Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O.[OH-].[Na+]>ClCCl>[Br:19][C:8]1[CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Temperature: 35 °C
Yield: 89.6 %

Procedure:
To a solution of 1-nitro-3-trifluoromethyl-benzene (41.1 mL, 300 mmol, 97%, purchased from Aldrich) in dichloromethane (240 mL) is added 98% sulfuric acid (45.7 mL, 840 mmol) over 10 minutes. The vigorously stirred resulting biphasic mixture is warmed to 35° C. and 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (53.1 g in total, 180 mmol) is added in six equal portions over five hours. The mixture is stirred at 35° C. for additional 19 hours. Thereafter, more than 97% of the starting material is converted according to HPLC analysis. The reaction mixture is allowed to cool to room temperature and added over 20 minutes to a stirred 2 M aqueous NaOH solution (210 mL) of 0-5° C. while cooling with an ice-water bath. The internal temperature rises temporarily to about 35° C. The two layers are separated. The aqueous layer is extracted with hexane (3×200 mL). The combined organic layers are washed with water (200 mL), 5% aqueous sodium metabisulfite solution (2×200 mL), 8% aqueous NaHCO3 solution (200 mL) and 10% aqueous NaCl solution (200 mL) and, thereafter, the solvents are evaporated at reduced pressure and 45° C. The obtained liquid is distilled at 0.71 mbar and a bath temperature of 70-80° C. to give 1-bromo-3-nitro-5-trifluoromethyl-benzene as a pale yellow liquid. Yield: 89.6% (1H-NMR purity: about 95%). 1H-NMR (400 MHz, CDCl3): 8.11 ppm (m, 1 H), 8.45 ppm (m, 1 H), 8.58-8.59 ppm (m, 1 H). Boiling point: approximately 68° C. at 0.71 mbar.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)O1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)=[CH:7][C:6]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(c1ccccc1)c1cc(-c2ccc3[nH]ncc3c2)ccc1F
Temperature: 150 °C
Yield: 60 %

Procedure:
The following reagents were mixed in no particular order and heated to 150° C. in a microwave for 1000 seconds: (5-bromo-2-fluorophenyl)(phenyl)methanone (from example 9, step 1) (278 mg, 1.0 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (486 mg, 2.0 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (70 mg, 0.10 mmol), dimethoxyethane (2 mL), ethanol (1 mL) and a 2M aqueous solution of sodium carbonate (1 mL, 2.0 mmol). The reaction mixture was then filtered through a plug of celite, rinsed with methanol and concentrated to dryness. Purification from silica gel eluting with a 50% solution of ethyl acetate and hexanes affords [2-fluoro-5-(1H-indazol-5-yl)phenyl](phenyl)methanone (187 mg, 0.6 mmol) 1H NMR (400 MHz, DMSO-D6) δ ppm 13.1 (s, 1 H) 8.1 (s, 1 H) 8.1 (s, 1 H) 8.0 (m, J=5.9 Hz, 1 H) 7.8 (m, J=7.5 Hz, 3 H) 7.7 (m, 2 H) 7.6 (m, 3 H) 7.5 (dd, J=9.1, 9.1 Hz, 1 H)
Reaction SMILES: [NH2:1][OH:2].C(N(CC)CC)C.[C:10](Cl)(Cl)=[O:11].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[O:2]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:20][C:10](=[O:11])[NH:1]1
Reactant: NO
Reactant: O=C(Cl)Cl
Reactant: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2ON1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
The amino-alcohol was dissolved in THF (15 ml) and cooled to -10° C. under N2. To the mixture was added triethylamine (5.4 ml) and phosgene in toluene (4.6 ml). The addition of phosgene caused an exotherm which was maintained below 20° C. by the rate of addition. The progress of the reaction was monitored by HPLC and was typically complete in 15 minutes.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[CH:5]=1.[C:12](Cl)(=O)[CH3:13]>N1C=CC=CC=1.C(OCC)(=O)C>[I:10][C:6]1[CH:5]=[C:4]([C:3]2[N:11]=[C:12]([CH3:13])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: NC(=NO)c1cccc(I)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2cccc(I)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
N′-Hydroxy-3-iodobenzamidine (1.80 g, 6.87 mmol) obtained in Step 1 was dissolved in pyridine (14 mL), and the mixture was stirred at room temperature for 1 hour after adding acetyl chloride (0.551 mL, 6.87 mmol). The mixture was cooled to room temperature after further stirring at 90° C. for 4 hours. After diluting the mixture with ethyl acetate, the organic layer was washed with 1 mol/L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give 3-(3-iodophenyl)-5-methyl-1,2,4-oxadiazole (756 mg, 39%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[O:19].Cl>O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=2)=[CH:26][CH:25]=1
Reactant: NC(=O)C(N)c1ccc(F)cc1
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 28 g of sodium carbonate and 100 ml of water was added dropwise 18.0 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 125 ml of water and then 8.4 g of 2-amino-2-(4-fluorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 20 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 2.45 g (yield, 19%) of the desired compound, 3-(4-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1001).
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26](I)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1.C([Sn](CCCC)(CCCC)[C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)CCC>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of tri(2-furyl)phosphine (0.036 g) and tris(dibenzylideneacetonedipalladium (O) (0.26 g) in toluene (50 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H- benz[b]azepine (1.0 g), followed by 2-tributylstannylthiophene (1.24 g). The reaction was heated to reflux for 1.5 hours, was allowed to cool, and the toluene was evaporated. The residue was triturated with hot hexanes (75 mL). The title compound was afforded upon filtration (0.76 g); mp >240; NMR: 11.47 (bs, 1), 7.73 (dd, 1, J=5.1, 0.8), 7.60 (d, 1, J=7.9), 7.51 (dd, 1, J=4.0), 7.33 (d, 1, J=7.8), 7.31 (s, 1), 7.14 (dd, 1, J=5.1, 4.1), 3.88 (s, 3). Analysis for C15H10O3SClN: Calculated: C, 56.34; H, 3.15; N, 4.38; Found C, 55.96; H, 3.34; N, 4.33.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CO/N=C(\COc1ccc(C=O)cc1)c1ccccc1C
Product: CO/N=C(\COc1ccc(CNc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1C

