Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[OH:32][C:33]1[CH:42]=[C:41]2[C:36]([CH2:37][CH2:38][N:39]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][C:49]=3[CH3:50])[C:40]2=[O:43])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.CCCCCC.C(OC(=O)C)C>[CH3:50][C:49]1[CH:48]=[CH:47][N:46]=[CH:45][C:44]=1[N:39]1[CH2:38][CH2:37][C:36]2[C:41](=[CH:42][C:33]([O:32][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=3)=[CH:34][CH:35]=2)[C:40]1=[O:43]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccncc1N1CCc2ccc(Oc3cc(C(F)(F)F)ccn3)cc2C1=O
Temperature: 110 °C
Yield: 12.7 %

Procedure:
2-Chloro-4-trifluoromethyl-pyridine (97 mg, 0.59 mmol), KOH (26.4 mg, 0.471 mmol) and 18-crown-6-ether (156 mg, 0.59 mmol) were added to a solution of 7-hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (35B: 100 mg, 0.393 mmol) in toluene (3 mL). The resulting mixture was heated to 110° C. for 3 hours. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was filtered and the filtrate was concentrated to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 20 mg of the product (12.8% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>>[C:12]1([CH:10]2[N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:19]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C=Cc1ccccc1O)c1ccccc1
Reactant: NNc1ccccn1
Product: Oc1ccccc1C1=NN(c2ccccn2)C(c2ccccc2)C1

Procedure:
Example 3 is prepared using 2-hydroxychalcone and 2-hydrazinopyridine following the procedure described for Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2O.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[NH:43][C:40]1[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Oc1nc(C(F)(F)c2ncc(F)cn2)nc2c(Cl)cccc12
Agent: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(F)(F)c3ncc(F)cn3)nc3c(Cl)cccc23)n[nH]1
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
To 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (200 mg, 0.61 mmol) were added phosphoryl tribromide (1.2 g) and toluene (2 mL) followed by DIEA (0.214 mL, 1.22 mmol). The mixture was heated at 105° C. for 45 min. The mixture was allowed to cool and was partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the crude residue was added a solution of 5-methyl-1H-pyrazol-3-amine (137 mg, 1.41 mmol) in DMF (4 mL) and the mixture was stirred at rt for 45 min. The crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (75 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.91 (s, 1H) 7.63 (t, J=8.01 Hz, 1H) 8.07 (d, J=7.54 Hz, 1H) 8.67 (d, J=8.29 Hz, 1H) 9.14 (s, 2H) 10.91 (br s, 1H) 12.24 (br s, 1H); LC-MS (ESI) m/z 406 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[OH-].[Na+].[C:13](Cl)(=[O:24])[O:14][CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1.Cl>C(Cl)Cl>[Cl:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([Cl:23])[CH:19]=1)[CH2:15][O:14][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)=[O:24]
Reactant: O=C(O)CC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(piperidin-4-yl)acetic acid (1 g, 6.98 mmol) in DCM (23 ml) was added 2M NaOH (10.48 ml, 20.95 mmol) and 3,5-dichlorobenzyl carbono-chloridate (1.673 g, 6.98 mmol) to give a white biphasic mixture. After vigorous stirring at RT for 1 hr the reaction mixture was acidified with HCl (6M, 3.49 ml) and then extracted with DCM. The organics were dried with MgSO4, filtered and concentrated under pressure to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.OC(C(F)(F)F)=O.[NH2:20][C@@H:21]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:32]=[CH:33][C:28]([CH2:27][C@H:21]([NH:20][C:9]([C:4]2([CH2:3][C:2]([Cl:1])=[CH2:12])[CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:11])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:29][CH:30]=1
Reactant: C=C(Cl)CC1(C(=O)O)CCCC1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 70 %

Procedure:
To a solution of 1-(2-chloroallyl)cyclopentanecarboxylic acid (51 mg, 0.27 mmol) in DMF (1 mL) and CH2Cl2 (2 mL) was added (S)-2-amino-3-(biphenyl-4-yl)-N,N-dimethylpropanamide TFA salt (109 mg, 0.41 mmol) and TEA (0.19 mL, 1.35 mmol). To the mixture at room temperature was added HATU (154 mg, 0.41 mmol) and stirred at room temperature for 47 hours. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 70% EtOAc/heptane to give (S)—N-(3-(biphenyl-4-yl)-1-(dimethylamino)-1-oxopropan-2-yl)-1-(2-chloroallyl)cyclopentanecarboxamide (83 mg). HPLC retention time=1.76 minutes (condition B); MS (m+1)=439.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.66 (m, 5H), 1.89-2.05 (m, 3H), 2.64 (d, J=15.3 Hz, 1H), 2.70 (d, J=15.3 Hz, 1H), 2.85 (s, 3H), 2.95 (s, 3H), 2.95 (dd, J=13.6, 6.1 Hz, 1H), 3.05 (dd, J=13.6, 6.1 Hz, 1H), 5.05 (s, 1H), 5.10 (s, 1H), 5.08-5.13 (m, 1H), 6.70 (d, J=8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.32-7.38 (m, 1H), 7.44 (t, J=7.7 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.58-7.65 (m, 2H).
