Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:44])([F:43])[F:45])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccc(Sc2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(OC(F)(F)F)cc3)cc2)c1C
Yield: 55.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(4-(trifluoromethoxy)phenylsulfanyl)benzene (0.214 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.154 g, 55%) as a solid.
Reaction SMILES: [C:1]([Si:7]([CH3:19])([CH3:18])[O:8][C:9]1[CH2:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2].[Li][CH2:21][CH2:22][CH2:23][CH3:24].Br[CH:26](Br)[CH3:27]>C1COCC1>[C:1]([Si:7]([CH3:19])([CH3:18])[O:8][C:9]1[CH:10]([CH:23]([CH:22]2[C:21]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[C:9]2[O:8][Si:7]([CH3:18])([CH3:19])[C:1]([CH2:2][CH2:26][CH3:27])([CH3:4])[CH3:3])[CH3:24])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2]
Reactant: CCCC(C)(C)[Si](C)(C)OC1=Cc2ccccc2C1
Reactant: [Li]CCCC
Reactant: CC(Br)Br
Solvent: C1CCOC1
Product: CCCC(C)(C)[Si](C)(C)OC1=Cc2ccccc2C1C(C)C1C(O[Si](C)(C)C(C)(C)CCC)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 2-(t-hexyldimethylsiloxy)indene (68.62 g, 250.0 mmol) in THF (250 mL) at 0° C. was added dropwise n-BuLi (100.0 mL of a 2.5 M solution in hexanes, 250.0 mmol), and the reaction mixture was stirred overnight at room temperature. The resulting solution was then cooled to −80° C. and treated dropwise with a solution of dibromoethane (23.48 g, 125.0 mmol) in THF (100 mL). After completed addition the reaction mixture was stirred overnight at room temperature and washed with saturated ammonium chloride solution (350 mL). Solvents from the organic phase were evaporated, and the product was dissolved in Et2O (350 mL), washed with water (2×300 mL) and dried over sodium sulphate. Repeated crystallizations at −15° C. afforded 37.48 g (52.2%) of the title compound as off-white crystals. The first crystalline fraction consisted of diastereomerically pure material that was used for spectral characterization. EIMS (calcd/found): m/e 574.3662/574.3659. 1H NMR (CDCl3, δ): 7.22-7.07 (m, 6H); 6.97 (td, 3J=7.4 Hz, 4J=1.2 Hz, 2H); 5.65 (s, 2H); 3.15 (m, 2H); 1.91-1.84 (m, AA′, 2H); 1.67 (sept, 3J=6.8 Hz, 2H); 1.57-1.50 (m, BB′, 2H); 0.89 (m, 24H); 0.27 (s, 6H); 0.24 (s, 6H). 13C NMR (CDCl3, δ): 164.75; 144.45; 140.58; 126.46; 122.60; 122.33; 118.68; 104.96; 49.24; 33.93; 25.03; 24.32; 20.14; 20.02; 18.51; 18.47; −2.66; −2.95.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=2)[CH:9]=[CH:8][N:7]=1)=[O:4].[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH:11]=2)=[CH:18][CH:17]=1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 0 °C

Procedure:
A solution of 1,1-dimethyl-3-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (6.2 g, 20.4 mmol) in MeOH (100 mL) and THF (100 mL) was treated with NH4Cl (332.8 g, 613 mmol) and cooled to 0° C. with stirring. Zinc dust (13.37 g, 204 mmol) was added portion-wise over 10 min and the mixture was stirred overnight as the cooling bath expired. The mixture was diluted with EtOAc and the solids were removed via filtration, and washed with EtOAc. The filtrate was concentrated to dryness, then suspended in EtOAc. The solids were removed by filtration and the filtrate was concentrated to dryness. The resultant brown solid was suspended in MeCN and sonicated for a few minutes. The light brown solid was collected to afford a first crop of 3-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea. The MeCN filtrate was concentrated to dryness and again suspended in MeCN. The light brown solid was collected and dried to afford a second crop of 3-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea (5.57 g combined, 100%). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.05 (d, J=5.7 Hz, 1H), 7.77 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.9, 2.9 Hz, 1H), 6.53-6.49 (m, 2H), 6.00 (br s, 2H), 2.88 (s, 6H); MS (ESI) m/z: 274.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>ClCCl>[CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: Cc1c(O)ccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1c(O)ccc2c1cnn2C1CCCCO1
Reaction time: 48 h
Yield: 60.9 %

