Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C1(C)C=CC=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=1>O>[F:3][C:4]([F:12])([F:13])[C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:24]1[CH:23]=[C:22]([Br:21])[CH:27]=[CH:26][CH:25]=1
Reactant: Brc1cccc(Br)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cccc(Oc2cccc(Br)c2)c1
Reaction time: 18 h
Yield: 45 %

Procedure:
The reaction is performed in a 1 L 3-necked flask equipped with a mechanical stirrer, a Dean-Stark trap topped with a condenser and a nitrogen bubbler, and a stopper. The flask is flushed with nitrogen and charged firstly with potassium hydroxide (22.4 g, 0.4 mol), α,α,α-trifluoro-m-cresol (64.8 g, 0.4 mol), and toluene (500 mL). The mixture is stirred and heated at reflux for 2 h, during which time water collected in the trap (ca. 6mL). 1,3-Dibromobenzene (50 mL, 0.42 mol) and cuprous chloride (39.6 g, 0.4 mol) are added to the reaction mixture, and heating at reflux is continued for another 18 h. Then it is analyzed by capillary GC, which shows ca.45% of the title product along with ca.12.5% of the product resulting from dialkylation, with the rest being starting materials. The reaction mixture is filtered with the aid of ether (200 mL), and washed successively with 2×100 mL portions of 5% HCl (to remove any residual copper impurities), water, and brine. It is dried with (MgSO4) and concentrated on the rotary evaporator to a red oily residue. Fractional distillation afforded 47 g (38%) of the title compound, distilling at 113-117° C. @ 1 mm. Also, 112 g (10.5%) of the dialkylation product is obtained, distilling at 160-165° C. @ 1 mm. Other fractions from the distillation show mixtures containing the desired product, but no further effort is made to obtain the rest of it.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:27]=[CH2:28])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Yield: 29.6 %

Procedure:
A solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.462 mmol), tributyl-vinyl-stannane (198 mg, 0.624 mmol), Pd2(dba)3 (23 mg, 0.005 mmol) and BINAP (6.84 mg, 0.011 mmol) in toluene (20 mL) was heated to reflux overnight. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 30%). 1H NMR (CDCl3): 0.81 (m, 2H), 1.07-1.28 (m, 5H), 1.53 (d, 3H), 1.83-1.97 (m, 4H), 2.22 (m, 3H), 2.83 (m, 1H), 3.55 (m, 2H), 5.09 (m, 1H), 5.21 (m, 1H), 5.58 (m, 1H), 6.63-6.77 (m, 2H), 7.04-28 (m, 13H), 7.43 (m, 2H), 7.68 (m, 1H).
Reaction SMILES: C(O)(=O)C.[OH:5][CH:6]1[CH2:9][NH:8][CH2:7]1.[C:10](Cl)(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[C:10]([N:8]1[CH2:9][CH:6]([OH:5])[CH2:7]1)(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: OC1CNC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC(O)C1
Temperature: 0 °C

Procedure:
Stir a suspension of 6.31 g of 3-hydroxyazetidine acetate in 150 ml dry pyridine until a solution results. Add 15.8 g stearoyl chloride at room temperature during ten minutes and stir for 21 hours at room temperature. Pour into 450 ml of an ice-water mixture, and extract once with 300 ml ethyl ether and then twice with 250 ml portions chloroform. Wash the combined extracts with three 150 ml portions of water, dry over anhydrous sodium sulfate and remove the solvents in vacuo. Stir the residue in 250 ml hexane and filter the resultant solid. Recrystallization from hexane affords pure 1-octadecanoyl-3-hydroxyazetidine, m.p. 86°-87.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:16]O>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-(3-methoxy-4-nitrophenyl)acetic acid (4.6 g, 21.78 mmol) and concentrated H2SO4 (2 drops) in methanol (200 mL) was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature then the solvents were removed under reduced pressure. The residue was partitioned between water (100 mL) and EtOAc (100 mL), then the separated organic layer was washed with sodium bicarbonate solution (100 mL), brine (200 mL), dried (Na2SO4) and evaporated under reduced pressure to give the title compound (4.5 g, 92%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([O:13][CH2:14][CH3:15])=[CH:7][C:6]=1[CH3:16])=[O:4].C(O)C[OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]2([O:19][CH2:15][CH2:14][O:13]2)[CH2:7][C:6]=1[CH3:16])=[O:4]
Reactant: CCOC1=CC(C)=C(C(=O)OC)C(C)(C)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)CC2(CC1(C)C)OCCO2

