Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].[H-].[Na+].Br[CH2:33][C:34]([O:36]CC)=[O:35].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:15]([C:16]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:33][C:34]([OH:36])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: CC(C)(C)COc1ccc(NC(=O)c2cccn2-c2ccc(F)cc2)cc1C#N
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(N(CC(=O)O)C(=O)c2cccn2-c2ccc(F)cc2)cc1C#N
Temperature: 25 °C
Yield: 65.3 %

Procedure:
N-[3-Cyano-4-neopentyloxyphenyl]-1-(4-fluorophenyl) pyrrole-2-carboxamide (4.0 g) and sodium hydride (60% content, 0.6 g) were reacted in dimethylformamide (40 ml) under ice-cooling for 1 h. Dimethylformamide solution (3 ml) containing ethyl bromoacetate (3.4g) was added and the mixture was stirred under ice-cooling for 1 h, and after allowed to warm to room temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added ethanol (40 ml) and then 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reduced pressure. Dilute hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of chloroform-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (3.0 g), melting point: 140–143° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[NH:16][CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(F)c1)nc2=O
Solvent: CN(C)C=O
Product: O=c1nc(OCc2ccc(Oc3ccnc(C(F)(F)F)c3)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E71 using tert-butyl 7-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyri-midine-1(5H)-carboxylate (50 mg, 0.096 mmol) in DMF (2 mL) and silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][N+:19]([O-])=O)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:19][CH2:18][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(F)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CC(CN)c1ccc(F)cc1

Procedure:
A solution of 11.6 g of isobutyl 2-(4-fluorophenyl)-3-nitro-propyl(methyl)phosphinate in 100 ml of ethanol is added to 114 g of a 8% solution of ammonia in ethanol. To this are added 9 ml of Raney Nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give isobutyl 3-amino-2-(4-fluorophenyl)-propyl-(methyl)phosphinate as a viscous oil, 31P N.M.R. spectrum: δ=+54.0 and +53.4 ppm (CDCl3).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][N+:23]([O-:25])=[O:24]>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:22]2[N+:23]([O-:25])=[O:24])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: O=[N+]([O-])CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
To a mixture of N-benzylmaleimide (7.40 g) and K2CO3 (5.50 g) in 500 mL of CH3CN was added bromonitromethane (5.60 g) dropwise. The reaction mixture was stirred for 24 h at room temperature and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 4:1 (v/v) PE/EA) to give the title compound as a pale yellow solid (3.90 g, 40.00%), HPLC: 93.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 247.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 3.34 (d, J=1.8 Hz, 2H), 4.51 (t, J=1.6 Hz, 1H), 4.53 (s, 2H), 7.22-7.42 (m, 5H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH2:13]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][N:14]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:19]2[CH2:20][CH2:21][C:16]3([CH2:15][N:14]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:13]3)[CH2:17][CH2:18]2)=[O:12])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN(C(=O)OC(C)(C)C)C3)cc1
Reaction time: 15 h

Procedure:
To a solution of p-methoxyphenylacetic acid (1.26 g, 7.61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.00 g, 7.61 mmol) in dichloromethane (25 mL) was added triethylamine (2.12 mL, 15.2 mmol) and HATU (3.47 g, 9.12 mmol). The reaction was stirred for 15 hours. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate and the aqueous phase was washed with dichloromethane (2×20 mL). The combined organic layers were washed with water and brine, and dried over anhydrous MgSO4. Filtration and solvent removal afforded a crude product which was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.), 100/0 to 50/50 heptanes/ethyl acetate gradient. The final product (I-1a) was obtained as clear oil which solidified upon standing at ambient temperature (2.75 g, 96%). MS (ES+) 375.4 (M+H)+. 1H NMR (CDCl3) δ 1.41 (s, 9H), 1.50 (br t, 2H), 1.65 (br t, 2H), 3.32 (br t, 2H), 3.52 (br t, 2H), 3.57-3.64 (m, 6H), 3.77 (s, 3H), 6.83 (d, 2H), 7.12 (d, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH2:24]([N:26]=[C:27]=S)[CH3:25].O>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:27]([NH:26][CH2:24][CH3:25])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(OC)cc2)c1=O
Reactant: CCN=C=S
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c2c(NCC)n[nH]c2n(Cc2ccc(OC)cc2)c1=O
Reaction time: 14 h
Yield: 70 %

