Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([Se]Cl)C=CC=CC=1>C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cl[Se]c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C=CC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 11.0 grams (0.063 mole) of 4-phenylcyclohexanone in 400 mL of ethyl acetate was stirred, and 14.5 grams (0.076 mole) of phenylselenenyl chloride was added in one portion. The reaction mixture was stirred for one hour and then was washed with three 100 mL portions of water. Tetrahydrofuran, 200 mL, was added, and the reaction mixture was cooled in an ice-bath. The reaction mixture was stirred, and 18.1 mL (0.160 mole) of aqueous 30% hydrogen peroxide was added at a rate to maintain the reaction mixture temperature below 35° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for about one hour. The reaction mixture was then washed with one 100 mL portion of water and two 50 mL portions of aqueous 20% sodium carbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished commencing with 10% diethyl ether in petroleum ether and finishing with 20% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.6 grams of 85% pure 4-phenyl-2-cyclohexenone. The NMR spectrum was consistent with the proposed structure. This reaction was repeated on a larger scale.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O-:15][CH2:16][CH3:17].[Na+]>C(O)C>[CH2:16]([O:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])[CH3:17]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1c(C#N)cnc2ccc(I)cc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 94.9 %

Procedure:
To the suspension of 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) (14 g, 0.039 mol) in anhydrous ethanol (180 mL) was added sodium ethoxide (4.16 g, 0.07 mol). The mixture was heated to 100° C. under a pressure tube and stirred for 10 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried to obtain 4-Ethoxy-6-iodo-quinoline-3-carbonitril (12 g, 92%) as a yellow solid. LC-MS m/e 325 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH:23]=[C:24]([CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:25]=2)=[CH:17][CH:16]=1.Cl>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH:23]=[C:24]([CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH:28]4[CH3:32])[N:25]=3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1CCCN1Cc1coc(-c2ccc(Br)cc2)n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl
Product: CC1CCCN1Cc1coc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)n1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 4 using 4-methylsulfonylphenylboronic acid and (+/−)-2-(4-Bromo-phenyl)-4-(2-methyl-pyrrolidin-1-ylmethyl)-oxazole; hydrochloride (See Example 5). MS (m/e) 397.1 (M+1)
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([Cl:32])[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3ccc4c(-c5cc(Cl)cc(Cl)c5)ccc5ccc2c3c54)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
A mixed solution of 8.0 g of 1-bromo-6-(4-methylphenyl)pyrene, 4.5 g of 3,5-dichlorophenylboronic acid, 9.2 g of tripotassium phosphate, 1.4 g of tetrabutylammonium bromide, 97 mg of palladium acetate and 215 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 120° C. for 5 hours. The solution was cooled to room temperature and 1.0 L of water was poured into the solution, followed by extraction with 600 ml of dichloromethane. The organic layer was washed twice with 200 ml of water, dried over magnesium sulfate and then filtered through Celite. The filtrate was evaporated and the residue was washed twice with 200 ml of ethyl acetate, and then the precipitated solid was collected by filtration. The precipitated solid was recrystallized from 100 ml of dimethylformamide and then vacuum-dried to obtain 5.5 g of 1-(3,5-dichlorophenyl)-6-(4-methylphenyl)pyrene.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:8][O:7]1)=[O:5])C.[OH-].[Na+:25]>O1CCCC1>[F:22][C:20]([F:21])([F:23])[C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1([C:4]([O-:5])=[O:3])[CH2:8][O:7]1.[Na+:25]
Reactant: CCOC(=O)C1(CCCCOc2cccc(C(F)(F)F)c2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])C1(CCCCOc2cccc(C(F)(F)F)c2)CO1

Procedure:
4.0 g of 2-[4-(3-trifluoromethylphenoxy)butyl]oxirane-2-carboxylic acid ethyl ester, 12 ml of 1 N sodium hydroxide solution and 16 ml of tetrahydrofuran are stirred for 2 hours at room temperature. The solution which has formed is concentrated to one half of its volume in vacuo and is then extracted 2 times with 50 ml of diethyl ether each time. On standing a precipitate crystallizes out of the aqueous solution, which is filtered off and washed with little water and diethyl ether. 2.44 g of the title compound of m.p. 94° to 97° C. are obtained by gradual concentration of the filtrates to a small volume.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:11]([C:19]([F:21])([F:20])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M74) (0.54 g, 0.95 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 54%).
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[C:7]([CH:11]([CH3:13])[CH3:12])([CH3:10])[N:6]=[C:5]1[C:14]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1.CCOCC>C(Cl)Cl>[C:1]([N:4]1[C:8](=[O:9])[C:7]([CH:11]([CH3:13])[CH3:12])([CH3:10])[N:6]=[C:5]1[C:14]1[N+:23]([O-:33])=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C)nc1C1=NC(C)(C(C)C)C(=O)N1C(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1ccc(C)[n+]([O-])c1C1=NC(C)(C(C)C)C(=O)N1C(C)=O

