Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].[N:14]1([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:10]=[C:6]1[NH:5][C:4]2[S:11][CH:12]=[CH:13][C:3]=2[C:2]([N:17]2[CH2:18][CH2:19][N:14]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:16]2)=[C:7]1[C:8]#[N:9]
Reactant: N#Cc1c(Cl)c2ccsc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccsc2[nH]c1=O

Procedure:
To yield a compound of structure (III) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, the intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (50), was reacted with piperazin-1-yl-thiophene-2-yl-methanone to yield 6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (51). The compound of formula (51) was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield the target compounds of structure (III) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, as shown in Scheme 26.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1C=O.C1([OH:18])C=CC=CC=1.Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][O:18][C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: COC(CBr)OC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(F)c(OCC(OC)OC)c1

Procedure:
2-Fluoro-5-methoxybenzaldehyde was subjected to a Baeyer-Villiger reaction, followed by basic ester hydrolysis. The resulting phenol was reacted with 2-bromo-1,1-dimethoxyethane and potassium carbonate to provide 2-(2,2-dimethoxyethoxy)-1-fluoro-4-methoxybenzene. Cyclization was effected with Amberlyst 15 (see A. Goel and M. Dixit, Synlett 2004, 1990-1994) to afford 7-fluoro-4-methoxy-1-benzofuran, which was demethylated using boron tribromide.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:8](=[O:21])[CH2:7][CH2:6]1)=O.[NH3:22]>CO>[OH2:2].[OH2:2].[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]#[C:11][CH2:10][N:9]2[C:8](=[O:21])[CH2:7][CH2:6][CH:5]2[C:3]([NH2:22])=[O:2])[CH2:15][CH2:16]1
Reactant: COC(=O)C1CCC(=O)N1CC#CCN1CCN(C)CC1
Reactant: N
Solvent: CO
Product: CN1CCN(CC#CCN2C(=O)CCC2C(N)=O)CC1
Product: O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-[4-(4-methyl-1-piperazinyl)-2-butynyl]-2-pyrrolidinone (5.02 g) in sieve dried methanol (150 ml) was treated with anhydrous ammonia for fifteen minutes and was allowed to stand at ambient temperture overnight. The solution was concentrated to an amber oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH2:11]>CC(C)=O>[NH2:11][C:10]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:3][CH3:4])[N:1]=1
Reactant: CN
Reactant: Nc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: CNc1nc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4,6-dichloro-1,3,5-triazine (0.2 mole) in 200 ml reagent grade acetone was cooled to 0° C. Two equivalents of 40% aqueous methylamine were added dropwise keeping the temperature less than 10° C.; solids precipitated during the addition. The reaction was then warmed to room temperature and stirred overnight under N2.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:9]=2[S:8][C:7]=1[S:20][CH3:21])=[O:5])C.C(O)(=O)C.S(=O)(=O)(O)O>O>[C:4]([C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:9]=2[S:8][C:7]=1[S:20][CH3:21])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(SC)sc2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CSc1sc2c(F)c(F)c(F)cc2c(=O)c1C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
A mixture of 300 mg (0.897 mmol) of the compound of Example 111, 0.54 ml of acetic acid, 0.072 ml of concentrated sulfuric acid and 0.36 ml of water was stirred for 3 hours at 100° C. After cooling by allowing to stand, the crystals deposited were collected by filtration, washed with water, and dried to obtain 147 mg (0.481 mmol) of title compound (yield 54%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[N:27]1[N:28]=[C:29]([NH:32][CH:33]2[CH2:36][CH:35]([C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38])[CH2:34]2)[NH:30][CH:31]=1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:18])[N:32]([CH:33]3[CH2:34][CH:35]([C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38])[CH2:36]3)[C:29]3[N:28]([N:27]=[CH:31][N:30]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCOC(=O)C1CC(Nc2nnc[nH]2)C1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCOC(=O)C1CC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)C1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (12 g), propyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate (4 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) and N,N-diethylaniline (50 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a mixture of geometric isomers (5 g, 55%).
Reaction SMILES: CC([N:5]([C@H:9]([CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]3[CH:26]=2)=[CH:13][CH:12]=1)[C:6](=O)[O-:7])(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:67]=[CH:68][C:69]=1[O:70][CH:71]([CH3:73])[CH3:72])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O1CCOCC1.C(OCC)(=O)C>[Br:25][C:24]1[C:19]2[N:20]([CH:26]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][C@H:9]([NH:5][C:6](=[O:7])[C:52]4[CH:67]=[CH:68][C:69]([O:70][CH:71]([CH3:72])[CH3:73])=[C:50]([Cl:49])[CH:51]=4)[CH2:27][N:28]4[C:29](=[O:38])[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:36]4=[O:37])=[CH:16][CH:15]=3)[N:18]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl{(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)methyl]ethyl)carbamate (3.5 mmol) and hydrogen chloride in 1,4-dioxane (20 mL, 4.0 M) was stirred for 1 h at RT. The reaction was concentrated to dryness and redissolved in N,N-dimethylformamide (35 mL). Added to the solution was diisopropylethylamine (10.5 mmol) and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (3.8 mmol), followed by stirring at RT for half an hour. The reaction was dissolved in ethyl acetate (80 mL) and washed with water (3×50 mL) and brine (1×50 mL). To the separated organic layer was added hexanes (150 mL) upon which a precipitate was formed, filtered, and dried to afford the title compound as an off white solid (65%). ESMS [M+H]+: 672.2.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:2].[CH2:16]([Zn]CC)C.ICI.C([O-])(=O)C.[NH4+]>C(OCC)C>[CH:1]1([O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][CH2:2]1
Reactant: CC[Zn]CC
Reactant: C=COCCCCOCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ICI
Product: c1ccc(COCCCCOC2CC2)cc1

