Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:57])=[N:50][C:51]([CH3:56])=[CH:52][C:53]=1[NH:54][CH3:55]>ClCCl.O>[OH:57][C:49]1[C:48]([CH2:47][NH:46][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:53]([NH:54][CH3:55])[CH:52]=[C:51]([CH3:56])[N:50]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CNc1cc(C)nc(O)c1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1cc(C)nc(O)c1CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a solution of 4-phenoxybenzoic acid (54 mg, 0.25 mmol) in dichloromethane (15 mL) were added 1-Hydroxybenzotriazole (49 mg, 0.36 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) and triethylamine (73 mg, 0.72 mmol). The resulting solution was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-6-methyl-4-(methylamino) pyridin-2-ol (60 mg, 0.36 mmol) was added to the solution, and it was stirred at room temperature for 16 hours. Water (20 mL) was added to the mixture. It was extracted with dichloromethane (50 mL). The organic layer was concentrated to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford N-((2-hydroxy-6-methyl-4-(methylamino)pyridin-3-yl)methyl)-4-phenoxybenzamide (10 mg, 11% yield) as a white solid. LRMS (M+H+) m/z: calcd 364.16. found 364. HPLC Purity (214 nm): 98%. 1H NMR (300 MHz, CD3OD): δ 7.78-7.81 (d, J=8.7 Hz, 2H), 7.37-7.43 (m, 2H), 7.20 (d, J=7.5 Hz, 1H), 6.97-7.06 (m, 4H), 5.90 (s, 1H), 4.40 (s, 2H), 2.90 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7](=[O:16])[C:6]([C:17](OCC)=[O:18])=[C:5]2[OH:22].Cl.[C:24]([O:28][C:29](=[O:32])[CH2:30][NH2:31])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][CH2:14][CH2:15]1)[C:7](=[O:16])[C:6]([C:17]([NH:31][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])=[O:18])=[C:5]2[OH:22]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclopentane-1,1′-naphthalen]-3′-carboxylate (0.66 g, 2 mmol) and glycine tert-butyl ester hydrochloride (0.5 g, 3 mmol) in 10 mL dioxane was treated with DIPEA (1 mL, 6 mmol). The mixture was warmed to 85° C. and stirred for 4 hours, M+1=406. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc hexane to give the title compound (0.8 g) as a pale yellow solid. MS (m/z)=406 (M+Na)+.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])(=O)[CH3:2].[CH2:10]1[CH2:15][CH2:14][C:13]([CH2:20][NH2:21])([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH2:11]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CO>[O:6]=[C:5]1[C:4](=[CH:1][CH2:2][NH:21][CH2:20][C:13]2([CH2:16][C:17]([O-:19])=[O:18])[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12]2)[CH2:9][CH2:8][O:7]1.[NH2+:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)C1CCOC1=O
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: C1CCNCC1
Solvent: CO
Product: C1CC[NH2+]CC1
Product: O=C([O-])CC1(CNCC=C2CCOC2=O)CCCCC1

Procedure:
2-Acetylbutyrolactone (108 μL, 1 mmol), gabapentin (171 mg, 1 mmol), and piperidine (99 μL, 1 mmol) were mixed in anhydrous methanol (10 mL). After heating under reflux for 6 h, the solvent was removed under reduced pressure to afford the title compound with purity greater than 90%. 1H NMR (CDCl3, 400 MHz): δ 1.34-1.62 (m, 12H), 1.71 (m, 4H), 1.94 (s, 3H), 2.24 (s, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.99 (m, 4H), 3.31 (d, J=6.4 Hz, 2H), 4.23 (t, J=7.6 Hz, 2H), 5.17 (s, br, 2H), 8.64 (t, J=6.4 Hz, 1H). MS (ESI) m/z 280.34 (M−H−).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH3:7].[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:5]([CH2:3][OH:2])[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C1CCCCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N
Product: OCC1CCCCN(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 117.5 %

