Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:8][C:7]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][N:15]=2)([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:6]1.[Br:25]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:25][C:11]1[S:10][C:9]([C:7]2([C:14]3[N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]4=[N:16][N:15]=3)[CH2:8][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COCOC1CC(c2ccc(Br)s2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
3-[3-(Methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (343 mg) was dissolved in acetic acid (3 ml) and then N-bromosuccinimide (193 mg) was added, followed by stirring at room temperature for 7 hours under light-shielding. The reaction solution was diluted with chloroform (40 ml) and then washed with water (10 ml), a 1M aqueous sodium hydroxide solution (10 ml), and brine (10 ml). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 392 mg of 3-[1-(5-bromo-2-thienyl)-3-(methoxymethoxy)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (reddish purple syrup).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:11]([OH:28])[C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([NH:5][CH:6]([CH3:10])[CH2:7][CH2:8][CH3:9])=[O:4].[C:29]1([CH3:39])[CH:34]=CC(S(O)(=O)=O)=C[CH:30]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>CO>[CH2:13]([C@H:12]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C@H:11]([OH:28])[C@H:2]1[C:3](=[O:4])[N:5]([CH:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[CH:30]([CH:29]([CH3:39])[CH3:34])[NH:1]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC(C)NC(=O)[C@@H](N)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)N1C(=O)[C@H]([C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)NC1C(C)C
Temperature: 65 °C

Procedure:
To a solution of (2S,3R,4S)-2-amino-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-N-(1-methylbutyl)-5-phenylpentanamide (46 mg, 0.117 mmol) in MeOH (500 mL) was added isobutylaldehyde (100 mL), a small amount of p-toluene sulfonic acid, and Na2SO4 (10 mg). The mixture was capped and heated to 65° C. overnight. The reaction was filtered and the resulting filtrate purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions separately afforded the earlier and later eluting diastereomer products as the trifluoroacetate salts. Earlier eluting diastereomer: 1H NMR (400 MHz, CD3OD) δ 7.29-7.25 (m, 4H), 7.19-7.18 (m, 1H), 4.23 (br s, 1H), 4.05-3.88 (m, 2H), 3.75-3.63 (m, 1H), 3.15-3.05 (m, 1H), 2.80-2.74 (m, 1H), 2.33-2.27 (m, 1H), 1.98 -1.89 (m, 1H), 1.76-1.70 (m, 1H), 1.60-1.51 (m, 1H), 1.48-1.24 (m, 11H), 1.22-1.20 (m, 2H), 1.13 -1.08 (m, 4H), 0.99-0.87 (m, 6H); HRMS (FT-ICR) C25H41N3O4+H=448.3195; calculated 448.3170; Later eluting diastereomer: 1H NMR (400 MHz, CD3OD) δ 7.28-7.25 (m, 4H), 7.19-7.18 (m, 1H), 4.26-4.24 (m, 1H), 4.08-3.99 (m, 2H), 3.77-3.70 (m, 1H), 3.10-3.07 (m, 1H), 2.83 -2.77 (m, 1H), 2.38-2.37 (m, 1H), 1.85-1.77 (m, 2H), 1.62-1.56 (m, 1H), 1.42-1.27 (m, 11H), 1.24 (m, 3H), 1.11 (t, J=5.6 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 0.99-0.93 (m, 3H); HRMS (FT-ICR) C25H41N3O4+H=448.3168; calculated 448.3170.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[I-].[Na+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>O.C(O)C>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(OCCCCCCO)cc1
Yield: 90.9 %

Procedure:
To a solution of 40 g (1 mole) of sodium hydroxide in 60 ml of water and 400 ml of ethanol were added 122.12 g (1 mole) of 4-hydroxybenzaldehyde, 30 g of sodium iodide and 136.62 g (1 mole) of 1-chloro-6-hydroxyhexane. The mixture was heated at reflux for 24 hours under a nitrogen atmosphere. After cooling, the mixture was filtered and the solvent was removed under reduced pressure. Water (400 ml) was added to the residue and the mixture was extracted twice with 400 ml of ethyl acetate. The ethyl acetate layers were extracted twice with 200 ml of 5% aq. sodium hydroxide, and once with 200 ml of brine, dried over magnesium sulfate, and the solvent was evaporated. A brown oil (202 g, 91%) was obtained, which crystallized slowly.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]#[CH:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1>[Cu]I.C(N(CC)CC)C>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]#[C:13][C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:24])([F:23])[F:14])=[CH:17][CH:18]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C#C[C@H]1CC[C@H](CCCCC)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 0.06 mol of trans-4-pentylcyclohexylacetylene, 0.06 mol of 4-trifluoromethyl-bromobenzene, 250 ml of triethylamine, 1.2 mmol of Pd(II) catalyst and 0.6 mmol of CuI is stirred at room temperature for 15 hours. The reaction mixture is diluted with petroleum ether and filtered. Evaporation and purification give 1-(trans-4-pentylcyclohexyl)-2-(4-trifluoromethylphenyl)acetylene of M.=43°.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>C1(C)C=CC=CC=1.CO>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)[CH3:28]
Reactant: CCN(CC)CCCCl
Reactant: Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1

