Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:17])=[O:7])=[CH:4][C:3]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: O=Cc1ccc(O)c(OC(F)(F)F)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(O)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (901 mg, 4.37 mmol) in acetone (10 ml) was added 4 ml of the Jones reagent. The ice bath was removed and the reaction was stirred at room temperature for ca. 1 h. Isopropanol was added to destroy the excess Jones reagent. The mixture was diluted with ethyl acetate, the precipitate was filtered off, and the filtrate concentrated in vacuo. The residue was diluted with 1M HCl and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound. Mass spectrum (ESI) 221.1 (M−1).
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[N:4]1.Br[CH2:12][CH2:13]Br.O>CN(C)C=O>[O:3]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[N:4]1
Reactant: BrCCBr
Reactant: N#CCc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccon2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (136 mg, 5.39 mmol) in N,N-dimethylformamide (5 mL) was added a solution of 2-(isoxazol-3-yl)acetonitrile (233 mg, 2.16 mmol) in N,N-dimethylformamide (2.5 mL) at 0° C. After the addition, the mixture was warmed to room temperature and stirred for 1 h. The mixture was cooled to 0° C. and 1,2-dibromoethane (0.3 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 4 h. Water was added to the mixture. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with water, washed with aqueous hydrochloric acid (1N), washed with aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved with dichloromethane and washed with aqueous lithium chloride solution (10%). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure and dried under a stream of nitrogen to afford 1-(isoxazol-3-yl)cyclopropanecarbonitrile (243 mg). 1H NMR (500 MHz, CDCl3) δ 1.71-1.76 (m, 2H), 1.79-1.83 (m, 2H), 6.51 (s, 1H), 8.40 (s, 1H). The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].S(C1C=CC(C)=CC=1)(OC)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reaction time: 16 h

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.1 g) in THF (5 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.23 ml), followed by methyl tosylate (0.206 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was quenched with sodium acetate (0.074 g), stirred for 1 h and partitioned between water and ethyl acetate. The separated organic layer was washed with water, dried (over magnesium sulphate), and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 8:1, 5:1, 3:1, 2:1,1:1) to give the title compound (0.101 g) as a colourless gum.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[CH2:8](Br)[CH:9]=[CH2:10].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:10]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH:9]=[CH2:8]
Reactant: O=Cc1ncc[nH]1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1ccnc1C=O
Yield: 60.3 %

Procedure:
A solution of 2-imidazole carboxaldehyde (15.0 g, 156 mmol), allyl bromide (22.6 g, 187 mmol) and diisopropylethylamine (40.7 mL, 234 mmol) was stirred in N,N-dimethylformamide (500 mL) for 23 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (370 mL). The solution was washed once with a saturated solution of sodium carbonate (185 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×280 mL). The combined organic portions were dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. The crude material was then purified by flash chromatography (99:1 CH2Cl2/methanol) to provide the desired compound (12.8 g, 60%) as yellow oil. 1H NMR (300 MHz, CDCl3, δ ppm) 5.04 (d, 2H, J=5.5 Hz), 5.11 (d, 1H, J=17.5 Hz), 5.25 (d, 1H, J=10.0 Hz), 5.90-6.05 (m, 1H), 7.16 (s, 1H), 7.30 (s, 1H), 9.81 (s, 1H); 13C NMR (75 MHz, CDCl3, δ ppm) 49.77, 118.61, 126.00, 131.74, 132.39, 143.17, 182.05.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[C:18]([C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22])#[N:19]>>[C:18]([C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)#[N:19]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1ccc(C#N)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-cyano-5-methylaniline (38 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (8 mg, 12%). 1H NMR (CDCl3): 9.62-9.61 (m, 1H), 8.75-8.69 (m, 2H), 8.08 (s, 1H), 7.62 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.46-7.41 (m, 1H), 7.12 (dd, J=0.9, 8.1 Hz, 1H), 7.00 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12](O)=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>ClCCl>[O:1]=[C:2]1[C:11]([C:12]([Cl:24])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cccnc2n(-c2ccccc2)c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2cccnc2n(-c2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.62 g (6.1 mmol) of 2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (60 mL), and 3.7 mL (44 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction mixture was concentrated under reduced pressure, and thus 2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (60 mL), and 0.75 g (6.7 mmol) of 1,3-cyclohexanedione and 1.03 mL (7.3 mmol) of triethylamine were added to the above solution. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 2.16 g (yield: 99%) of the title compound was obtained as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])(=[O:11])=[O:10].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH3:21])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])(=[O:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCN1CCNS(=O)(=O)c1cccc(Cl)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN(CCN1CCNC1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.57 g (1.69 mmol) of 2,3-dichloro-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzenesulphonamide and 0.23 g (1.7 mmol) of potassium carbonate in 10 ml dimethylformamide was stirred at room temperature for 10 minutes, 0.16 ml (1.69 mmol) of dimethyl sulphate were then added and the mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate and concentrated. The product obtained in this manner was crystallized using diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C:15]1([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16]1)=[O:13].O[Li:32].O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C:15]1([C:18]2[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH2:16][CH2:17]1)=[O:13].[Li+:32]
Reactant: [Li]O
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(C)c3)CC2)cc1
Solvent: O
Product: Cc1cccc(CN2CCCC[C@@H]2C(=O)NC2(c3ccc(C(=O)[O-])cc3)CC2)c1
Product: [Li+]

