Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[N:6]1[C:11]2[NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[NH:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:22][CH:23]([CH2:27][C:28]#[CH:29])[C:24](Cl)=[O:25]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[O:25]=[C:24]([N:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](=[O:17])[NH:16][C:10]2[CH:9]=[CH:8][CH:7]=[N:6][C:11]1=2)[CH:23]([CH3:22])[CH2:27][C:28]#[CH:29]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: C#CCC(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCC(C)C(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
At 0° to 10° C., with stirring, 416 ml (0.65 mol) of an n-butyl-lithium solution in n-hexane are added dropwise to a suspension of 63 g (0.3 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 1500 ml of absolute tetrahydrofuran. THe mixture is stirred for a further hour at ambient temperature, then cooled to 5° to 10° C. and this temperature 46.8 g (0.36 mol) of 2-methyl-4-pentynoic acid chloride (not purified) dissolved in 100 ml of absolute tetrahydrofuran are added dropwise to the reaction solution. The mixture is stirred for a further 3 hours at ambient temperature, then added to 2000 ml of a saturated saline solution and diluted with about 2000 ml of ethyl acetate. The organic phase is separated off, extracted twice with 500 ml of saturated saline solution, dried over magnesium sulphate and evaporated to dryness in vacuo. The desired compound is obtained as a brownish-yellow product which is used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15].C(=O)([O-])[O-].[K+].[K+].[Br-].[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CC(=O)CC>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:15][C:14]1[CH:21]=[CH:20][C:18]([O:19][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCC
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCOc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 500 ml 2-necked bottle equipped with a condenser tube, butanone (200 ml), and then 2,4-dinitrofluorobenzene (18.61 g, 0.100 mol), hydroquinone (11.33 g, 0.100 mol), and potassium carbonate (15.28 g, 0.110 mol) were introduced. The mixture were agitated at room temperature for 2 hours. Then, potassium carbonate (15.27 g, 0.110 mol), dodecane bromide (15.26 g, 0.110 mol), and butanone (20 ml) were added to the bottle. The mixture were stirred at room temperature for 6 hours. Thereafter, distilled water (300 ml) was added to the bottle, and the mixture was extracted by ethyl acetate (300 ml×3). The collected organic layers were dried by anhydrous sodium sulfate, filtered, and concentrated, and recrystallized by ethanol to obtain 1-[4-(2,4-dinitrophenoxy)phenoxy]dodecane (35.58 g, 0.080 mol). Yield: 80%. Spectrum: IR (KBr) 3121,3088, 2918, 2853, 1611, 1530, 1470, 1350, 1287, 1159, 1097, 1075 cm−1. 1H NMR (DMSO-d6, 300 MHz). δ8.84 (d, J=2.5 Hz, 1H), 8.40 (dd, J=2.5, J=9.3 Hz, 1H), 7.17 (d, J=8.9 Hz, 2H), 7.03 (t, J=9.9 Hz, 3H), 3.94 (t, J=6.4 Hz, 2H), 1.70 (quintet, J=6.8 Hz, 2H), 1.4˜1.2 (m, 18H), 0.83 (t, J=6.0, 3H) 13C NMR (DMSO-d6, 75 MHz) δ157.0, 156.1, 146.5, 141.0, 139.0, 129.6, 121.9, 118.3, 116.2, 68.2, 68.1, 31.5, 29.2, 29.0, 28.9, 25.7, 22.3, 14.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:17])=[C:7]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:17])=[C:7]([C:9]([CH:11]2[CH2:12][CH2:13][N:14]([C:19]3[N:20]=[C:21]4[CH:29]=[CH:28][N:27]=[CH:26][C:22]4=[N:23][C:24]=3[Cl:25])[CH2:15][CH2:16]2)=[O:10])[CH:8]=1
Reactant: O=C(c1cc(Cl)ccc1F)C1CCNCC1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(Cl)ccc1F)C1CCN(c2nc3ccncc3nc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
A mixture of (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (153 mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol) and DIPEA (261 μL, 1.500 mmol) in DCM (1.67 mL) was stirred at rt for 30 min. The mixture was partitioned between aqueous NH4Cl and EtOAc. The organic layer was filtered through a pad of silica, washing with EtOAc, and the filtrate was concentrated under reduced pressure to give (5-chloro-2-fluorophenyl)(1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone (205.5 mg) as an orange solid. ESI-MS m/z [M+H]+ 405.2.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.O>C1COCC1>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.1 %

