Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)OC(=S)NC2C=CC(C3N(C)C(C#N)=CC=3)=CC1=2.[H-].[Na+].[C:24](=[O:26])=[O:25].CC([O:30][C@@H:31]1[C@@H:36]([O:37]C(C)=O)[C@@H](Br)[O:34][C@H:33]([C:42](OC)=[O:43])[C@H:32]1[O:46]C(C)=O)=O>CN(C)C=O>[O:37]=[CH:36][C@@H:31]([C@H:32]([C@@H:33]([C@@H:42]([C:24]([OH:26])=[O:25])[OH:43])[OH:34])[OH:46])[OH:30]
Reactant: COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C=O
Agent: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of tanaproget (0.292 g, 1.0 mmol) in anhydrous dimethyl formamide (DMF) (10 mL) was added dropwise under a nitrogen atmosphere to a solution of sodium hydride (NaH) (0.052 g, 2.2 mmol) in DMF (50 mL) that was cooled to approximately −70° C. (dry ice). After stirring for 10 min, a solution of acetobromo-α-D-Glucuronic acid methyl ester (0.396 g, 1 mmol) in DMF (10 mL) was added dropwise. The reaction solution was then warmed to room temperature, and stirred for a total of 24 hours. After 24 hours, the reaction solution was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The combined organic layers were washed with saturated sodium chloride (NaCl) solution (100 mL), dried (magnesium sulfate, MgSO4), and the solvent removed in vacuo. Aliquots of the crude material were chromatographed under low-pressure reversed-phase C18 (RediSep/ISCO, 125×25 mm ID, 40 μm particle size) conditions with a gradient of 50-95% acetonitrile/water. Fractions eluting with 75-80% acetonitrile/water contained the S-protected (D)-Glucuronic acid derivative (2) of tanaproget. A total of approximately 200 mg of (2) was obtained at 95% purity based on NMR spectroscopic analysis (32% isolated yield). All chemicals were purchased from Aldrich (Milwaukee, Wis.) and used without further purification or drying.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[NH2:49])[C:44]#[N:45]>C(Cl)(Cl)Cl>[NH2:49][C:48]1[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][C:41]=1[NH:40][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH3:7])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCCN(CCC)Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(C(=O)Nc2cc(C#N)ccc2N)cc1
Reaction time: 2 h
Yield: 52.3 %

Procedure:
The compound (1.01 g) obtained in Example 29-3, WSCI hydrochloride (973 mg), and HOBt (894 mg) were dissolved in chloroform (30 ml), and the whole was stirred for 2 hours. Then, the compound (445 mg) obtained in Example 29-1 was added thereto and the whole was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform and washed with a saturated ammonium chloride aqueous solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. After that, the resultant was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (613 mg) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1(C)[O:18]C(=O)CC(=O)[O:14]1.Cl>C(N(CC)CC)C>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[CH:12][C:13]([OH:18])=[O:14])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(F)c(Br)cc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1cc(F)c(Br)cc1F
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2,5-difluorobenzaldehyde (15.0 g) in triethylamine formiate (80 mL) at room temperature was added 2,2-dimethyl-1,3-dioxane-4,6-dione (9.77 g). After being stirred for 1 h, the mixture was heated at 95° C. with stirring for 15 hours. After cooling down, ice water was added. The mixture was adjusted to pH ˜1 with HCl (6 M) and then extracted with ethyl acetate (200 mL×3). The organic phase was washed with brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM/petroleum ether (7:1) to give the subtitle compound as a white solid. MS ESI+: m/z=263 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[CH2:31]=O.[Na]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCNCC3)ncc1Cl
Reactant: C=O
Agent: [Na]
Solvent: CC#N
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C)CC3)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[5-Chloro-2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was suspended in acetonitrile (5 mL). Aqueous formaldehyde (37%, 325 μL/4 mmol) and sodium cyanoborohydide (210 mg/3.3 mmol) were added sequentially and the reaction stirred at room temperature for two hours. The material was concentrated onto celite and the desired product was isolated by sequential column chromatography on silica gel (eluting with 0→50% methanol/methylene chloride) followed by basic alumina (eluting with 0→40% methanol/methylene chloride). Yield 50 mg/35%. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.41 (s, 1H), 8.82-8.69 (m, 2H), 8.22 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.56-7.41 (m, 3H), 7.19 (dd, J=7.3, 7.3 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.19-2.78 (m, 14H). LC/MS found 436 (M+H). mp 125-130° C. (dec.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH2:30])[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nc(-c2ccc3cnccc3c2)no1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCc1nc(-c2ccc3cnccc3c2)no1)Cc1ccc(C(F)(F)F)cc1

