Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.Cl.N([O-])=O.[Na+].[Na+].[I-:23]>O>[F:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([I:23])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Oc2cc(F)ccc2F)cc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(F)c(Oc2ccc(I)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
Into a 250 mL 4-necked round-bottom flask, was placed 4-(2,5-difluorophenoxy)-aniline (9 g, 40.69 mmol, 1.00 equiv), hydrogen chloride (37%) (10.2 g, 100 mmol, 2.5 equiv) and water (20 mL). A solution of NaNO2 (3.1 g, 44.93 mmol, 1.10 equiv) in water (10 mL) was added dropwise with stirring at 0° C. over 5 min. After stirring at 0° C. for 30 min., the mixture was added into a solution of NaI (18 g, 120.00 mmol, 3.0 equiv) in water (20 mL) dropwise with stirring at 25° C. The resulting solution was stirred for 12 h at 25° C. and then extracted with ethyl acetate and the organic layers combined. The combined organics were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 10.5 g (78%) of 1,4-difluoro-2-(4-iodophenoxy)benzene as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:19]C)=[C:12](Cl)[N:11]=1>>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH3:19])=[C:12]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]=1
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: Sc1ccc(Cl)cc1
Product: Cn1cnc2c(Sc3ccc(Cl)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from 4-chlorobenzenethiol and 2,6-dichloro-9-ethyl-9H-purine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[CH:10]([CH3:12])[CH3:11].[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[CH:10]([CH3:12])[CH3:11])[CH3:14]
Reactant: CCN
Reactant: Cc1nc(O)c(C(C)C)c(Cl)n1
Product: CCNc1nc(C)nc(O)c1C(C)C
Temperature: 90 °C

Procedure:
A mixture of 3.00 g (16.1 mmol) of 6-Chloro-2-methyl-5-(1-methylethyl)-4-pyrimidinol and 10.4 mL (7.24 g, 161 mmol, 10 equiv.) of ethylamine as a 70% w/w aqueous solution was sealed in a glass flask, heated at 90° C. for 5 days, and then cooled to 23° C. The mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 50 mm column, 500 mL 4:1 EtOAc:hexane then EtOAc as eluent, mixed fractions rechromatographed) to provide 1.32 g (7.01 mmol, 44%) of recovered starting material and, after recrystallization from EtOAc, 1.70 g (8.70 mmol, 54%) of analytically pure product as a dense white crystalline solid, m.p. 179.5°-180° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C@H:28]3[CH2:30][O:29]3)[CH:21]=2)=[N:13]1>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:30][C@@H:28]([OH:29])[CH2:27][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[C:15]3[S:19][CH:18]=[CH:17][C:16]=3[N:12]([CH3:11])[N:13]=2)[CH:21]=1
Reactant: Cn1nc(-c2cccc(OC[C@H]3CO3)c2)c2sccc21
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: Cn1nc(-c2cccc(OC[C@H](O)CN3CCc4ccccc4C3)c2)c2sccc21

