Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:7][CH:6]=[C:5]([O:20]C)[N:4]=1.[BrH:22].CCOCC>C(O)(=O)C>[BrH:22].[O:19]=[C:10]1[C:11]2[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:14])[N:9]1[C:8]1[C:3]([OH:2])=[N:4][C:5]([OH:20])=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1c1ccc(O)nc1O
Temperature: 70 °C
Reaction time: 54 h
Yield: 71 %

Procedure:
1,3-Dioxo-2-(2,6-dihydroxypyridin-3-yl)-isoindoline hydrobromide (7) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (150 mg, 0.528 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at an 70° C. oil bath under N2 for 54 h. The mixture was cooled to room temperature, dry ether was added, and the supernatant liquid was decanted. Then ethyl acetate was added, solid precipitated, filtered and washed with ethyl acetate to afford 7 (126 mg, 71%) as a white solid: 1H NMR (CD3OD) δ 7.83-7.77 (n, 4H), 6.37 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H); MS (CI/CH4) 256 [M]+; HRMS (DEI) m/z calcd for C13H8N2O4 256.0484. found 256.0483.
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]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH2:22])[CH3:21])=[CH:7]2.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH3:21])=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(2-chloro-5-fluoro-phenyl)quinolin-3-yl)ethanamine (0.072 g, 0.215 mmol), 6-chloropurine (0.040 g, 0.26 mmol, 1.2 eq) and DIEA (0.42 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.68 (s, 1H), 8.60 (s, 1H), 8.02-8.10 (m, 2H), 7.92-7.99 (m, 1H), 7.85-7.93 (m, 1H), 7.54-7.63 (m, 1H), 7.50 (dd, J=8.80, 4.89 Hz, 1H), 7.07 (td, J=8.61, 3.13 Hz, 1H), 5.48-5.65 (m, 1H), 1.71 (d, J=7.04 Hz, 3H), Mass Spectrum (ESI) m/e=454 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=O)=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH:42]([N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][S:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1)([CH3:44])[CH3:43]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:56][C:55]4[CH:57]=[CH:58][C:52]([S:51][CH2:50][C:46]5[N:45]([CH:42]([CH3:44])[CH3:43])[CH:49]=[CH:48][N:47]=5)=[CH:53][CH:54]=4)=[O:31])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: CC(C)n1ccnc1CSc1ccc(N)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C(C)C)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, to the solution was added thionyl chloride (0.15 ml) at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[[(1-isopropylimidazol-2-yl)methyl]sulfanyl]aniline (515 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→ethyl acetate), which was recrystallized from ethanol-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isopropylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (417 mg)(Compound 120) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](O)=[CH:6][CH:7]=[N:8]2.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1>[Cl:27][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc(OC)c2c(O)ccnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c2c(Cl)ccnc2c1

Procedure:
To a mixture of crude 5,7-dimethoxyquinolin-4-ol (5.36 g, 26 mmol) and Hunig's Base (9.1 ml, 52 mmol) in toluene, was added POCl3 (29 ml, 313 mmol). The mixture was refluxed for 5 h. Excess POCl3 was removed under reduced pressure and azeotroped with toluene. The resultant gum was treated with sat. NaHCO3 until no gas generated. The mixture was extracted with EtOAc, the organic extracts were combined and washed with sodium bicarbonate and solvent removed under reduced pressure. The crude product was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 0-50% EtOAc/DCM) to afford 4-chloro-5,7-dimethoxyquinoline as a yellow solid. MS Found m/z=[M+H]+. 224.2 Calc'd for C11H10ClN: 223.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCCNC1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 3-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperidine-1-carboxylate (1.002 g) in DCM (10 ml) was added TFA (10 ml). The reaction was allowed to stir at ambient temperature for 2 hours. The solvents were removed in vacuo, the residue partitioned between DCM and 2M NaOH, extracted twice and the combined organics dried (Na2SO4), filtered and evaporated to give the product, 1-(3,4-dichlorophenyl)-4-(piperidin-3-ylcarbonyl)piperazine, as a yellow foam (703 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+:17].[Cs+]>O>[Cs+:17].[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of N-(tert-butoxycarbonyl)glycine (42.0 g) in water (250 ml) was added cesium carbonate (39.1 g). The mixture was stirred at room temperature for 10 minutes. The water was removed by azeotropic distillation with toluene to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.Cl.CCOCC>CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: ClCCN1CCCCC1
Reactant: O=C1C(Cc2ccc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C1C(Cc2ccc(-c3ccc(OCCN4CCCCC4)cc3)cc2Cl)CCN1C1CCCCC1
Temperature: 25 °C
Yield: 196.5 %