Procedure:
A solution of 3-butyl-6-hydrazino-1-(4-methoxybenzyl)uracil 0.64 g, 2 mM) and ethyl isothiocyanate (0.53 ml, 6 mM) in DMF (6 ml) was stirred at 90° C. for 14 hours and then at 110° C. for 14 hours. To the solution was added water (2 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/ethanol/water gave colorless needles (0.52 g, 70%), m.p. 234°-236° C.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8](=[O:14])[CH2:9][O:10][C:11](=[O:13])[NH2:12])(=O)C>CO>[OH:6][CH2:7][C:8](=[O:14])[CH2:9][O:10][C:11](=[O:13])[NH2:12]
Reactant: CC(=O)OCC(=O)COC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)OCC(=O)CO

Procedure:
Aqueous sodium hydroxide (35 ml. of a 2.5 N solution) is added dropwise over 30 minutes to a stirred solution of 1-acetoxy-3-carbamoyloxy-2-propanone (14.9 g., 0.085 g.) in methanol (10 ml.). The methanol is evaporated under reduced pressure and the aqueous residue extracted with chloroform (3×25 ml.). The combined extracts are dried, and the solvent is removed in vacuo to afford 1-hydroxy-3-carbamoyloxy-2-propanone.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]([Cl:11])[CH:7]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cc(Cl)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)ccc2F)[nH]1
Reaction time: 2 h

Procedure:
21.6 g of 2-fluoro-5-chlorobenzylhydrazine were added dropwise under nitrogen to a solution of 19.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 0.5 g of p-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 20° to 30°. After stirring for 2 hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 160°, 17 g (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccc(N3CCCC3)cc21
Product: CC1c2cc(N3CCCC3)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27]([Mg]Br)[CH:28]=[CH2:29]>C(Cl)Cl.CCCCCC>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH:27]=[CH:28][CH3:29])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: C=CC[Mg]Br
Solvent: ClCCl
Solvent: CCCCCC
Product: CC=CC(O)c1c(C(C)C)nc(C(C)C)c(CCCCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and allylmagnesium bromide according to the procedures described in Example 114. 1H NMR (300 MHz, CDCl3): δ 7.09 (m, 4 H), 6.58 (m, 1 H), 5.06 (s, 1 H), 5.01 (m, 1 H), 4.47 (m, 1 H), 3.71 (septet, J=6.6 Hz, 1 H), 3.20 (septet, J=6.6 Hz, 1 H), 2.59 (m, 1 H), 2.35 (m, 1 H), 2.18 (t, J=4.8 Hz, 2 H), 1.72 (d, J=2.9 Hz, 1 H), 1.28 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C26H36FNO) 397, found 398 (M+H). Anal. Calcd for C26H36FNO: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 78.10; H, 9.21; N, 3.43; F, 4.89. mp 70-72° C. Rf=0.2 (50% CH2Cl2/hexane).
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)=[O:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Reactant: Cc1ncc(Br)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.24 mL, 0.6 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (107.8 mg, 0.616 mmol) in dry THF (6 mL) in a dry ice-acetone bath. After 1-2 minutes, (4-chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.217 g, 0.512 mmol, Intermediate 46: step b) in dry THF (2 mL) was added to the mixture via syringe. After 5 minutes, the reaction was removed from the cold bath and was allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the aqueous mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-10% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.30-7.25 (m, 2H), 6.97-6.92 (m, 2H), 6.19 (s, 1H), 6.12 (s, 2H), 4.22 (s, 2H), 4.07 (s, 3H), 3.37 (s, 6H), 2.24 (s, 6H); MS m/e 520.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:16](=[O:17])[C:15](=[O:18])[NH:14][C:13](=[S:19])[N:12]1[CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N+]=[N-])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:16](=[O:17])[C:15](=[O:18])[N:14]=[C:13]([S:19][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:12]1[CH3:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=S)[nH]c(=O)c(=O)n1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1c(SC(c2ccccc2)c2ccccc2)nc(=O)c(=O)n1C(=O)OCc1ccccc1
Reaction time: 40 h