Procedure:
Add a solution of 1,2,3,4-tetrahydroisoquinoline (Aldrich Chemical Company) in absolute ethanol (0.0465 g, 0.200 M solution, 1.745 mL, 2.0 equiv.) to a reaction tube. Add absolute ethanol (3 mL) to the reaction tube and then add a solution of (R)-1-methyl-3-(3-oxiranylmethoxy-phenyl)-1H-thieno[3,2-c]pyrazole and absolute ethanol (example 8, 0.050 g, 0.200 M solution, 0.875 mL). Shake the reaction mixture under Argon at reflux temperature overnight in a Bohdan apparatus. Cool and concentrate to remove the solvent. Purify the residue by flash chromatography (5 g silica gel SepPak cartridge) eluting in step gradient fashion sequentially with 2% and 5% methanol in dichloromethane, and dichloromethane:methanol:ammonium hydroxide solution, 90:9:1. Combine and concentrate the desired fractions to give the title compound (0.0796 g), LC/MS (APCI, condition 3) m/e 420 (MH+), retention time 5.16 min.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][NH:6][C:7]1[CH2:8][C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1>C(O)(=O)C.O>[N:1]([CH2:5][NH:6][C:7]1[CH2:8][C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:3]
Reactant: O=N[O-]
Reactant: CNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NCNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium nitrite, 5.9 g (0.086 moles), was added in 3 portions over a period of 30 minutes to a stirred solution of 18.9 g (0.071 m) of 3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one in 200 ml of acetic acid. After the addition was completed, the mixture was stirred for 20 minutes at room temperature and was then diluted with water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was crystallized from ether to yield product. Additional material was obtained from the concentrated mother liquors. For analysis, the material was recrystallized from ethyl acetate/hexane, mp 139°-140° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5][C:6]1[NH:11][C:10](=[O:12])[C:9]([CH2:13][CH2:14][OH:15])=[C:8]([CH3:16])[N:7]=1)[CH3:4].I[CH3:18].O>CS(C)=O>[CH2:3]([S:5][C:6]1[N:11]([CH3:18])[C:10](=[O:12])[C:9]([CH2:13][CH2:14][OH:15])=[C:8]([CH3:16])[N:7]=1)[CH3:4]
Reactant: CCSc1nc(C)c(CCO)c(=O)[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1nc(C)c(CCO)c(=O)n1C
Temperature: 65 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Potassium hydroxide (8.4 g) was added to a solution of intermediate 2 (33 g) in dimethyl sulfoxide (150 ml). The mixture was stirred for 1 hour at 60-70 ° C. The mixture was cooled to 20° C. and iodomethane (21.3 g) was added dropwise. The reaction mixture was stirred overnight at RT. The mixture was poured out into water and extracted with toluene. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from 4-methyl-2-pentanone and the precipitate was filtered off and dried, yielding 16 g (46%) of 2-(ethylthio)-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone (intermediate 3).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 55.6 %

Procedure:
4-fluoro-2-(trifluoromethyl)benzonitrile (194853-86-6) (2.0 g, 10.6 mmol) was mixed together with H-D-Thr-OH (1.51 g, 12.69 mmol) in DMSO (30 mL). K2CO3 (3.06 g, 22.21 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the pure final product (1.7 g): 1H NMR (500 MHz, CDCl3, δ in ppm) 9.02 (br s, 1H), 7.76 (d, J=9 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J=9 Hz, 1H), 6.41d, J=9 Hz, 1H), 4.42 (m, 1H), 4.01 (m, 1H), 1.24 (d, J=6 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:31][C:32]([NH2:34])=[O:33].CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:31][C:32]([NH2:34])=[O:33])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: NC(=O)CI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(N)=O)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 123.2 %

Procedure:
A solution of 50 mg of amine prepared in Example 11, 33 mg of iodoacetamide and 0.05 mL of DIPEA in 0.5 mL of acetonitrile was heated in a sealed vial at 50° C. for 2 h (or room temperature for 16 h). The volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with 5% MeOH in methylene chloride to afford 70 mg of title compound. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C([Li])CCC.[I:28]I>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([I:28])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: II
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](Cn1ncnc1I)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 18.8 %

