Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)([O-:12])=[O:11].[H-].[Na+]>CN(C=O)C.O>[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:17]=[CH:16]2)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Dissolve 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.36 g, 13.9 mmol) and 5-nitro-1H-indole (1.50 g, 9.23 mmol) in DMF (25 mL) and carefully treat with sodium hydride (60% dispersion, 1.50 g, 37.5 mmol). Stir the mixture at room temperature overnight, then dilute with cold water (100 mL) and extract with EtOAc (3×50 mL). Was the combined organic portions with water (2×50 mL) and brine (50 mL). Dry, filter and concentrate under vacuum. Purify the crude material by flash chromatography, using 100% acetone as eluant, to give the title compound as a yellow oil (2.08 g, 87%). MS (ES+) 260.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, 1H, J=2.2 Hz), 8.10 (dd, 1H, J=9.2, 2.2 Hz), 7.37 (d, 1H, J=9.2 Hz), 7.30 (d, 1H, J=3.1 Hz), 6.67 (d, 1H, J=3.1 Hz), 4.29 (t, 2H, J=7.3 Hz), 2.89 (t, 2H, J=7.0 Hz), 2.54 (m, 4H), 1.78 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH2:29]Br.C(Br)C1C=CC=CC=1>O.C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([O:16][CH2:29][C:28]1[CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=[CH:34][C:27]=1[C:26]([F:25])([F:39])[F:40])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
(1R*,2R*,5R*)-8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 151 mg, 0.52 mmol) was treated with sodium hydride (41 mg, 60% in oil, 1.03 mmol) at 0° C. in a solution of THF (2 ml) and allowed to warm to room temperature. The mixture was recooled to 0° C. and 2,5-bis(trifluoromethyl)benzyl bromide (0.24 ml, 1.30 mmol) added and the mixture heated to 50° C. for 2 days. A further 1.30 mmol of the benzyl bromide was added and the mixture further heated for 50° C. for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow solid. This was purified by flash column chromatography [25% ethyl acetate in iso-hexane] to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:6][C:7]=1[F:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][C:5]1[N:6]=[C:7]([F:8])[C:2]([CH:30]=[O:31])=[CH:3][CH:4]=1
Reactant: Fc1nc(NCc2ccccc2Cl)ccc1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccccc2Cl)nc1F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 93.5 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (17, 1.85 g, 5.86 mmol) in 25.0 mL of tetrahydrofuran under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (3.00 mL, 2.00 M in tetrahydrofuran, 6.00 mmol) was added over 10 minutes. After 50 minutes, tert-butyllithium (7.80 mL, 1.70 M in hexane, 13.3 mmol) was added over 5 minutes. After 20 minutes, N,N-dimethylformamide (1.09 mL, 14.0 mmol) was added and the reaction mixture stirred at −78° C. for 20 minutes, then brought to room temperature over 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 35% ethyl acetate in hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (18, 1.45 g). MS (ESI) [M+H+]+=265.4.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:12]#[N:13])[CH3:2].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:12]#[N:13])[CH3:2]
Reactant: C1CCOCC1
Reactant: CCc1c(C#N)ccc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCc1c(C#N)ccc2c1ncn2C1CCCCO1
Yield: 68.5 %