Procedure:
670 g. of crude 2,6,6-trimethyl-4-ethoxy-1,3-cyclohexadien-1-carboxylic acid methyl ester and 185 g. of ethylene glycol were heated in 3 l. of benzene in the presence of 3 g. of p-toluene sulfonic acid. The reaction was stopped after 1.5 l. of benzene had distilled over. The cold solution was washed with sodium bicarbonate solution and water, dried, and evaporated. The remaining oil was dissolved in 1 l. of petroleum ether and crystallized at -10°. A yield of 320 g. (m.p. 67°-69°) was obtained after recrystallization from petroleum ether. This product was identified as 7,9,9-trimethyl-1,4-dioxaspiro[4,5]dec-7-on-8-carboxylic acid methyl ester.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:8])=[N:5][S:6][CH:7]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[CH3:8][C:4]1[C:3]([CH2:2][S:13][CH2:12][CH2:11][NH2:10])=[CH:7][S:6][N:5]=1
Reactant: Cc1nscc1CO
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cc1nscc1CSCCN

Procedure:
Reacting 4-hydroxymethyl-3-methylisothiazole (3.0 g.) with cysteamine hydrochloride (2.8 g.) in 48% aqueous hydrobromic acid (50 ml.) by the procedure of Example 1 gives 3-methyl-4-[(2-aminoethyl)thiomethyl]-isothiazole hydrobromide. Treatment of this intermediate with aqueous potassium carbonate, extracting with chloroform, drying the chloroform extract over magnesium sulphate and concentrating gives the free base, 5.0 g. of which is then reacted with methyl isothiocyanate (1.94 g.) in ethanol (25 ml.) under reflux for 30 minutes. The product is purified on a column of alumina and elution with benzene gives N-methyl-N'-[2-((3-methyl-4-isothiazolyl)methylthio)ethyl]thiourea. Reaction of this product by the procedure of Example 121 gives N-cyano-N'-methyl-N"-[2-((3-methyl-4-isothiazolyl)methylthio)ethyl]guanidine.
Reaction SMILES: [CH:1]1([N:6]([C:8]([C:10]2[CH:14]=[C:13]([CH3:15])[O:12][C:11]=2[CH3:16])=[O:9])[OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.S(OC)(O[CH3:24])(=O)=O>ClCCl>[CH3:24][O:7][N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:8]([C:10]1[CH:14]=[C:13]([CH3:15])[O:12][C:11]=1[CH3:16])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(C(=O)N(O)C2CCCC2)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CON(C(=O)c1cc(C)oc1C)C1CCCC1
Reaction time: 1 h

Procedure:
14.3 Parts of N-cyclopentyl-2,5-dimethylfuran-3-hydroxamic acid is dissolved in 100 parts of dichloromethane; to this solution there is added a solution of 7.7 parts of sodium hydroxide in 50 parts of water. 16.1 parts of dimethyl sulfate is then dripped into this mixture. After stirring the mixture for 1 hour, the dichloromethane phase is separated, washed with water until neutral, dried over anhydrous sodium sulfate and evaporated. There is obtained 12.1 parts of O-methyl-N-cyclopentyl-2,5-dimethylfuran-3-hydroxamic acid having a boiling point at 0.1 mm Hg of from 103° to 105° C and the refractive index ND25 : 1.5060. ##SPC10##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@H]2CNCCO2)CC1
Reaction time: 1 h
Yield: 161.2 %