Procedure:
Under nitrogen, the 4-methyl-1H-indazol-5-ol (500 mg, 3.37 mmol) obtained in Example 402 was suspended in dichloromethane (20 ml), followed by adding thereto 3,4-dihydro-2H-pyran (239 μl, 3.71 mmol) and p-toluenesulfonic acid monohydrate (64 mg, 0.337 mmol). Tetrahydrofuran (25 ml) was added thereto to effect dissolution, and the reaction was carried out at room temperature for 2 days. The solvent was distilled off under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (477 mg, yield 60.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:21]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)c3c(F)cccc3F)cc2)OC1(C)C
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (a) (5.2 g, 24 mmol), TEA (5 mL) in dry DCM (50 mL) at 0° C. was added 2,6-difluoro-benzoyl chloride (b) (3.0 mL, 24 mmol) dropwise. The mixture was allowed to warm to room temperature over 2 h before it was washed with water (2×100 mL) and dried. Removal of solvents gave 2,6-difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (c) (8.4 g, 23 mmol) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:34]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:35]=[N-:36]
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (E)-3-(3-bromophenyl)acrylic acid (100 g, 0.44 mol) and triethylamine (0.48 mol) in toluene (1000 mL) was added diphenylphosphoryl azide (127.4 g, 0.45 mol) dropwise at 0-10° C. The mixture was stirred at room temperature overnight. Thin layer chromatography (petroleum ether/ethyl acetate=8:1) indicated completion of reaction. The resulting mixture was washed with 1 N sodium hydroxide (500 mL) and extracted with ethyl acetate (2000 mL×3). The organic layer was concentrated to give crude (E)-1-azido-3-(3-bromophenyl)prop-2-en-1-one, which was used in the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>O1CCCC1.C(Cl)Cl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[O:9][CH3:10])=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(Cl)ccc1N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Into a stirred solution containing 10.0 grams (0.06 mole) of 4-chloro-2-methoxyaniline and 6.42 grams (0.06 mole) of triethylamine in 200 milliliters of tetrahydrofuran was added 7.65 grams (0.06 mole) of trimethylacetyl chloride in a small amount of tetrahydrofuran solvent. The resulting mixture was stirred for two hours at room temperature. Triethylamine hydrochloride precipitated and was filtered off and the filtrate vacuum stripped to give a dark liquid which was taken up in methylene chloride. This solution was washed with 2N HCl (2×100 milliliters), then with water (1×100 milliliters), dried over magnesium sulfate and solvent evaporated to give a crude product which was crystallized from hexane to give 6.82 grams (0.03 mole) of 2,2-dimethyl-N-(4-chloro-2-methoxyphenyl)propanamide as a first and second crop. NMR analysis of the product indicated the following:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:35][CH2:34][CH2:33][NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A suspension of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylic acid (101 mg, 0.292 mmol), 2-(2-pyridylamino)ethylamine (60.2 mg, 0.436 mmol), and triethylamine (60.7 μL, 0.435 mmol) in DMSO (1.5 mL) was stirred at 100° C. for 3 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. Recrystallization of the filtered precipitates from CH2Cl2-EtOH gave 5-amino-6-fluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-7-[2-(2-pyridylamino)ethylamino]-3-quinolinecarboxylic acid (103 mg, 76%) as a pale brown powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2)#[N:12].Br[CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:30][C:31]([O:33][CH3:34])=[O:32].[Br-]>C1COCC1>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:23]=[CH:22]2)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: CCCCCCC(Br)CC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(CC(=O)OC)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (5.6 ml of 1M solution in THF) in 40 ml THF was added dropwise at 0° C. to a solution of 5-(2-cyanophenyl)indole (5.04 mmoles, 1.1 g) in 100 ml THF and stirred at 0° C. for 30 minutes. Methyl 3-bromononanoate (5.6 mmoles, 1.32 g) in 20 ml THF was added dropwise. The reaction was stirred at room temperature for 12 hours. An additional 5 mmoles of the base and the bromide were added. The reaction was stirred an additional 12 hours, added to ice water and extracted into ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The intermediate was chromatographed over silica gel eluted with 50% ether in hexane to yield 700 mg of methyl 3-[5-(2-cyanophenyl)indol-1-yl]nonanoate.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[SH:15].Cl[C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1.[OH-].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[S:15][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Sc2ccc(Cl)cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
Potassium t-butoxide (1.1 g) was added to a solution of 2,4-dichlorothiophenol (1.8 g) in N,N-dimethylformamide (DMF) (5 mL). The mixture was stirred at room temperature for 10 minutes and then 6-chloro-2H-pyridazin-3-one (1.31 g) was added. The reaction mixture was stirred at 100° C. for five hours. The mixture was then cooled to room temperature, poured into water (20 mL) and 20% potassium hydroxide (5 mL) was added. The resulting dark solution was extracted with ethyl acetate (2×10 mL). The aqueous layer was collected and the pH was adjusted to 3 with concentrated hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product, which was purified by silica gel chromatography (1:1 ethyl acetate/hexane as eluent) to afford 6-(2,4-dichloro-phenylsulfanyl)-2H-pyridazin-3-one (418 mg, 15%); NMR 6.88 (d, 1H), 7.10 (d, 1H), 7.24(dd, 1H), 7.48 (d, 1H), 7.52 (d, 1H).
Reaction SMILES: [Zr:1].N.[N+:3]([O-:6])([OH:5])=[O:4]>>[N+:3]([O-:6])([O-:5])=[O:4].[Zr+4:1].[N+:3]([O-:6])([O-:5])=[O:4].[N+:3]([O-:6])([O-:5])=[O:4].[N+:3]([O-:6])([O-:5])=[O:4]
Reactant: [Zr]
Reactant: O=[N+]([O-])O
Agent: N
Product: O=[N+]([O-])[O-]
Product: [Zr+4]