Procedure:
Compound 6 was synthesized from 4-{[(2Z)-2-(methoxyimino)-2-(2-methylphenyl)ethyl]oxy}benzaldehyde and 3-(4-aminophenyl)propanoic acid by following the procedure described in Scheme 4
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]12[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]1[CH2:9][O:8][NH:7]2.[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:21]([NH:29][C:30]([N:7]1[C:6]2([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]2[CH2:9][O:8]1)=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2cccs2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2cccs2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 6a-(2-thienyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (7.16 g, 24.2 mmol) in THF (161 mL) is added benzoyl isothiocyanate (3.94 g, 24.2 mmol). The reaction is stirred for 1 hour at room temperature, concentrated under reduced pressure, and triturated with hexane/ethyl acetate (1:1) to give the title compound. ES/MS (m/e): 459 (M+H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH2:15][C:16]1[N:17]=[C:18]([CH3:44])[N:19]([CH2:38][C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)[C:20](=[O:37])[C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][C:16]1[N:17]=[C:18]([CH3:44])[N:19]([CH2:38][C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)[C:20](=[O:37])[C:21]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:3][C:4](=[O:7])[O:5][N:36]=2)=[CH:27][CH:28]=1
Reactant: COCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.29 g), sodium hydrogen carbonate (1.94 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(methoxymethyl)-2-methyl-6-oxo-1-(2-thienylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.4 g, 52%).
Reaction SMILES: ClCC(O)[CH2:4][OH:5].ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.[CH:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:26])[CH2:24][OH:25])=[CH:19][CH:18]=1>>[C:4]1(=[O:5])[O:25][CH2:24][CH:23]([C:20]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)[O:26]1.[CH2:24]([OH:25])[CH:23]([OH:26])[CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: OCC(O)c1ccccc1
Reactant: OCC(O)CCl
Agent: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Product: CCCCC(O)CO
Product: O=C1OCC(c2ccccc2)O1