Procedure:
Trifluoroacetic acid/Dichloromethane (20 ml, 1:1) was added to tert-butyl (2S)-2-[(4-{[(3,4-dichlorophenyl)amino]-carbonyl}piperazin-1-yl)methyl]morpholine-4-carboxylate (2.10 g) under argon and stirred for 1 h. The solvent was then removed on a rotavapor and azeotroped (2×20 ml) with toluene and dried for 24 h under high vacuum to afford the title compound (2.67 g) as a brown oil which was used without further purification.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][N:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7]1)(=O)=O.O[C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]3[CH:44]=[CH:43][C:34]4[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=4[CH:32]=3)[CH:24]=2)=[C:18]([CH3:45])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:45][C:18]1[CH:17]=[C:16]([O:5][C@@H:6]2[CH2:10][CH2:9][N:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7]2)[CH:21]=[C:20]([CH3:22])[C:19]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]2[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=2)[CH:24]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCN(S(C)(=O)=O)C5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
(s)-1-(Methylsulfonyl)pyrrolidin-3-yl methanesulfonate 11c (41 mg, 0.17 mmol), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (70 mg, 0.17 mmol) and cesium carbonate (165 mg, 0.50 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction solution was heated to 80° C., and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 11d (71 mg, yield 75.1%) as a light yellow slime.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:41][C:42]([F:62])([F:61])[C:43]1[CH:44]=[C:45]([S:49]([N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]2[C:58]([OH:60])=O)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1.[NH2:63][C@@H:64]([CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)/[CH:65]=[N:66]/[C:67]1[C:68]([NH:73][CH3:74])=[CH:69][CH:70]=[CH:71][CH:72]=1>C(Cl)Cl>[CH2:75]([C@H:64]([NH:63][C:58]([C@@H:53]1[CH2:54][CH2:55][CH2:56][CH2:57][N:52]1[S:49]([C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([C:42]([F:41])([F:61])[F:62])[CH:44]=1)(=[O:50])=[O:51])=[O:60])/[CH:65]=[N:66]/[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[NH:73][CH3:74])[C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: CNc1ccccc1/N=C/[C@@H](N)Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1ccccc1/N=C/[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
PyBOP (0.11 g, 0.22 mmoles) and triethylamine (0.076 mL, 0.55 mmoles) were added to a room temperature solution of (S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (0.074 g, 0.22 mmol) in CH2Cl2 (5 mL). After stirring at room temperature for 20 min, a solution of N-[(S)-2-amino-3-phenyl-prop-(E)-ylidene]-N′-methyl-benzene-1,2-diamine (0.052 g, 0.22 mmoles) in CH2Cl2 (5 mL) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give a yellow oil. Purification of the residue by flash chromatography on silica gel, eluting with 10-50% EtOAc/heptane afforded 0.078 g (64%) of the title compound as a colorless powder: ES+ LC/MS m/e 557 (M+H), RT=2.92 min; 1H NMR CDCl3: δ9.99 (bd s, 1), 8.05 (s, 1), 7.94 (d, 1, J=8.0 Hz), 7.83 (d, 1, J=7.9 Hz), 7.62 (t, 1, J=7.9 Hz), 7.23-7.56 (m, 8), 7.00 (d, 1, J=7.5 Hz), 5.45 (m, 1), 4.40 (bd s, 1), 3.72 (dd, 1, J=14.5, 5.1 Hz), 3.54 (d, 1, J=14.1 Hz), 3.44 (dd, 1, J=14.5, 10.8 Hz), 2.13-2.26 (m, 2), 1.37 (m, 1), 1.22 (m, 1), 0.92-1.10 (m, 4).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]2[CH2:10][C@H:8]2[NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:13]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a solution of tert-butyl-(trans)-2-(4-hydroxyphenyl)cyclopropylcarbamate (Intermediate N, 5 g, 20.0 mmol), K2CO3 (6.8 g, 50.0 mmol) in dry DMF (10 vols) was added 3-Bromo benzyl bromide (5 g, 20.0 mmol) and stirred at RT for 16 h. After completion, the reaction mixture was poured into ice water (150 mL) and extracted with EtOAc (2×75 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography to give (tert-butyl(trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylcarbamate (5.2 g, 62%) as a white solid. The crude was carried to next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:24][NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:11]2[C:12]([CH2:20][CH:21]([OH:23])[CH3:22])=[CH:13][C:14]3[O:18][CH2:17][O:16][C:15]=3[CH:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[S:40]([O:23][CH:21]([CH3:22])[CH2:20][C:12]1[C:11]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:24][NH:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)(=[O:42])(=[O:41])[CH3:39]
Reactant: CC(O)Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
2.35 g (5.58 mmol) of the compound prepared in Step A was dissolved in 50 ml of dry dichloromethane. The solution was cooled to 0° C. and after addition of 2.1 ml (15.07 mmol) of triethylamine 0.87 ml (11.22 mmol) of methanesulfonyl chloride was added over a period of 20 min, then the mixture was stirred at room temperature for 3 h. After washing with water it was dried and concentrated to yield 2.69 g (54%) of the title compound as an intermediate; Mp.: 122-124° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:28]2[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=2[F:26])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 53 %