Procedure:
To a solution of 0.177 g. (7.7 g.-atom) of sodium dissolved in 25 ml. of dry methanol was added a solution of 2.4 g. (7.3 mmol.) of 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuran in 75 ml. of toluene and 10 ml. of methanol. The mixture was refluxed for 15 minutes, then the methanol was removed by distillation. A solution of 1.15 g. (7.7 mmol.) of 3-diethylaminopropyl chloride in 25 ml. of toluene was then added and the resulting mixture was refluxed for 6 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]2[CH2:25][CH2:26][OH:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]2[CH2:25][CH2:26][O:27][C:30](=[O:32])[CH3:31])=[O:11])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
(2R,4R)-1-p-Nitrobenzyloxycarbonyl-2-(2-hydroxyethyl)-4-t-butyldimethylsilyloxypyrrolidine (900 mg) was dissolved in 2.25 ml of dry pyridine, and 2.25 ml of acetic anhydride was added to the solution at room temperature, followed by stirring for 1 hour. The reaction mixture was diluted with diethyl ether, washed successively with brine, a diluted aqueous hydrochloric acid, brine, a diluted aqueous sodium hydroxide solution and brine, dired over anhydrous sodium sulfate to give (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-acetoxyethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1)NO
Reaction time: 72 h
Yield: 41 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to III (47 mg, 0.11 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5) to furnish IV as a colourless oil (19 mg, 41%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O[C:23]1[C:28]([C:29]2[NH:30][C:31](=[O:48])[C:32]3[C:33](=[C:35]([CH2:45][CH2:46][CH3:47])[N:36]([CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[N:37]=3)[N:34]=2)=[CH:27][C:26]([S:49]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH3:59])[CH2:54][CH2:53]2)(=[O:51])=[O:50])=[CH:25][N:24]=1)C>>[CH2:58]([N:55]1[CH2:56][CH2:57][N:52]([S:49]([C:26]2[CH:27]=[C:28]([C:29]3[NH:30][C:31](=[O:48])[C:32]4[C:33](=[C:35]([CH2:45][CH2:46][CH3:47])[N:36]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)[N:37]=4)[N:34]=3)[C:23]([O:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:24][CH:25]=2)(=[O:51])=[O:50])[CH2:53][CH2:54]1)[CH3:59]
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Reactant: OCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCN3CCOCC3)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of potassium bis(trimethylsilyl)amide (180 mg, 0.88 mmol) and 4-(2-hydroxyethyl)morpholine (4 ml) was stirred at 100° C. for 1 hour, then the title compound of Example 26 (100 mg, 0.17 mmol) added and the reaction mixture stirred at 110° C. for 18 hours. The resulting, cool mixture was partitioned between water (10 ml) and dichloromethane (20 ml), the phases separated and the organic phase washed with water (10 ml), dried (MgSO4) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate:methanol (90:10 to 80:20), to yield the title compound (33 mg, 30%) as a white solid. δ (CDCl3): 0.95 (3H, t), 1.04 (3H, t), 1.74 (2H, m), 2.42 (2H, q), 2.56 (4H, m), 2.64 (4H, m), 2.90 (2H, t), 2.99 (2H, t), 3.15 (4H, m), 3.80 (4H, m), 4.75 (2H, t), 5.68 (2H, s), 7.12 (1H, d), 7.25 (1H, m), 7.63 (1H, m), 8.58 (1H, d), 8.62 (1H, s), 8.92 (1H, s), 11.16 (1H, s). LRMS: m/z 652 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C1(C)C=CC=CC=1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:17]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9])#[N:18]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)c(F)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a deoxygenated solution of 4-bromo-3-fluorotoluene (25.0 g, 132 mmol) in DMF (500 mL) was added Zn(CN)2 (10.1 g, 86 mmol) and Pd(PPh3)4 (15 g, 13 mmol). The reaction was stirred at 100° C. for 18 hrs, then cooled to room temperature. The solution was poured into toluene (1 L), washed with 30% aqueous NH4OH (2×1 L), then brine (800 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography, eluting with a gradient of hexane −0% to 7% EtOAc, yielded the titled product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([NH:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc2[nH]ccc12
Product: CS(=O)(=O)Nc1cc(Br)cc2[nH]ccc12
Yield: 101.8 %

