Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](/[C:9](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)/[C:10]([O:12][CH3:13])=[O:11])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>ClCCCl>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)/C(=C\c1ccc(Cl)c(Cl)c1)C(=O)c1ccc(Br)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C1C(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A mixture of methyl (2Z)-2-[(5-bromo-2-thienyl)carbonyl]-3-(3,4-dichlorophenyl)acrylate (36.64 g, 87.22 mmol) and aluminum trichloride (14.0 g, 105 mmol) in 1,2-dichloroethane (687.2 mL) was heated at 80° C. under argon overnight. The mixture was then cooled to rt and water (20.4 mL) was added. The mixture was stirred for 30 min and then dryloaded on silica gel. Purified on two ISCO columns, 400 g, EtOAc in hex, 0-80% to afford the product as a yellow solid (31.6 g, 81.3%). LCMS: (AA) ES−: 417, 419. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.3 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.02-6.94 (m, 2H), 4.88 (d, J=3.5 Hz, 1H), 3.83 (s, 3H), 3.76 (d, J=3.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[NH:7][CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:5])[CH3:4].OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>>[N+:20]([C:9]1[C:10](=[O:12])[CH:11]=[C:6]([C:3]([CH3:5])([CH3:4])[C:2]([F:1])([F:13])[F:14])[NH:7][CH:8]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(c1cc(=O)cc[nH]1)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(c1cc(=O)c([N+](=O)[O-])c[nH]1)C(F)(F)F
Temperature: 90 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
To a mixture of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (300 mg, 1.462 mmol) in H2SO4 (8 mL, 150 mmol) was added nitric acid (3.27 mL, 73.1 mmol). The mixture was stirred at 90° C. for 15 h. Then the mixture was added to ice water and basified by aqueous NaOH solution. The mixture was filtered. The filtrate was concentrated and purified by preparative TLC (DCM/MeOH=9:1, Rf=0.1) to yield a light yellow solid of 5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (100 mg, 0.380 mmol, 26.0% yield): 1H NMR (400 MHz, CD3OD): δ 8.82 (s, 1H), 6.95 (s, 1H), 1.64 (s, 6H). ES-LCMS m/z 251.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([N:16]1[C:25](=[O:26])[C:24]2[NH:23][C:22]([C:27]3[N:31]([CH3:32])[N:30]=[C:29]([O:33][CH2:34][C:35](O)=[O:36])[CH:28]=3)=[N:21][C:20]=2[N:19]([CH2:38][CH2:39][CH3:40])[C:17]1=[O:18])[CH2:14][CH3:15]>>[CH3:40][CH2:39][CH2:38][N:19]1[C:17](=[O:18])[N:16]([CH2:13][CH2:14][CH3:15])[C:25](=[O:26])[C:24]2[C:20]1=[N:21]/[C:22](/[N:23]=2)=[C:27]1/[CH:28]=[C:29]([O:33][CH2:34][C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:36])[NH:30][N:31]/1[CH3:32]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc(C(=O)OCC)cc3)NN1C)N=2

Procedure:
Using ethyl 4-(amino)benzoate and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19]Br>>[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]1[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Fc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1cc(F)ccc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 44 g of isatin in 200 ml of N,N-dimethylformamide was added dropwise to a suspension of 16.0 g of sodium hydride (60%) in 100 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After the mixture was stirred at that temperature for 30 minutes, a solution of 61.5 g of benzyl bromide in 100 ml of N,N-dimethylformamide was added thereto. The whole mixture was stirred for 1 hour and then concentrated. Chloroform was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was washed with hexane and recrystallized from ethanol to give 47.3 g (67%) of the title compound as red needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([OH:22])=[CH:20][C:19]3[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>CC(C)=O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([O:22][CH2:42][C:41]3[CH:44]=[CH:45][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:39][CH:40]=3)=[CH:20][C:19]3[C:18]([CH3:23])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)c2cc3c(cc2OCc2ccc(C(C)(C)C)cc2)C(C)(C)CCC3(C)C)cc1
Reaction time: 10 h
Yield: 95.3 %