Procedure:
The title compound (E10) (61 mg) was prepared according to the general procedure for esters hydrolysis starting from (R)-methyl 4-(1-(1-(3-methylbenzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D27) (63 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: P(Cl)(Cl)(Cl)=[O:2].ClC1[N+]([O-])=N[C:10]([O:14][C:15]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:16]=2[CH2:17][C:18]3([CH3:24])C)=CC=1.[Cl:25][C:26]1N=[N+]([O-])C(OC2C=CC=C3C=2CC3(C)C)=C[CH:31]=1>>[Cl:25][CH2:26][CH2:31][CH2:24][CH:18]1[C:19]2[C:16](=[C:15]([O:14][CH3:10])[CH:22]=[CH:21][CH:20]=2)[C:17]1=[O:2]
Reactant: CC1(C)Cc2c(Oc3ccc(Cl)n[n+]3[O-])cccc21
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)Cc2c(Oc3ccc(Cl)[n+]([O-])n3)cccc21
Product: COc1cccc2c1C(=O)C2CCCCl

Procedure:
0.50 mL (5.4 mmol) of phosphorus oxychloride was added to 61.7 mg (0.223 mmol) of a mixture of 6-chloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]-pyridazine 1-oxide and 3-chloro-6-[(7,7-dimethylbicyclo-[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine 1-oxide obtained in (4), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=5:1) to obtain 43.7 mg (0.148 mmol, Yield: 66.4%) of 4,6-dichloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2C=CC=CC=2I([C:29]([F:32])([F:31])[F:30])O1>C([O-])(=O)C.[Cu+]>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:29]([F:32])([F:31])[F:30])[N:13]2[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2c(OCc3ccccc3)cccc21
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Agent: [Cu+]
Agent: CC(=O)[O-]
Product: Cn1c(C(F)(F)F)cc2c(OCc3ccccc3)cccc21

Procedure:
4-(Benzyloxy)-1-methyl-1H-indole and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole were treated with copper(I) acetate to give 4-(benzyloxy)-1-methyl-2-(trifluoromethyl)-1H-indole. Debenzylation via transfer hydrogenation with ammonium formate afforded 1-methyl-2-(trifluoromethyl)-1H-indol-4-ol.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.[OH-].[K+].CCO[C:18]([S-])=[S:19].[K+].C(O)(=O)C>C(O)(C)C.O>[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]2[N:11]=[C:18]([SH:19])[NH:12][C:6]=2[CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(F)c(F)cc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Fc1cc2nc(S)[nH]c2cc1F