Procedure:
13.2 g of tetrahydro-2-methyl-5,6-dioxo-3-thioxo-as-triazine-1(2H)-carboxylic acid benzyl ester are dissolved in 500 ml of ethyl acetate and treated with a solution of diphenyldiazomethane in 90 ml of low-boiling petroleum ether. The initially violet solution is left to stand for 40 hours at 25° C., the colour becoming pink. 3 ml of glacial acetic acid are added and, after 1 hour, the mixture is evaporated in vacuo at 40° C. A yellow oil is obtained as the evaporation residue. This is separated by column chromatography on silica gel using benzene, benzene/ethyl acetate (95:5) and benzene/ethyl acetate (90:10) for the elution. The fractions containing the desired substance are combined and evaporated in vacuo at 40° C. After recrystallization from ethanol, there is obtained colourless pure substance of m.p. 90°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:18]([NH:17][CH3:16])=[O:19])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CNC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Fluorobenzyl)piperazin-2-one (0.40 g, 1.9 mmol, Example 1, Step 4) was dissolved in anhydrous THF (20 mL) under nitrogen and methyl isocyanate (0.96 mL, 1.9 mmol, 2M solution in THF) was added. The reaction was allowed to stir for two hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel using a 0-5% MeOH/CHCl3 gradient elution. Collection and concentration of the appropriate fractions provided the title compound as a white solid. 1H NMR (400 MHz, d6 DMSO) δ 7.29 (m, 2H), 7.16 (m, 2H), 6.55 (d, 1H, J=4.2 Hz), 4.51 (s, 2H), 3.97 (s, 2H), 3.50 (t, 2H, J=5.4 Hz), 3.22 (t, 2H, J=5.4 Hz), and 2.56 (d, 3H, J=4.4 Hz); ES MS (M+1)=266.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[O:6]=[CH:7][CH2:8][C@@:9]1([C:22]([N:24]2[CH2:33][CH2:32][C:31]3[N:30]=[CH:29][C:28]([C:34]([F:37])([F:36])[F:35])=[CH:27][C:26]=3[CH2:25]2)=[O:23])[CH2:13][C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:10]1.[NH4+].[Cl-]>C1COCC1>[CH:1]1([CH:7]([OH:6])[CH2:8][C@@:9]2([C:22]([N:24]3[CH2:33][CH2:32][C:31]4[N:30]=[CH:29][C:28]([C:34]([F:35])([F:36])[F:37])=[CH:27][C:26]=4[CH2:25]3)=[O:23])[CH2:13][C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:10]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC=O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC(O)C2CC2)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 0.75 h