Procedure:
A solution of the 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7; 225 mg, 0.61 mmol) in acetone (3 mL) was stirred with K2CO3 (1.0 mmol) at room temperature for one hour. The yellow solution was treated with a solution of 4-t-butylbenzylbromide (168 mg, 0.74 mmol) and allowed to stir for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was extracted 3 times with EtOAc; the organic layers were combined, and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated. Purification by cyrstallization (CH2Cl2/hexanes) gave 4-[(3-(4-t-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester 298 mg (95%) as a white solid: mp 168-169.5° C; 1H NMR (400 MHz, CDCl3) δ 8.04 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.81 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.44 (s, 1H, ArH), 7.19 (1/2ABq, J=8.2 Hz, 2H, ArH), 6.89 (s, 1H, ArH), 6.87 (1/2ABq, J=8.4 Hz, 2H, ArH), 4.89 (s, 2H, OCH2), 3.94 (s, 3H, OCH3), 1.69 (m, 4H, 2CH2), 1.28 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 1.25 (s, 9H, 3CH3).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[OH-:10].[K+].Cl.[Cl-].[Na+]>[Cu].O>[NH2:1][C:2]1[C:7]([OH:10])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Nc1ncc(Br)cc1Br
Agent: [Cu]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Nc1ncc(Br)cc1O
Temperature: 170 °C
Reaction time: 10 h
Yield: 46.3 %

Procedure:
A mixture of 6.5 parts of 2-amino-3,5-dibromopyridine, 12 parts of potassium hydroxide (85%), 0.5 part of copper powder and 100 parts of water is stirred under nitrogen in an autoclave for 10 hours at 170° C. The dark-coloured solution is neutralised with concentrated hydrochloric acid, saturated with sodium chloride and extracted three times in the warm state with an ethyl acetate/tetrahydrofuran mixture (9:1). The combined organic extracts are filtered through Hyflo, dried with sodium sulphate and filtered. After the solvent has been evaporated off, the residue is taken up in a small amount of hot ethyl acetate and chromatographed through silica gel. After removal of the ethyl acetate, there are obtained 2.2 parts (46.3% of theory) of 2-amino-3-hydroxy-5-bromopyridine, m.p. 205°-208° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=[C:28]4[C:32]=3[N:31](C)[N:30]=[CH:29]4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC1C=CC(C2(COCC3C4C(=CN(C)N=4)C=C(C(F)(F)F)C=3)CCN(C(OC(C)(C)C)=O)CC2)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=[C:28]4[C:32]=3[NH:31][N:30]=[CH:29]4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate and tert-Butyl 4-(4-fluorophenyl)-4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate. To a solution of tert-butyl 4-(4-fluorophenyl)-4-(((5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (115 mg, 0.227 mmol) in dimethylformamide (2 mL) at 0° C. was added sodium hydride (60% in mineral oil, 18.1 mg, 0.45 mmol). After 5 min, the reaction was treated with iodomethane (0.028 mL, 0.45 mmol). After 30 min, the reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The organics were washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→75% EtOAc/Hex) gave two fractions. The faster eluting fraction was concentrated to give tert-butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (66 mg, 56%). The second fraction was concentrated to give tert-butyl 4-(4-fluorophenyl)-4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (26 mg, 22%). tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.31 (s, 1H), 7.17 (m, 2H), 6.91 (m, 2H), 4.72 (s, 2H), 4.03 (s, 3H), 3.67 (m, 2H), 3.46 (s, 2H), 3.02 (m, 2H), 2.10 (m, 2H), 1.79 (m, 2H), 1.44 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 162.3, 160.3, 139.6, 135.4, 128.7, 128.6, 124.7 (q, J=272 Hz), 123.3 (q, J=32 Hz), 122.9, 121.8, 120.3 (q, J=2.9 Hz), 118.4 (q, J=4.8 Hz), 115.8, 115.6, 80.4, 71.9, 51.8, 46.3, 40.3, 32.9. tert-Butyl 4-(4-fluorophenyl)-4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.89 (s, 1H), 7.35 (m, 2H), 7.24 (s, 1H), 7.03 (m, 2H), 4.85 (s, 2H), 4.24 (s, 3H), 3.72 (m, 2H), 3.55 (s, 2H), 3.10 (m, 2H), 2.18 (m, 2H), 1.94 (m, 2H), 1.46 (s, 9H); 3C-NMR (CDCl3, 126 MHz) δ 162.4, 160.5, 155.1, 147.6, 138.7, 129.0, 128.9, 128.8, 125.6, 124.8 (q, J=273 Hz), 124.1 (q, J=32 Hz), 120.8, 118.8, 117.7 (q, J=4.8 Hz), 115.3, 115.1, 79.6, 79.4, 68.7, 41.4, 40.7, 40.2 (br), 32.2, 28.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].[NH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH2:21])=[O:16])=[C:5]2[OH:20]
Reactant: N
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Product: CC1(C)C(=O)C(C(N)=O)=C(O)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 16 h
Yield: 2.9 %