Procedure:
7 g of zirconium metal is dissolved in concentrated nitric acid (by HF treatment). Ammonia solution is added to this to precipitate zirconium as its hydroxide. The precipitate is washed with distilled water till it is free from fluoride ions and then dissolved in dilute nitric acid (1 volume of 69% acid mixed with 3 volumes of distilled water) to obtain zirconium nitrate solution.
Reaction SMILES: C(=O)(O)[O-].[K+].[F:6][C:7]1[C:13](F)=[CH:12][C:10]([NH2:11])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:13]2[CH:12]=[C:10]([NH2:11])[C:9]([N+:15]([O-:17])=[O:16])=[CH:8][C:7]=2[F:6])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Temperature: 60 °C
Yield: 71.6 %

Procedure:
2.4 g of potassium bicarbonate and 1 g of 4,5-difluoro-2-nitroaniline are added to a solution of 3.3 g of piperazine-1-carboxylic acid tert-butyl ester in 30 mL of anhydrous DMF. The reaction medium is heated at 60° C. using an oil bath for 30 minutes. The reaction medium is cooled to ambient temperature, then 150 mL of water are added thereto, and precipitation occurs. The precipitate is filtered off through sintered glass. The solid is dried in an oven at 50° C. 1.4 g of 4-(5-amino-2-fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.42 (s, 9H); 3.14 (m, 4H); 3.46 (m, 4H); 6.43 (d, J=8.0 Hz, 1H); 7.36 (broad s, 2H); 7.66 (d, J=14.5 Hz, 1H). EI mass spectrum: m/z=340 M+., m/z=284 (M−C4H+., m/z=264 (m/z=284−HF)+, m/z=57 C4H+ (base peak).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.Cl.[CH2:17]([C:21]1[N:22]=[C:23]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[N:24]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:25]=1)[CH:18]([CH3:20])[CH3:19].CN1CCCC1=O.C(N(C(C)C)CC)(C)C>O>[CH2:17]([C:21]1[N:22]=[C:23]([CH:33]2[CH2:38][CH2:37][N:36]([C:2]3[C:3]4[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:35][CH2:34]2)[N:24]([CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:25]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Reactant: CC(C)Cc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)Cc1cn(CCN2CCCC2)c(C2CCN(c3ncnc4c3[C@H](C)CC(=O)N4)CC2)n1
Temperature: 200 °C
Yield: 23.7 %