Procedure:
Charge a vial with 3-(3-chloro-4′-hydroxy-biphenyl-4-ylmethyl)-1-cyclohexyl-pyrrolidin-2-one (70 mg, 0.18 mmol) and dissolve in acetone (0.3 M). Add K2CO3 (250 mg, 1.8 mmol) and Cs2CO3 (59 mg, 0.18 mmol) and stir at room temperature for 5 minutes. Add 1-(2-chloro-ethyl)-piperidine hydrochloride (77 mg, 0.42 mmol) and heat to 50° C. overnight. Cool to room temperature, filter, concentrate and purify over silica gel. Dissolve the residue in methylene chloride (0.1 M) and add 2 M HCl in ether (0.18 mL, 0.36 mmol) and concentrate in vacuo to afford 94 mg (97%) of the title compound: Mass spectrum (apci) m/z=495.4 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:3]21[CH:8]([OH:9])[O:7][CH2:6][CH2:5][CH2:4]2.[CH3:15]C1C=CC(S(O)(=O)=O)=CC=1>CO.CC(OC)(C)C>[CH3:15][O:9][CH:8]1[C:3]2([CH2:10][CH2:11][C:12]([CH3:14])=[CH:13][CH:2]2[CH3:1])[CH2:4][CH2:5][CH2:6][O:7]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=CC(C)C2(CCCOC2O)CC1
Solvent: COC(C)(C)C
Solvent: CO
Product: COC1OCCCC12CCC(C)=CC2C
Yield: 7041.6 %

Procedure:
A solution of 7,9-dimethyl-2-oxaspiro[5.5]undec-8-en-1-ol (5.0 g, 26 mmol) and p-TsOH (50 mg) in methanol (20 ml) was stirred at reflux temperature for 0.5 hours. The mixture was diluted with MTBE, washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled bulb-to-bulb to yield a colorless oil (4.3 g, 80%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][C:15]=1[O:30][CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][CH2:54][NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N+:57]=1[O-:62]>C1COCC1>[CH3:31][O:30][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([CH3:28])([CH3:29])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=1[O:13][CH2:52][CH2:53][CH2:54][NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N+:57]=1[O-:62]
Reactant: [O-][n+]1ccccc1NCCCO
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])c(OC)c1
Reaction time: 0.25 h

Procedure:
A solution of diethyl azodicarboxylate (174 mg, 1.0 mmol) in 3 ml THF was added to a solution of the product of STEP 6 (18 mg, 0.676 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in 7 ml THF at room temperature and stirred for 15 min. 2-(3-Hydroxypropylamino)pyridine N-oxide (168 mg, 1.0 mmol) was added. The reaction was stirred at room temperature for 18 h. THF was evaporated and the residue purified by chromatography (on silica gel, C2HC2I/CH3OH/NH4OH=97.5/2/0.5) to afford a pale brown oil in 81.5 mg). NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([C:11]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:33][C@@H:34]([CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[C:35](O)=[O:36])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH2:12][CH2:13][N:14]([C:35](=[O:36])[C@@H:34]([NH2:33])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[CH2:15][CH2:16]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: N#Cc1ccc(CC2(C(=O)OCC3CCCCC3)CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC2(C(=O)OCC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-cyano-benzyl)-piperidine-4-carboxylic acid cyclohexylmethyl ester (0.377 mmol; 0.128 g) in DMF (2 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (0.377 mmol; 0.102 g), N,N-diisopropyl-N-ethylamine (0.755 mmol; 0.134 mL) and HBTU (0.491 mmol; 0.186 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The residue was dissolved in a 4 M HCl solution in 1,4-dioxane (3 mL) and the resulting solution was stirred overnight at room temperature. The solution was then evaporated, and the residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-(4-cyano-benzyl)-piperidine-4-carboxylic acid cyclohexylmethyl ester as a hydrochloride salt.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6](=[O:8])[CH3:7].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][CH2:2][C@@H:3]2[CH2:5][C@H:4]2[C:6](=[O:8])[CH3:7])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)[C@@H]1C[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC[C@@H]2C[C@H]2C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 58.3 %