Procedure:
Ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.19 g, 4038 μmol, see Example 2) was dissolved in ammonia (0.5M in 1,4-dioxane (40376 μL, 20188 μmol)), and the resulting mixture was heated at 70° C. for 16 hours. The reaction mixture was then concentrated, dissolved in MeOH and ammonium hydroxide, and stirred at ambient temperature for 16 hours. The reaction mixture was then heated at 80° C. for 16 hours. The reaction mixture was concentrated, suspended in DCM, filtered, and washed with DCM. The mother liquor was purified via preparatory LC to give the title compound (31 mg) as an off-white solid. MS m/e=266 (M+H)+. Calculated for C13H12ClNO3 265.09.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reaction time: 8 h

Procedure:
At room temperature, 22.67 ml (294.3 mmol) of trifluoroacetic acid were added slowly to a solution of 6.6 g (14.7 mmol) of tert-butyl cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetate in 90 ml of dichloromethane, and the mixture was stirred overnight. The solvent was then removed under reduced pressure and the residue was taken up in 100 ml of ethyl acetate and extracted with 50 ml of water. The organic phase was dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure. This gave 4.8 g (12.23 mmol, 83% of theory) of a colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=4[C:30]([F:33])([F:32])[F:31])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>>[CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:19]([C:30]([F:31])([F:32])[F:33])=[CH:20][C:21]([CH2:22][OH:23])=[CH:24][C:25]=4[C:26]([F:29])([F:27])[F:28])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(CC4CCCCC4)c3c2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(CC4CCCCC4)c3c2)c(C(F)(F)F)c1

Procedure:
Preparation is carried out in analogy to the procedure of Example VI from 2.20 g (4.29 mmol) of aldehyde derivative from Example XX with 0.49 g (12.86 mmol) of sodium borohydride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
3-Chloro-4-fluoronitrobenzene (2.0 g, 11.4 mmol) was added to a stirred suspension of K2CO3 (1.6 g, 11.4 mmol) and N-methylpiperazine (1.3 mL, 1.17 g, 11.4 mmol) in dry DMSO (8 mL) and was heated at 100° C. for 1 h. The reaction was cooled to about 50° C. and poured into ice water (300 mL). The solid was collected by filtration, washed with water, and dried under vacuum to afford the title compound (2.43 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][C:20](I)=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C(=[NH:86])(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1COCC1.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][C:20]([NH2:86])=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(I)cnc23)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(N)cnc23)CC1
Yield: 46.8 %

Procedure:
In a 10-mL sealed tube was heated 4-(3-Iodoquinolin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (520.0 mg, 1.184 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)-xanthene (137 mg, 0.2367 mmol), tris(dibenzylideneacetone)dipalladium(0) (108.4 mg, 0.1184 mmol), sodium tert-butoxide (341.3 mg, 3.551 mmol), and benzophenone imine (218 L, 1.30 mmol) in 13 mL toluene at 100° C. for 5 hours. The reaction was cooled and water and sodium chloride were added. The product was extracted with DCM, dried with sodium sulfate, filtered, and conc. in vacuo. Purification via silica gel chromatography eluting with 100:1 DCM:MeOH afforded the crude imine which was dissolved in 10 THF and treated with 10 drops of 12.1M aq. HCl at room temperature. Upon reaction completion, water and sat. NaHCO3 were added to the reaction whose contents were extracted with DCM. The combined extracts were dried with sodium sulfate, filtered, and conc. in vacuo. The crude material was purified via silica gel chromatography eluting with 50:1 DCM:MeOH to provide 4-(3-Aminoquinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester as an off-white solid (182 mg, 44.5%). MP 168-173° C. LCMS (E/I+) 329.13 (M+H). 1H NMR (DMSO-d6)-8.37 (d, 1H, J=2.56 Hz), 7.23 (t, 1H, J=7.71 Hz), 7.18 (d, 1H, J=7.76 Hz), 7.08 (d, 1H, J=2.52 Hz), 6.74 (d, 1H, J=7.12 Hz), 5.58 (s, 2H), 3.59-3.51 (m, 4H), 3.25-3.19 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:3]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: C1CCNC1
Product: O=Cc1cccc(Cl)c1N1CCCC1

