Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:18][CH:17]=2)[CH:5]=[C:6]([F:15])[C:7]=1[O:8]C(=O)C(C)(C)C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])=[CH:18][CH:17]=2)[CH:5]=[C:6]([F:15])[C:7]=1[OH:8]
Reactant: CC(C)S(=O)(=O)Nc1cnccc1-c1ccc(-c2cc(F)c(OC(=O)C(C)(C)C)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1cnccc1-c1ccc(-c2cc(F)c(O)c(F)c2)cc1
Yield: 50 %

Procedure:
Dissolve 2,2-Dimethyl-propionic acid 3,5-difluoro-4′-[3-(propane-2-sulfonylamino)-pyridin-4-yl]-biphenyl-4-yl ester in THF (9 ml) and ethanol (1 ml). Add NaOH 2N (10 ml) and heat the mixture to 60° C. for 7 h. Evaporate solvents and add HCl 3N to acidify the mixture. Apply the acidic mixture to 2 g SCX cartridge. Elute the SCX cartridge with methanol (×3) to remove non-basic impurities. Elute the product with 2N ammonia in methanol to afford, after evaporation, 55.2 mg of the title compound as a yellow solid (50% yield). MS (ES−): 403.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc(COC(=O)c2ccncc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[N-(3-triethoxysilyl)propyl]-carbamoyl-2-nitrobenzyl isonicotinate (TCNI) which binds to silicon dioxide through the ethoxysilyl groups, and has a pyridine metal binding group and a nitrobenzyl radiation sensitive group was prepared according to the synthetic procedure represented in Scheme 2. 4-Bromomethyl-3-nitrobenzoic acid (A) was refluxed overnight with sodium carbonate in acetone/water (1:1). After cooling to room temperature, the reaction mixture was made acidic with 1 N hydrochloric acid and the product was extracted into ethyl acetate, dried over magnesium sulfate and rotary evaporated to yield 4-hydroxymethyl-3-nitrobenzoic acid. The 4-hydroxymethyl-3-nitrobenzoic acid (B) was dissolved in pyridine and reacted with isonicotinoyl chloride hydrochloride at room temperature for 2 days. The resultant solution was poured onto ice, stirred overnight at room temperature and extracted with ethyl acetate. The organics were dried over magnesium sulfate and rotary evaporated to remove the solvents. Residual pyridine was removed by the addition of toluene followed by rotary evaporation. The resultant solid was slurried in ethanol at room temperature and the product, 4-carboxy-2-nitrobenzyl isonicotinate, was isolated by filtration and dried under vacuum.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)[C@@H:59]([C@H:69](O)[CH3:70])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:63]=[CH:64][C:65]([Cl:68])=[CH:66][CH:67]=2)[C@@H:59]([C@@H:69]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:70])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.44 g, 1.69 mmol) in THF (50 mL) at 0° C. were added 5-chloro-pyridin-2-ol (0.15 g, 1.15 mmol) and then DBAD (0.28 g, 1.23 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.25 g, 0.79 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 0.22 g (65%) of the title compound as a colorless oil. ES-MS m/e: 427.8 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C@H:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>CCOC(C)=O>[OH:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C@H:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C[C@H]1CCn2c1cc1cc(OCc3ccccc3)ccc12
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1CCn2c1cc1cc(O)ccc12
Reaction time: 3.5 h

Procedure:
(R)-ethyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (81.1 g, 232 mmol was dissolved in EtOAc (1.0 L) and washed w/aq. 0.5 N HCl (2×350 mL). The organics were dried over MgSO4, filtered, and concentrated to a total volume of approximately 600 mL. The solution was transferred to a Parr bottle and 10% Pd/C (22 g) was added. The mixture was placed on a Parr shaker under 50 psi of hydrogen for 3.5 h. The mixture was filtered through celite and concentrated in vacuo. The crude material was treated with hexanes:MTBE (1:1, v/v, 500 mL), and concentrated to give a white paste. The resulting paste was suspended in a mixture of hexanes:MTBE (2:1, v/v, 350 mL) and filtered. The filter cake was washed with hexanes (twice) to provide a 1st crop of (R)-ethyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate as a white solid (˜70 g, wet). Upon standing the combined filtrates contained additional precipitated product that was filtered and washed with hexanes (twice) to give a 2nd crop (˜7 g, wet) of (R)-ethyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. All remaining filtrates were concentrated and purified by silica gel chromatography (45% EtOAc in hexanes gradient to 85% EtOAc in hexanes). Concentration of the fractions containing the product provided a white solid that was filtered and washed with hexanes to give an additional 6.73 g of desired product.