Procedure:
To a solution of trans-1-[2-(hydroxymethyl)cyclopropyl]ethanone (3.4 g, 30 mmol) (prepared as disclosed in Cossy, J.; Blanchard, N.; Meyer, C. Eur. J. Org. Chem. 2001, 339) in anhydrous DMF (60 mL) was added sodium hydride (60 percent dispersion in oil, 1.4 g, 36 mmol) in portions under N2 at 0° C. After the addition was complete, the mixture was stirred for 25 minutes and 4-methoxybenzyl chloride (5.2 g, 33 mmol) was added in one portion. The reaction was then allowed to warm to approximately 25° C. and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) followed by dilution with water and was extracted with ether (4×50 mL). The combined organic layer was then washed with half-saturated brine and dried over Na2SO4. After filtration and concentration, the residue was purified on silica gel (20 percent acetone/hexane) to give 4.1 g of product as a colorless oil in 58 percent yield.
Reaction SMILES: [Br:1][CH:2]([C:6]1[C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)C(O)=O>C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][N:7]=[C:6]([CH2:2][Br:1])[C:10]=2[CH:11]=1
Reactant: O=C(O)C(Br)c1noc2ccc(Cl)cc12
Solvent: Cc1ccccc1
Product: Clc1ccc2onc(CBr)c2c1
Temperature: 96 °C

Procedure:
A suspension of alpha-bromo-5-chloro-1,2-benzisoxazole-3-acetic acid (3.39 Kg, 11.7 moles) in toluene (12 L) is heated at 96° C. for 18 hours. The solution is cooled room temperature and washed with water (2×4 L), saturated sodium bicarbonate solution (2×4 L) and water (2×4 L) before drying over anhydrous sodium sulfate (1 Kg) and filtering. The filtrate is evaporated in vacuo to afford the crude 5-chloro-3-bromomethyl-1,2-benzisoxazole, m.p. 83-85° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14](OC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].CC(O)=O>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-carbomethoxy-4-hydroxypyrrolidine 36 (7.0 g, 28.6 mmol) was dissolved in dry THF (100 ml) and cooled in ice salt bath under argon atmosphere. To this cold solution was added lithium borohydride (1.88 g, 85.8 mmol) in small portions during 15 min period. After the addition of lithium borohydride, the reaction mixture was allowed to stir at 0° C. for 1 h followed by 15 h at room temperature under argon. The solution was cooled to 0° C. and diluted with water (50 ml) and the pH was adjusted with AcOH to 6. The reaction was evaporated to dryness and dissolved in EtOAc (200 ml), washed with water (100 ml) and brine (100 ml). The EtOAc extract was dried and evaporated to dryness. The residue was purified by flash column chromatography over silica gel using CH2Cl2 →EtOAc as the eluent. The pure fractions were collected and evaporated to dryness to afford 5.00 g (81%) of clear oil. The oil on standing gave colorless solid. mp: 95-97C. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40 -3.62 (m, 3H), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]=1[CH:4]=[O:5]
Reactant: C1COCCN1
Reactant: O=Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1c(Cl)cccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-fluorobenzaldehyde (8.00 g, 50.5 mmol, 1.00 equiv), morpholine (6.60 g, 75.8 mmol, 1.50 equiv), potassium carbonate (17.4 g, 126 mmol, 2.50 equiv), and dimethyl sulfoxide (50 mL). The resulting solution was stirred for 3 hour at 100° C. in an oil bath and then diluted with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to yield 5.00 g (44%) of 2-chloro-6-(morpholin-4-yl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 226 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]2=[N:16][S:17][N:18]=[C:14]2[CH:13]=1)C.Cl>O1CCCC1.[Li+].[OH-].O>[N:16]1[S:17][N:18]=[C:14]2[CH:13]=[C:12]([O:11][C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:21])=[O:3])[CH:20]=[CH:19][C:15]=12
Reactant: CCOC(=O)c1cccnc1Oc1ccc2nsnc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Yield: 23.4 %