Procedure:
The title compound was synthesized from 3-chloro-2-fluorobenzaldehyde and pyrrolidine as described in Example 67, Step 1 (800 mg, 30%). 1H NMR 300 MHz (CDCl3) δ 10.36 (s, 1H), 7.71-7.73 (m, 1H), 7.59-7.61 (m, 1H), 7.18-7.26 (m, 1H), 3.33-3.42 (m, 4H), 2.01-2.10 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [C:1]([C@H:3]1[C@H:7]([CH2:8]O)[S:6][CH2:5][CH2:4]1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:41]([OH:44])(=[S:43])[CH3:42].C(=O)(O)[O-].[Na+]>C1COCC1>[C:41]([S:43][CH2:8][C@@H:7]1[S:6][CH2:5][CH2:4][C@H:3]1[C:1]#[N:2])(=[O:44])[CH3:42]
Reactant: CC(O)=S
Reactant: N#C[C@@H]1CCS[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SC[C@@H]1SCC[C@H]1C#N
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a stirred solution of trans-4-cyano-5-hydroxymethyltetrahydrothiophene (78 mg) and triphenylphosphine (283 mg) in THF (3 ml), diethylazodicarboxylate (188 mg) dissolved in THF (1.2 ml) and thioacetic acid (82 mg) dissolved in THF (1.2 ml) were added dropwise under ice-cooling and the mixture was stirred for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the mixture and extracted with diethylether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 94 mg (86%) of trans-5-acetylthiomethyl-4-cyanotetrahydrothiophene.
Reaction SMILES: [NH2:1][C@H:2](C(N)=O)[CH2:3][C:4]1C=CC(O)=C[CH:5]=1.Cl.C([N:17]([CH2:20]C)[CH2:18][CH3:19])C>O1CCOCC1>[N:17]1[C:18]2[CH:19]=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH:20]=1
Reactant: CCN(CC)CC
Reactant: NC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2[nH]cnc2c1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a room temperature solution of intermediate 2 in anhydrous dioxane (200 mL) were added triethylamine (6 mL, 40 mmol) and tert-butyldimethylsilyltrifluoro methanesulfonate (8.6 g, 32 mmol). The resulting solution was then stirred overnight and quenched with saturated aqueous sodium bicarbonate solution. It was extracted with dichloromethane (3×100 mL), and the combined organic layers were dried over sodium sulfate and concentrate in vacuo. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide intermediate 3 (9.2 g, 72% overall), which was characterized by LC/MS (LRMS (M+H+) m/z: 458.16).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]2)[C:20]1=[O:39]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:31]4=[CH:32][C:33]5[O:37][CH2:36][O:35][C:34]=5[CH:38]=[C:30]4[O:29][CH2:28]3)[C:20]2=[O:39])=[CH:5][CH:4]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CSc1ccc(CBr)cc1
Agent: BrCC1CCCCO1
Product: CSc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(methylthio)benzyl bromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (86%) as a colorless solid: mp 128-130° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.28-7.19 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.68 (s, 1H), 6.14 (s, 1H), 5.89 (d, J=1.9 Hz, 2H), 4.87-4.79 (m, 3H), 4.67 (d, J=9.3 Hz, 1H), 2.40 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.3, 155.9, 148.8, 142.6, 142.2, 137.8, 133.3, 132.1, 129.3, 128.4, 126.6, 124.2, 123.6, 120.1, 109.9, 103.3, 101.9, 93.8, 80.4, 57.9, 43.2, 15.1; MS (ES+) m/z 418.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:12]([CH3:14])[CH3:13])=[N:7]2.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH2:22])[CH:21]=1>>[CH:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:22][C:20]3[CH:21]=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=3[S:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CC(C)c1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C(C)C)ccc23)c1

Procedure:
The product from Example 8b (0.098 g, 0.475 mmol) was reacted with the product from Example 1f (0.102 g, 0.475 mmol) for 18 h following the procedure from Example 1g to give the title compound, which was purified by HPLC with TFA. Converted to the hydrochloride salt by treatment with 4N HCl in dioxane at room temperature gave the hydrochloride salt (0.076 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.99 Hz, 6H) 2.38 (s, 3H) 3.30 (m, 1H) 6.32 (d, J=6.99 Hz, 1H) 7.24 (s, 5H) 7.34 (m, 3H) 7.86 (d, J=8.82 Hz, 1H) 8.39 (d, J=7.35 Hz, 1H) 9.08 (d, J=8.46 Hz, 1H) 11.16 (s, 1H) 14.36 (m, 1H); MS (ESI+) m/z 386.0 (M+H)+.