Procedure:
1-Benzyl-2-oxo-azepan-2-carboxylic acid methyl ester (143) (0.2154 g, 0.8243 mmol) dissolved in anhydrous THF (2.9 mL) was added to a stirring suspension of LiAlH4 in THF (1.5 mL) over approx. 1.5 hours. The reaction mixture was stirred overnight. The reaction was judged complete by TLC and was quenched by the sequential addition of H2O (0.4 mL), then 2N NaOH (1.0 mL) and H2O (0.4 mL). The mixture was stirred at room temperature for 30 minutes, then was filtered, dried with Na2SO4, and concentrated in vacuo. Crude material was purified by automated silica gel chromatography with 15:85:5 CH2Cl2:Hexanes:2N NH3 in EtOH to obtain 0.1062 g (59%) of pure (1-benzyl-azepan-3-yl)-methanol (144). 1H NMR (CDCl3) 7.40-7.23 (5H, m), 3.65 (2H, s), 3.54 (1H, dd, J=10.4, 3.5 Hz), 3.43 (1H, dd, J=10.4, 5.4 Hz), 2.82 (1H, J=13.3, 3.1 Hz), 2.77 (2H, m), 2.44 (1H, ddd, J=12.2, 8.6, 3.3 Hz), 1.90-1.45 (6H, m) ppm. 13C NMR (CDCl3, 75 MHz) 139.14, 128.97, 128.14, 126.91, 67.20, 63.85, 58.49, 56.87, 39.59, 29.68, 29.43, 25.23 ppm. LRMS: 219.64.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21].[C:22](OCC)(OCC)(OCC)[CH3:23]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:22]([CH3:23])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2c(F)cccc2F)c2cc(Cl)ccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3c(F)cccc3F)c3cc(Cl)ccc3n12

Procedure:
In the manner given in Example 2, 6-chloro-4-(2,6-difluorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-chloro-1-methyl-5-(2,6-difluorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26]([CH:29](C(OCC)=O)[C:30]([O:32]CC)=[O:31])[CH:27]=4)[N:22]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[N:21]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=4)[N:22]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[N:21]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc2c(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)nn(C3CCCCO3)c2cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(CC(=O)O)cc34)n2)CC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
A mixture of diethyl 2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate (117 mg (0.188 mmol) and 0.5 ml of 1 M aqueous solution of LiOH in 6 ml of methanol/THF mixture (2:1) was heated at 60° C. for 1 hour. The mixture was acidified with 1 N aqueous HCl to pH<1 and stirred for 20 min. The mixture was concentrated, the residue partitioned between ethyl acetate and water. The pH of the mixture was adjusted to 4 by careful addition of saturated aqueous sodium bicarbonate. The organic extracts were washed with brine, dried over MgSO4 and concentrated to afford 2-(3-(6-(4-(tertButoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetic acid (68 mg, 32% over two steps. ESI MS m/z 523.4 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of carbon tetrachloride (8.2 mL) of (4-phenoxy-phenyl)-methanol (410 mg) was added triphenylphosphine (640 mg) at room temperature, which was heated to reflux for 7 hours and 40 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the titled compound (410 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([C:38]([O:40][CH3:41])=[O:39])[CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>>[ClH:37].[ClH:42].[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:29]([C:38]([O:40][CH3:41])=[O:39])[O:28][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:21][CH2:20]3)=[CH:27][CH:26]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)Oc1ccc(N2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Product: COC(=O)C(Cc1ccc(Cl)cc1)Oc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1

Procedure:
Prepared from 4-[2-(1-tert-butyloxycarbonylpiperidin-4-yl)ethyl]-1-[4-(2-(4-chlorophenyl)-1-methoxycarbonylethyloxy)phenyl]piperazine and ethereal hydrochloric acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[OH-].[NH4+:16].O.CCOC(C)=O>C1COCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([NH2:16])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2nnc(C(F)(F)F)n2n1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.14 g, 5.1 mmol) and ammonium hydroxide (10 mL) in THF (10 mL) was heated to 60° C. for 18 h. The reaction mixture was cooled to room temperature and water and EtOAc were added. The aqueous layer was extracted with EtOAc (4×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 1 g of 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine as beige solid. 1H NMR (300 MHz, DMSO-d6) δ 8.12 (d, 1H), 7.23 (s, 2H), 6.97 (d, 1H).
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH2:16]Br)(=O)C.[C:18](=O)(O)[O-:19].[Na+]>CO>[CH3:18][O:19][CH2:16][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH3:15])[C:5]=1[OH:4])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C)c(OC(C)=O)c(CBr)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COCc1cc(C(=O)OC)cc(C)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of crude methyl 4-acetoxy-3-bromomethyl-5-methylbenzoate (4.63 g, 0.00154 mol) in methanol (100 mL) was mixed with sodium bicarbonate (6.48 g, 5 equivalents). The mixture was refluxed under a nitrogen atmosphere. After 1.5 hours, TLC analysis showed complete conversion. The reaction was cooled to room temperature and evaporated to dryness. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer was separated and washed with water. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product (1.5 g) was purified by flash chromatography on silica using 10% ethyl acetate/hexanes as eluent. Purified Yield=0.833 g (40%), white waxy solid.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][NH3+:18].[Cl:19][C:20]1[O:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1>>[Cl:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][NH:18][CH2:25][C:23]2[O:24][C:20]([Cl:19])=[CH:21][CH:22]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2
Reactant: O=Cc1ccc(Cl)o1
Reactant: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Agent: [Cl-]
Product: N#Cc1ccc2c(Cl)c(OCCNCc3ccc(Cl)o3)ccc2c1
Yield: 60 %