Procedure:
A solution of 2-(benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid ethyl ester (0.74 g, 2.5 mmol) in tetrahydrofuran (2.78 ml) and 1 M LiOH (2.7 ml) was stirred over night. The mixture was diluted with water and acidified to pH 1 with 2 N hydrochloric acid and filtered to give a pale yellow solid (160 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cccn2-c2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1

Procedure:
To a solution of 5 mmol of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=[O:14])=[CH:9][NH:10][C:3]=2[CH:2]=1.CS(C)=O.[O:21]=[C:22]1[NH:30][CH:29]=[N:28][C:27]2[N:26]([CH2:31][CH2:32][C:33](OC3C=CC([N+]([O-])=O)=CC=3)=[O:34])[CH:25]=[N:24][C:23]1=2>CC(C)=O>[O:21]=[C:22]1[NH:30][CH:29]=[N:28][C:27]2[N:26]([CH2:31][CH2:32][C:33]([NH:16][CH:12]([CH2:11][C:8]3[C:4]4[C:3](=[CH:2][CH:1]=[C:6]([OH:7])[CH:5]=4)[NH:10][CH:9]=3)[C:13]([OH:15])=[O:14])=[O:34])[CH:25]=[N:24][C:23]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7.3 %

Procedure:
100 mg (0.500 mmol) of DL-5-hydroxytryptophan and 3 ml of dry dimethylsulfoxide were placed in a 25 ml round bottom flask equipped with a magnetic stirring bar and stopper. Then 150 mg (0.456 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) were added and the heterogeneous mixture was stirred for 2.5 hours at room temperature in the closed flask. The mixture became completely homogeneous. The reaction mixture was poured into 20 ml of acetone and a semi-solid precipitate was obtained by filtration. The crude product was washed twice with 2 ml of acetone. The solid was resuspended in 10 ml of acetone and the insoluble material was removed by filtration. The acetone solution was evaporated to dryness. The yield of product 2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-3-(5-hydroxyl-1H-indol-3-yl)-propionic acid (AIT-0111) was 15 mg. Yield: 7.3% (Purity 93 %).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].S(=O)(=O)(O)O.[O:26]=[C:27](C)[CH2:28]C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O.[N+]([O-])([O-])=O.[Ag+]>[C:27]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:1]#[N:8])(=[O:26])[CH3:28]
Reactant: N#Cc1ccncc1
Reactant: CC(=O)CC(=O)O
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(C#N)ccn1
Yield: 71.2 %

Procedure:
To a solution of isonicotinonitrile (52 g, 0.5 mol) in dichloromethane (1300 mL) and water (1100 mL) were added ammonium persulfate ((NH4)2S2O8) (170 g, 0.75 mol), silver nitrate (6.8 g, 0.04 mol) and aqueous sulfuric acid (40 mL, 98% sulfuric acid in 400 mL). A solution of 3-oxo-butyric acid (110 g, 1.25 mol) in dichloromethane (100 mL) was added dropwise while keeping the mixture refluxing. The reaction mixture was refluxed for 2 h. The resulting mixture was basified to pH˜8-9 using sodium carbonate powder. The mixture was filtered and the filtrate was extracted with dichloromethane (500 mL×3). The combined organics were dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to afford 2-acetylisonicotinonitrile (52.0 g, 71.9%).