Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][CH2:33][C@@:34]1([CH2:48]CO)[CH2:38][N:37]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[C:36](=[O:47])[CH2:35]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][CH2:33][C@@:34]1([CH2:48][CH2:1][Br:5])[CH2:38][N:37]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[C:36](=[O:47])[CH2:35]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](c1ccccc1)N1C[C@](CCO)(COCc2ccccc2)CC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@](CCBr)(COCc2ccccc2)CC1=O
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
Carbon tetrabromide (3.17 g, 9.56 mmol) and triphenylphosphine (2.51 g, 9.56 mmol) were sequentially added to a solution of (4R)-4-benzyloxymethyl-4-(2-hydroxyethyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (3.22 g, 9.10 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→1:2) to give 3.18 g (84%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=2)[N:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]2[CH2:11][CH2:12][N:13]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:33])([F:35])[F:34])=[N:30][N:31]=4)[N:28]=3)[CH2:14][CH2:15]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: COc1ccc(C(c2ccccc2)N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-[(4-methoxyphenyl)-phenylmethyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methoxyphenyl)-phenylmethyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
tert-butyl 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine-carboxylate was synthesized according to the procedure for General Method 1, outlined above, starting with 3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 5 mmol of hydrazinecarboxylic acid tert-butylester. LC/MS [9.37 min; 473 (M+1)]
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[C@@H:10]([CH3:22])[CH2:9]2)=[C:4]2[CH:23]=[N:24][CH:25]=[CH:26][C:3]=12.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:15])[C@@H:10]([CH3:22])[CH2:9]3)=[C:4]3[CH:23]=[N:24][CH:25]=[CH:26][C:3]=23)=[CH:31][CH:30]=1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)N1CCCCC1
Reactant: OCc1ccc(B(O)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: [Na+]
Product: C[C@H]1CN(c2nnc(-c3ccc(CO)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1

Procedure:
Using methods described in Example 1, and starting with (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 7 (200 mg, 534 μmol), tetrakis(triphenylphosphine)palladium (31 mg, 27 μmol), 4-(hydroxymethyl)phenylboronic acid (122 mg, 800 μmol) and 2 M sodium carbonate (534 μl, 1067 μmol), (S)-(4-(1-(4-(hydroxymethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 9 was obtained. MS 446.2 (calc'd) 447.3 (M+H, found).
Reaction SMILES: [S:1]1[C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[Br:27][C:28]1C(Cl)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1>C(Cl)Cl>[Br:27][C:28]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[S:1][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:11]2)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cncs2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)c(N2CCN(Cc3cncs3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 73.8 %

Procedure:
tert-Butyl 4-(thiazol-5-ylmethyl)piperazine-1-carboxylate (0.350 g, 1.23 mmol, 1.1 eq) was dissolved in DCM (3.9 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (3.9 mL). Stirring was continued at this temperature for 1 h. Solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. The resulting 5-(piperazin-1-ylmethyl)thiazole (supposedly 0.230 g, 1.23 mmol, 1 eq) was suspended in iPrOH (2.4 mL) and DIPEA (0.70 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.280 g, 1.12 mmol, 1 eq) was added and the mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.330 g, 67%); 1H-NMR (500 MHz, DMSO-d6): δ 2.51-2.58 (br s, 4H, piperazine N(CH2)2), 3.01-3.10 (m, 4H, piperazine N(CH2)2), 3.82 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.78 (s, 1H, thiazole 4-H), 8.16 (s, 1H, pyridine 6-H), 9.03 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=2.17 min—399/401 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26](=[N:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:26]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: NNC(=Nc1ccccc1Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(Cl)cc4Cl)n3-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 8 (0.2 g, 0.75 mmol) in CH3CN was added POCl3 (0.37 g, 2.4 mmol). The mixture was stirred under reflex for 16 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in CH3CN, treated with a solution of N-amino-2,4-dichloro-N′-(2-chlorophenyl)benzamidine 4 (0.38 g, 1.2 mmol) in CH3CN and K2CO3 (0.38 g, 1.2 mmol). The mixture was stirred at ambient temperature for 1 hour, refluxed for 2 hours and filtered. The filtrate was concentrated. The residue was subjected to flash column chromatography (FCC) (50-60% EtOAc/hexanes) to afford the title compound 4-(5-((E)-2-(5-(2,4-dichlorophenyl)-4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a white solid. Yield: 0.11 g, 28%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:30]=2[CH3:31])=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].[CH3:41]I.O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([CH3:41])[C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:30]=2[CH3:31])=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2]
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N(C)c2ccc(N3CCC(O)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
N-[3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (1.5 g) and sodium hydride (60% content, 0.2 g) were reacted in dimethylformamide (10 ml) under ice-cooling for 1 h. Dimethylformamide solution (1 ml) containing methyl iodide (0.6 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to room temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Tetrabutylammonium fluoride (1.4 g), tetrahydrofuran (10 ml) and acetonitrile (10 ml) were added to the residue, and the mixture was stirred at 80° C. for 2 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of ethyl acetate-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound (0.8 g), melting point: 211–212° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29](Br)[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)nc1-2
