Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[C:5]([CH3:34])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=1)([CH3:16])[CH2:8][C:7]2=[O:33].CO.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[OH:33][CH:7]1[C:6]2[C:11](=[C:12]([CH3:15])[C:13]([CH3:14])=[C:4]([OH:3])[C:5]=2[CH3:34])[O:10][C:9]([CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)([CH3:16])[CH2:8]1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)C(O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
450 mg of sodium borohydride were added to a mixture of 278 mg of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine -2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996) and 9 ml of methanol, and the mixture was stirred for 2 hours at room temperature, after which a 1% w/v aqueous solution of acetic acid was added and the mixture was neutralized with an aqueous solution of potassium carbonate. It was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled from the extract under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a 5:3 by volume mixture of hexane and ethyl acetate as eluent, to give the title compound, melting at 102°-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[OH:29])[CH3:21])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[C:34]([O:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18](=[O:19])[C:17]1[CH:30]=[CH:31][C:14]([NH:13][C:11]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[NH2:1])=[O:12])=[C:15]([O:32][CH3:33])[CH:16]=1)(=[O:36])[CH3:35]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OC(C)=O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Reaction time: 4 h
Yield: 97.2 %

Procedure:
A mixture of 4-(2-amino-3-nitrophenyl)carbonylamino-N-(2-hydroxy-4-methylphenyl)-3-methoxy-N-methylbenzamide (400 mg), acetic anhydride (90.7 mg) and triethylamine (89.9 mg) in dichloromethane (20 ml) was stirred in an ice bath for 4 hours. The mixture was diluted with chloroform and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give N-(2-acetoxy-4-methylphenyl)-4-(2-amino-3-nitrophenyl)carbonylamino-3-methoxy-N-methylbenzamide (425 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19]>C1C=CC=CC=1.C(O)(C)C>[F:1][C:2]1[C:7]([C:8]([C:8]([C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])([OH:9])[C:10]2[C:15]([F:1])=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[F:19])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19]
Reactant: O=C(c1ccccc1)c1c(F)c(F)c(F)c(F)c1F
Solvent: CC(C)O
Solvent: c1ccccc1
Product: OC(c1ccccc1)(c1ccccc1)C(O)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Pentafluorobenzophenone (10.4 g) was dissolved in 250 ml of benzene/isopropanol (3.5:1). The solution was purged with nitrogen and irradiated for 6 hours with a Hanovia 450-watt Hg-arc lamp. The solvent was removed using a vacuum evaporator at a temperature less than 40° C. The crystallized product was washed twice with 25 ml of n-pentane. The slurry was centrifuged and n-pentane was decanted. The product was spread on a watch glass and air dried. Recovery of 2,3,4,5,6,2',3',4',5',6'-decafluorobenzopinacol was 9.1 g or 87.5%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][C:23]1[CH:24]=[C:25](OB(O)O)[CH:26]=[CH:27][CH:28]=1)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][CH:24]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: CCCOc1cccc(OB(O)O)c1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Reaction time: 17 h
Yield: 65 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-propoxyphenylboric acid (536 mg), cupric acetate (271 mg), MS 4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 17 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) as a light yellow, oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[O:4][CH:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[Cl:13][C:8]1[CH:7]=[CH:6][C:5]2[O:4][CH:3]=[C:2]([NH:1][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11](=[O:12])[C:10]=2[CH:9]=1
Reactant: Nc1coc2ccc(Cl)cc2c1=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1coc2ccc(Cl)cc2c1=O)C(=O)OCC
Yield: 68.6 %

Procedure:
A mixture of 3-amino-6-chlorochromone (1.95 g, 0.01 mole) and diethyl ethoxymethylenemalonate (3.5 g, 0.016 mole) was heated under nitrogen at 120° for 4 hrs. The reaction mixture was cooled. The product, which precipitated, was filtered off and washed with ethyl acetate. Recrystallization from ethyl acetate gave white crystals (2.51 g, 68%), m.p. 143°-145°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:31][C:22]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COc1ccc(C(=O)NNC(=O)c2ccc3nc(-c4c(C)cccc4C)[nH]c3c2)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(-c3ccc4nc(-c5c(C)cccc5C)[nH]c4c3)o2)cc1
Reaction time: 0.25 h