Procedure:
To a solution of 4-ethyl-1H-benzo[d]imidazole-5-carbonitrile (6.8 g, 0.04 mol) in dry toluene (70 mL) was added tetrahydro-2H-pyran (10.53 g, 0.12 mol, 3 equiv.) and pyridinium-p-toluenesulfonate (4 g, 0.02 mol, 0.5 equiv.) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated, quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and then dried (Na2SO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with 50% EtOAc/hexane to afford 4-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (7 g, 69% yield) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH:6]([CH3:8])[CH3:7].[S-:10][C:11]#[N:12].[K+]>O.Cl>[CH2:5]([C:4]1[N:12]=[C:11]([SH:10])[NH:2][CH:3]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CC(=O)CN
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)Cc1c[nH]c(S)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
Dissolve 1-amino-4-methyl-2-pentanone hydrochloride (1.4 g, 9.2 mmol) and potassium thiocyanate (1.3 g, 12.9 mmol) in water (3 mL). Stir the solution at 100° C. in a sealed flask for 2 h. Cool the mixture and concentrate in vacuo. Purify the residue by chromatography on silica gel (10 g) eluting with EtOAc to obtain a yellow solid (980 mg, estimated 1:1 product to starting material by NMR). Dissolve the yellow solid (980 mg) in water (2 mL) and concentrated hydrochloric acid (0.5 mL). Add potassium thiocyanate (0.7 g, 7.2 mmol) and heat the mixture at 100° C. for 16 h. Cool the mixture and concentrate in vacuo. Purify the residue by chromatography on silica gel (25 g) eluting with hexane/EtOAc (1:1) to obtain the title compound as a yellow solid (550 mg, 38%). MS (ES+) m/z: 157.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].C(=O)([O-])[O-].[Na+:12].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(OCC)C>C(OCC)C.O>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:16])=[CH:24][CH:23]=1)([O-:27])=[O:26].[Na+:12]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(NCCS(=O)(=O)[O-])OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
A mixture of 2-aminoethanesulfonic acid (5.0 g) and sodium carbonate (9.4 g) in ethyl ether-water (100 mL, 1:1, v/v), at 0° C., was treated with 4-nitrobenzyl chloroformate (8.6 g). After stirring vigorously at 0° C. for 10 min and at room temperature for 15 hr, ethyl ether was added to the reaction mixture. The precipitates were collected by filtration and washed with ethyl ether to afford the title compound (9.2 g) as a white powder: 1H NMR (400 MHz, D2O) δ 2.94 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.4 Hz, 2H), 5.09 (s, 2H), 7.44 (d, J=8.3 Hz, 2H), and 8.11 (d, J=8.3 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][CH:22]=[CH:23][CH2:24]Br>CN1C(=O)CCC1>[Br:20][CH2:21][CH:22]=[CH:23][CH2:24][O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: BrCC=CCBr
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc([N+](=O)[O-])c(OCC=CCBr)c1
Temperature: 45 °C

Procedure:
A mixture of 2,5-dinitrophenol (4.0 g), potassium carbonate (4.6 g), NMP (40 mL) and 1,4-dibromo-2-butene (14.0 g) is heated to 45° C. for 2 hr. Extraction in the normal fashion and Kugelrohr distillation of the excess dibromide (0.1 mm Hg, 80° C.) gives 1-bromo-4-(2,5-dinitrophenyloxy)but-2-ene (mp 81-83° C.).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[N:14][CH3:15])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH:24]([N+:35]#[C-:36])S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:35]=[CH:36][N:14]([CH3:15])[C:13]=1[C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][N:6]=2)[N:9]=1
Reactant: CN=Cc1ccc2nnc(C(C)C)n2n1
Reactant: [C-]#[N+]C(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)ncn3C)nn12
Temperature: 60 °C
Yield: 23.1 %

Procedure:
N-((3-Isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)methylene)methanamine (0.154 g, 0.758 mmol; Preparation #AP.1.1) and 2,4-difluoro-1-(isocyano(tosyl)methyl)benzene (0.233 g, 0.758 mmol, J. W. Pharmlab) were added to a 25 mL flask in DMF (4 mL). To the mixture was added K2CO3 (0.105 g, 0.758 mmol) and the mixture was heated to about 60° C. for about 17 h. The solvent was removed in vacuo and the material was washed with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (using MeOH/DCM 0-5% gradient) and then triturated with Et2O and dried in a vacuum oven overnight to afford the title compound as an off-white solid (0.062 g, 23%): LC/MS (Table 1, Method g) Rt=2.03 min; MS m/z: 355.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][CH:11]1[NH:13][CH2:12]1>C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:10][CH:11]([NH2:13])[CH3:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC1CN1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)cc(OCC(C)N)c1
Yield: 69107.1 %