Procedure:
To a solution of {[4-(vinyloxy)butoxy]methyl}benzene (3.16 g) in diethyl ether (63 mL) was added diethyl zinc (1.0M, hexane solution) (30.6 mL) under nitrogen atmosphere, and a solution of diiodomethane (8.49 g) in diethyl ether (13 mL) was added dropwise thereto. The reaction liquid was stirred under reflux for 1 hour, followed by stirring at room temperature for 12 hours. A saturated aqueous ammonium acetate solution (80 mL) was added to the reaction liquid, followed by extraction with diethyl ether (400 mL). The organic layer was washed sequentially with a saturated aqueous ammonium acetate solution and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=95/5) to obtain {[4-(cyclopropyloxy)butoxy]methyl}benzene (2.41 g).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.9 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in acetonitrile (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopentylcarbamate (0.44 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered to afford N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopentylamino)carboxamide (0.2 g, 27%) as a white solid: mp 151-153° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 0.31 (t, 1H), 6.17 (d, J=6.9 Hz, 1H), 5.18-5.11 (dd, J=4.6 and 12.3 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 3.83 (q, J=6.4 Hz, 2H), 2.96-2.85 (m, 1H), 2.64-2.50 (m, 2H), 2.07-2.04 (m, 1H), 1.70-1.29 (m, 8H); 13C NMR (DMSO-d6) δ 172.77, 169.83, 167.59, 167.04, 157.63, 141.12, 134.64, 133.43, 131.52, 128.99, 121.64, 51.09, 48.83, 38.70, 32.91, 30.94, 23.16, 21.99; Anal. Calcd. For C20H22N4O5: C, 60.29; H, 5.57; N, 14.06. Found: C, 60.09; H, 5.66; N, 14.15.
Reaction SMILES: [Zn:1].[Br:2]CCBr.Cl[Si](C)(C)C.Br[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=1>O1CCCC1>[Br-:2].[C:23]([C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=1)[CH2:12][Zn+:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: BrCCBr
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: [Zn]
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C[Zn+])cc(C(C)(C)C)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
In a dried flask was zinc powder (2.493 g, 38.13 mmol) suspended in anhydrous tetrahydrofuran (23 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.137 mL, 1.59 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.161 mL, 1.27 mmol) was added and stirred at room temperature for 45 min. Then, 1-(bromomethyl)-3,5-di-tert-butylbenzene (9 g, 31.77 mmol) dissolved in anhydrous tetrahydrofuran (23.00 mL) was added over 10 min. Stirring continued at room temperature for 16 h, then stirring was switched off to let the solids settle. The supernatant was used in the next transformation.
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.C[O-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>C(OCC)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH2:24][C:4]([C:5]2[CH:6]=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
A mixture of ethyl-4-bromobenzoate and sodium methoxide in dry diethyl ether was stirred under an argon atmosphere After 30 min, a solution of 4′-bromoacetophenone in dry diethyl ether was then added drop-wise under stirring. The reaction mixture was stirred for 48 h under argon at room temperature. The muddy mixture was acidified and filtered under reduced pressure. The filtrate was washed with water until pH reaches about 7. The crude product was decolourized with activated charcoal and further purified by recrystallization from ethyl acetate. The white needle crystals obtained was dried in a vacuum oven at 40° C. for 24 h. Yield: 5.40 g (28.3%). M.P.: 193.2-195.4° C. The structure was confirmed by EI-MS, 1H NMR, 13C NMR, FT-IR, UV-Vis spectroscopy, and elemental analysis.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([N:19]2[C:27]3[C:22](=[C:23](O)[CH:24]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH:16]1([N:19]2[C:27]3[C:22](=[C:23]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:24]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:17][CH2:18]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(O)c2ccn(C3CC3)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccn(C3CC3)c2c1
Reaction time: 0.5 h