Procedure:
To a 5 mL microwave vial was added 0.2225 g (0.537 mmol) of 4-Methoxy-benzoic acid N′-[2-(2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carbonyl]-hydrazide, 4 mL of THF, and 0.2558 g (1.07 mmol) of burgess reagent. The suspension was placed in the microwave at 150° C. for 15 min. The crude solution was concentrated and the residue was purified by silica gel column chromatography (EtOAc/DCM, 1:9 to 6:4) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 6H) 4.02 (s, 3H) 7.35 (dd, J=15.73, 8.27 Hz, 4H) 7.50 (t, J=7.64 Hz, 1H) 7.87 (d, J=8.34 Hz, 0.5H) 8.04 (d, J=8.46 Hz, 0.5H) 8.15 (dd, J=12.19, 8.65 Hz, 1H) 8.24-8.29 (m, 2H) 8.38 (s, 0.4H) 8.60 (s, 0.5H) 13.15 (d, J=14.27 Hz, 1H). MS (m/z) 397.2 M (+1), tR=1.48, Meth 10
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.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:13]=1>C(Cl)Cl>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1cccnc1
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)NCCc1cccnc1

Procedure:
A mixture of 4.44 g of phthalic anhydride and 75 ml of methylene chloride was stirred and 3.66 g of 2-(3-pyridinyl)ethylamine was added. Solution occured followed by separation of a white precipitate. The desired product was separated by filtration and melted at 183°-185° C.
Reaction SMILES: [C:1]([O:7]CC)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10](#[N:12])[CH3:11]>>[CH3:5][C:2]([CH3:3])([CH3:4])[C:1](=[O:7])[CH2:11][C:10]#[N:12]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(C)C
Product: CC(C)(C)C(=O)CC#N

Procedure:
Using analogous procedures to those described in the portion of Note [36] immediately above that is concerned with the preparation of starting materials, ethyl pivaloate was reacted with acetonitrile to give 4,4-dimethyl-3-oxopentanenitrile which in turn was reacted with hydrazine hydrate to give the required starting material.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:18]C)=[CH:13][CH:14]=2)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)n(Cc3ccccc3)[nH]c2c1
Agent: BrB(Br)Br
Product: O=c1c2ccc(O)cc2[nH]n1Cc1ccccc1
Yield: 21 %

Procedure:
Using an analogous procedure to that described in Examples 48-51 treatment of 1,2-dihydro-2-benzyl-6-methoxy-3H-indazol-3-one (Ex. 174) with boron tribromide gave 1,2-dihydro-2-benzyl-6-hydroxy-3H-indazol-3-one as a solid, m.p. 206-207° C. in 21% yield.
Reaction SMILES: [CH2:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](C=O)[C:5]=2[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2.[Br:17]C1C=CC=C2C=1CCC(=O)C2.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[Br:17][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:1]2
Reactant: O=C1CCc2c(Br)cccc2C1
Reactant: O=Cc1cccc2c1CCC1(C2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: OCCO
Solvent: c1ccccc1
Product: Brc1cccc2c1CCC1(C2)OCCO1
Yield: 98 %

Procedure:
3′,4′-Dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-5′-carbaldehyde, designated as 37 in FIG. 15, was prepared as follows: A solution of 5-bromo-3,4-dihydronaphthalen-2(1H)-one (625 mg, 2.78 mmol), ethylene glycol (0.23 mL, 4.17 mmol), and p-toluenesulfonic acid (5.70 mg, 0.03 mol) in benzene (46 mL) was stirred and heated to reflux for 10 h. The solution was cooled, diluted with ether, and sequentially washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography, using a 2:1 mixture of hexanes and AcOEt as eluant, furnished 5′-bromo-3′,4′-dihydro-1′H-spiro[[1,3]-dioxolane-2,2′-naphthalene](730.4 mg, 98% yield) as a yellow oil. Yield: 65%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]3[CH2:20][CH2:19][CH2:18][CH:17]4[C:12]3([CH2:13][CH2:14][NH:15][CH2:16]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:21]1([CH2:27][N:15]2[CH2:14][CH2:13][C:12]34[C:8]5[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=5[O:10][CH:11]3[CH2:20][CH2:19][CH2:18][CH:17]4[CH2:16]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOc1cccc2c1OC1CCCC3CNCCC231
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc2c1OC1CCCC3CN(CC4CCCCC4)CCC231