Procedure:
6-Bromo-1H-indol-4-amine (500 mg, 1.97 mmol) was treated with methanesulfonyl chloride (167 μl, 2.16 mmol) according to the method described in Preparation 15b to give 580 mg (91% yield) of the title compound. Purity 89%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:19]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: C1CNCCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCNCC3)cc21
Temperature: 140 °C
Yield: 40.2 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Med. Chem., 23, 1358 (1980)] (2.7 g, 10 mmol) and homopiperzine, (5.0 g, 50 mmol) was heated at 140° C. for 51/2 hours. The excess homopiperazine was removed by distillation at 85°-95° C./10 mm Hg. The residue was triturated with water and filtered. The solid collected was dissolved in glacial acetic acid (1.5 mL), water (10 mL) was added, and the pH was adjusted to 8.0 with solid sodium bicarbonate. The resulting precipitate was collected by filtration, washed with water (3×5 mL) and air dried to give the product as a white crystalline solid (1.34 g, 40% yield): mp 196°-198° C.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:15][C:1]1[CH:2]=[CH:3][C:4]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1ccc(CBr)cc1
Temperature: 10 °C

Procedure:
To the suspension of diethyl p-tolylphosphonate (0.73 g, 3.2 mmol) was added a small amount of azobisisobutyronitrile (0.016 g, 0.1 mmol, in portions) and N-bromosuccinimide (0.57 g, 3.2 mmol) in anhydrous CCl4 (30 mL). The mixture was refluxed for 4 h, then cooled to 10° C. and filtered to remove succinimide. The filtrate was washed with water (30 mL) and brine (30 mL) and then dried over anhydrous Na2SO4. After filtration, the crude product was obtained via evaporation of solvent and purified by chromatography on silica gel (hexene/ethyl acetate: 2/l as eluent) to provide diethyl 4-(bromomethyl)phenylphosphonate as a colorless oil. 1H NMR (500 MHz, CD3Cl): δ 7.79-7.83 (m, 2H), 7.50-7.52 (m, 2H), 4.51 (s, 2H), 4.09-4.18 (m, 4H), 1.33-1.36 (t, 6H).
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH:31]=[CH:30][C:13]=3[N:14]=[C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH3:19])[N:16]=2)C2C=CC=CC=2N=N1.[CH:41]1(O)[CH2:43][CH2:42]1>COCCOC>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:32]2[CH:31]=[CH:30][C:13]3[N:14]=[C:15]([NH:17][C@@H:18]([C:20]4[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=4)[CH3:19])[N:16]=[C:11]([O:10][CH:41]4[CH2:43][CH2:42]4)[C:12]=3[N:33]=2)=[CH:35][CH:36]=1
Reactant: C[C@@H](Nc1nc(On2nnc3ccccc32)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Reactant: OC1CC1
Solvent: COCCOC
Product: C[C@@H](Nc1nc(OC2CC2)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (R)-4-(1-(4-(1H-benzo[d][1, 2, 3]triazol-1-yloxy)-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide (80 mg), cyclopropanol (0.1 ml) and CsCO3 (94 mg) in DME (3 ml) was stirred at room temperature over the weekend. The reaction mixture was concentrated and purified by reverse phase HPLC (eluting with ACN/H2O+0.1% TFA) to give the title compound, which was characterized by its NMR and mass spectrum as follows: 1H NMR (CD3OD): d 0.83-1.04 (m, 4H), 1.66-1.70 (m, 3H). 4.50-4.58 (m, 1H), 5.40-5.49 (m, 1H), 7.19 (t, 2H), 7.61-7.88 (m, 4H), 7.99-8.02 (m, 1H), 8.08-8.13 (m, 2H), 8.30 (s, 1H); MS (m/z): 480.3 ([M+H]+, 100).
Reaction SMILES: [O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18](O)O)[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:21][S:22]([CH2:25][CH2:26][NH:27][CH2:18][CH2:17][N:16]1[C:9]2[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH:14]=[CH:15]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)CCN
Reactant: OC(O)Cn1ccc2ncnc(Oc3ccccc3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)CCNCCn1ccc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
2-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-1,1-diol (500 mg) and 2-(methylsulfonyl)ethylamine (341 mg) were dissolved in N,N-dimethylformamide (29 mL)/acetic acid (2.9 mL), and the mixture was stirred at room temperature for 1.5 hrs. Sodium triacetoxyborohydride (579 mg) was added, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) to give the title compound (508 mg) as a candy-like substance.
Reaction SMILES: OCCC[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1.CC(OI1(OC(C)=O)(OC(C)=O)O[C:48](=[O:49])[C:47]2C1=CC=C[CH:46]=2)=O.C(=O)(O)[O-].[Na+].O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:48]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1)(=[O:49])[CH2:47][CH3:46]
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CCCO
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.5 h