Procedure:
tert-Butyl(R)-4-(3-(isoquinolin-6-yl)-1,2,4-oxadiazol-5-yl)-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (0.016 g, 0.03 mmol) was treated with TFA (1 mL, 13 mmol) in 1 mL DCM for 1 hour. After removing the solvent and making the remaining residue basic with 2M ammonia in MeOH, the residue was subjected to a silica gel plug using 3% 2M ammonia in MeOH in DCM as the eluant to yield an off-white solid as the desired product. LCMS (API-ES) m/z (%): 413.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.07-2.18 (m, 1H) 2.22 (s, 1H) 2.95-3.03 (m, 1H) 3.05-3.13 (m, 1H) 3.17-3.28 (m, 2H) 3.48-3.58 (m, 1H) 7.52 (d, J=7.53 Hz, 2H) 7.68 (d, J=8.03 Hz, 2H) 7.95 (d, J=5.52 Hz, 1H) 8.23-8.31 (m, 2H) 8.54 (d, J=6.02 Hz, 1H) 8.64 (s, 1H) 9.33 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.[Pd]>[O:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:13]=2[O:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cccc2c1OCCO2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc2c1OCCO2
Yield: 102 %

Procedure:
5-Nitro-2,3-dihydro-1,4-benzodioxin (5.4 g; 29.83 mmol) was dissolved in ethanol (130 ml) and conc.HCl added (1.13 ml; 29.83 mmol) this was then stirred with 10% Pd/C under hydrogen at rt and atmospheric pressure overnight. The catalyst was then filtered off and washed with MeOH. The solvents were removed and the crude purified by SCX. Fractions containing product were concentrated to give the desired product (4.6 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37](=[O:50])[NH:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([OH:49])=[CH:41][CH:40]=1)([CH3:35])([CH3:34])[CH3:33].[O:51]1[CH2:56][CH2:55][CH:54](O)[CH2:53][CH2:52]1>C1COCC1>[C:32]([O:36][C:37](=[O:50])[NH:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([O:49][CH:54]2[CH2:55][CH2:56][O:51][CH2:52][CH2:53]2)=[CH:41][CH:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: OC1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC2CCOCC2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Triphenylphosphine (2.8 g, 10.8 mmol) was dissolved in THF (5 mL) and cooled to 0° C. To this colorless solution diethylazodicarboxylate (1.9 grams, 10.8 mmol) was added dropwise to afford an orange solution. After 15 min at 0° C., a copious precipitate had formed. 4-Hydroxy-naphthalen-1-yl-carbamic acid tert-butyl ester (934 mg, 3.6 mmol) and tetrahydro-4H-pyran-4-ol (552 mg, 5.4 mmol) were then added in one portion as a solution in 2 mL of THF. The purple suspension was stirred at 0° C. for one h then at room temperature for 48 h. The solvent was then evaporated and chromatographed on silica gel (40% EtOAc-hexanes) to provide 680 mg (55%) of [4-(tetrahydro-pyran-4-yloxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester as a purple solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][C@H:22]5[C@H:28]([F:29])[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl-].[CH3:38][Zn+].[NH4+].[Cl-].O>C1COCC1.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>[F:29][C@H:28]1[C@H:22]([O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:6]4[CH:7]=[C:2]([CH3:38])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(Br)cn45)nc23)CC1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nnc(-c3ccc4cccc(O[C@@H]5CCN(C(=O)OC(C)(C)C)CC[C@H]5F)c4n3)n2c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (trans)-tert-butyl 4-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (0.125 g, 0.225 mmol) and Pd(PPh3)4 (0.0519 g, 0.0449 mmol) in 1.9 mL THF was added 2M methyl zinc chloride in THF (0.225 mL, 0.449 mmol) by syringe, and the reaction mixture was heated in an 80° C. reaction block. After 6 hours, the reaction mixture was cooled to ambient temperature and saturated NH4Cl and water were added, causing a precipitate to form. The solids were isolated by vacuum filtration through qualitative filter paper, rinsed with water, air dried, and dried in vacuo. The crude was purified on silica gel (1-8% MeOH in DCM gradient) to give the racemic (trans)-product. The resulting mixture was separated by chiral HPLC using a Chiracell OJ-H column, 9.5% EtOH in hexanes, flow rate 16 mL/min to give Peak 1 trans-product (0.018 g, 16%, 99% ee) as a white solid, and Peak 2 trans-product (0.014 g, 13%, 92% ee) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:15]O>C(=O)(O)[O-].[Na+]>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][CH:5]=1