Procedure:
Treating 9-ethoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline with cyclohexylmethyl bromide in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide gives 3-cyclohexylmethyl-9-ethoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline ##STR77##
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:23][C:24]1([CH3:37])[O:28][CH:27]([C:29]2[CH:30]=[CH:31][C:32]([CH:35]=[O:36])=[N:33][CH:34]=2)[CH2:26][O:25]1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:37])[O:28][CH:27]([C:29]2[CH:30]=[CH:31][C:32]([C:35](=[O:36])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:33][CH:34]=2)[CH2:26][O:25]1
Reactant: CC1(C)OCC(c2ccc(C=O)nc2)O1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCC(c2ccc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)nc2)O1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution (10 mL) of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (500 mg) in ethanol were added 5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-2-carbaldehyde (350 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (45.0 mg) and triethylamine (93 μL), and the mixture was stirred with heating under reflux for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (232 mg, yield 28%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 530 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].[I-:17].[OH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][C:7]=1[I:17]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: [I-]
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2ccc(O)c(I)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4′-Hydroxy-1,1′-biphenyl-4-carbonitrile (25.0 g, 128 mmol), purchased commercially, NaI (19.19 g, 128 mmol), and sodium hydroxide (5.12g, 128 mmol) were combined in methanol (500 mL) at 0° C. and treated with bleach (5.25%, 181.0 g) dropwise over 1 hour. After stirring at 0° C. for 1 hour, the mixture was treated with 10% aqueous sodium thiosulfate (250 mL). The mixture was adjusted to pH 6.8 with 10% aqueous HCl and then the mixture was filtered. The filter cake was crystallized from hot CH2Cl2/hexane to provide the title compound (40% yield). 1HNMR (300 MHz, CDCl3) δ5.40 (s, 1H), 7.10 (m, 1H), 7.50 (m, 1H), 7.60 (m, 2H), 7.77(m, 2H), 7.90 (m, 1H); MS (CDI) m/z 339 (M+NH4)+.
Reaction SMILES: [OH-].[K+].[CH:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[S:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25][CH2:24]4)(=[O:20])=[O:19])=[C:13]([F:46])[CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1>C(O)C.O>[CH:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[S:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)(=[O:19])=[O:20])=[C:13]([F:46])[CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc(CN(c2ccc(OCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C(=O)C(F)(F)F)C3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(c2ccc(OCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
An aqueous solution (1 mL) of potassium hydroxide (29 mg, 0.51 mmol) was added to a solution of N-[4-(2-cyclopentylethoxy)-2-fluorophenyl]-N-(4-methoxybenzyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (163 mg, 0.26 mmol) in ethanol (4 mL), and the mixture was stirred at room temperature for 15 hr. The mixture was diluted with water and extracted with chloroform. The organic layer was concentrated under reduced pressure to afford the title compound as a colorless oil (145 mg).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][S:5](=[O:19])(=[O:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].[OH-].[Na+].Cl>O1CCOCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][S:5]([CH2:4][C:3]([OH:20])=[O:2])(=[O:19])=[O:18])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1
Reactant: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
2.2 g (6.98 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid methyl ester is dissolved in 20 ml of dioxane, and the solution is combined with 10 ml (20 mmol) of 2N sodium hydroxide solution. The mixture heats up slightly, and saponification is completed after 10 minutes. The solution is neutralized with 2N hydrochloric acid under pH control and gently evaporated to dryness under vacuum. The residue is extracted with 30 ml of ethyl acetate, the solution is extracted once by shaking with 10 ml of water, the organic phase is dried over magnesium sulfate, filtered, and evaporated to dryness, thus obtaining 1.96 g (6.51 mmol)=93.2% of theory.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].N([O-])=O.[Na+].[C:17](=[S:22])([O:19][CH2:20][CH3:21])[S-:18].[K+]>O>[C:17](=[S:18])([O:19][CH2:20][CH3:21])[S:22][C:6]1[CH:8]=[CH:9][C:3]([Cl:2])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=S)Sc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To concentrated hydrochloric acid (30 mL) was added 4-chloro-3-nitroaniline (5.18 g) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. To the mixture was added a solution of sodium nitrite (3.1 g) in water (30 mL). The mixture was heated to 50° C. To the mixture was added a solution of potassium O-ethyl dithiocarbonate (14.4 g) in water (60 mL), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and the mixture was extracted with diethyl ether twice. The extracts were combined and washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=7/3) to give O-ethyl S-(4-chloro-3-nitrophenyl) dithiocarbonate (2.96 g). This material was dissolved in tetrahydrofuran (50 mL). The solution was added to a suspension of lithium aluminum hydride (1.62 g) in tetrahydrofuran (50 mL) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled in ice. To the mixture were added water (1.8 mL), 15% aqueous sodium hydroxide solution (1.8 mL) and water (5.4 mL), and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was diluted with ethyl acetate. The resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−1/9) to give the title compound (1.28 g).
Reaction SMILES: C(C1C=CC(C2C=CC=CC=2F)=CC=1)#C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[CH:25][CH:24]=1.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])=[CH:24][CH:25]=1)[CH3:30]
Reactant: CC(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: C#Cc1ccc(-c2ccccc2F)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccccc2Cl)cc1
Reaction time: 13 h
Yield: 64.5 %

