Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])([O-])=O.O.Cl>CCO>[CH3:21][N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[CH2:15][CH2:14][NH:13][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=1
Reactant: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1N
Temperature: 65 °C
Yield: 45 %

Procedure:
(2,4-Dinitro-phenyl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine 31 (0.979 g, 3.329 mmol) was dissolved in anhydrous EtOH (16 mL) in a 2 neck 100 mL argon purged flask. The reaction vessel was fitted with a condenser and dropping funnel and heated in an oil bath to 65° C. H2O (16 mL), EtOH (32 mL) and aqueous (NH4)2S (50 wt %, 1.59 g, 11.652 mmol) were charged to the dropping funnel and added to the hot reaction mixture dropwise over 45 minutes. The reaction was heated at 65-70° C. for 2 hours then cooled to room temperature overnight. Mixture was acidified by the addition of aqueous 4M HCl to adjust pH to 2. The reaction mixture was filtered to remove any insoluble material and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting aqueous solution was basified by the addition of aqueous 2M ammonium hydroxide solution to adjust pH to 10. The aqueous solution was diluted with dichloromethane and transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with H2O, brine, and dried over magnesium sulphate, filtered and concentrated to afford a dark red oil. The product was purified using silica gel dry column chromatography with a solvent system of (5% 2M NH3 in methanol/95% dichloromethane to 10% 2M NH3 in methanol/90% dichloromethane) to afford an orange-red oil/solid 32 N1-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-4-nitro-benzene-1,2-diamine Yield: 0.396 grams (45.1%). 1H NMR (DMSO) δ: 1.39-1.69 (m, 5H), 1.86-1.98 (m, 2H), 2.01-2.10 (m, 1H), 2.10-2.16 (m, 1H), 2.22 (s, 3H), 2.91-2.98 (m, 1H), 3.16-3.24 (m, 2H), 5.11 (br s, 2H), 5.92-5.98 (m, 1H), 6.46 (d, 1H, J=8.8), 7.40 (d, 1H, J=2.5), 7.52 (dd, 1H, J=8.9, 2.5); MS (ESI): 265 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C.CN(C=O)C>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.CCOC(C)=O.O>[F:16][C:11]1[CH:10]=[C:9]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1F
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 100 °C
Yield: 69.7 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(cycloheptylidene) methyl]-2-fluorophenol (133) (0.30 g, 0.80 mmol), ethyl acrylate (0.88 mL, 8.00 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol), triethylamine (0.56 mL, 4.00 mmol) and DMF (10 mL). The stirred reaction mixture was heated overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of water and EtOAc (100 mL). The layers were separated and the organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give reddish brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.22 g (70%) of compound 134 as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=7.1 Hz, 3H), 1.57 (br s, 8H), 2.25-2.35 (m, 4H), 4.25 (q, J=7.1 Hz, 2H), 4.99 (d, J=4.0 Hz, 1H), 6.39 (d, J=15.9 Hz, 1H), 6.75-6.88 (m, 2H), 6.91 (t, J=8.7 Hz, 1H), 7.14 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65 (d, J=16.0 Hz, 1H). LCMS (ES): m/z, 395 (M+H)+, 393 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=3)=[C:12]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:11]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC(C2C=C(C3C=CC=CC=3)C(C3C=CC([N+]([O-])=O)=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)=CC=1)([O-])=O>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[C:12]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:13]([C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)=[C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2c(-c3ccccc3)c(-c3ccccc3)c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Agent: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3)c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Product: Nc1ccc(-c2c(-c3ccccc3)c(-c3ccccc3)c(-c3ccc(N)cc3)c(-c3ccccc3)c2-c2ccccc2)cc1

Procedure:
1,4-bis(4-aminophenyl)-2,3,5,6-tetraphenylbenzene was prepared according to the procedure set forth in Example 2 with 1,4-bis(4-nitrophenyl)-2,3,5,6-tetraphenylbenzene being used at the same molar amount as 1,4-bis(4-nitrophenyl)-2,3,5-triphenylbenzene in Example 3, but the yield was only 45%. The crude product was recrystallized from pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=C(C3C=NC=CN=3)C=[CH:20][N:19]=2)=[CH:12][CH:11]=1.N1C=CN=CC=1C(=O)C.[OH:40][CH2:41][C:42]1[C:46]([C:47](=O)[CH3:48])=[C:45]([CH3:50])[O:44][N:43]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:47]([C:46]3[C:42]([CH2:41][OH:40])=[N:43][O:44][C:45]=3[CH3:50])[CH:48]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)c1c(CO)noc1C
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Agent: CC(=O)c1cnccn1
Product: Cc1onc(CO)c1-c1ccnc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)n1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material the ketone 324 (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: [NH2:1][CH:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH3:8][N:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28](Cl)=[O:29])[C:24]=3[CH:31]=2)[C:10]1=[O:32]>O1CCCC1.C(OCC)C>[CH3:8][N:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28]([NH:1][CH:2]([CH2:3][OH:4])[CH:5]([CH3:7])[CH3:6])=[O:29])[C:24]=3[CH:31]=2)[C:10]1=[O:32]
Reactant: CC(C)C(N)CO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)Cl)c3c2)c1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(CO)NC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 86.2 %