Procedure:
Similarly, 1,2-butanediol and 2,3-butanediol were heated with equivalent quantities of hexachloroacetone in the presence of K2CO3 or other such basic catalyst as previously defined to produce comparable yields of 1,2-butylene carbonate and 2,3-butylene carbonate, respectively. Also, 3-chloro-1,2-propanediol was reacted in this way with hexachloroacetone to make 4-(chloromethyl)-1,3-dioxol-2-one (chloromethylethylene carbonate). In the same way, styrene glycol (1-phenyl-1,2-ethanediol) is reacted with hexachloroacetone in the presence of a basic catalyst to produce 1-phenylethylene carbonate (4-phenyl-1,3-dioxol-2-one), 1,2-hexanediol is reacted with hexachloroacetone to produce 1,2-hexylene carbonate (4-butyl-1,3-dioxol-2-one), and 1-cyclohexyl-1,2-ethanediol is reacted with hexachloroacetone to make 4-cyclohexyl-1,3-dioxol-2-one (cyclohexylethylene carbonate).
Reaction SMILES: C[C:2]1([C:14]([O-:16])=O)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:14]([CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:16])[NH2:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)[O-])C1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)C1
Temperature: 25 °C

Procedure:
A solution of 1-tert-butyl 3-methylpyrrolidine-1,3-dicarboxylate (1.00 equiv.) and hydrazine (excess of 50% aq. solution) in ethanol (0.2 M final conc.) is heated to reflux. After the reaction is deemed complete, the reaction mixture is cooled to rt and partially concentrated. The resulting mixture is diluted with EtOAc, and the resulting organics are washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-12a.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:7][CH2:6]1)=O.[CH3:21]C(C)([O-])C.[K+].O>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:4]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:7][CH2:6]1)[CH2:3][CH:1]=[CH2:21]
Reactant: O=CCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reaction time: 0.5 h

Procedure:
7.0 g of 1-((trans-4-(2-formylethyl)cyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 30 mL of THF, and 10.6 g of methyl triphenylphosphonium bromide was added thereto. To this solution, the THF (15 mL) solution containing 3.3 g of potassium-t-butoxide was added dropwise at an internal temperature of 5 to 20° C., and the solution was stirred for 30 min. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. The solvent was evaporated under reduced pressure, to thereby obtain 3.0 g of 1-((trans-4-(3-butenyl)cyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7])([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)=[CH:18][CH:17]=1.C1C=CC=CC=1.CO.[Cl:41]C(Cl)Cl>>[ClH:41].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3([CH2:27][CH2:28][N:29]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]4[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=4[N+:1]([O-:3])=[O:2])[CH2:30][CH2:31]3)[C:25](=[O:32])[NH:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(c1ccccc1[N+](=O)[O-])N1CC1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Solvent: CO
Solvent: c1ccccc1
Product: Cl
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 7.6 parts of 1-(2-nitrobenzoyl)aziridine, 9.97 parts of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 43.2 parts of benzene and 6.4 parts of methanol is stirred and refluxed for 1.50 hours. Trichloromethane is added and the whole is washed three times with water. The undissolved precipitate is filtered off and the organic phase is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt is filtered off and crystallized from a mixture of ethanol and water. It is filtered off and dried in vacuo, yielding 2.7 parts of N-{2-[1-(4-fluorophenyl)-4-oxo1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}-2-nitrobenzamide hydrochloride; m.p. 267.2° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:23])[C:11]([F:22])=[C:12]([F:21])[C:13]=2[NH:17]C(=O)C)[N:8]([CH:24]2[CH2:26][CH2:25]2)[CH:7]=1)=[O:5])C.C(OC(=O)CC(=O)C1C(F)=C(F)C(F)=C(F)C=1NC(=O)C)C.C(OC(OCC)OCC)C.C(OC(=O)C)(=O)C>>[CH:24]1([N:8]2[C:9]3[C:14](=[C:13]([NH2:17])[C:12]([F:21])=[C:11]([F:22])[C:10]=3[F:23])[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NC(C)=O)c2c1=O
Agent: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1NC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
This product can be converted to 5-acetylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester by a three step reaction. The 2-acetylamino-3,4,5,6-tetrafluoro-β-oxobenzene-propanoic acid ethyl ester is first treated with triethylorthoformate and acetic anhydride. After removal of the solvent the residue is treated with a solution of cyclopropylamine in t-butanol. After the reaction is complete a solution of potassium t-butoxide in t-butanol is added. The resulting product is 5-acetylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester. The ester is hydrolyzed to form 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[C:12]([C:13]#[C:14][C:15]2[C:16]([NH2:21])=[N:17][CH:18]=[N:19][CH:20]=2)=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=[CH:9]1.O.C(Cl)Cl>CN1C(=O)CCC1>[CH3:7][N:8]1[C:12]([C:13]2[NH:21][C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[CH:14]=2)=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=[CH:9]1
Reactant: Cn1cnc(-c2ccccc2)c1C#Cc1cncnc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1cnc(-c2ccccc2)c1-c1cc2cncnc2[nH]1
Temperature: 60 °C
Yield: 33.2 %