Procedure:
In a 500-mL egg plant-type flask, a chloroform (50 mL) solution of trifluoromethanesulfonic acid anhydride (6.30 mL, 37.5 mmol) was dropwise added to a chloroform (100 mL) solution of ethyl 1-cyclopropyl-4-hydroxy-1H-indole-6-carboxylate (6.12 g, 25 mmol) and pyridine (6.06 mL, 75 mmol) with cooling with ice, and stirred at that temperature for 30 minutes, then poured into aqueous hydrochloric acid solution, extracted with chloroform, washed with aqueous saturated sodium hydrogencarbonate solution, and dried with sodium sulfate. The reaction solution was filtered, concentrated, and purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a colorless oil.
Reaction SMILES: [C:1]([O-:4])(O)=O.[Na+].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12]O.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1S([O-])(=O)=O)([O-])=O>C(#N)C>[CH2:18]([CH:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)[CH2:12][NH:14][C@H:17]1[CH2:22][CH2:21][C:20]2[C:1]([OH:4])=[CH:11][CH:7]=[CH:8][C:19]=2[CH2:18]1)[CH2:17][CH3:22]
Reactant: OCCc1cccs1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)[O-]
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCC(CN[C@H]1CCc2c(O)cccc2C1)c1cccs1
Yield: 130.9 %

Procedure:
10 g of (S)-(−)-2-(N-propylamino)-5-hydroxytetraline, S-(III), obtained according to Example 2 were mixed with 9 g of NaHCO3 (2.2 equivalents) and 16 g of 2-(2-thienyl)ethanol 2-nitrobenzenesulfonate (1.05 equivalents) in 80 mL of acetonitrile. The mixture was refluxed for 9 hours, and then cooled and filtered for removal of suspended salts. 60 mL of water were added to the filtrate and concentrated by distillation for removal of acetonitrile. 40 mL of toluene were added and the layers were separated. The organic layer was twice washed with 10% NaHCO3. Then, 50 mL of water and H3PO4 were added to pH=1-2. After layer separation, the aqueous acid layer was neutralized with 30% K2CO3 to pH=7-7.5 and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of water, concentrated by distillation from the solvent to provide 10 g of (6S)-(−)-5,6,7,8-tetrahydro-6-[propyl-(2-thienyl)ethyl]amino-1-naphthol, S-(I), as a white solid (70% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.O.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>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1F
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: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4ccccc4)cc23)c1F
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To 5-bromo-3-(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (32, 55.0 mg, 0.10 mmol) in tetrahydrofuran (10 mL) were added 1.0 M potassium carbonate in water (3.5 mL), phenylboronic acid (18.8 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) under an atmosphere of nitrogen. The reaction was stirred at 65° C. for 3 hours, and then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give crude compound 33 that was used in the next step.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1
Reactant: NCCCNc1ccccn1
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCCCN(Cc1cccc(Cl)c1)c1ccccn1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Sodium hydride (1.32 g) was dissolved in DMSO (25 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(3-aminopropylamino)pyridine (7.56 g) in DMSO (20 ml) added at room temperature. 3-Chlorobenzyl chloride (8.86 g) in DMSO (15 ml) was added dropwise maintaining the temperature at 20°-25° C. After a further 1 hour, water was added (200 ml) and the mixture extracted with ether. The ether extracts were washed with 2N hydrochloric acid and the aqueous layer adjusted to pH 3.5. After extracting with chloroform the pH was raised to 14 and extracted with ether. After drying (K2CO3), the final ether extracts were stripped to give 2-[N-(3-aminopropyl)-N-(3-chlorobenzyl) amino]pyridine (8.34 g) as an oil which was used without further purification. (ii) 2-[N-(3-aminopropyl)-N-(3-chlorobenzyl)amino]pyridine (1.65 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.3 g) were heated together under reflux in pyridine (15 ml) for 20 hr. On cooling, the mixture was stripped, the residue triturated with wet ether and recrystallised twice from ethanol/water to give 2-[3-[N-(3-chlorobenzyl)-N-pyrid-2-ylamino]propylamino]-5-(6-methylpyrid-3-ylmethyl) pyrimid-4-one 0.6H2O, 1.29 g (53%) mp 100°-104° C.
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.C(OC(=O)N[C@H]1C[C@H](N)C1)(C)(C)C.[NH2:31][NH2:32]>C(O)C>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@H:6]([NH:31][NH2:32])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Agent: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](NN)C1
Temperature: 130 °C

