH2:32]1>>[Cl:44][C:38]1[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C@@H:31]([CH2:30][NH:29][C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:32]1
Reactant: NC[C@@H]1CCN(Cc2cccc(Cl)c2Cl)C1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Product: O=C(Cc1ccc(O)c(F)c1)NC[C@@H]1CCN(Cc2cccc(Cl)c2Cl)C1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3-fluoro-4-hydroxyphenyl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-(S)-aminomethyl-1-(2,3-dichlorobenzyl)pyrrolidine gave N-[1-(2,3-dichlorobenzyl)pyrrolidin-3-(S)-ylmethyl]-2-(3-fluoro-4-hydroxyphenyl)-acetamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]1(=O)[C:26]2[C:18]([C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:16]=[CH:15]1>CCOCC>[CH:7]1[C:2]2[C:25]3([C:26]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]4[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: Brc1ccccc1-c1ccccc1
Solvent: CCOCC
Product: c1ccc2c(c1)-c1ccccc1C21c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 80 %

Procedure:
As shown in the following reaction 1, 6.1 g of 2-bromobiphenyl and 0.585 g of dried Mg were dissolved with ether, and 4.2 g of fluorenone dissolved in ether was added thereto, and refluxed while stirring overnight. The produced yellow precipitate was filtered, and stirred in cold ammonium chloride, and then the obtained crystal was filtered again and dried. Thereafter, acetic acid was added to the solid product, and the solution was refluxed while stirring. A small amount of hydrochloric acid was added thereto to obtain the solid target compound. The solid target compound was filtered and washed to obtain pure target compound with the yield of 80%.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=1.C(N(CC)CC)C.O=[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36])[CH2:31][CH2:30]1>C(O)C>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:12][CH2:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:40])[Cl:41])=[O:36])[CH2:31][C:30]=3[C:4]=2[CH:3]=1
Reactant: O=C1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Reactant: Cc1ccc(NN)cc1
Reactant: Cc1ccc(CCBr)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C(=O)OCC(Cl)(Cl)Cl)C1
Yield: 10.4 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (5 g, 31.5 mmol), 5-(2-bromoethyl)-2-methylpyridine (6.3 g, 31.5 mmol), triethyl amine (13 ml, 94.5 mmol) and 2,2,2-trichloroethyl 4-oxopiperidine-1-carboxylate (563 mg, 2 mmol) were taken in ethanol (15 ml) to obtain 100 mg of 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate after purification on silica gel (230-400 mesh) chromatography eluting with acetone-hexane gradient.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36]3[S:37][CH:38]=[CH:39][N:40]=3)=[CH:24][C:23]=2[CH2:41][CH3:42])[C:12]=1[CH2:43][CH2:44][CH3:45].B(F)(F)F.CCOCC>C(S)C.O>[CH2:41]([C:23]1[CH:24]=[C:25]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:43][CH2:44][CH3:45])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:46])=[O:2])[CH3:42]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3nccs3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: FB(F)F
Solvent: CCS
Solvent: O
Solvent: CCOCC
Product: CCCc1c(OCCCOc2cc(O)c(-c3nccs3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 45.4 %

Procedure:
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (282 mg, 0.442 mmol) in ethanethiol (3 mL) was treated with boron trifluoride etherate (0.56 mL, 4.4 mmol) at room temperature for 3 h. The reaction mixture was diluted with water, concentrated in vacuo, and extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, ethyl acetate/hexane) provided 107 mg (44%) of the title compound. 1H NMR (CDCl3) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=4 Hz, 1H), 7.35 (dt, J=8, 2 Hz, 1H), 7.28 (d, J=4 Hz, 1H), 7.24 (s, 1H), 7.09 (dt, J=9, 2 Hz, 1H), 7.05 (t, J=9 Hz, 1H), 6.79 (d, J=9 Hz, 1H), 6.66 (d, J=9 Hz, 1H), 6.61 (s, 1H), 6.42 (d, J=9 Hz, 1H), 4.24 (t, J=6 Hz, 2H), 4.18 (t, J=6 Hz, 2H), 3.81 (s, 3H), 2.63 (t, J=7 Hz, 2H), 2.58 (q, J=7 Hz, 2H), 2.34 (quintet, J=6 Hz, 2H), 1.52 (hextet, J=8 Hz, 2H), 1.17 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H); MS ES+ m/e 548 (p+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]#N.[CH2:22]([OH:24])[CH3:23].[OH:25]S(O)(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([O:24][CH2:22][CH3:23])=[O:25]
Reactant: N#CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Reactant: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl

Procedure:
To a solution of 2,3-dichloro-4-(p-nitrophenoxy)phenyl acetonitrile (from Example 29) (6.5 g., 0.02 mole) in 15 ml. of 95% ethanol was added 5 ml. of concentrated H2SO4. The solution was refluxed for 24 hours. The ethanol was evaporated and the residue was diluted with water. The aqueous mixture was extracted with chloroform. The organic solution was washed with brine, dried over Na2SO4 and evaporated to provide 6.9 g. of the desired ethyl ester. NMR (CDCl3): 3.87 (2H, s, ArCH2CO2Et); IR (CHCl3) 1730 cm-1.
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:3].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:1][CH:2]([C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:3])(=[O:18])[CH3:17]
Reactant: C=C(C(=O)OC)C(C)O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C(=O)OC)C(C)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2-(1-hydroxyethyl)acrylate (50 g) and pyridine (32.6 ml) in dichloromethane (200 ml) was added dropwise acetyl chloride (34.8 g) at 0° C. After the reaction mixture was stirred for 1 hour, the mixture was allowed to warm to room temperature, and quenched with water (500 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layer were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated, and the residue was distilled in vacuo to give methyl 2-(1-acetoxyethyl)acrylate (28.2 g).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[C@@H:31]12[CH2:37][C@@H:34]([NH:35][CH2:36]1)[CH2:33][O:32]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C@@H:31]12[CH2:37][C@@H:34]([N:35]([CH2:25][C@@H:24]([N:6]3[C@H:7]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C@@H:8]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=4)[CH2:9][C@@:4]([CH2:1][CH:2]=[CH2:3])([CH3:30])[C:5]3=[O:29])[CH2:27][CH3:28])[CH2:36]1)[CH2:33][O:32]2
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: C1O[C@H]2CN[C@@H]1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2C[C@H]3C[C@@H]2CO3)C1=O
Reaction time: 8 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (100 mg, 0.224 mmol; Example 91, Step C) in DCE (2 mL) was added (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (Butora, G.; Goble, S.; Pastemak, A.; Yang, L.; Zhou, C.; Moyes, C. U.S. Patent Publication No. 2008/0081803 (50 mg, 0.504 mmol) followed by sodium triacetoxyborohydride (95 mg, 0.448 mmol) and acetic acid (1.2 μL, 0.022 mmol). After stirring overnight, the mixture was quenched with sat. aq. NaHCO3 solution. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 1 to 5% methanol/dichloromethane) to afford the title compound.