Procedure:
Prepared from 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride and 5-chlorofuran-2-carbaldehyde in 60% yield as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1F)C2
Temperature: 110 °C
Reaction time: 2 h
Yield: 158.6 %

Procedure:
To a mixture of 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.33 g) and aminoguanidine hydrochloride (0.133 g) in ethanol (4 ml) was added concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath) for 2 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 175) (0.345 g) as blue gray crystals.
Reaction SMILES: C=O.[C:3](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:17][C:18]1[CH:44]=[CH:43][C:21]([CH2:22][NH:23][C:24]([C:26]2[C:27](=[O:42])[C:28]3[CH:35]=[C:34]([CH2:36][NH:37][CH2:38][CH:39]([OH:41])[CH3:40])[O:33][C:29]=3[N:30]([CH3:32])[CH:31]=2)=[O:25])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C(Cl)CCl>[Cl:17][C:18]1[CH:44]=[CH:43][C:21]([CH2:22][NH:23][C:24]([C:26]2[C:27](=[O:42])[C:28]3[CH:35]=[C:34]([CH2:36][N:37]([CH2:38][CH:39]([OH:41])[CH3:40])[CH3:3])[O:33][C:29]=3[N:30]([CH3:32])[CH:31]=2)=[O:25])=[CH:20][CH:19]=1
Reactant: CC(O)CNCc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(O)CN(C)Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
Aq. formaldehyde (0.19 mL) and sodium triacetoxy borohydride (0.526 g) were added to a suspension of N-(4-chlorobenzyl)-2-(((2-hydroxypropyl)-amino)methyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 33, 0.500 g) in],2-dichloroethane (50 mL). The reaction mixture was stirred at room temperature for 18 h. A sat. aq. sodium bicarbonate solution (30 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 97/3, 96/4) followed by recrystallization from ethyl acetate to yield 0.301 g of the title compound as a white solid. Physical characteristics. M.p. 152° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.41-7.32, 6.87, 4.55, 4.35, 3.92, 3.80-3.73, 3.69, 2.36-2.31, 2.28-2.20, 1.04; MS (EST+) m/z 418 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[C:29]([N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.4 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (7.34 g, 25 mmol) and 4-dimethylaminopyridine (100 mg) in dichloromethane (25 ml) and triethylamine (3.9 ml, 27.5 mmol) is added benzoyl chloride (3.58 g, 25.5 mmol). The mixture is stirred 6 h at room temperature, diluted with hexane (200 ml), washed with water (4×20 ml), dried over MgSO4 and evaporated. The residue is chromatographed on silica gel (hexanes-ethyl acetate 4:1) and the pure fractions are recrystallized from hexane to afford 7.2 g of the title compound as white crystals, mp 74-78° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.2 %

Procedure:
To a mixture of 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 15.0 mg (0.131 mMol) polyvinyl-pyridine in 3.0 mL dichloromethane were added 4.3 mg (0.0458 mMol) methyl chloroformate. The reaction mixture was mixed for 18 hours at ambient temperature. To this mixture were then added 170 mg (0.137 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 10.2 mg (81%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4](=[O:13])[NH:3]1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2](=[O:1])[N:3]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:4]2=[O:13])#[N:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc2c(c1)C(=O)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(C#N)cc2C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
1,3-Dioxoisoindoline-5-carbonitrile (0.522 g, 3.03 mmol) was dissolved in dry DMF (10 ml), then tert-butyl 2-bromoacetate (0.672 ml, 4.55 mmol) and K2CO3 (0.629 g, 4.55 mmol) were added. The resulting suspension was stirred at 90° C. for 3 hours. The solvent was evaporated under vacuum, and the crude was dissolved in ethyl acetate. The precipitate was filtered and washed with ethyl acetate; the filtrate was evaporated under vacuum and the residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate=9:1 to 70:30) affording tert-butyl 2-(5-cyano-1,3-dioxoisoindolin-2-yl)acetate (0.507 g, 1.771 mmol, 58.4% yield, MS/ESI+ not detectable [MH]+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[CH2:6][CH2:5]1)(=O)C.Cl>CO.O>[N+:13]([C:11]1[CH:10]=[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:8]=[C:7]2[C:12]=1[NH:4][CH2:5][CH2:6]2)([O-:15])=[O:14]
Reactant: COC(=O)Cc1cc2c(c([N+](=O)[O-])c1)N(C(C)=O)CC2
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cc2c(c([N+](=O)[O-])c1)NCC2