Procedure:
Cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (intermediate in the synthesis of tert-butyl(trans-3-aminocyclobutyl)carbamate from Radchenko, D. S., Pavlenko, S. O., et al J. Org. Chem. 2010, 75, 5941-5952, 10 g, 37.7 mmol) and hydrazine (anhydrous, 5 ml, 159 mmol) were added to ethanol (100 mL) and scaled in a pressure vessel. The mixture was heated at 130° C. for 1½ hours. The crude was evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% (2 N ammonia in methanol) in dichloromethane gradient, visualize with iodine chamber) gave the desired tert-butyl(trans-3-hydrazinylcyclobutyl)carbamate (4.1 g, 20.37 mmol, 54.0% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][N:7]([CH3:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CO>[Br-:1].[Cl:5][CH2:4][CH2:3][CH2:2][N+:7]([CH3:6])([CH3:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: ClCCCBr
Reactant: CCCCCCCCN(C)C
Solvent: CO
Product: CCCCCCCC[N+](C)(C)CCCCl
Product: [Br-]

Procedure:
(3-chloropropyl)dimethyloctylammonium bromide was prepared by the reaction of 1-bromo-3-chloropropane and dimethyloctylamine in methanol.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14](=[O:17])[CH2:15][SH:16].CCN(CC)CC.O>CS(C)=O>[CH3:12][O:13][C:14]([C:15]1[S:16][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:17]
Reactant: COC(=O)CS
Reactant: COc1ccc(C=O)c(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(OC)cc2s1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
To a solution of 2-fluoro-4-methoxy-benzaldehyde (4.0 g, 26 mmol) in DMSO (200 mL) was added mercapto-acetic acid methyl ester (3.6 mL, 3.9 g, 39 mmol) and Et3N (10.8 mL, 7.8 g, 78 mmol) and the reaction mixture was heated (80° C., 12 h). The reaction mixture was cooled (rt) and treated with H2O (100 mL). The suspension was filtered to afford the title compound as a yellow solid (4.1 g, 71%). MS (ESI): mass calcd. for C11H10O3S, 222.0; m/z found, 223.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.97 (d, J=0.6, 1H), 7.74 (d, J=8.8, 1H), 7.28 (d, J=2.3, 1H), 7.02 (dt, J=8.7, 4.3, 1H), 3.92 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: COc1ccc(SCCN)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(SCCNC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of compound 1-HCl (0.44 g) in CH2Cl2 (15 mL) cooled to ˜0° C. was added acetyl chloride (1.0 mL) and triethylamine (1.0 mL). The reaction mixture was stirred for 1 hour at 0° C. and washed with 1N HCl, sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 10 as solid (pure by TLC and NMR). Yield: 0.5 g.