Procedure:
A solution of 3.14 g (0.010 mol) of bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane in 15 ml of THF was lithiated as described in Example 1, using 7.1 ml (0.011 mol) of 1.55M n-butyllithium in hexane. To this solution was added 1.4 g (0.011 mol) of iodine. The reaction mixture was allowed to warm to 0°, stirred 3 hours, poured into 1:1 ether/hexanes, washed with 7% aqueous NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. The crude product was flash chromatographed (5% ether/methylene chloride) to give 0.83 g of the title compound as a white solid: m.p. 102°-104°; nmr (CDCl3) δ 0.7 (3H, s), 4.2 (2H, s), 7.1 (4H, m), 7.5 (4H, m), 7.8 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>CN(C=O)C.CCOCC>[F:8][C:7]1[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:3][C:4]([O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C=NOc2ncc(F)c(N)n2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C=NOc2ncc(F)c(N=CN(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a magnetically stirred suspension of 4-methoxybenzaldehyde O-(4-amino-5-fluoropyrimidin-2-yl)oxime (0.075 g, 0.29 mmol) in anhydrous DMF (0.2 mL) was added DMF-DMA (0.068 g, 0.57 mmol) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with Et2O (10 mL) and then was cooled to 0° C. The resulting solid was collected by vacuum filtration, and the cake was washed with cold Et2O followed by hexanes. The precipitate that formed in the filtrate was collected by vacuum filtration and the combined solids were dried under vacuum to give N′-{5-fluoro-2-[1-(4-methoxyphenyl)-methylideneaminooxy]pyrimidin-4-yl}-N,N-dimethylformamidine (0.069 g, 76%) as a white solid: mp 243-245° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.60 (s, 1H), 8.26 (d, J=2.7 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 3.82 (s, 3H), 3.21 (s, 3H), 3.10 (s, 3H); ESIMS m/z 318 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Commercially available p-hydroxybenzaldehyde (50 g) was dissolved in pyridine (400 ml), followed by dropwise adding octanoyl chloride (80 g) under ice cooling, allowing the mixture to stand overnight, adding toluene (300 ml) and 6N hydrochloric acid, separating the solution, further washing with an aqueous solution of 2N NaOH, washing with water, drying and distilling off toluene to obtain a raw product, which was then distilled under reduced pressure to obtain p-octanoyloxybenzaldehyde (b.p. 174°~7° C./7 mmHg) (58.2 g). This product was dissolved in acetic acid (80 ml), followed by dropwise adding to the solution, a mixed solution of chromium trioxide (23.4 g), water (25 ml) and acetic acid (48 ml), stirring at room temperature for 4 hours, pouring on ice, separating solids by filtering, dissolving them in ethanol (300 ml), adding active carbon, shaking, filtering on heating, ice cooling, filtering crystals and recrystallizing from ethanol (300 ml) to obtain p-octanoyloxybenzoic acid (35 g). M.P.: 151° C. This product (5 g) and oxalic acid chloride (7.2 g) were heated on a water bath at 60° C., followed by allowing the reaction mixture to stand overnight, and distilling off excess oxalic acid chloride in vacuo to obtain p-octanoyloxybenzoyl chloride (5 g). This product was used in the following step without purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[C:33](=[O:34])[NH2:35])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: NC(=O)c1ccccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(N)=O)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-aminobenzamide. 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.07 Hz, 6H), 3.25 (d, J=21.50 Hz, 2H), 3.76 (s, 3H), 3.93-4.03 (m, 4H), 6.85 (dt, J=8.08, 2.15 Hz, 1H), 7.02 (s, 1H), 7.06 (t, J=7.83 Hz, 1H), 7.38 (t, J=8.21 Hz, 1H), 7.52 (d, J=8.34 Hz, 1H), 7.75 (dd, J=7.96, 1.39 Hz, 1H), 7.77 (br. s., 1H), 8.27 (br. s., 1H), 8.36 (s, 1H), 8.47 (br. s., 1H), 8.80 (s, 1H), 11.82 (s, 1H). MS (ES+): m/z 406.04 (100) [MH+]. HPLC: tR=4.01 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18]([C:15]1([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[F:1])[C:5]2=[O:7])[CH2:17][CH2:16]1)=[O:19])[CH3:22]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(N2C(=O)c3cccc(F)c3C2=O)CC1