Reaction SMILES: [NH:1]([C@@H:8]([C:40]1[CH:52]=[CH:51][C:43]([O:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:42][CH:41]=1)[C@@H:9]([S:24][CH2:25][C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][O:27]1)[C:10](=[O:23])N1[C@@H](C2C=CC=CC=2)COC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:33][C:29]1([CH3:32])[CH2:28][O:27][C:26]([CH2:25][S:24][C@H:9]2[C:10](=[O:23])[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:8]2[C:40]2[CH:41]=[CH:42][C:43]([O:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:51][CH:52]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][CH2:30]1
Reactant: CCOC(=O)COc1ccc([C@H](Nc2ccccc2)[C@@H](SCC2(c3ccccc3)OCC(C)(C)CO2)C(=O)N2C(=O)OC[C@@H]2c2ccccc2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc([C@@H]2[C@@H](SCC3(c4ccccc4)OCC(C)(C)CO3)C(=O)N2c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Ethyl (4-{(1S,2R)-1-anilino-2-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (2.1 g, 2.9 mmol) was dissolved in dry toluene (200 ml) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 2.1 ml, 8.7 mmol) was added and the mixture was stirred at 90° C. for one hour. At 45° C. tetrabutylammonium fluoride (TBAF, cat., 0.1 g) was added and the mixture was stirred at 45° C. for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by flash-chromatography (hexane:EtOAc 5:1). This afforded 0.98 g (60%) of the title compound as a yellow oil. 1H-NMR (CDCl3, 200 MHz): 0.6 (s, 3H), 1.2-1.4 (m, 6H), 3.0-3.2 (t, broad, 2H), 3.3-3.5 (m, 4H), 3.95 (d, 1H), 4.2-4.4 (q, 2H), 4.6 (s, 2H), 4.8 (d, 1H), 6.9-7.1 (m, 3H), 7.2-7.6 (m, 1H). MS (CI) M/z: 584.2 (M++Na).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:36])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)N3CCOCC3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 100 mg, 0.25 mmol) in dry DMF (5 mL), sodium hydride (12 mg, 0.27 mmol) was added at 0° C. under nitrogen atmosphere. After 15 minutes morpholine-4-carbonyl chloride (56.1 mg, 0.37 mmol) was added, and the reaction mixture was heated at 60° C. for 48 hours. The reaction mixture was concentrated in vacuum. The crude product was purified by column chromatography (silica gel, 3% acetone in chloroform) to obtain the title compound. Yield: 15 mg (11.73%); 1H NMR (CDCl3, 300 MHz): δ 9.09 (s, 1H), 7.973-8.004 (d, 1H, J=9.3 Hz), 7.772-7.8 (d, 2H, J=8.4 Hz), 7.621-7.658 (dd, 1H, J=9 Hz, 2.1 Hz), 7.517-7.545 (d, 2H, J=8.4 Hz,), 7.057-7.064 (d, 1H, J=2.1 Hz), 3.67 (t, 4H,), 3.26 (t, 4H), 1.84 (s, 6H); MS: m/z 520 (M+).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH3:13][O:14][C:15]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:16]=1[CH2:17][N:18]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=[CH:23][C:22]=2[N:21]=[C:20]([NH:32][NH2:33])[C:19]1=[O:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:33][NH:32][C:20]1[C:19](=[O:34])[N:18]([CH2:17][C:16]2[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:15]=2[O:14][CH3:13])[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=[CH:23][C:22]=2[N:21]=1)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)c(NN)nc3ccc4ccccc4c32)c(OC)c1
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)NNc1nc2ccc3ccccc3c2n(Cc2ccc(OC)cc2OC)c1=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (480 mg, 2.2 mmol) in dry tetrahydrofuran (10 ml) was added to a mixture of 1-(2,4-dimethoxybenzyl)-3-hydrazinobenzo[f]quinoxalin-2(1H)-one (750 mg, 2 mmol) and dry triethylamine (220 mg, 2.2 mmol) in dry tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 1.5 h and filtered. The filtrate was evaporated to give 1.1 g of the title compound as a crude product.
