Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].Br[C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([Cl:17])=[C:14]([CH3:16])[CH:15]=1>O1CCCC1.CN(C)C=O>[Cl:18][C:12]1[CH:11]=[C:10]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])[CH:15]=[C:14]([CH3:16])[C:13]=1[Cl:17]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: Cc1cc(Br)cc(Cl)c1Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(c1cc(C)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (19 mL) was added a solution of 5-bromo-2,3-dichlorotoluene (2.2 g) in N,N-dimethylformamide (10 mL), then tetrahydrofuran was distilled off under reduced pressure. Dichlorobis(triphenylphosphine)palladium(II) (0.26 g) was added to the residual N,N-dimethylformamide solution, which was stirred at 100° C. for 3.5 hours under nitrogen atmosphere and then cooled to room temperature. To the resulting mixture was added tetrahydrofuran-hexane 2:5 mixture (200 mL) and filtered, and the filtrate was washed with water (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as a brown oil (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.OS(O)(=O)=O.[N+:29]([O-])([O-:31])=[O:30].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:29]([O-:31])=[O:30])=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2cc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a mixture of methyl 2-[(2,6-dichlorophenyl)amino]-6-hydroxy-1H-benzimidazole-5-carboxylate (0.050 g, 0.142 mmol) and conc. H2SO4 (2.0 mL) was added KNO3 (0.014 g, 0.142 mmol) at 10-15° C. The reaction mass was stirred for 30 minutes at the same temperature. The reaction mass was quenched in water and filtered off to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 3.91 (s, 3H), 7.43 (t, J=8.1 Hz, 1H), 7.61-7.77 (m, 3H), 10.80 (s, 1H), 11-12.00 (s, 2H); MS [M+H]+: 397.02.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=O)(C)(C)C.[CH2:16]([O:23][C:24]([NH:26][C:27](=[NH:30])SC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([NH:26][C:27]([N:13]1[CH2:14][CH2:15][CH:11]([CH2:10][CH2:9][NH2:8])[CH2:12]1)=[NH:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCN)C1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67529.2 %

Procedure:
2.18 g (0.0102 mmole) (3RS)-3-(N-tert-butyloxycarbonylaminoethyl) pyrrolidine and 2.81 g (0.0125 mole) N-benzyloxycarbonyl-S-methylisothiourea was dissolved in 30 ml toluene and heated to 60-70° C. for eight hours followed by stirring at room temperature for one day. 0.3 M KHSO4-solution was added and the water layer was washed with a mixture of the toluene and ethyl acetate and left for 2 days under which time the Boc group was removed. The acidic water phase was made alkaline and extracted four times with CH2Cl2 The combined organic layer was dried (Na2SO4), filtered and evaporated to yield 2.0 g (51%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[N:48]=[CH:47][N:46]=[C:45]2[C:41]=1[N:42]=[CH:43][N:44]2[CH2:49][C:50](O)=[O:51])=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:44]1[CH:43]=[N:42][C:41]2[C:45]1=[N:46][CH:47]=[N:48][C:40]=2[NH:39][C:37]([O:36][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:38])[CH3:2]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Yield: 79.9 %

Procedure:
The title compound (2.91 g, 80%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [6-N-(benzhydryloxycarbonyl)-adenin-9-yl]-acetic acid (2.02 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.93 (s, 1H), 9.00 (s, 0.6H), 8.60 (s, 0.4H), 8.59 (s, 0.4H), 8.54 (s, 0.6H), 8.33(d, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 7.69 (m, 2H), 7.52-7.29 (m, 10H), 6.83 (s, 1H), 5.47 (s, 1.2H), 5.37 (s, 0.8H), 4.47 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.03 (q, 1.2H), 3.71 (t, 1.2H), 3.61 (q, 1.2H) 3.49 (t, 0.8H) 3.42 (q, 0.8H), 1.24 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12].O>C1COCC1>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([N:8]1[CH2:7][CH2:6][S:5][C:4]1=[S:3])=[O:12]
Reactant: SC1=NCCS1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a suspension of NaH (60 percent, 1.06 g, 26.5 mmol) in dry THF (10 mL) cooled at zero degrees C. was added a solution of 2-mercaptothiazoline (3.0 g, 25.17 mmol) in dry THF (20 mL) followed by stirring at zero degrees C. for 10 minutes. To the mixture was added trimethylacetyl chloride (3.1 mL, 25.17 mmol), the resultant mixture was then sirrted at 25° C. for two hours. Water was added to the reaction mixture followed by extraction with ethyl acetate (100 mL), dry over anhydrous Na2SO4 l and removal of the solvent in vacuo to give a crude product. Flash column chromatography of the crude product (silica gel, 17 percent ethyl ether in petroleum ether) afforded Compound 226 (4.68 g, 91 percent): pale-yellow solid; mp 48°-50° C.; Rf =0.19 (silica, 17 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2980, 1808, 1738, 1480, 1463, 1396, 1388, 1286, 1251, 1139, 1044, 1003, 874 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 4.21 (t, J=7.3 Hz, 2 H, NCH2CH2S), 3.51 (t, J =7.3 Hz, 2 H, NCH2CH2S), 1. 4 1 (s, 9 H, C(CH3)3); MS (FAB+) m/e (rel intensity) 204 (M+H, 100), 120 (27); HRMS for C8H14NOS2 (M+H), calcd 204.0517, found 204.0500.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Na].[C:10](#[N:13])[CH:11]=[CH2:12].O>C(O)C>[NH2:13][C:10]1[CH2:11][CH2:12][N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: C=CC#N