Procedure:
Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.23 g, 1.18 mmol), 4-(4-isobutyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine trihydrochloride (0.64 g, 1.3 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (1.65 mL, 8.0 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 200° C. for 40 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with hexanes to ethyl acetate to 5% methanol/ethyl acetate to 3% to 5% to 7% to 10% methanol/dichloromethane, to give the title compound (0.13 g, 23%). MS (ES) m/z=466 [M]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:18]1[CH2:35][CH:19]1[CH2:20][O:21][CH2:22][CH:23]([CH2:29][O:30][CH2:31][CH:32]1[O:34][CH2:33]1)[O:24][CH2:25][CH:26]1[O:28][CH2:27]1.[OH-:36].[K+]>CO>[OH:18][CH:19]([CH2:35][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:20][O:21][CH2:22][CH:23]([CH2:29][O:30][CH2:31][CH:32]([OH:34])[CH2:33][N:6]1[C:5](=[O:36])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[O:24][CH2:25][CH:26]([OH:28])[CH2:27][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9]
Reactant: [OH-]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Reactant: C(OCC1CO1)C(COCC1CO1)OCC1CO1
Agent: [K+]
Solvent: CO
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COCC(COCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)OCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O

Procedure:
12.0 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]-decane-2,4-dione, 4.1 g of glycerol tris(2,3-epoxypropyl)ether and 1.1 g of potassium hydroxide were reacted in 80 ml of methanol, following substantially the same procedure as in Example 1. The desired Compound No. 177 was obtained in the form of a white powder, having an Rf value of 0.45 on thin-layer chromatography on silica gel using a 4:4:4:1:1 by volume mixture of benzene, ethyl acetate, chloroform, methanol and triethylamine as developing solvent.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH:19]=[C:20]([C:28]([CH3:30])=O)[C:21]([O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)=[O:22])([O-:15])=[O:14].[NH3:34]>C(O)C>[CH3:30][C:28]1[NH:34][C:3]([CH3:5])=[C:2]([C:1]([O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[O:6])[CH:19]([C:18]2[CH:31]=[CH:32][CH:33]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[C:20]=1[C:21]([O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)=[O:22]
Reactant: CC(=O)CC(=O)OCCN(C)C
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC1CC1
Reactant: N
Solvent: CCO
Product: CC1=C(C(=O)OCCN(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC2CC2)=C(C)N1
Reaction time: 7 h
Yield: 42.3 %

Procedure:
A mixture of 13.0 g (75 mmol) of 2-(N,N-dimethylamino)ethyl acetoacetate, 21.7 g (75 mmol) of cyclopropylmethyl 2-(3-nitrobenzylidene)-acetoacetate, 6.0 ml of 28% aqueous ammonia and 70 ml of ethanol was stirred at the reflux temperature for 7 hours, and then the solvent was removed under reduced pressure. The residue was chromatographed on silica gel column and crystallized from ethyl ether to afford 3-cyclopropylmethyl 5-[2-(N,N-dimethylamino)ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (14.1 g, 42.3%) as yellow crystals.
Reaction SMILES: Br[CH:2](Br)[CH3:3].[CH:5]1[C:10]([CH2:11]Br)=[CH:9][CH:8]=[C:7]([C:13]#[N:14])[CH:6]=1.IC1[N:20]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:18][CH:17]=1>C1COCC1.[Zn]>[C:21]([N:20]1[C:2]([CH3:3])=[C:17]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[CH:6][CH:5]=2)[N:18]=[CH:19]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Ic1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(Br)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(C#N)cc2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a suspension of activated zinc dust (0.262 g, 3.99 mmol) in THF (1 mL) was added dibromoethane (0.035 mL, 0.039 mmol) and the reaction stirred under argon at 20° C. for 45 minutes. The suspension was cooled to 0° C. and a-bromo-p-tolunitrile (0.51 g, 2.60 mmol) in THF (3 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20° C. for 45 minutes and bis(triphenylphosphine)Nickel II chloride (0.130 g, 0.399 mmol) and 5-iodo-1-trityl imidazole (15.95 g, 36.6 mmol) were added in one portion The resulting mixture was stirred 3 hours at 20° C. and then quenched by addition of saturated NH3 solution (2 mL) and the mixture stirred for 3 hours, extracted with EtOAc (2×25 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 20% EtOAc in CH2Cl2 to afford the title compound as a white solid.