Procedure:
24.4 Grams (0.20 mol) of 3,5-dimethylphenol and 3.8 g (0.067 mmol) of propyleneimine in 20 ml of toluene were allowed to react in an autoclave at 10 kg/cm2G at 200° C. for 1 hour. The reaction product was dispersed in 50 ml of ether, and then subjected to extraction with 50 ml of 5% hydrochloric acid three times. The water layer of the product was neutralized with sodium hydroxide, and the product was subjected to extraction with 50 ml of ether three times. The ether layer was washed and dried. Then, ether was distilled off, and the residue was distilled under reduced pressure to give 8.3 g of 1-(3,5-dimethylphenoxy)-2-propylamine as a component having a boiling point of 87° to 89° C./0.3 mmHg. Its yield was as high as 70%.
Reaction SMILES: [CH2:1](O)[CH3:2].[Br:4][C:5](=[CH:9][OH:10])[C:6](=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[Br:4][C:5](=[CH:9][O:10][CH2:1][CH3:2])[C:6](=[O:8])[CH3:7]
Reactant: CCO
Reactant: CC(=O)C(Br)=CO
Solvent: Cc1ccccc1
Product: CCOC=C(Br)C(C)=O
Yield: 100 %

Procedure:
A mixture of 400 ml absolute ethanol and 60 ml toluene was heated to reflux and 20 ml of azeotrope was removed via a Dean Stark trap. To the ethanoltoluene solution was added 33.0 g (0.2 mole) of 3-bromo-4-hydroxy-3-buten-2-one and reflux was continued for 2 hours during which period three aliquots of 20 ml of ethanol-toluene were removed via the trap. The solution was concentrated in vacuo to give 38.6 g (100%) of 3-bromo-4-ethoxy-3-buten-2-one as a mobile oil. 1H-NMR(DMSO-d6)ppm(delta): 8.21 (s, 1H), 4.23 (q, 2H), 2.33 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:32]([O:34]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:38][NH2:39]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:38][NH:39][C:32](=[O:34])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(F)(F)F)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.30 mmol) and hydrazine monohydrate (0.5 mL) in methanol (10 mL) was stirred at 30° C. overnight. The mixture was concentrated under reduced pressure to give crude product, which was purified by flash chromatography to give the title compound (60 mg, yield 34.5%) as a white solid. LC-MS (ESI) m/z: 465 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.64 (s, 3H), 2.65 (s, 3H), 4.19-4.20 (d, J=4.0 Hz, 2H), 4.53-4.55 (d, J=9.2 Hz, 1H), 4.88-4.90 (d, J=9.2 Hz, 1H), 7.20-7.22 (d, J=7.6 Hz, 1H), 7.35-7.46 (m, 7H), 7.50 (s, 1H), 7.56-7.63 (m, 3H), 9.69-9.71 (br s, 1H), 12.20 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To a suspension of 508 mg of 4-carbamoylimidazolium-5-olate and 486 mg of triethylamine in 6 ml of anhydrous dimethylformamide was added 770 mg of p-chlorobenzoyl chloride in 3 ml of anhydrous dimethylformamide at a temperature below 5° C. The mixture was stirred under ice cooling for 4 hours. The insoluble crystals were filtered off, then the filtrate were concentrated to a residue under reduced pressure, and the resulting residue was dissolved in chloroform. The chloroform solution was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5-carbamoyl-1H-imidazol-4-yl p-chlorobenzoate. The crude solid was washed with ethyl acetate to give 340 mg of pure product, m.p. 220° C. (charred).
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([Cl:13])[C:6]=1[Cl:14].[CH3:16][N:17]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]([OH:26])=O)=[CH:18]1>>[Cl:14][C:6]1[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[CH:4]([CH3:3])[C:24]([C:19]1[CH:20]=[CH:21][C:22](=[O:23])[N:17]([CH3:16])[CH:18]=1)=[O:26]
Reactant: Cn1cc(C(=O)O)ccc1=O
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1Cl
Product: COc1ccc(C(C)C(=O)c2ccc(=O)n(C)c2)c(Cl)c1Cl

Procedure:
The title compound was prepared in analogy to Example 189, steps 1-3, from (2,3-dichloro-4-methoxyphenyl)acetic acid methyl ester and 1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid. Colorless solid. MS (m/e)=340.1 [M+H+].
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)C(C)C)(C)C.[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>C(#N)C>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[O:26]
Reactant: NC1Cc2ccccc2C1
Reactant: O=C=NCCCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCl)NC1Cc2ccccc2C1
Yield: 46.8 %