Procedure:
3-Fluorophthalic anhydride (2.0 g), ethyl 1-aminocyclopropane carboxylate hydrochloride (4.0 g) and triethylamine (4 ml) were stirred in chloroform (30 ml) for 0.5 h. Volatile material was evaporated and the residue was heated at 210° for 0.25 h in a nitrogen atmosphere; the residue was dissolved in THF (insoluble triethylame hydrochloride was discarded) and the ethereal solution was evaporated to dryness. This residue was recrystallised from dichloromethane/light petroleum (40°-60°) to give the title compound m.p. 164°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=O)[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>CCO.O=[Pt]=O>[CH2:17]([NH:21][CH2:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: COc1cc(C=O)c2ccccc2c1OC
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCCNCc1cc(OC)c(OC)c2ccccc12
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A suspension of PtO2 (40 mg) in EtOH (2 mL) was stirred with H2 at 25 psi for 30 min. Naphthaldehyde 18 (596 mg, 2.8 mmol) was dissolved in EtOH and added into the suspension followed by the addition of butylamine (219 mg, 3 mmol). The reaction mixture was hydrogenated for 6 h at 50 psi. The catalyst was filtered through Celite, washed with acetone and the filtrate was concentrated to dryness to give 19 as an oil (665 mg, 87%). The product was utilized in the following step without further purification. 1H NMR (CDCl3) 8.16 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H), 7.40-7.60 (m, 2H), 7.35 (s, 1H), 4.19 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 2.76 (t, J=7.0 Hz, 2H), 1.64 (bs, 1H), 1.45-1.60 (m. 2H), 1.30-1.45 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1
Reactant: FC(F)(F)c1cc(Cl)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 5-chloro-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Example 10, Step C) (2.1 g, 12.3 mmol) and potassium carbonate (3.6 g, 26.0 mmol) in 20 mL of N,N-dimethylformamide was added ethyl bromoacetate (2.1 mL, 18.8 mmol), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate, washed with water, and dried (MgSO4). The reaction mixture was concentrated in vacuo and further purified by medium-pressure liquid chromatography using 0-50% of ethyl acetate in hexanes as eluant to give 940 mg of the title compound as an oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9]4=[C:10]([NH:17][C:18](=[O:19])[N:8]24)[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[Br:20][C:13]1[CH:12]=[CH:11][C:10]2[NH:17][C:18](=[O:19])[N:8]3[C:9]=2[C:14]=1[CH2:15][CH2:16][CH:7]3[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CC3
Solvent: CC#N
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A suspension of 4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (0.200 g, 0.799 mmol) in acetonitrile (10.0 mL) and acetic acid (2.42 mL) was heated to dissolve residual solids and the resultant solution was cooled to 0° C. The resulting solution was treated with a solution of N-bromosuccinimide (0.144 g, 0.807 mmol) in acetonitrile (3.0 mL), added dropwise, at 0° C. and subsequently stirred at 0° C. for 1 h. The reaction mixture was concentrated to a residue which was dissolved in chloroform (50 mL) and washed with saturated aqueous sodium bicarbonate (40 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a crude solid. Purification by flash column chromatography (100% hexanes to 50% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.177 g, 67%) as a racemic mixture along with an additional other brominated isomer, 8-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (which was not be separated) in a 4.4:1 ratio. LCMS calculated for C16H14BrN2O (M+H)+: m/z=329.0, 331.0. found: 329.0, 331.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:26]#[N:27])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>[Fe]>[NH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([O:24][CH3:25])[CH:17]=1)[N:14]=[CH:13][C:12]([C:26]#[N:27])=[C:11]2[NH:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1
Reactant: COc1ccc(Nc2c(C#N)cnc3c(OC)cc([N+](=O)[O-])cc23)cc1O
Agent: [Fe]
Product: COc1ccc(Nc2c(C#N)cnc3c(OC)cc(N)cc23)cc1O

Procedure:
Using the method described in Example 196, 0.1 g of 4-(3-hydroxy-4-methoxy-phenylamino)-8-methoxy-6-nitro-quinoline-3-carbonitrile and 0.09 g of iron was converted to the title compound: :MP=215° C. (dec)
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:11]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:13][CH2:14][CH3:15])=[O:12]>CCO>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:19]3[CH2:20][CH2:21][N:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:17][C:18]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCc2[nH]c3ccc(C)cc3c2C1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
Following a literature procedure (Harbert et al., J. Med. Chem. 1980, 23, 635-643) p-tolylhydrazine hydrochloride (0.500 g, 3.15 mmol) and 1-carbethoxy-4-piperidone (0.18 mL, 1.17 mmol) were suspended in EtOH (0.880 mL) and heated to reflux for 2 hours. The reaction mixture was removed from heat and allowed to stand overnight at ambient temperature. The resulting mixture was filtered and washed with 50% aqueous EtOH to afford the desired product as a beige powder (259 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N[OH:17].C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[N:14][OH:17])=[CH:11][CH:12]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C=NO)cc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
In 100 ml of methanol were dissolved 20.5 g of 4-cyanobenzoic acid t-butyl ester and 13.9 g of hydroxylamine. To the solution was added, while stirring at room temperature, 128 g of triethylamine, and the mixture was stirred for one hour at 85° C. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, and the solution was washed with water. The organic layer was concentrated under reduced pressure to give a crude product, which was recrystallized from isopropyl ether to afford 11.45 g of the title compound as a colorless crystalline product.