Procedure:
Potassium tert-butoxide (84 mg) was added to 5-[(1-methyl-4-phenyl-1H-imidazol-5-yl)ethynyl]pyrimidin-4-amine (intermediate 28) (41 mg) stirred in NMP (2 mL) and heated to 60° C. for 5 hours. After cooling to ambient temperature, water (3 mL) and then DCM (10 mL) was added. The reaction mixture was washed with water (4×10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with DCM:MeOH (20:1 to 10:1) afforded the title compound as a white solid (13.6 mg, 33%);
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25].C(N(CC)CC)C.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:21][C:12]1[C:11]2[N:10]=[C:9]([CH2:22][O:23][CH2:24][CH3:25])[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][N:3]([O:2][CH3:1])[C:37]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:38])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Reactant: CC(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(=O)NC(C)C
Temperature: -8 °C
Reaction time: 8 h

Procedure:
The preparation of O-methyl-N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-hydroxylamine is described in Parts A-C of Example 20. Triethylamine (0.14 mL, 1.01 mmol) was added to a solution of O-methyl-N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyrdin-1-yl)butyl]hydroxylamine (0.29 g, 0.84 mmol) in dichloromethane (8 mL) and cooled to −8° C. Isopropyl isocyanate (0.08 mL, 0.84 mmol) was added dropwise to the reaction mixture, allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was then diluted with dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (30 mL) and the phases were separated. The aqueous phase was extracted with dichloromethane (20 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford a yellow solid. The material was then purified by HPFC (eluting with 0-25% CMA in chloroform) and crystallized from acetonitrile, filtered, dried at 80° C. in a vacuum oven over the weekend to afford 0.178 g of 1-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-3-isopropyl-1-methoxyurea as a white powder, mp 146-147° C. Anal. calcd for C21H31N7O3: C, 58.72; H, 7.27; N, 22.83. Found: C, 58.54; H, 7.27; N, 22.78.
Reaction SMILES: [F:1][B-](F)(F)F.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][C:8]=1[N+]#N>C1C2C(CCCC2)CCC1.C(Cl)(Cl)Cl>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][C:8]=1[F:1]
Reactant: F[B-](F)(F)F
Reactant: COc1ccc2ncc([N+]#N)c(Br)c2n1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: COc1ccc2ncc(F)c(Br)c2n1
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-diazonium tetrafluoroborate (31.42 g, 89.0 mmole) in decalin (mixed isomers, 500 mL) in a 2 L flask* was heated to 180° C. and held at this temperature for 5 min. The mixture was cooled and diluted with CHCl3 (500 mL, to keep the product in solution), and the resulting mixture was stirred vigorously for 30 min to break up a black solid byproduct. The mixture was then poured onto a column of silica gel and the column was eluted with CHCl3 to remove decalin and then with 3% EtOAc/CHCl3 to afford the title compound (9.16 g, 40%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1.Cl.[F:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>COCC(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH:14]([F:13])[CH2:15]2)[N:3]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:5]=1
Reactant: Clc1cc(Cl)nc(C2CC2)n1
Reactant: FC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCC(C)O
Product: FC1CN(c2cc(Cl)nc(C3CC3)n2)C1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
A mixture of 4,6-dichloro-2-cyclopropylpyrimidine 19 (1.05 g, 5.5 mmol), 3-fluoroazetidine hydrochloride 162 (0.68 g, 6 mmol) and potassium carbonate (2.48 g, 18 mmol) in 1-methoxy-2-propanol (10 ml) is heated at 65° C. for 2 hours. The mitre is cooled, concentrated in vacuo, diluted with dichloromethane and washed three times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford 4-chloro-2-cyclopropyl-6-(3-fluoro-azetidin-1-yl)-pyrimidine 163 (1.16 g, 92%) as a yellow oil which is used in the next step without further purification.