Yield: 77 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho-[1,2-d]thiazol-6-yl)oxy]acetate and bis(4-chlorophenyl)methyl bromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 77%. Amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15]2)=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH2:15]1[C:16]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:17][CH2:18][CH:14]1[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(OCC2CCC3(CCCCCC3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCC2CCC3(CCCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
To a solution of 3-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionic acid methyl ester (75 mg) obtained in Step 8 in a mixed solvent of ethanol (1 mL)-tetrahydrofuran (1 mL) was added 1N aqueous sodium hydroxide solution (0.22 mL), followed by stirring the reaction mixture at room temperature for 5 hours. Then, after concentrating the reaction mixture, to the residue was added dropwise 2N aqueous hydrochloric acid solution. The precipitate was filtered, washed with water and dried in vacuo to give 3-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionic acid (70.6 mg) as the desired compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:9].O.[OH-].[Li+]>O1CCCC1.O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)NCCOCCO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round bottom flask, was placed a solution of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate (10 g, 37.45 mmol, 1.00 equiv) in tetrahydrofuran (40 mL), and a solution of lithium hydroxide hydrate (23.4 g, 558.33 mmol, 15.00 equiv) in water (30 mL). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 3-4 with hydrochloric acid (2 mol/L). The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (50:1). This resulted in 5 g (53%) of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid as a yellowish solid. 1H-NMR (300 MHz DMSO-d6, ppm): δ 13.25 (s, 1H), 8.71 (m, 1H), 8.48 (d, J=8.5 Hz 1H), 8.06 (m, 2H), 7.62 (m, 1H), 4.59 (s, 1H), 3.41˜3.60 (m, 8H). MS (ES, m/z): 254 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].S(O[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH:7]=[CH:8]2)[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2ccn(CC3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To 6-cyanoindole (1.7 g, 12 mmol) in N,N-dimethylformamide (100 mL) was added a 60% mineral oil dispersion of sodium hydride (0.48 g, 12 mmol). The mixture was stirred at room temperature under nitrogen for 30 min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.8 g, 12 mmol) added and the mixture heated at 80° C. under nitrogen for 15 hours. The solvent was removed in vacuum and replaced with methylene chloride (400 mL). The solution was washed with 350 mL portions of water, saturated aqueous sodium bicarbonate, and saturated brine and dried over sodium sulfate. Filtration, concentration in vacuum and column chromatography on silica gel with methylene chloride as eluent gave 4.4 g of 4-(6-cyano-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester. This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon (0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixture refluxed under nitrogen for 15 hours. Filtration through celite, followed by concentration in vacuum gave 1.9 g of the title compound as a white solid. 1H-NMR (CDCl3): doublet 7.6 δ (1 H); singlet 7.55 δ (1 H); doublet 7.2 δ (1 H); singlet 7.13 δ (1 H); singlet 6.25 δ (1 H); doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet 2.45 δ (2 H); doublet 1.45 δ (2 H); multiplet 1.18 δ (2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:54]=[CH:53][C:41]2[N:42]([CH3:52])[C:43](=[O:51])[C:44]([CH3:50])([CH3:49])[C:45](=[O:48])[N:46]([CH3:47])[C:40]=2[CH:39]=1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:54]=[CH:53][C:41]2[N:42]([CH3:52])[C:43](=[O:51])[C:44]([CH3:49])([CH3:50])[C:45](=[O:48])[N:46]([CH3:47])[C:40]=2[CH:39]=1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Reactant: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (1.8 g, 5.8 mmol) and potassium carbonate (1.0 g, 7.2 mmol) were added to a DMF solution (30 ml) of 7-(3-iodopropoxy)-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.0 g, 4.8 mmol) and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2→ethyl acetate→ethyl acetate:methanol=20:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.29 g (yield: 80%) of 2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide as a yellow amorphous solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][CH:6]1[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7]1=[O:15].CCN(CC)CC.S([Cl:31])(C)(=O)=O.[Li+].[Cl-]>CN(C=O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[CH:6]1[CH2:5][C:4]1[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=1[CH2:2][Cl:31]
Reactant: CN1CC(=O)N(C)C(Cc2ccccc2CO)C1=O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(C)C(Cc2ccccc2CCl)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[2-(hydroxymethyl)benzyl]-1,4-dimethylpiperazine-2,5-dione (1.48 g, 5.64 mmol) and Et3N (1.57 ml, 11.28 mmol) in DMF was cooled to 0° C. Mesyl chloride was added via syringe at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting overnight. More Et3N (2 equivalents) and mesyl chloride (1.1 equivalents) was added at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting for 6 hours. LiCl (478 mg, 11.28 mmol) was added and the reaction stirred at ambient temperature for 1.5 hours. The mixture was partitioned between NH4Cl and EtOAc and extracted with EtOAc (3×). The combined organic solutions were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by normal phase chromatography (0-3% MeOH(NH3)/CH2Cl2) to give a yellow oil (1.47 g).