Procedure:
(±)-2-[2-(Hydroxypropyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 657, 81 mg, 0.17 mmol), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 0.11 g, 0.25 mmol, 1.5 equiv), sodium bicarbonate (71 mg, 0.85 mmol, 5 equiv) and water (8.0 μL, 0.44 mmol, 2.6 equiv) were combined in dichloromethane (8 mL) and stirred vigorously for 30 minutes. Additional Dess-Martin periodinane (0.11 g, 0.25 mmol, 1.5 equiv) was added and the mixture was stirred for an additional 45 minutes. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated) and sodium thiosulfate (3 mL, aqueous saturated) and stirred vigorously for 30 minutes. The mixture was poured into sodium bicarbonate (15 mL, aqueous saturated) and extracted with dichloromethane (2×50 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.45 (1H, s), 8.37 (1H, dd, J=7.2, 2.2 Hz), 7.94-7.91 (2H, m), 7.74-7.72 (3H, m), 7.57-7.43 (5H, m), 7.35 (1H, d, J=7.6 Hz), 7.31 (2H, d, J=8.4 Hz), 6.47 (1H, m), 5.49 (2H, s), 2.73 (2H, q, J=7.6 Hz), 1.13 (3H, t, J=7.2 Hz) ppm; high resolution mass spectrometry (ES+) m/z 474.1919 [(M+H)+; calculated for C29H24N5O2: 474.1925].
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:5]=1[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:5]=1[C:6]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:7]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCOCC2)c(N)c1
Yield: 94.5 %

Procedure:
A two liter autoclave was charged with 130.6 g of N-(2,4-dinitrobenzoyl)-morpholine, 1200 ml methanol and 6.2 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 800 psi while maintaining the temperature between 60°-100° C. Hydrogen uptake ceased after 30 min. The mixture was cooled, filtered and methanol removed at reduced pressure. The residue was crystallized from toluene to yield 97.1 g of N-(2,4-diaminobenzoyl)morpholine, mp 114°-115° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][N:35]1[CH:39]=[N:38][C:37]([C:40]([OH:42])=O)=[N:36]1.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:61])[C:55]4[CH:56]=[N:57][NH:58][C:59]=4[CH:60]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:61][C:40]([C:37]4[N:38]=[CH:39][N:35]([CH3:34])[N:36]=4)=[O:42])[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: Cn1cnc(C(=O)O)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
HATU (248 mg) and DIPEA (0.211 ml) were added to a flask containing 1-methyl-1H-1,2,4-triazole-3-carboxylic acid (51 mg) in DMF (1 ml). The reaction was stirred for 30 min under nitrogen. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (50 mg) was added and the mixture was stirred for 3 h at RT under nitrogen. The reaction mixture was applied to an aminopropyl SPE cartridge (5 g) and left for 3 h. The column was washed with 10% methanol in DCM. The appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in methanol:DMSO (1 ml, 1:1) and purified by mass directed preparative HPLC (Method A) to give title compound (37 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([OH:16])=O)=[CH:4][C:3]=1[Cl:17].NC1N2C=CN=C2C(C([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:33][CH2:32]2)=O)=CC=1Cl>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:33][CH2:32]2)=[O:16])=[CH:4][C:3]=1[Cl:17]
Reactant: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Reactant: CCCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Product: CCCc1cn2c(N)c(Cl)cc(C(=O)NC3CCN(CCCOC)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-6-chloro-2-propylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 16, Step 2) and 1-[3-(methyloxy)propyl]-4-piperidinamine (EXAMPLE 3).