Procedure:
A solution of 29 g of methyl 2-(1-acetyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-6-methylnicotinate and 28.7 g of 80% M-chloroperbenzoic acid in 250 mL of methylene chloride is stirred and heated at reflux for 31/2 hours. The reaction mixture is filtered, and the solid is thoroughly washed with methylene chloride. The combined filtrates are cooled and treated cautiously with saturated aqueous sodium bisulfite until a negative starch-iodide test is obtained. The mixture is again filtered, and the organic layer is washed with saturated sodium bicarbonate solution, dried, and concentrated in vacuo to give an oil. Trituration of this oil with ether affords the desired product as a pale yellow solid, mp 135°-138.5° C.
Reaction SMILES: O1CCCC1.Cl.[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.[Br:32][C:33]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O>[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH:21][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([N+:42]([O-:44])=[O:43])[CH:40]=[CH:41][C:33]=4[Br:32])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:16]1)[CH2:8]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1Br
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 300 mg of 4-(1-adamantyl)-2-methylaniline hydrochloride and 120 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 290 mg of 2-bromo-5-nitrobenzoylchloride was dropwise added under cooling with ice. After stirring for about 30 minutes, water was added thereto, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 310 mg of N-(4-(1-adamantyl)-2-methylphenyl)-2-bromo-5-nitrobenzamide (Compound No. 46) having a melting point of 229° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[S:14])=[CH:5][CH:4]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[C:13]([SH:14])=[N:17][N:16]=[N:15]2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCCN=C=S)cc1
Agent: [Na+]
Product: COc1ccc(CCCn2nnnc2S)cc1
Yield: 55.1 %

Procedure:
3-(4-Methoxyphenyl)propylisothiocyanate (0.0174 mol) and sodium azide (0.0261 mol) were reacted substantially as described in Example 7H to give 2.4 g (55%) of an orange oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][NH:13][CH2:12]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:11][CH2:12][N:13]([C:2]2[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:14]1
Reactant: N#Cc1nccnc1Cl
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nccnc1N1CCc2ccccc2CC1

Procedure:
In analogy to the procedure as described in example 12 the 2-chloro-3-cyanopyrazine (J. Chem. Soc., Perkin Trans. 1 1991, 11, 2877-81) was treated with 2,3,4,5-tetrahydro-1 H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyl-diisopropylamine in N,N-dimethylformamide at room temperature followed by 60° C. to yield the 3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as light yellow solid; MS: 251 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2.O[CH:29]([C:35]1C2C(C3C=CC=CC=3C=1O)=CC=CC=2)[C:30](OCC)=O>>[O:26]=[C:20]([C:7]1[C:6]2[C:5]([C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=1[O:12][S:13]([C:16]([F:17])([F:19])[F:18])(=[O:15])=[O:14])=[CH:35][CH:29]=[CH:30][CH:27]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(O)c1c(O)c2ccccc2c2ccccc12
Product: CCOC(=O)C(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccccc2c2ccccc12

Procedure:
Prepared by the similar method to make ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate in Example 20, using ethyl 2-hydroxy-2-(10-hydroxyphenanthren-9-yl)acetate instead of ethyl 2-(6-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate. 1H-NMR: 400 MHz, (CDCl3) δ: 8.77-8.74 (m, 2H), 8.25 (d, J=4.0 Hz, 1H), 7.87-7.84 (m, 2H), 7.81-7.77 (m, 2H), 7.70-7.67 (m, 2H), 4.44-4.38 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). 17F-NMR: 400 MHz, (CDCl3) δ: −73.18 (s).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[C:33]([NH:37][CH2:38][CH3:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:38][CH3:39])[C:12]=2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCNC(C)(C)C
Reactant: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCC(=O)c1c(CN(CC)C(C)(C)C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 1, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline was reacted with N-tert-butyl-N-ethylamine to give 4-(3,4-dimethoxyphenyl)-2-(N-tert-butyl-N-ethylaminomethyl)-6,7-dimethoxy-3-valerylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 137°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:58][C:59]12[CH2:66][CH2:65][C:62]([C:67]([O:69][CH3:70])=[O:68])([CH2:63][CH2:64]1)[CH2:61][CH2:60]2>CN(C=O)C.C(#N)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:58][C:59]34[CH2:64][CH2:63][C:62]([C:67]([O:69][CH3:70])=[O:68])([CH2:61][CH2:60]3)[CH2:65][CH2:66]4)=[O:17])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: COC(=O)C12CCC(N)(CC1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C12CCC(NC(=O)c3c(C)nn4c(OCc5c(F)cccc5F)cc(C)cc34)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A mixture of 80 mg 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (75% purity, 0.181 mmol) from Example 4A, 76 mg of HATU (0.199 mmol) and 94 μl (0.542 mmol) of N,N-diisopropylethylamine in 0.54 ml of DMF was stirred at RT for 10 min Subsequently, 40 mg (0.217 mmol) of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate were added and the mixture was stirred at RT overnight. The reaction mixture was admixed with water and acetonitrile and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid). 62 mg of the target compound were obtained (70% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13])[CH3:16]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2ccccc2c1C=O
Temperature: 25 °C