Reaction SMILES: C([N:7]1[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([O:17]C)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:21])([CH3:20])[CH2:8]1)(=O)C(C)(C)C.[BrH:22]>>[BrH:22].[OH:17][C:12]1[C:11]([CH3:19])=[C:10]2[C:15](=[CH:14][C:13]=1[CH3:16])[NH:7][CH2:8][C:9]2([CH3:20])[CH3:21]
Reactant: COc1c(C)cc2c(c1C)C(C)(C)CN2C(=O)C(C)(C)C
Agent: Br
Product: Cc1cc2c(c(C)c1O)C(C)(C)CN2
Temperature: 100 °C
Yield: 92 %

Procedure:
In a round-bottom flask fitted with a reflux condenser were placed 19 (6 g, 20.8 mmol) and 49% hydrobromic acid (100 mL), and the mixture was heated at 100° C. for 18 h under a nitrogen atmosphere, and then cooled. The hydrobromic acid was removed under reduced pressure, and the resulting solid was washed with hexanes to yield 5-hydroxy-3,3,4,6-tetramethylindoline hydrobromide (5.2 g, 92% yield) as a colorless solid. Spectral data: 1H NMR (CD3OD): δ 1.50 (s, 6H), 2.25 (s, 3H), 2.30 (s, 3H), 3.50 (s, 2H), 7.00 (s, 1H); 13C NMR (CD3OD): δ 12.0, 17.1, 26.6, 44.6, 59.9, 119.2, 123.2, 126.7, 127.1, 140.6, 156.2.
Reaction SMILES: [CH2:1](Br)[CH3:2].[F:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:11]1[CH2:12][CH2:13][C@@H:9]([CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[C:5]([F:4])[CH:6]=2)[CH2:10]1)[CH3:2]
Reactant: CCBr
Reactant: Fc1cccc(C[C@@H]2CCNC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN1CC[C@@H](Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.6 %

Procedure:
Ethyl bromide (0.22 g) was added to a suspension of 3-(R)-(3-fluorobenzyl)pyrrolidine (Intermediate 98, 0.36 g) and potassium carbonate (0.55 g) in acetonitrile and the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate, filtered and the filtrate was evaporated to dryness. The residue was triturated with DCM, the solvent was decanted off and evaporated to dryness to give (R)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (0.24 g) as an oil.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O>CN(C=O)C>[O:3]=[C:2]1[NH:1][CH2:7][C:5](=[O:6])[N:4]1[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C1CNC(=O)N1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CNC1=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of hydantoin (10.0 g, 0.10 mol) in DMF (100 ml) at 60° C. were added potassium carbonate (20.7 g, 0.15 mol) and benzyl bromoacetate (18.9 ml, 0.12 mol). After stirring the mixture at 60° C. overnight, the reaction mixture was poured into water (250 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with 5% aqueous citric acid solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with diethyl ether, and dried to give phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (14.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[C:13]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH3:25])([CH2:20][CH2:21]2)[CH2:18][CH2:17]3)=[N:12][N:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[C:13]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH3:25])([CH2:20][CH2:21]2)[CH2:18][CH2:17]3)=[N:12][N:11]=1
Reactant: CCC12CCC(c3nnc(-c4ccc(OC)cc4Cl)n3C)(CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC12CCC(c3nnc(-c4ccc(O)cc4Cl)n3C)(CC1)CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triazole 9-D (30 mg, 0.08 mmol) was dissolved in 0.5 mL of dry methylene chloride, placed under an inert atmosphere, and cooled to 0° C. To this solution was added BBr3 (1 M in CH2Cl2, 0.25 mL, 0.25 mmol) and the cooling bath was immediately removed. The reaction was stirred for 2 h then diluted with 20 mL of methylene chloride and washed with 1 N aqueous NaOH and brine. The residue was chromatographed by reverse-phase HPLC, eluting with a gradient of 0 to 100% acetonitrile in water. The product, 3-chloro-4-[5-(4-ethylbicyclo[2.2.2]oct-1-yl)4-methyl-4 H-1,2,4-triazol-3-yl]phenol (9-E), was isolated as a white powder. MS (ESI+)=346.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.85 (3H, t, J=7.5 Hz), 1.25 (2H, q, J=7.5 Hz), 1.55 (6H, m), 2.13 (6H, m), 3.58 (3H, s), 6.68 (1H, dd, J=8.4 Hz, J=2.6 Hz), 6.91 (1H, d, J=2.6 Hz), 7.10 (1H, d, J=8.4 Hz).