Reactant: NNc1ccccn1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC1=NN(c2ccccn2)CC1

Procedure:
2-Hydrazinopyridine (0.545 g) was added to a solution of sodium (50 mg; 0.43 atoms) in dry absolute ethanol (2 ml) in a nitrogen atmosphere. Acrylonitrile (0.265 g; 0.32 ml; 1 mol) was added dropwise and the resulting solution heated for 4 hours on the steam bath. The reaction mixture was cooled, giving some crystals, and treated with water (10 ml) to give a suspension of a solid. The solid was collected and washed with water. Recrystallisation from ethanol (ca. 5 ml) gave the title compound m.p. 168°-169.5°. Thin Layer Chromatography: On Al2O3 in CHCl3 gave a single spot Rf 0.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([NH:19][CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:21]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([N:19]([CH3:21])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=O
Reactant: CNC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Solvent: O=CO
Product: CN(C)C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Referring to Scheme 1, the beta-tetralone analog 5 is derived from the alpha-tetralone 1 in four steps. The reduced ketone (Compound 2) is dehydrated and the resultant alkene (Compound 3) is converted to the diol (Compound 4). Elimination of water from the diol gives the beta-tetralone (Compound 5). Compound 5 is then condensed with ammonium chloride under reductive amination conditions to give Compound 6, a compound of the invention (e.g., using the preferred 3,4-dichorophenyl as an example, to give [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-amine). Alternatively, compound 5 is condensed with methylamine hydrochloride under the same conditions to give a compound of the invention, [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-methyl-amine (Compound 7). Additionally, the monomethyl amine (Compound 7) can be further elaborated under Eschweiler-Clark conditions (using formic acid (HCO2H) and formaldehyde (HCHO)) to give a compound of the invention, [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-dimethyl-amine (Compound 8). Compounds 6, 7, or 8 may be synthesized as a mixture of racemic cis and trans, or may be separated to give an enantiomerically enriched or an enantiomerically pure form of one of its four isomers. Cis and trans assignments may be made using methods known in the art (e.g., on the basis of NMR coupling patterns). The absolute configuration can, for instance, be determined by synthesis from a precursor of known configuration, or by X-ray crystallographic determination using a suitable crystal of the compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:38]=[N+:39]=[N-:40])(CCCC)CCCC)CCC.N([O-])=O.[Na+].S(=O)(=O)(O)N>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[NH:40][N:39]=[N:38][N:22]=2)=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(C=Cc2ccccc2OCc2ccccc2)cc1
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1OCc1ccccc1)c1ccc(-c2nnn[nH]2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[2-(2-benzyloxyphenyl)ethenyl]-benzonitrile as a mixture of isomers (7.88 g) and tri-n-butyltin azide (20.03 ml, 2.53M solution in toluene) in toluene 100 ml was heated at reflux for 66 hours. The mixture was cooled (ice bath) and added dropwise to excess sodium nitrite and stirred for 30 minutes. Sulphamic acid (9 g) was added and the mixture left to stand at 5° C. for 18 hours. The resulting yellow precipitate (9.7 g) was filtered off, dried and mixed with potassium carbonate (7.56 g) in DMF (20 ml) and stirred for 10 minutes. Pivaloyloxymethyl chloride (4.78 ml) was added to the mixture and it was stirred for 18 hours, diluted with ethyl acetate (200 ml), and washed with 1M HCl (100 ml), sodium bicarbonate (100 ml) and brine (100 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using methanol : dichloromethane (0:100 to 30:70 gradient) as eluant. There was thus obtained N-2-(pivaloyloxymethyl)-5-{-4-[2-(2-benzyloxyphenyl)ethenyl]-phenyl}tetrazole (7.64 g) and N-1-(pivaloyloxymethyl)-5-{-4-[2-(2-benzyloxyphenyl)ethenyl]-phenyl}tetrazole (1.67 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]2)=[CH:37][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]2)=[CH:37][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a chloroform (2.0 mL) solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzamido)-4-phenylbenzoate (0.19 g), followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 7.4 with a