Procedure:
40.7 g of 4,5-difluoro-o-phenylenediamine dihydrochloride were suspended in 655 ml of isopropanol. A solution of 22.5 g of potassium hydroxide in 250 ml of water was added dropwise thereto while stirring and the mixture was treated with 39.7 g of potassium ethyl xanthogenate, whereupon the solution was boiled at reflux overnight, then diluted with 300 ml of water and made neutral with glacial acetic acid. The resulting suspension was stirred at 60°-70° for an additional hour. The isopropanol was largely removed from the mixture in a vacuum. After the addition of 1 liter of water, the solid was filtered off washed with water and then dissolved in ether. The solution was then extracted with 1.2 liters of water, treated with active charcoal, dried and evaporated in a vacuum. The residue was suspended in petroleum etber (low boiling) and filtered off. There was obtained 5,6-difluoro-2-benzimidazolethiol of melting point above 300°.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH2:27])([CH2:4][O:5]2)[CH2:2]1.[CH3:28][N:29]([CH3:35])[C:30](=[O:34])[C:31](O)=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:28][N:29]([C:30]([C:31]([NH:27][C:3]12[CH2:4][O:5][CH:6]([CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:17])[N:10]=[C:9]31)[CH2:1][CH2:2]2)=[O:32])=[O:34])[CH3:35]
Reactant: NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepine-2-carboxamide (70 mg, 0.187 mmol) and 2-(dimethylamino)-2-oxoacetic acid (32.8 mg, 0.280 mmol) in DMF (3 mL) was added diisopropyl-ethylamine (0.175 mL, 1.002 mmol), 4-(dimethylamino)pyridine (DMAP) (4.57 mg, 0.037 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (107 mg, 0.280 mmol) and the resulting mixture stirred at room temperature for 3 h. After work-up the crude was purified by preparative HPLC to afford the title compound as an off-white solid (35 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.11 (s, 1H), 8.73 (brs, 1H), 7.47 (s, 1H), 7.34 (dd, 2H, J=8.39 & 5.34 Hz), 6.98-7.03 (m, 2H), 4.62-4.70 (m, 2H), 4.53 (d, 2H, J=6.71 Hz), 4.49-4.52 (m, 1H), 4.29 (d, 1H, J=11.6 Hz), 4.08 (d, 1H, J=16.79 Hz), 3.21 (s, 3H), 2.89 (s, 3H), 2.46-2.53 (m, 1H), 2.33-2.38 (m, 1H), 1.86-1.92 (m, 1H), 1.53-1.58 (m, 1H). LCMS (M+H)=474.24. HPLC purity>95%.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([N+]([O-])=O)[CH:8]=1)([O-:3])=[O:2].[CH2:27]([P:29]([O:32]C)[O:30][CH3:31])[CH3:28]>>[CH2:27]([P:29]([C:9]1[CH:8]=[C:7]([NH:6][C:5]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:4]=2[N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])(=[O:32])[O:30][CH3:31])[CH3:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CCP(OC)OC
Product: CCP(=O)(OC)c1cc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 11, 4-(2-nitro-4-trifluoromethylanilino)-1,2-dinitrobenzene and dimethyl ethylphosphonite are reacted together to give methyl P-ethyl-2-nitro-5-(2-nitro-4-trifluoromethylanilino)-phenylphosphinate.
Reaction SMILES: [CH2:1]([C:3]1([C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]2)[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([C:3]1([C:15]2[CH:16]=[C:17]([NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]2)[CH3:2]
Reactant: CCCCCCN1CC2C(C1)C2(CC)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(CC)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.7 %