Procedure:
Synthesized according to general procedure 40. The reaction was set up with 2-aminoindan hydrochloride (5.0 g, 29.5 mmol), N,N-diisopropylethylamine (10.3 mL, 58.9 mmol), acetonitrile (100 mL), and 2-chloroethylisocyanate (2.52 mL, 29.5 mmol). Purification via silica gel chromatography using 50% EtOAc in hexanes gave the desired urea as a white solid (3.3 g, 13.8 mmol, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.18 (m, 2H), 7.15-7.11 (m, 2H), 6.38 (d, J=7.3 Hz, 1H), 6.03 (t, J=5.7 Hz, 1H), 4.36-4.28 (m, 1H), 3.57 (t, J=6.2 Hz, 2H), 3.38-3.29 (m, 2H), 3.12 (dd, J=7.1, 15.8 Hz, 2H), 2.68 (dd, J=5.5, 15.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:18][C:15]([CH3:16])([CH2:14][CH2:13][O:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH3:17])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C)(C)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of the alcohol 4 (0.500 g, 1.6 mmol), ZrOCl28.H2O (0.0025 g, 0.5 mol %) in methylene chloride (5 mL), acetyl chloride (0.251 g, 3.2 mmol) is added and the reaction is stirred for overnight at 20° C. The reaction on completion, is diluted with methylene chloride (5 mL) and washed with saturated sodium bicarbonate (2×10 mL), brine (1×10 mL) and dried. The solvent is evaporated to get the crude product. 1H NMR (400 MHz, CDCl3) δ1.56 (d, J=8.0, 6H), 1.60 (d, J=8.0, 5H), 2.14 (t, J=6.8, 2H), 4.33 (t, J=6.8, 2H), 7.82 (d, J=8.1, 2H), 8.04 (d, J=8.0, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(CC)CC.Br[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([CH:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(c1ccccc1)N1CCc2c(cnc3c2cnn3Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.506 g, 1.72 mmol) in dichloromethane (10 mL) and Et3N (0.72 mL, 5.16 mmol) was added ethyl 2-bromo-2-phenylacetate (0.41 mL, 1.89 mmol). The reaction mixture was stirred at room temperature for 16 hours followed by addition of aqueous NaHCO3 (30 mL). The reaction was extracted with EtOAc (60 mL) and the organic layer was then washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, 50% EtOAc in hexanes) to give the desired product, ethyl 2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylacetate as a yellow solid (0.134 g, 86%). 400 MHz 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 8.10 (s, 1H), 7.5-7.34 (m, 5H), 7.19-7.4 (m, 2H), 6.86-6.8 (m, 2H), 5.76 (s, 1H), 5.56 (s, 2H), 4.46 (s, 1H), 4.13 (q, J=7.2 hz, 2H), 3.76 (s, 2H), 3.69 (s, 3H), 3.05 (t, J=6 hz, 2H), 2.88-2.72 (m, 2H), 1.64 (t, J=7.2 Hz, 3H); LCMS [M+H]:457.5.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH3:7][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.C(N(CC)CC)C>C(#N)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][N:8]([CH3:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: NC(=O)CCCl
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CCC(N)=O)cc1OC
Yield: 64.1 %

Procedure:
6.42 g (60 mmol) 3-Chloropropanamide, 5.85 g (30mmol) N-methyl-3,4-dimethoxybenzeneethanamine and 7.7 g (75 mmol) triethylamine in 100 ml acetonitrile were stirred under reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on silicagel using methylene chloride/methanol: 92/8 to yield 5.12 g (64.1%) of the desired compound as an orange oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: Cc1ccc(F)cc1Br
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-methylbenzene (10.6 g, 0.056 mol) in anhydrous THF (150 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (22 mL, 0.056 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10 g, 0.037 mol) in anhydrous THF (120 mL) was added dropwise, After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl (100 mL) solution and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide crude (R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate (10.5 g, yield 88%), which was used in the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:42][OH:43])[C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[CH:25][CH:24]=1>CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:43][N:42]=[C:22]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)cc1COC

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 23 (162 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (c-Hex/(DCM/EtOAc 1:1), 90/10 to 50/50) afforded the title compound as a yellowish oil. LC/MS (method B): 555.5 (M+H)+. HPLC (Method A) Rt 4.98 min.