Procedure:
To a solution of cyclopropyl magnesium bromide (6.88 mL of a 0.5 M solution in THF, 3.44 mmol, 8 eq) in THF (5 mL) at 0° C. under Ar was added a solution of the product of Step A (195 mg, 0.43 mmol, 1 eq) in THF (17 mL) dropwise over 30 min. After 45 min, saturated NH4Cl was added, the solution extracted with ethyl acetate, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (12 g column) eluting with 30 to 100% EtOAc/heptane afforded the title compound of Step B as a mix of diastereomers. 1H NMR (CHLOROFORM-d) δ: 8.70 (br. s., 1H), 7.70 (br. s., 1H), 6.11-6.42 (m, 1H), 5.77 (t, J=5.1 Hz, 1H), 4.81 (d, J=12.2 Hz, 4H), 4.03 (dt, J=12.8, 6.2 Hz, 1H), 3.81-3.98 (m, 1H), 3.59-3.75 (m, 2H), 3.03-3.25 (m, 2H), 2.69-3.00 (m, 2H), 2.19-2.67 (m, 3H), 1.91-2.18 (m, 3H), 1.55-1.88 (m, 5H), 1.42 (s, 9H), 0.88-0.99 (m, 1H), 0.42-0.56 (m, 2H), 0.14-0.35 (m, 2H). Calculated for C25H32F3N3O4: 496.2 (M+1). found: 496.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]Br.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500 mL) was added drop-wise bromine (17.7 mL, 0.36 mol) over 1 hour. The reaction mixture was stirred for 1 hour at 0-5° C. in an ice bath. The reaction mixture was basified with saturated Na2CO3 and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give the 2-bromo-5-fluoro-4-nitroaniline (45.6 g, 84%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=7.6 Hz, 1H), 653 (d, J=12.4 Hz, 1H), 4.94 (br s, 2H).
Reaction SMILES: [C:1]([CH:3]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])#[N:2].[OH-].[Na+]>CO.O>[C:1]([CH:3]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)CCCCC(C#N)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CC(CCCCC(=O)O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
In 50 ml of methanol was dissolved 7.38 g (25 mmol) of ethyl 6-cyano-6-(1-naphthyl)hexanoate followed by addition of 50 ml of iN aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with 150 ml of pure water and washed with 150 ml of ethyl acetate. The aqueous layer was acidified with 100 ml of 1 N HCl and extracted with 200 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (hexane-ethyl acetate=1:4) to provide 6.66 g (yield 99.7%) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10](=O)[CH2:11]Br)=[CH:8][CH:9]=1)=[O:4].CC([O-])=O.[Na+].[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[N:19]=[C:20]([NH2:22])[S:21][CH:11]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: NC(N)=S
Reactant: COC(=O)c1ccc(C(=O)CBr)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(-c2csc(N)n2)o1

Procedure:
5-(2-Bromo-acetyl)-furan-2-carboxylic acid methyl ester (0.39 g, 1.61 mmol) was treated with NaOAc (0.185 g, 2.25 mmol) and thiourea (0.12 g, 1.6 mmol) in EtOH to give 5-(2-Amino-thiazol-4-yl)-furan-2-carboxylic acid methyl ester; MS: 225.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C:4]1[NH:5][N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH2:27][CH2:28]I.CN(C=O)C>O>[Cl:25][CH2:26][CH2:27][CH2:28][N:5]1[C:4]([CH2:3][CH:2]([CH3:18])[CH3:1])=[C:16]2[C:7]([C:8]([NH2:17])=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1
Reactant: CC(C)Cc1[nH]nc2c(N)nc3ccccc3c12
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1c2c(nn1CCCCl)c(N)nc1ccccc12
Temperature: 40 °C

Procedure:
1-(2-Methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (2.4 g, 9.99 mmol, prepared as described in Example 9), potassium carbonate (5.5 g, 39.9 mmol), 3-chloroiodopropane (1.2 mL, 11.0 mmol), and DMF (110 mL) were combined and heated at 40° C. overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate. The combined extracts were washed with water and concentrated under reduced pressure. The residue was purified twice by chromatography on a HORIZON HPFC system (silica gel eluting with ethyl acetate) to provide 2-(3-chloropropyl)-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine.
Reaction SMILES: O.Cl.[O:3]=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(OCC)C.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17].[OH-].[Na+]>O>[Cl:20][CH2:19][O:18][C:16]([N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)=[O:17]
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C1CCN(C(=O)OCCl)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 1 g of 4-oxopiperidine hydrochloride monohydrate in 0.7 ml of water was added 2.2 ml of diethyl ether, and the mixture was stirred at 0° C. Chloromethyl chloroformate (0.3 ml) was added dropwise, and the mixture was stirred at 0° C. for 5 minutes. Next, 0.8 ml of a 17N aqueous sodium hydroxide solution and 0.3 ml of chloromethyl chloroformate were divided into three portions and alternately added dropwise, and the resulting mixture was stirred at 0° C. for additional 20 minutes. The reaction mixture was diluted with 5 ml of a saturated aqueous saline, and extracted three times with 5 ml of diethyl ether. The organic layer thus obtained was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 1.7 g (100%) of 1-chloromethoxycarbonyl-4-oxopiperidine.