Procedure:
To a solution of 3-(6-ethyl-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 20, 500 mg, 1.56 mmol) in pyridine (5 ml) at 0° C. under nitrogen was added dropwise over 5 minutes methanesulfonylchloride (0.20 ml, 0.30 g, 2.6 mmol). The mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was concentrated in vacuo and the residue was purified by silica (25 g) column chromatography eluting with 50:50:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (180 mg, 33%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH2:25][CH2:26][O:27][CH3:28])[N:15]=[CH:14][N:13]=[C:12]2[S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3]
Reactant: Nc1cccc(S)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a suspension of sodium hydride (422 mg, 17.6 mmol) in anhydrous tetrahydrofuran (100 mL) cooled to 0° C., 3-aminothiophenol (125 mg, 16.8 mmol) was added dropwise as a solution in tetrahydrofuran (5 mL). The mixture was stirred at 0° C. for 30 minutes. 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline, previously synthesized, was added and the resulting mixture heated to 50° C. overnight. After removal of the solvent the residue was taken into ethyl acetate/water, the organic layer separated and the aqueous phase extracted twice. The organics were combined, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated in methanol to give 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline (2.8 g, 49%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.33 (d, 2H), 7.16-7.10 (m, 1H), 6.81 (s, 1H), 6.75-6.67 (m, 2H), 5.35 (bs, 2H), 4.33 (bs, 2H), 4.02 (s, 6H), 3.77 (bs, 2H); LC-MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[OH:15].Br[C@H:17]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@@H:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>CN(C=O)C.CCOC(C)=O.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C@@H:17]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@@H:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Cc1cc(Cl)cc2c(O)ccnc12
Reactant: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)[C@H](Br)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)[C@@H](Oc1ccnc2c(C)cc(Cl)cc12)c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60 wt % in mineral oil, 15.5 mg, 0.387 mmol) was washed with hexanes (2 mL), then a solution of 6-chloro-8-methylquinolin-4-ol (50.0 mg, 0.258 mmol) in DMF (2 mL) was added. Once gas evolution had ceased, the product of Step A (170 mg, 0.387 mmol) was added in one portion, then the mixture was stirred at 120° C. overnight. After being allowed to cool to room temperature, the mixture was diluted with EtOAc (20 mL) and water (15 mL), then the organic layer was concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 8.51 (d, J=5 Hz, 1H); 7.93 (d, J=8.5 Hz, 2H); 7.89 (d, J=2.5 Hz, 1H); 7.47 (s, 1H); 7.26 (dd, J=6.5, 6.0 Hz, 4H); 7.12 (d, J=8.5 Hz, 2H); 6.43 (d, J=5 Hz, 1H); 5.44 (d, J=6.5 Hz, 1H); 3.29-3.23 (m, 1H); 2.69 (s, 3H); 1.90-1.80 (m, 1H); 1.74-1.64 (m, 1H); 1.58 (s, 9H); 1.30-1.10 (m, 2H); 0.83 (t, J=7.5 Hz, 3H); LC4 2.78 min. (M+H)+ 550.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[C:19]([CH:21]1[CH:29]2[N:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][CH2:22]1)=O)C>O.CCOCC>[C:1]1([C:19]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:21]2[CH:29]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:23][CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: Brc1ccccc1
Reactant: CCOC(=O)C1CCN2CCCCC12
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: c1ccc(C(=C2CCN3CCCCC23)c2ccccc2)cc1

Procedure:
To a phenyl lithium solution prepared by dissolving 0.51 g. of metallic lithium and 6.32 g. of bromobenzene in 50 ml. of absolute ether, was dropwise added a solution of 2.40 g. of 1-ethoxycarbonylindolizidine in 20 ml. of absolute ether under ice cooling. After refluxing for about 10 mins., water was dropwise added thereto, followed by extraction with ether. The ethereal layer was further extracted with dil. hydrochloric acid. The aqueous layer was rendered alkaline with an aq. sodium hydroxide solution and then extracted with ether. The ethereal layer was washed with water and dried. After removing the solvent by distillation, 3.58 g. of light yellow viscous substance was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Br[CH2:22][C:23]([O:25]CC)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]([F:19])([F:20])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:22][C:23]([OH:25])=[O:24])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(=O)O
Reaction time: 16 h

Procedure:
To the above phenol (6.0 g=20 mmol) in 100 ml acetonitrile add ethyl bromoacetate (3.0 g=24 mmol) and potassium carbonate (5.4 g=39 mmol). Stir 16 hours, filter, concentrate, and partition between ether and 1.0 N HCl. Dry and concentrate the ether. Partition between 1:1 ether-hexane and 1.0 N NaOH. Acidify the aqueous layer with concentrated HCl and extract with ether. Dry and concentrate. Recrystallize from ether-hexane and dry at 0.1 mm pressure to obtain 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylphenoxy]acetic acid, m.p. 111°-113° C.