Procedure:
2-Hydroxy-1-naphthaldehyde (10 g., 0.058 mole) was combined with acetone (120 ml.), iodoethane (9.9 g., 0.063 mole) and anhydrous potassium carbonate (8.0 g., 0.058 mole) and the mixture heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered and filtrate evaporated to solids (9.0 g.) Recrystallization from isopropyl ether afforded purified 2-ethoxy-1-naphthaldehyde in two crops (4.5 g. and 0.5 g., m.p. 106°-109° C.).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]1[C:18]([O:20]CC)=[O:19])(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]1[C:18]([OH:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1

Procedure:
Dissolve 0.69 g of the compound obtained in Step B in 10 ml of absolute ethanol and add 2.5 ml of sodium hydroxide solution (1M) and reflux for 16 hours. Cool and add 20 ml of water and acidify the reaction mixture with hydrochloric acid (5M). Filter off the precipitate and wash it with water. The title product is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]1[C:6](=O)[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][CH:6]3[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:2][CH2:1]3)=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
1-(2-Phenethyl)-4-piperidone (142 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (104 mg, yield 65%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][C:8]=1[Cl:31])C>[OH-].[Na+].C(O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:15][CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:32])=[O:3])=[C:8]([Cl:31])[CH:9]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1Cl

Procedure:
A solution of {{4-[3,3-bis-(4-chloro-phenyl)-allylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (100 mg, 0.2 mmol) in 1N NaOH (1 ml) and ethanol (10 ml) was stirred at room temperature for 18 hours. The reaxtion mixture was evaporated and the residue dissolved in water (5 ml) and 1 N HCl (1.2 ml). The aquous phase was extracted with ethyl acetate (3×15 ml), dried (MgSO4) and evaporated to give the title compound in 95 mg (100%) yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12].[Br:15]Br.S(=O)(=O)(O)O>C(O)(=O)C.CO.CO.ClCCl>[Br:15][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][NH:7]2)=[CH:3][C:2]=1[I:1]
Reactant: COC(=O)c1c[nH]c2ccc(I)cc12
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1c[nH]c2cc(Br)c(I)cc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a suspension of methyl 5-iodo-1H-indole-3-carboxylate (1.20 g, 3.09 mmol) in acetic acid (30 ml) was added a solution of bromine (0.15 ml, 2.9 mmol) in acetic acid (5 ml). Reaction was heated to reflux and stirred for 3 hours. The reaction was then cooled and poured onto ice water, then partitioned between water and dichloromethane. The aqueous layer was extracted with 10% MeOH/DCM (2×100 mL). The organics were combined, washed with brine, and dried over sodium sulfate, filtered and concentrated to give a dark red semi solid. The residue was taken up in methanol (30 ml). Concentrated sulfuric acid (0.5 ml) was added and mixture was heated to 70° C. for 2 days. The reaction was cooled then concentrated in vacuo and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The layers were separated and organic washed with brine, dried over sodium sulfate, filtered and concentrated to give a reddish solid. The residue was dissolved in methanol/dichloromethane and adsorbed onto silica gel and purified by silica gel chromatography (50 g, 20-100% ethyl acetate/heptane). The major peak was isolated to afford a mixture of the title compound and methyl 5-iodo-1H-indole-3-carboxylate confirmed as a brown solid (260 mg) that was taken forward without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]3[CH:29]=[CH:30][C:31]4[C:36]([C:37]=3[CH:38]=2)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[C:39](Cl)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([C:48]1[CH:55]=[CH:54][C:51]([O:52][CH3:53])=[CH:50][CH:49]=1)[C:40]1[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=1>CO>[OH:17][CH2:16][C:14]1[CH:13]=[C:12]([C:25]2[C:38]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]=3[CH:28]=[CH:27][CH:26]=2)[CH:11]=[C:10]([CH2:9][O:8][C:39]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:48]2[CH:55]=[CH:54][C:51]([O:52][CH3:53])=[CH:50][CH:49]=2)[C:40]2[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=2)[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccc4ccccc4c3c2)c1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Product: COc1ccc(C(OCc2cc(CO)cc(-c3cccc4c3ccc3ccccc34)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 27 h

Procedure:
14.5 ml of pyrizine was added to dissolve 0.932 g of Compound (10) in an Ar atmosphere, and 1.27 g (3.77 mmol, 1.3 eq) of DMTrCl were added. This was agitated for 27 hours in an Ar atmosphere. After extraction with chloroform, the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure, and 0.3473 g (0.56 mmol, 3-step 23%) of Compound (11) was isolated by silica gel chromatography (chloroform only→chloroform:methanol=100:1).