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NN[C:7]=2[CH:6]=CC=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([OH:53])=O)=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1.N[C@H](CC)CO>C1COCC1>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([NH:10][C@@H:11]([CH2:3][OH:2])[CH2:7][CH3:6])=[O:53])=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: CC[C@@H](N)CO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Hydroxybenzotriazole hydrate (45.3 mg, 0.29 mmol), N-ethyldiisopropylamine (253 μL, 1.45 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56.7 mg, 0.29 mmol) were added at 0° C. to a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) and (R)-(−)-2-amino-1-butanol (34.0 μL, 0.35 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature overnight. Extraction with 1 N aqueous hydrochloric acid/ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:1 to 100:0) afforded the title compound (60 mg, 50%) as a white solid. MS: m/e=414.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:5])[CH3:2].B.N1C=CC=CC=1>C(O)(=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[NH:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCCC(C)C)CCC1
Agent: B
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Product: CCOC(=O)[C@@H]1CCC[C@H]1NCCC(C)C
Reaction time: 0.25 h
Yield: 34 %
Yield: 17 %

Procedure:
To a solution of 2-(3-methylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (6.84 g, 30.4 mmol) in acetic acid (100 mL) was added a 8.0 M solution of borane in pyridine (4.6 mL, 36.8 mmol) at 25° C. After stirring for 15 min, the reaction mixture was concentrated in vacuo. The crude material was triturated with 1.0 M aqueous hydrochloric acid solution (25 mL) and stirred for 0.5 h (until the gas evolution ceased). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-10% methanol in dichloromethane) to afford cis-2-(3-methylbutylamino)-cyclopentanecarboxylic acid ethyl ester (2.37 g, 10.4 mmol, 34%) as a colorless oil and trans-2-(3-methylbutylamino)-cyclopentanecarboxylic acid ethyl ester (1.18 g, 5.2 mmol, 17%) as a white solid. cis-2-(3-Methylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.90 (6H, d, J=6.3 Hz), 1.26 (3H, t, J=7.0 Hz), 1.34-1.46 (3H, m), 1.57-1.74 (4H, m), 1.81-1.90 (1H, m), 1.94-2.04 (2H, m), 2.53 (1H, q, J=8.1 Hz), 2.59 (2H, t, J=7.5 Hz), 3.27 (1H, q, J=7.6 Hz), 4.11-4.17 (2H, m). trans-2-(3-Methylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ: 0.92 (6H, d, J=6.8 Hz), 1.28 (3H, t, J=7.3 Hz), 1.41-1.47 (2H, m), 1.51-1.90 (5H, m), 2.00-2.09 (3H, m), 2.62-2.74 (3H, m), 3.38 (1H, q, J=7.2 Hz), 4.16 (2H, q, J=7.0 Hz). LC-MS (ESI) calcd for C13H25NO2 227.19, found 228.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:11][C:12]([C:15](O)([CH3:17])[CH3:16])([CH3:14])[CH3:13].[NH2:19][NH2:20]>>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]2[O:11][C:12]([CH3:14])([CH3:13])[C:15]([CH3:17])([CH3:16])[O:8]2)[C:5]([NH:19][NH2:20])=[N:4][CH:3]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: NN
Reactant: O=Cc1cc(Br)cnc1F
Product: CC1(C)OC(c2cc(Br)cnc2NN)OC1(C)C

Procedure:
Scheme 3 describes a method for preparation of 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-b]pyridine derivatives (XXVII) by first selective deprotonation at position-3 of 5-bromo-2-fluoropyridine (XVII) with LDA followed by N-formylpiperidine quench to produce 5-bromo-2-fluoronicotinaldehyde (XVIII). Aldehyde XVIII was condensed with pinacol followed by nucleophilic aromatic substitution by hydrazine to give 5-bromo-2-hydrazinyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine (XIX). XIX was then cyclized under acidic conditions to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine (XX). The 1H-pyrazolo[3,4-b]pyridine NH was THP protection followed by reaction of the bromide (XXI) with bis(pinacolato)diboron to form the borate ester (XXII). Suzuki coupling with various bromides (XVIII) or chlorides yields 1H-pyrazolo[3,4-b]pyridine derivatives (XXIII). Iodization of position-3 of 1H-pyrazolo[3,4-b]pyridine (XXIII) with N-iodosuccinimide followed by Suzuki Coupling with various Boc-protected 1H-indol-2-ylboronic acids (XXV) to produce (XXVI). Final deprotection of the pyrazole and indole nitrogens yields the desired 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-b]pyridine derivatives (XXVII).