Procedure:
Propionyl chloride (5.53 g, 0.0597 mol) was added dropwise to a solution of tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate (15.0 g, 0.0543 mol) and TEA (16.5 g, 0.163 mol) in THF (200 mL) and the mixture was stirred at room temperature for 3 h. Water (50 mL) was added to the reaction mixture, the aqueous layer was extracted with CH2Cl2 (3×100 mL), and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/EtOAc (10:1) to afford the product (18.8 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H) 7.34–7.21 (m, 3H), 6.93 (d, 1H, J=7.4 Hz), 2.77 (t, 2H, J=11.5 Hz), 2.68–2.58 (m, 1H), 2.38 (q, 2H, J=7.6 Hz), 1.87–1.67 (m, 4H), 1.67–1.54 (m, 2H), 1.48 (s, 9H), 1.25 (t, 3H, J=7.5 Hz); ESMS m/e: 333.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH:24]=[CH2:25])[C:4]=1[CH3:26])#[N:2].Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.C(N(CC)CC)C>[C:1]([C:3]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][CH:18]=2)=[CH:10][C:6]([C:7]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[OH:35])=[O:9])=[C:5]([CH:24]=[CH2:25])[C:4]=1[CH3:26])#[N:2]
Reactant: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of 4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid (0.10 g), trans-2-aminocyclohexanol hydrochloride (0.06 g), 1-hydroxybenzotriazole (0.06 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.08 g) in dichloromethane (5.00 mL) was added triethylamine (0.11 g), and the mixture was stirred for 16 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.10 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[CH:17]=2)[CH:9]=1.[CH3:31][C:32]([CH3:34])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[CH:17]=2)[CH:9]=1)([CH3:34])[CH3:31]
Reactant: CC(C)=O
Reactant: CSc1nc(-c2ccnc(NC(C)c3ccccc3)c2)cc(N2CC3CC2CN3)n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CSc1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc(N2C[C@@H]3C[C@H]2CN3C(C)C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 0.13 g (0.31 mmol) {4-[6-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-methylsulfanyl-pyrimidin-4-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.2 mL (3.1 mmol) acetone, 0.19 g (3.1 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+): 461 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15])([O-:7])=[O:6].N1C=CC=CC=1.O>CN(C)C=O>[OH:4][CH2:3][CH2:2][NH:1][S:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])(=[O:15])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCO
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO
Temperature: -10 °C
Reaction time: 0.83 h
Yield: 78.1 %

Procedure:
2-Aminoethanol (4.0 mL, 66 mmol) was dissolved in N,N-dimethylformamide (50 mL). After the solution was cooled to −10° C., 2-nitrobenzenesulfonyl chloride (12 g, 52 mmol) and pyridine (4.7 mL, 58 mmol) were added dropwise thereto, followed by stirring for 50 minutes, while the temperature was raised to room temperature. To the reaction mixture was added water (0.20 L), and the mixture was extracted with ethyl acetate (0.10 L×6). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide (10 g, 62%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[NH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH2:1]([N:17]1[C:18]2[C@@:19]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:22]([CH2:21][CH2:20]3)[C:23]=2[C:24](=[O:25])[N:16]1[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(Cc3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(Cc2ccccc2)n1Cc1ccccc1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A mixture of benzyl bromide (300 μL, 2.5 mmol), (4S,7R)-2-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 23; 159 mg, 0.56 mmol), and tetra-n-butylammonium iodide (160 mg, 0.43 mmol) in N,N-dimethylformamide (2 mL) was heated in an oil-bath at 100° C. for 17 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane (125 mL). The solution was washed with water (5×25 mL) and sodium thiosulfate solution (25 mL), dried (magnesium sulfate), filtered, and evaporated and the residue was purified on an Isco 40 g column, eluting with 20-100% ethyl acetate/hexanes to give (4S,7R)-1,2-dibenzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (89 mg, 42%) as a yellow gum. ES(+)-MS (M+H) 373.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: Fc1cccnc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc(F)c1Br
Temperature: 50 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A mixture of 2-bromo-3-fluoropyridine (1.0 g, 5.7 mmol) and 3-chloroperbenzoic acid (1.5 g, 7.4 mmol) in chloroform (3.5 mL) was stirred at 50° C. for 18 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 5:95) to give 2-Bromo-3-fluoropyridine 1-oxide as a white solid (878 mg, 80%). 1H NMR (400 MHz, CHCl3-d): δ 8.25 (dt, J=6.6, 1.3 Hz, 1H); 7.25-7.17 (m, 1 H); 7.06 (ddd, J=8.7, 6.6, 1.3 Hz, 1 H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[C:7]([C:13]([OH:15])=[O:14])[C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.N1C2C(=CC(C(O)=O)=C(C(O)=O)C=2)C=C1>>[N:3]1[C:4]2[CH:9]=[C:8]3[C:10](=[O:12])[O:15][C:13](=[O:14])[C:7]3=[CH:6][C:5]=2[NH:1][CH:2]=1
Reactant: O=C(O)c1cc2nc[nH]c2cc1C(=O)O
Agent: O=C(O)c1cc2cc[nH]c2cc1C(=O)O
Product: O=C1OC(=O)c2cc3[nH]cnc3cc21