saturated aqueous solution of sodium bicarbonate, chloroform was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.15 g of methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:58]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60][CH2:59]1>>[N:58]1([S:62]([NH:65][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:30][CH2:29]3)[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[CH:33][C:34]=2[F:40])(=[O:64])=[O:63])[CH2:61][CH2:60][CH2:59]1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoic acid and making variations as required to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a white solid (0.045 g, 44%): 1H NMR (300 MHz, DMSO-d6) δ11.57 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.00 (d, J=13.3 Hz, 1H), 4.62-4.54 (m, 1H), 4.04 (t, J=7.8 Hz, 4H), 2.74-2.55 (m, 2H), 2.29-1.97 (m, 2H), 1.84-1.73 (m, 2H), 1.69-1.51 (m, 4H), 1.38-1.23 (m, 11H), 0.90-0.86 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 465.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)-benzenesulfonamide was synthesized (63%) from 3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236), 2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(C=Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(C=Cc2ccccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxystilbene (2 g), potassium carbonate (7.04 g) and 1-bromo-3-chloropropane (5 mL) in N,N-dimethylformamide (10 mL) affords 2.06 g of 4-(3-chloropropoxy)stilbene as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14](=[O:16])[CH3:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:18][C:19]#[N:20]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:13]([CH2:18][C:19]#[N:20])[C:14](=[O:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: N#CCBr
Reactant: CC(=O)CS(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(CC#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofuran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane:dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:26]([F:29])([F:28])[F:27])=[CH:18][C:19]=4[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:13]3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(OCC)(=O)C>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:26]([F:29])([F:27])[F:28])=[CH:18][C:19]=4[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:13]3)[CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc2ccn(Cc3ccc4c(c3)CNCC4)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(F)(F)F)cc2ccn(Cc3ccc4ccncc4c3)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 61.3 %

Procedure:
To a mixture of ethyl 1-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (0.14 g) and ethyl acetate (10 mL) was added manganese dioxide (0.30 g) at room temperature. The reaction liquid was stirred for 6.5 hours under the condition for heating with reflux. In addition, to the reaction liquid were added toluene (10 mL) and manganese dioxide (0.30 g) at room temperature, followed by stirring at 110° C. for 1 day and then at 130° C. for 1 day. The reaction liquid was left to be cooled to room temperature, and filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25-30:70) to obtain ethyl 1-(isoquinolin-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (85 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:11])[CH:7]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:11][C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:47]3[CH:46]=[CH:45][C:44]([N:41]4[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]4)=[CH:49][CH:48]=3)[CH:3]=[C:4]([O:12][C@@H:13]([C@@H:15]3[CH2:16][C:17](=[O:30])[N:18]([C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH3:21])[CH2:19]3)[CH3:14])[C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(Cl)c34)CC2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(Cl)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, (R)-4-((R)-1-((6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.36 (118 mg, 0.239 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (73.3 mg, 0.239 mmol), cesium carbonate (234 mg, 0.718 mmol), dioxane (2.0 mL) and water (0.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) catalyst (27.7 mg, 0.0239 mmol) was added and the solution was heated at 100° C. for 18 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 4-(4-(3-chloro-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate 6.38.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].Cl.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1.C(N=C=NC(C)C)(C)C>>[OH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([NH:28][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:26])[CH2:30][CH2:31]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)N[C@H]1CC[C@H](O)CC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and trans-4-aminocyclohexanol hydrochloride in a manner similar to that described in Example 11 but using 1,3-diisopropylcarbodiimide instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.