Reaction SMILES: [CH3:1]OC.[CH3:4][C@@H:5]1[NH:40][C:38](=[O:39])[C@@H:37]2[N:41]([CH3:44])[C:42](=[O:43])[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[C:34]([CH2:36]2)[CH:33]=[CH:32][C:31]=4[OH:45])=[CH:25][CH:24]=3)[N:20]([CH3:46])[C:18](=[O:19])[C@@H:17]([CH3:47])[NH:16][C:14](=[O:15])[C@H:13]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:12]([CH3:57])[C:10](=[O:11])[C@H:9]([CH3:58])[NH:8][C:6]1=[O:7].C[C@@H]1NC(=O)[C@@H]2N(C)C(=O)[C@@H](CC3C=CC(OC4C=C(C2)C=CC=4O)=CC=3)N(C)C(=O)[C@@H](C)NC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H](C)NC1=O.C[C@@H]1NC(=O)[C@@H]2N(C)C(=O)[C@@H](CC3C=CC(OC4C=C(C2)C=CC=4O)=CC=3)N(C)C(=O)[C@@H](C)NC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H](C)NC1=O.C[C@@H]1NC(=O)[C@@H]2N(C)C(=O)[C@@H](CC3C=CC(OC4C=C(C2)C=CC=4O)=CC=3)N(C)C(=O)[C@@H](C)NC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H](C)NC1=O.O.O.O.O.O.CI>COCCOC>[CH3:4][C@H:5]1[NH:40][C:38](=[O:39])[C@H:37]2[N:41]([CH3:44])[C:42](=[O:43])[C@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[C:34]([CH2:36]2)[CH:33]=[CH:32][C:31]=4[O:45][CH3:1])=[CH:25][CH:24]=3)[N:20]([CH3:46])[C:18](=[O:19])[C@H:17]([CH3:47])[NH:16][C:14](=[O:15])[C@H:13]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:12]([CH3:57])[C:10](=[O:11])[C@H:9]([CH3:58])[NH:8][C:6]1=[O:7]
Reactant: COc1ccc(C[C@H]2C(=O)N[C@H](C)C(=O)N(C)[C@@H]3Cc4ccc(cc4)Oc4cc(ccc4O)C[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N2C)N(C)C3=O)cc1
Reactant: COC
Solvent: COCCOC
Solvent: CI
Solvent: O
Product: COc1ccc(C[C@H]2C(=O)N[C@@H](C)C(=O)N(C)[C@H]3Cc4ccc(cc4)Oc4cc(ccc4OC)C[C@@H](C(=O)N[C@H](C)C(=O)N[C@@H](C)C(=O)N2C)N(C)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 ml of anhydrous 1,2-dimethoxy ethane, 100 mg of the methylether derivative of TPC-A was dissolved and 240 mg of potassium fluoride-alumina and excess amount of methyl iodide were added and the mixture was shielded from the light while stirring at room temperature overnight. After completion of the reaction, the solution was filtered, the filtrate was subjected to distillation in vacuo to remove solvent and the residue obtained was purified by P-TLC followed by the recrystallization from methanol to obtain N-methyl derivative of the methylether of TPC-A (98 mg) as colorless crystal having m.p. of 285° to 292° C. (decomp) and [α]D27 of -166° (CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:37][CH2:38][CH2:39][F:40])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: FCCCBr
Product: COc1ccc(CC2c3c(OCCCF)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[S:6]1(=[O:18])=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[C:29]1[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[C:29]1[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=[CH:14]3)[CH2:10][CH2:9][CH2:8][N:7]4[S:6]2(=[O:18])=[O:17])[CH2:33][CH:34]=1
Reactant: O=S1(=O)N(CCCCl)c2cccc3c2N1CCC3
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)N(CCCN2CC=C(c3c[nH]c4ccc(F)cc34)CC2)c2cccc3c2N1CCC3
Reaction time: 48 h
Yield: 40.4 %

Procedure:
The operation is as in Example 3, starting with 1-(3-chloropropyl)-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (3.8 g), 4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydropyridine (2.9 g) and sodium bicarbonate (3.3 g) in a mixture of dimethylformamide (40 cc) and tetrahydrofuran (25 cc). The mixture is heated to boiling for 48 hours and is then cooled to a temperature close to 20° C. After purification by flash chromatography on a silica column, under a stream of argon at moderate pressure (0.5-1.5 bars) with ethyl acetate as eluent and recrystallization from boiling acetonitrile (200 cc), 1-[3-(4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (2.5 g) is obtained, melting at 178° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 90 °C