Reactant: CO
Reactant: O=C(O)c1cncc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cncc(Cl)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 5-chloro-nicotinic acid (20.0 g, 127 mmol, purchased from Matrix Scientific, Columbia, S.C., USA) in methanol (200 mL) at 0° C. was added thionyl chloride (18.6 mL, 255 mmol). The reaction mixture was refluxed for 4 hours. After cooling to room temperature the mixture was diluted with saturated aqueous sodium bicarbonate, extracted with AcOEt (3×300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude 5-chloro-nicotinic acid methyl ester (17.2 g, 79%). 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (d, J=1.4 Hz, 1 H), 8.75 (d, J=2.3 Hz, 1 H), 8.29 (d, J=2.0 Hz, 1H), 3.98 (s, 3 H). MS m/z 171.8
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:11](I)=[CH:10]2.[O:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1>C1COCC1.[Cl-].[NH4+]>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:11]([C:31]1([OH:34])[CH2:32][CH2:33][O:28][CH2:29][CH2:30]1)=[CH:10]2
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2C2(O)CCOCC2)cc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
Isopropylmagnesium chloride, 2M THF (1.322 mL, 2.64 mmol) was added to a solution of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (1.24 g, 2.64 mmol) in THF (25 mL) cooled to −20° C. After stirring for 5 min, an additional amount of iso-propylmagnesium chloride, 2M THF (1.322 mL, 2.64 mmol) was added and the solution was stirred 10 min at this temperature. Next, dihydro-2H-pyran-4(3H)-one (0.293 mL, 3.17 mmol) was added and the reaction was allowed to come to 0° C. After 20 min, the reaction mixture was diluted with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material which was purified by silica gel chromatography by eluting with 1:3 to 1:1 EtOAc in hexane, to provide 4-(6-bromo-2-(4-methoxybenzylamino)quinolin-3-yl)tetrahydro-2H-pyran-4-ol as light-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].CC1C=C(C)N=C(C)C=1.CC1C([IH+:40])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([I:40])[N:6]=1)=[O:4]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)c1nc(I)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (200 mg, 0.645 mmol) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (0.83 g, 1.61 mmol) in 10 mL of CH2Cl2 was stirred at r.t. for 16 h. The mixture was diluted with CH2Cl2 and washed with dilute NaHSO3 and 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (100% CH2Cl2) to give 113 mg of the title compound as a pale yellow solid. MS: (+) m/z 437.13 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH:34]3[CH2:35][CH2:36]3)=[CH:32][CH:33]=2)=[C:20]([C:37]([F:38])([F:39])[F:40])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(C4CC4)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(C3CC3)cc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Compound 81-1 (440 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (300 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)[CH2:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:51].Cl>>[ClH:51].[ClH:51].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][N:18]=4)[CH2:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(N4CCN(c5ccc(C(F)(F)F)cn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(N4CCN(c5ccc(C(F)(F)F)cn5)CC4=O)cc31)CNCC2
Yield: 46 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (72 mg, 0.14 mmol) was deprotected and converted to the dihydrochloride salt according to Example 2 (step g) to provide the title compound (32 mg, 46%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.49 (s, 1H), 7.90-7.88 (dd, J=9.1, 2.5 Hz, 1H), 7.49 (d, J=6.6 Hz, 1H), 7.48 (s, 1H), 7.04-7.00 (dd, J=8.4, 1.7 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 4.39 (s, 2H), 4.35-4.30 (m, 2H), 4.08-4.04 (m, 2H), 3.91-3.88 (m, 2H), 3.65 (s, 3H), 3.54-3.40 (m, 3H), 3.09-3.04 (m, 2H); ESI MS m/z 430 [M+H]+; HPLC (Method B) 99% (AUC), tR=14.4 min.