Procedure:
To a solution of 2-amino-3-methyl-1-butanol (1.39 g, 13.5 mmol) in anhydrous tetrahydrofuran at 0° C. is added dropwise a solution of 5-[3,6-Dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid chloride (2.10 g, 5.39 mmol) in tetrahydrofuran. The resultant mixture is stirred 7.5 hours at ambient temperature, diluted with diethyl ether, washed with 1M aqueous hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with hexanes-ethyl acetate to afford the title compound as a solid (2.12 g, 86.2%, mp 120° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH:21]([CH3:24])[C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH:22]([CH3:23])[C:21]#[CH:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: C#CC(C)Cl
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C#CC(C)N1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 50.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2.5 g) is alkylated using (rac)-3-chloro-but-1-yne (0.86 g; 9.5 mmol) and K2CO3 (3.28 g; 23.7 mmol) at 50° C. for 14 days. After aqueous work-up the crude material (1.51 g) is de-acetylated in MeOH (40 ml) using DBU (0.3 ml) at reflux. After aqueous work-up (rac)-5-amino-3,3-dimethyl-1-(1-methyl-prop-2-ynyl)-6-nitro-1,3-dihydro-indol-2-one (1,3 g) is obtained and used without further purification.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH2:10]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[CH:21]1[C:22]2[C:17](=[C:16]([NH:15][CH:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC(Nc2cccc3cnccc23)C1
Agent: Cl
Solvent: CO
Product: NC1CCCC(Nc2cccc3cnccc23)C1
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 43 (171 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (149 mg) as light yellow powdery solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:11][C:10]([C:21](O)=[O:22])=[C:9]2[CH2:24][CH2:25][CH2:26][OH:27])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([C:41]([NH2:43])=[O:42])[CH2:36][CH2:37][N:38]([C:21]([C:10]3[CH:11]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:9]=3[CH2:24][CH2:25][CH2:26][OH:27])=[O:22])[CH2:39][CH2:40]2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CCCO
Reactant: NC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)n(-c3ccc(Cl)cc3)c2CCCO)CC1

Procedure:
Into a round-bottomed flask under nitrogen are introduced 300 mg of the acid obtained in step 3a) in 30 ml of DMF, 246 mg of 4-(4-chlorophenyl)piperidine-4-carboxamide (prepared according to the procedure described in patent application US 2005/0070549, in particular in Example 460, paragraphs 1394 to 1397), 0.62 ml of DIPEA and 250 mg of TBTU.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[C:15]([OH:20])=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([O:31][CH3:32])=[O:30].[I-].[K+]>CN(C)C=O>[C:1]([NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[C:15]([O:20][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCc2c(O)cccc21)c1ccccc1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCCC2NC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
50 mmol of 5-benzoylamino-1-hyroxy-5,6,7,8-tetrahydro-naphthalene and 100 ml of anhydrous potassium potassium carbonate are stirred at 50° C. in 100 ml of absolute dimethylformamide for 20 minutes. A solution of 60 mmol of methyl chloroacetate and 25 mmol of potassium iodide in 25 ml dimethylformamide is added dropwise and the mixture is stirred at 50° C. for 6 to 8 hours. It is filtered under the influence of heat, the residue is rinsed thoroughly with ethyl acetate and the filtrate is evaporated. The residue is stirred in a mixture of 10% strength NaOH and ethyl acetate or tetrahydrofuran for 10 minutes. The ethyl acetate phase is extracted by shaking once with 10% strength NaOH, dried over Na2SO4 and evaporated. The residue is recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CCCC1
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@]1(C)F
Yield: 76 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.50 g, 1.08 mmol) in ethanol (about 5 ml) was added cyclopentylamine (about 1.28 ml, 12.9 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 6% methanol in dichloromethane as eluent furnished title compound (0.42 g) as a colorless solid. Yield: 76%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.06-7.96 (m, 3H), 7.57-7.42 (m, 3H), 6.54 (d, 1H, J=23.1 Hz), 5.92 (d, 1H, J=7.5 Hz), 4.83-4.77 (m, 2H), 4.48-4.44 (m, 1H), 2.15 (s, 3H), 2.08-1.91 (m, 1H), 1.89-1.88 (d, 3H, J=2.1 Hz), 1.78-1.58 (m, 8H), 1.44 (d, 3H, J=23.1 Hz); ES Mass: [M+1]+ 526 (20%), [M+Na] 548 (100%); IR cm−: 3437, 2925, 2855, 1733, 1612, 1232, 1059, 951, 711; HPLC: 98%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(N1CC(C)(C)N(C)C1)([C:16]1C=CC(C)=CC=1)(=O)=O>>[CH2:16]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: Cc1ccc(S(=O)(=O)N2CN(C)C(C)(C)C2)cc1
Reactant: NCCc1c[nH]c2ccccc12
Product: c1ccc2c3c([nH]c2c1)CNCC3