Procedure:
A solution of 16 (417 mg, 1.5 mmol) in a mixture of methanol (25 mL), water (5 mL) and conc. HCl (2.5 mL) was heated under reflux for 4 h. The solution was diluted with water (7 mL) and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give a viscous oil. Trituration with ether and recrystallization (Et2O-hexanes) afforded 12 as red microcrystals (255 mg, 72%), mp 113-115° C.; UV: λmax (EtOH)/nm 246 (ε/M−1cm−1 16 600), 431 (5600); λmax [EtOH-25 mM Na phosphate, pH 7.0 (1:40)]/nm 238 (ε/M−1cm−1 16 400), 289 (6060), 450 (5060); IR: νmax/cm−1 3420, 3380, 1740, 1645, 1600, 1520; 1H NMR: δH (90 MHz) 7.64 (br s, 1H), 7.16 (br s, 1H), 6.71 (br s, 1H), 3.87 (t, J=8.3 Hz, 2H), 3.69 (s, 3H), 3.51 (s, 2H) and 3.15 (t, J=8.3 Hz, 2H). Anal. Calcd for C11H12N2O4: C, 55.93; H, 5.12; N, 11.85. Found: C, 55.74; H, 5.07; N, 11.68.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(C2C=CC(C)=CC=2)C=CC=CC=1.[Br:28]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:2]([Br:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC(Br)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-(Bromomethyl)biphenyl: A mixture of 4-phenyltoluene (4.83 g, 28.7 mmol), N-bromosuccinimide (5.64 g, 31.7 mmol), benzoyl peroxide (catalytic), and anhydrous carbon tetrachloride (35 mL) was refluxed for 24 hours. The mixture was cooled to room temperature and filtered to give a mixture (7.32 g) of 4-(dibromomethyl)biphenyl, 4-(bromomethyl)biphenyl, and 4-phenyltoluene (14:82:4 molar ratio by 1H-NMR). The product was used without further purification in the next step. 1H-NMR of the title compound (300 MHz, CDCl3) δ 7.56-7.60 (m, 4H), 7.33-7.48 (m, 5H), 4.55 (s, 2H). Partial 1H-NMR of 4-(dibromomethyl)biphenyl (300 MHz, CDCl3) δ 6.71 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](CCl)=[CH:6][CH:5]=1.[P:12]([O:19]CC)([O:16]CC)[O:13]CC>C1C=CC=CC=1>[PH:12](=[O:13])([OH:19])[OH:16].[CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: ClCCc1ccc(CCl)cc1
Reactant: CCOP(OCC)OCC
Solvent: c1ccccc1
Product: C=Cc1ccccc1
Product: O=[PH](O)O
Reaction time: 2 h

Procedure:
Vinyl benzene phosphonate was prepared by chloromethylating benzene by the procedure of Kindler, Hansen and Koebk (Ann. Chem. 617, 25, 1958). 1 mole p-(2-chloroethyl)-α-chlorotoluene was heated to 140°-155° C. under N2 and 95 ml triethyl phosphite was added. The mixture was heated for one hour and then diethyl-p-(2-chloroethyl)-benzyl phosphonate was distilled off at 140°-150° C./0.2 torr. The ethyl ester was hydrolysed for two hours using a 2:3 v/v mixture of 48% HBr and formic acid. The product was dehydrochlorinated using potassium ethoxide followed by acidification with HCl. The monomer was then flash distilled using 10-5 torr vacuum at room temperature.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:21]=[CH:20][C:19](CO)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1(C)C=CC(S(Cl)(=O)=[O:31])=CC=1.C[O:36][P:37]([O:40]C)[O:38]C>>[P:37]([OH:40])([OH:31])([OH:38])=[O:36].[C:16]1([N:9]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COP(OC)OC
Reactant: OCc1ccc(N(c2ccccc2)c2ccc(CO)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: O=P(O)(O)O
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
Bis(4-formylphenyl)phenylamine was reduced in ethanol with 2 equivalents of sodium borohydride to obtain bis(4-hydroxymethylphenyl)phenylamine. The obtained bis(4-hydroxymethylphenyl)phenylamine was reacted with equimolar p-toluenesulfonylchloride to replace a hydroxyl group at one end with a toluenesulfonyl group, and then the resultant compound was reacted with trimethylphosphite to yield a triphenylamine phosphate derivative having the structure represented by the Formula (6), as an intermediate compound.