Procedure:
This was prepared essentially as in example 24 step f except that benzimidazole-5,6-dicarboxylic acid was used as substrate instead of indole-5,6,-dicarboxylic acid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[O:21][CH2:22][CH2:23][OH:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[O:21][CH2:22][CH2:23][O:24][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCO)c(C3CCCCC3)c2s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCOS(C)(=O)=O)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 6-cyclohexyl-5-[2-(2-hydroxyethyloxy)-3-nitrophenyl]-4H-thieno[3,2-b]pyrrole-2-carboxylate (628 mg, 1.41 mmol) in chloroform (10 ml) were added triethylamine (0.230 ml, 1.65 mmol) and methanesulfonyl chloride (0.120 ml, 1.55 mmol) in this order under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The obtained methyl 6-cyclohexyl-5-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]-4H-thieno[3,2-b]pyrrole-2-carboxylate was used for Step 5 without further purification.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[NH2:20][CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28]>C(O)(=O)C>[O:28]=[C:22]1[CH:21]([N:20]2[C:16](=[O:18])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:10]2=[O:12])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: CCCCCNc1cccc(C(=O)O)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 53 %

Procedure:
To a stirred solution of 3-pentylamino-phthalic acid (2.51 g, 10 mmol) in acetic acid (50 ml) was added 3-amino-piperidine-2,6-dione hydrochloride (1.81 g, 11 mmol). The reaction mixture was heated to reflux overnight. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate (100 ml). The ethyl acetate mixture was washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (1×100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the solid residue was purified by chromatography (25% ethyl acetate/hexane) to give 1.82 g (53%) of product as a yellow solid: mp 141-143° C.; 1H NMR (DMSO-d6) d 11.09 (s, 1H); 7.58 (t, J=8.3 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.519 (t, J=5.7 Hz, 1H), 5.06 (dd, J=5.3 and 12.4 Hz, 1H), 3.32-3.25 (m, 2H), 2.97-2.82 (m, 1H), 2.62-2.46 (m, 2H), 2.06-2.01 (m, 1H), 1.61-1.55 (m, 2H), 1.35-1.32 (m, 4H), 0.88 (t, J=6.7 Hz, 3H); 13C NMR (DMSO-d6) d 172.72, 170.01, 168.92, 167.25, 146.39, 136.21, 132.14, 117.08, 110.31, 108.99, 48.52, 41.77, 30.94, 28.46, 28.33, 22.12, 21.82, 13.85; Anal. Calcd. For C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 62.92; H, 6.17; N, 12.15.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[C:18]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:19]=1)=[N:1]2
Reactant: COc1ccc(C=O)cc1CN1CCOCC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC)c(CN4CCOCC4)c3)nc2c1
Yield: 28 %

Procedure:
5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-methoxy-3-morpholin-4-ylmethyl-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one (65 mg, 28%) was isolated as a light yellow solid. Selected data: MS (m/z): 412.07; MP 282.7-284.5° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][NH:6][NH2:7])[CH3:2].CO[C:13](=[CH2:16])[C:14]#[N:15].C(OCC)(=O)C>O>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][N:6]1[C:14]([NH2:15])=[CH:13][CH:16]=[N:7]1)[CH3:2]
Reactant: CCOC(CNN)OCC
Reactant: C=C(C#N)OC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(Cn1nccc1N)OCC
Yield: 19.3 %