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2.5 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (726 mg, 2.76 mmol), 4-nitrobenzoic acid (462 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 2.5 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was then carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (579 mg, yield: 90%/(S)-2-octanol).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH3:12])[C:5]2=[N:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:12][NH:11][C:10]1[C:5]2[N:6]([C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CNc1nccn2c(Br)cnc12
Product: CNc1nccn2c(-c3ccccc3)cnc12
Yield: 63 %

Procedure:
Using Method 1, the title compound was prepared from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (Example 1) and phenylboronic acid (from Aldrich) in 63% yield.
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:10]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([O-:13])(=[O:12])=[S:11].[K+]>C(O)C>[C:3]1([CH2:2][CH2:1][O:13][S:10]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[S:11])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCCc2ccccc2)cc1

Procedure:
The title compound was prepared according to General Method 2 using phenethyl bromide (0.088 mmol), potassium thiotosylate(0.088 mol), and absolute ethanol (250 mL). A clear liquid was obtained which was used without purification. 1H NMR (CDCl3) δ 2.47 (s, 3 H), 2.92 (t, 2 H), 3.24 (t, 2 H), 7.1-7.4 (m, 7 H), 7.84 (d, 2 H).
Reaction SMILES: I.CS[C:4]1([NH2:16])[C:12]2[CH:13]=[CH:14][CH:15]=[C:10]3[C:11]=2[C:6](=[CH:7][CH:8]=[CH:9]3)[NH:5]1.[N:17]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]N)[CH:21]=[CH:20][N:19]=[CH:18]1.[OH-].[Na+]>C(O)C>[N:17]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:16][C:4]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:10]4[C:11]=3[C:6](=[CH:7][CH:8]=[CH:9]4)[N:5]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CSC1(N)Nc2cccc3cccc1c23
Reactant: NCCCCCCCn1ccnc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCCCCn1ccnc1)=N2

Procedure:
A mixture consisting of 5.0 grams of 2-methylthiobenz(cd)indol-2-amine hydriodide, 2.8 grams of 7-(1H-imidazol-1-yl)heptylamine, and 75 ml of ethanol as stirred and heated under reflux for 16 hours. After addition of 20 ml of 1N NaOH solution, the reaction mixture was taken to dryness in vacuo. The residue was partitioned between 150 ml of dichloromethane and 100 ml of water. A solid appeared at the interface. It was collected by filtration, added to the dichloromethane filtrate, and the mixture taken to dryness in vacuo. The residual orange oil was dissolved in 100 ml of acetone and added to a stirred boiling solution of 3.5 grams of fumaric acid in 800 ml of acetone. The resultant yellow precipitate was collected, washed with acetone, and dissolved in 200 ml of hot water. The solution was clarified by treatment with activated charcoal. The clear aqueous solution was cooled and made basic with 0.5 N NaOH solution. The resultant orange precipitate was collected, washed with water and dried in vacuo at room temperature. The yield of the title compound was 2.2 grams, and the mp was 48° C.-50° C.