Procedure:
treating the 3-(2-amino)ethyl indole with 1-tosyl-3,4,4-trimethylimidazolidine to produce a tetrahydro-β-carboline derivative; and
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:37])([C:14]2[N:15](COCC[Si](C)(C)C)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)C.Cl>>[F:27][C:25]([F:26])([F:28])[C:21]1[CH:20]=[C:19]([C:17]2[N:18]=[C:14]([C:11]3([OH:37])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(-c3cccc(C(F)(F)F)c3)cn2COCC[Si](C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: OC1(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CCNCC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a microwave vial add 4-hydroxy-4-[4-(3-trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.453 g; 1.00 equiv; 836.28 μmoles; 453.00 mg), ethanol (5 mL; 85.88 mmoles; 5.00 mL; 3.96 g), and hydrogen chloride (5 mL; 5.00 mmoles; 1N aqueous) and heat to 70° C. in a microwave with stirring on and hold for 4 h. Concentrate the reaction mixture to give 4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-4-ol salt (0.32 g; 1.00 equiv; 832.84 μmoles; 320.00 mg; 99.59% yield).
Reaction SMILES: [C:1]([S:9][CH:10]([CH2:18][CH2:19][S:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]1[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=O)SSC1.C1[C@@H](CCCCC(O)=O)SSC1.SC(CCS)CCCCC(O)=O.[BH4-].[Na+].C(Cl)(=O)C1C=CC=CC=1.Cl>O.C(N(CC)CC)C>[C:38]([O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([S:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:18][CH2:19][S:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:40])[C:37]1[CH:29]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1
Reactant: O=C(O)CCCCC1CCSS1
Agent: Cl
Agent: O=C(O)CCCCC(S)CCS
Agent: O=C(O)CCCC[C@@H]1CCSS1
Solvent: CCN(CC)CC
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: O=C(CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1)OC(=O)c1ccccc1

Procedure:
In overview, 6,8-Bisbenzoylmercaptooctanoic acid was prepared by a three step procedure from commercially available a-lipoic acid. The lipoic acid was first reduced to 6,8-bismercaptooctanoic acid with sodium borohydride in water under slightly alkaline conditions. The product was benzoylated with three equivalents of benzoyl chloride in the presence of triethylamine to scavenge the HCl byproduct to produce 6,8-bisbenzoylmercaptooctanoic benzoic anhydride. The anhydride was selectively hydrolyzed with dioxane/water to produce 6,8-bisbenzoylmercaptooctanoic acid without any undesired hydrolysis of the benzoylthio ester groups. The product was purified by column chromatography on Silica Gel. The purified acid was dissolved in methanol and converted to the sodium salt by the slow addition of an aqueous solution containing one mole equivalent of sodium bicarbonate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].CC1(C)C(C2C=C(C=CC=2[O:30][S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32])C(OC)=O)=CCC1>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1

Procedure:
Compound 66.41B was synthesized from methyl 3-formyl-4-hydroxybenzoate 66.41A (commercially available from Aldrich) using a method analogous to the method used to prepare compound 66.6I from 66.6H. MS ESI m/e: 313.2 (M+H)+.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]#[N:11])[CH:2]=1.[BH4-].[Na+]>CO>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([C:10]#[N:11])[CH:2]=1
Reactant: N#Cc1cnn2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnn2c1NCCC2
Yield: 42.6 %

Procedure:
To a stirred mixture of 4.0 g of pyrazolo[1,5-a]-pyrimidine-3-carbonitrile in 200 ml of methyl alcohol under nitrogen at, room temperature, was added, one at a time, 3 pellets of sodium borohydride. The mixture was stirred for several hours and then was allowed to stand at room temperature. The product was collected by filtration to give 1.75 g of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile, mp 206°-207° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.BrC1C=C(O)C=CC=1.[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:35]3[C:30](=[C:31]4[S:38][CH:37]=[N:36][C:32]4=[CH:33][CH:34]=3)[C:29](=[O:39])[C:28]2=[O:40])=[CH:24][CH:23]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:39][C:29]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:30]2[C:35](=[CH:34][CH:33]=[C:32]3[N:36]=[CH:37][S:38][C:31]3=2)[N:27]([CH2:26][C:25]2[CH:41]=[CH:42][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:28]1=[O:40]
Reactant: COc1ccc(CN2C(=O)C(=O)c3c2ccc2ncsc32)cc1
Reactant: Oc1ccc2c(c1)OCCO2
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COc1ccc(CN2C(=O)C(O)(c3cc4c(cc3O)OCCO4)c3c2ccc2ncsc32)cc1

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 6-(4-methoxybenzyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one was obtained (39%) as a colorless solid: MS (ES+) m/z 477.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]#[C:12][Si](C(C)C)(C(C)C)C(C)C)[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]#[CH:12])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)[Si](C#Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 143 %

Procedure:
To a cooled solution of 8-chloro-2-methyl-5-((triisopropylsilyl)ethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (8.0 g, 0.02 mol) in THF (100 mL) was added tetrabutylammonium fluoride solution (1.0M in THF, 40 mL, 0.04 mol) at 0° C. over 15 min. The reaction mixture was stirred for 1 h at 0° C., after completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a brown colored oil (7.0 g).