Procedure:
A mixture of hydrazinoacetaldehyde diethyl acetal (21 g) and methoxyacrylonitrile (11.8 g) in water (150 ml) was refluxed for 2 days. After the reaction mixture was cooled, to the mixture was added a mixture of water and ethyl acetate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2,2-diethoxyethyl)-5-aminopyrazole (5.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=3)[C:15]#[N:16])=[N:7][C:6]=2[CH:20]=1.[OH2:21].N>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=3)[C:15]([NH2:16])=[O:21])=[N:7][C:6]=2[CH:20]=1
Reactant: O
Reactant: N#Cc1ccnc(OCc2nc3cc(Cl)ccc3s2)c1
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)c1ccnc(OCc2nc3cc(Cl)ccc3s2)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
2-[(5-Chloro-1,3-benzothiazol-2-yl)methoxy]isonicotinonitrile (40 mg, 0.13 mmol) was dissolved in conc. H2SO4 (0.36 ml) and the solution was heated at 40° C., under vigorous stirring. Water (50 mg) was added dropwise and the mixture was stirred at 40° C. for 3 h. After cooling at −5° C., crushed ice (25 ml) was added quickly, with vigorous stirring, and the mixture was stirred at r.t. for two more hours. Ammonia solution was added (pH 10) and the precipitant solid was filtered, rinsed with H2O and dried. The brown solid was purified by preparative TLC, eluted with EtOAc, to give 20 mg (47% yield), mp 220-222° C., HPLC-MS (method 1): m/z 320 [M+H]+, Rt=3.76 min.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=CC=CC=1)=[O:10].[Br:22]C1C(=O)NC(=O)NC=1>>[Br:22][C:5]1[C:6](=[O:8])[NH:7][C:2](=[O:1])[N:3]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:21])=[O:10])[CH:4]=1
Reactant: O=C(NCCCCc1ccccc1)n1ccc(=O)[nH]c1=O
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Product: CCCCCCNC(=O)n1cc(Br)c(=O)[nH]c1=O
Yield: 62 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of compound of Example 1, starting from 5-bromouracil (0.03 g, 1.57 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (petroleum ether:EtOAc from 60:40 to 100% EtOAc) to afford the title compound (0.31 g, 62%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (t, J=6.5 Hz, 3H), 1.24-1.32 (m, 6H), 1.40-1.61 (m, 2H), 3.26 (td, J=7.0, 5.7 Hz, 2H), 8.47 (s, 1H), 9.07 (t, J=5.7 Hz, 1H), 12.20 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 14.12, 22.65, 26.61, 29.23, 31.49, 41.63, 100.15, 138.41, 148.91, 150.70, 158.08. MS (ESI) m/z: 317 [M-H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.ClC(Cl)(O[C:42](=[O:48])OC(Cl)(Cl)Cl)Cl.CC[N:52]([CH:56]([CH3:58])[CH3:57])C(C)C.C1(N)CC1>>[CH:56]1([NH:52][C:42](=[O:48])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)[CH2:58][CH2:57]1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: NC1CC1
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of the aniline 46 (400 mg, 0.758 mmol) was added triphosgene (1125 mg, 5 eq, 3.79 mmol) and iPr2NEt (490 mg, 5 eq, 3.79 mmol) and the reaction mixture was stirred at RT for an hour. Cyclopropylamine (6103 mg, 141 eq, 107 mmol) was added and the reaction mixture was stirred at RT overnight. The mixture was concentrated then diluted with DCM and washed with water. The organic phase was collected, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (eluent 20% MeOH in EtOAc) to afford the desired compound 347 as a yellow oil (426 mg, 92% yield). MS (m/z)=611.4 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:6]=1)C>C(O)C.[OH-].[Na+]>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][O:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Yield: 73 %

Procedure:
A solution of 3.6 g (9.8 mmol) of 3-[2-(2,4-dichlorophenyl)ethoxy]4-methoxybenzoic acid ethyl ester in 30 ml of ethanol and 5.4 ml of 2N sodium hydroxide solution was stirred at room temperature for 12 h. The precipitate was filtered off. The resulting solid was stirred with 5 ml of 2N HCl and filtered to give 2.44 g (73%) of the title compound.