Procedure:
The procedure of Example 1 was repeated, except that the 1-ethynyl-4-(2-fluorophenyl)benzene was replaced with 23.1 g of 4'-(2-chlorophenyl)acetophenone, the amount of benzene was increased to 150 ml, the amount of catalyst was increased to 3 g, the amount of sulfuric acid was increased to 2 ml, and the reduction was allowed to proceed for 13 hours. Evaporation of the benzene left a residue which was vacuum distilled to give 14 g of 1-ethyl-4-(2-chlorophenyl)benzene, bp 110°-112°/0.4 mm. The following elemental analysis was obtained:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][N:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[CH3:30].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:34]4[CH:35]=[CH:36][C:31]([N:29]([CH3:30])[CH3:28])=[CH:32][CH:33]=4)[CH:18]=[C:13]3[C:12]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(C#Cc2ccccc2)c2cc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2cnc3c(c2)c(C#Cc2ccccc2)cn3S(=O)(=O)c2ccccc2)cc1
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 63.8 %

Procedure:
A mixture of acetylene 20 (53 mg, 0.121 mmol), 4-(N,N-dimethylamino)phenylboronic acid (30 mg, 0.182 mmol), PdCl2(PPh3)2 (9.0 mg, 0.012 mmol), LiCl (15 mg, 0.363 mmol) and 1.0 M aq. Na2CO3 (300 μL, 0.302 mmol) in EtOH (2 mL) and toluene (2 mL) was stirred for 2 h 45 min. at 105° C. The reaction mixture was then poured onto brine (5 mL) and extracted with ethyl acetate (4×10 mL) and the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by preparative LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water-acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give product 21 as a yellow solid (36.85 mg, 64%); 1H NMR (400 MHz, CDCl3) δ 3.01 (s, 6H), 6.82 (d, J=8.82 Hz, 2H), 7.35-7.42 (m, 3H), 7.45-7.65 (m, 7H), 7.95 (s, 1H), 8.08 (d, J=2.14 Hz, 1H), 8.23 (m, 2H), 8.68 (d, J=2.13 Hz, 1H).