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O[C:17](=O)[NH:18][C@@H:19]1[CH2:24][CH2:23][C@@H:22]([CH:25]=[O:26])[O:21][CH2:20]1)(C)(C)C.[O:28]=[C:29]1[NH:34][C:33]2[CH:35]=[C:36](C=O)[CH:37]=[CH:38][C:32]=2[S:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:25]([C@H:22]3[O:21][CH2:20][C@H:19]([NH:18][CH2:17][C:36]4[CH:37]=[CH:38][C:32]5[S:31][CH2:30][C:29](=[O:28])[NH:34][C:33]=5[CH:35]=4)[CH2:24][CH2:23]3)=[O:26])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C=O)OC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1cccc2scnc12
Product: COc1cccc2sc(C(=O)[C@@H]3CC[C@@H](NCc4ccc5c(c4)NC(=O)CS5)CO3)nc12

Procedure:
Using the same protocol as for example 23, steps 23.a) to 23.f, the title compound was synthesised using 4-methoxybenzothiazole (8.7 mmol), (3R,6S)-(6-formyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (4.6 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (0.7 mmol) and obtained after chromatography on SiO2 (EtOAc/MeOH 9:1 +1% NH4OH) and crystallisation from ether/MeOH as a yellowish solid (35 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: Cc1ccncc1
Reactant: BrCCCC/C=C\C=C/CCCCBr
Solvent: CC#N
Product: Cc1cc[n+](CCCC/C=C\C=C/CCCC[n+]2ccc(C)cc2)cc1
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 4-picoline (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline left in the aqueous layer The resulting aqueous solution of the product was lyophilized to yield the pure product. (75%). 1HNMR (300 MHz, D2O, ppm), 8.45 (d, J=6.9, 4H), 7.68 (d, J=6.9, 4H), 6.14-6.19 (m, 2H), 5.31-5.39 (m, 2H), 4.35 (t, J=7.2, 4H), 2.47 (s, 6H), 2.07 (q, J=7.2, 4H), 1.83 (p, J=7.5, 4H), 1.25 (p, J=7.5, 4H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH:38]([OH:40])[CH2:37]2)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:39][CH:38]([OH:40])[CH2:37]5)[CH2:32][CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: OC1CN(C2CCNCC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC(O)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.157 g, 0.40 mmol), 1-piperidin-4-ylazetidin-3-ol (0.075 g, 0.48 mmol) and 4 Å molecular sieves (0.4 g) in DCE (5 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.17 g, 0.80 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 20:80) to give 554 as a white solid (0.145 g, 68%). LCMS (Method I): RT=2.20 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d): δ 8.04-7.98 (m, 1 H); 7.65-7.60 (m, 1 H); 7.27-7.20 (m, 2 H); 4.27-4.19 (m, 4 H); 3.80 (s, 3 H); 3.77 (t, J=4.7 Hz, 4 H); 3.74 (s, 2 H); 3.44 (t, J=7.1 Hz, 2 H); 3.26 (q, J=7.4 Hz, 3 H); 2.78-2.70 (m, 2 H); 2.62 (t, J=7.1 Hz, 2 H); 2.12 (t, J=11.0 Hz, 2 H); 1.99-1.90 (m, 1 H); 1.60 (d, J=11.0 Hz, 2 H); 1.33 (t, J=7.4 Hz, 3 H); 1.21-1.10 (m, 2 H)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C1(C)C=CC=CC=1>[CH2:13]([S:20][C:8](=[S:22])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: SCc1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C(=S)SCc2ccccc2)cc1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
A mixture of 4-nitrobenzoic acid (1.67 g), benzyl mercaptan (1.24 g) and phosphorus pentasulfide (4.44 g) in toluene (40 ml) was refluxed for 20 h. A dark red color was developed immediately after heating. After the reaction was complete (as monitored by GC-MS), it was cooled to room temperature and purified by a column chromatography packed with neutral alumina, eluting with benzene. Removal of the solvent by distillation gave the single compound, benzyl-4-nitrodithiobenzoate (1.48 g, 51%). It was further characterized by 1H and 13C-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=4)[C:15]3=[O:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:28][S:29](O)(=[O:31])=[O:30].O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([S:29]([Cl:28])(=[O:31])=[O:30])=[C:21]([F:26])[CH:20]=4)[C:15]3=[O:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)cc(F)c1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCCl
Product: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Cl)c(F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Synthesized according to General Procedure 11. To a solution of (3′S)-3-(3,5-dichlorophenyl)-1′-(3,5-difluorophenyl)-1,3′-bipyrrolidin-2′-one (50 mg, 0.12 mmol) in DCE (0.4 mL) at 0° C. was added chlorosulfonic acid (71 mg, 40 μL, 0.61 mmol) dropwise and the reaction mixture stirred from 0° C. to RT over 1 hour, the temperature was raised to 50° C. and the reaction mixture stirred at this temperature for 2 hours. More chlorosulfonic acid was added (71 mg, 40 μL, 0.61 mmol) and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaHCO3, water, and brine, dried (Na2SO4) and evaporated to dryness. The crude product was used without further purification in the next reaction step. (LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=411.3; tR=1.46 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:21][CH:22]=1)([O-:16])=[O:15].C(N(C(C)C)CC)(C)C>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:13])([F:12])[F:1])=[O:6])[CH2:27][CH2:28]2)=[N:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride (2.0 mL, 11.0 mmol) was added slowly to a solution of 1-(5-nitropyridin-2-yl)piperazine (2.0 g, 10 mmol) and diisopropylethylamine (3.5 mL, 20 mmol) in Dichloromethane (15 mL) at 0° C. under argon. The mixture was then stirred at 25° C. for 2 h. The reaction was quenched with H2O. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated NaCl and dried over anhydrous MgSO4. The organic phase was concentrated and then purified by column chromatography to yield [4-(5-nitropyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone as a yellow solid (1.55 g, 41% yield). MS (ES+) m/z 381.1 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[N:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[Cl:28][C:29]([Cl:33])([Cl:32])[S:30]Cl>O1CCCC1>[CH2:14]([N:13]([S:30][C:29]([Cl:33])([Cl:32])[Cl:28])[C:9](=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Reactant: ClSC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCN=C(SCC)N(CCCCCCC)SC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
3 g (0.01 mole) 1,3-di-n-heptyl-2-ethyl isothiourea was mixed with 50 ml tetrahydrofuran in a stirred round bottom flask and cooled in an ice bath. 1.4 ml (0.01 mole) triethylamine was added and the mixture stirred for 10 minutes. 1.1 ml (0.01 mole) trichloromethyl sulfenyl chloride was added to the mixture dropwise over 2 minutes. A white precipitate formed and the mixture was stirred for 1 hour while coming to ambient temperature. The resultant reaction mixture was allowed to sit overnight. The mixture was suction filtered to remove the white solid which was rinsed twice with 10 ml of fresh tetrahydrofuran. The filtrate was evaporated under vacuum resulting in 4.55 g of the title product at a yield of 101.2 percent. The resulting liquid had a nD30 of 1.5084 and was identified as the title compound by IR spectrum and mass spectroscopy. Compound No. 297 in Table I.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCCCCN
Solvent: C1CCOC1
Product: NCCCCCCNC(=O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.00 g (86.1 mmol) of 1,6-diaminohexane and 400 ml of tetrahydrofuran. A solution prepared by dissolving 8.44 g (86.1 mmol) of maleic anhydride in 25 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 2 hours, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited solid was isolated by filtration, and dried under reduced pressure. The resultant solid was dissolved in 100 ml of methanol, 100 ml of chloroform was added, and the solvent was distilled off under reduced pressure, the resultant solid was dried under reduced pressure at 35° C., to obtain 17 g of (2Z)-4-[(6-aminohexyl)amino]-4-oxo-2-butenoic acid as a white solid. NMR measurement thereof revealed a content of (2Z)-4-[(6-aminohexyl)amino]-4-oxo-2-butenoic acid of 38.4%. Net quantity: 8.1 g, yield: 43.9%.