Yield: 39.2 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethylamine (81 mg, 0.32 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (83 mg, 0.35 mmol) and DIPEA (162 μL, 0.95 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 65 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which and with MeOH followed by 2M NH3/MeOH (purification by SCX cartridge repeated three times). The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) and then triturated with MeOH to afford 176 as an off-white solid (47 mg, 40%). LCMS (Method K): RT 2.75 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.65 (1H, s), 8.79 (1H, d, J=2.46 Hz), 8.61 (1H, s), 8.15-7.91 (4H, m), 7.71 (1H, dd, J=8.80, 4.84 Hz), 7.55-7.46 (1H, m), 7.11 (1H, td, J=9.33, 2.43 Hz), 6.93 (1H, dd, J=8.91, 2.44 Hz), 5.49 (1H, s), 1.62 (3H, d, J=6.83 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[H-].[Na+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]I)=[CH:16][N:15]=1.[Cl-].[NH4+]>CN(C=O)C>[Br:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:10])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: Brc1ccc(CCI)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(Br)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.4 %

Procedure:
A solution of ethyl(methylsulfonyl)acetate (1090 mg, 6.6 mmol, 1.0 equiv) in DMF (11 mL) was added dropwise to a mixture of 60% sodium hydride in mineral oil (315 mg, 7.9 mmol, 1.2 equiv) in DMF (11 mL) at 0° C. The reaction was warmed to room temperature and allowed to stir for 40 min. The reaction was cooled to 0° C. and a solution of 2-bromo-5-(2-iodoethyl)pyridine (2560 mg, 8.2 mmol, 1.3 equiv) in DMF (11 mL) was added dropwise, and the reaction was allowed to stir for 3 days. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3×70 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (7:3 heptane/ethyl acetate) to provide the title compound as a white solid (1628 mg, 71%). MS (LCMS) m/z 352.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29-1.35 (m, 3H) 2.30-2.44 (m, 2H) 2.62-2.78 (m, 2H) 3.00 (s, 3H) 3.71 (dd, J=9.37, 4.68 Hz, 1H) 4.21-4.35 (m, 2H) 7.36-7.46 (m, 2H) 8.19 (d, J=1.56 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][CH2:7][C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cc(Br)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring mixture of 5-bromo-2-nitrobenzaldehyde (0.46 g, 2.0 mmole (prepared according to a reference: Organic Letters (2003), 5(13), 2251-2253) in DCM (4.0 mL) was added p-methoxybenzyl amine (0.32 mL, 2.4 mmol) and three drops of AcOH. The mixture was stirred at RT for 5 min, after which was added NaB(OAc)3H (0.64 g, 3 mmol) and the entire mixture was stirred for additional 2 hrs. The reaction mixture was quenched with NaHCO3 (aq) and diluted with EtOAc (10 mL). The separated aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue, which was purified using flash column chromatography (100% hexane to 30% EtOAc/hexanes gradient) to obtain the desired product N-(4-methoxybenzyl)(5-bromo-2-nitrophenyl)methanamine as a pale yellow oil. MS m/e 351 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32]N)[CH:27]=2)=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:29]([C:11]4[CH2:10][CH2:9][C:8]5[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=5[C:2]=4[NH:32]3)=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: CCCCc1ccc(-c2cccc(NN)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(C(=O)O)cc2CC4)cc1
Temperature: 105 °C

Procedure:
A sample of commercially available 5-Oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (75 mg, 0.39 mmol) and (4′-Butyl-biphenyl-3-yl)-hydrazine hydrochloride (115 mg, 0.41 mmol) are treated with zinc chloride (134 mg, 0.99 mmol) and acetic acid (5 mL). The reaction is then heated to 105° C. overnight and cooled to room temperature. The reaction is filtered and the filtrate is washed with methanol and dried on the high vacuum line to afford the title material as a single regioisomer. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.90-7.84 (m, 2H), 7.75-7.71 (m, 1H), 7.62-7.57 (m, 4H), 7.35-7.31 (m, 1H), 7.28 (d, J=8.0 Hz, 2H), 3.11-3.05 (m, 2H), 2.99-2.92 (m, 2H), 2.62 (dd, J=7.6, 7.6 Hz, 2H), 1.65-1.55 (m, 2H), 1.40-1.29 (m, 2H), 0.92 (dd, J=7.3, 7.3 Hz, 3H); ESIMS m/z for (M++H+) calculated 396.2, found 396.2.