Procedure:
To a stirred solution of 66.61 (0.7595 g, 2.007 mmol) in DMF (5 mL) at 23° C. was added 2-fluoro-5-(trifluoromethyl)phenylboronic acid (commercially available from Aldrich Chemical Company, Inc.) (0.8352 g, 4.017 mmol) and potassium carbonate (0.8357 g, 6.047 mmol) followed by tetrakis(triphenylphosphine)palladium (0.2364 g, 0.2046 mmol). The mixture was heated to 90° C. After 17 hours, LCMS-showed that the reaction was complete. The mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to afford 66.53A as a clear oil that was used without further purification (414.2 mg, 53% yield).
Reaction SMILES: [Na].Cl[CH2:3][C:4]([OH:6])=[O:5].O.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11]>>[C:4]([OH:6])(=[O:5])[CH2:3][O:12][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(O)CCl
Reactant: CCCCO
Agent: [Na]
Solvent: O
Product: CCCCOCC(=O)O
Temperature: 25 °C

Procedure:
Sodium metal (16 g) was added to 92.5 ml of butanol and heated at reflux under nitrogen. After the sodium had reacted, chloroacetic acid (32.9 g) in 40 ml of butanol was added dropwise and then heated at reflux for twenty hours. The mixture, upon cooling to room temperature, was added to 1300 ml of water and extracted four times with 250-ml portions of diethyl ether. The aqueous phase was acidified to about pH 2 with aqueous hydrochloric acid and again extracted four times with 250-ml portions of diethyl ether. The organic extracts were combined and dried over sodium sulfate, filtered, and concentrated in vacuo. Distillation afforded the title compound as an oil. Structure assignment was supported by the proton nmr spectrum.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[C:25]([CH3:37])[CH:24]=1)=[O:10])=[O:4].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:37][C:25]1[CH:24]=[C:23]([NH:22][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:28]=[CH:27][C:26]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CCl)cc34)cc2C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CN5CCOCC5)cc34)cc2C)cn1
Temperature: 100 °C
Yield: 38 %

Procedure:
0.07 g of the compound obtained in Example 108 dissolved in 5 ml of N,N′-dimethylformamide was reacted with 0.02 ml of morpholine and 0.04 g of potassium carbonate for 10 hours while heating to 100° C. The reacted solution was diluted with distilled water, extracted with ethylacetate, washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (0.03 g, 38%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]([N+:17]([O-:19])=[O:18])[C:7]=1[NH:8][O:9][CH3:10])([O-:5])=[O:4].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O>[CH2:22]([N:8]([O:9][CH3:10])[C:7]1[C:6]([N+:3]([O-:5])=[O:4])=[CH:14][C:13]([CH2:15][CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCc1cc([N+](=O)[O-])c(NOC)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(OC)c1c([N+](=O)[O-])cc(CC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 0.017 mole of sodium hydride, obtained from 0.82 g. of a 50% dispersion of sodium hydride in mineral oil (by the process described in Example 11, supra), was added 50 ml. of dimethylformamide. To the suspension was added 3.0 g. (0.012 mole) of 2,6-dinitro-4-ethyl-N-methoxyaniline (Example 2), and the mixture stirred for about 5-10 minutes. Allyl bromide, 2.9 g. (0.024 mole), was added and the reaction mixture stirred at room temperature for about 30 minutes. A sample of the reaction mixture checked by NMR showed the presence of about 70-80 percent of the desired product, together with about 20-30 percent of starting material. The reaction mixture was then heated at about 90° C., with stirring, for about an hour. A check by NMR indicated the reaction had gone to completion. The reaction product mixture was worked up by adding dilute aqueous hydrochloric acid and toluene. The organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was chromatographed on a Florisil column. The fractions were examined by NMR spectrum, combined, and concentrated in vacuo to dryness. The residue was recrystallized from petroleum ether (b.p. 60°-71° C.) to give 1.7 g. of product having a melting point of about 83°-85° C. The product was identified by NMR spectrum and elemental analyses as N-allyl-2,6-dinitro-4-ethyl-N-methoxyaniline.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)[C:15](=[O:22])[NH:14][C:11]2=[CH:12][CH:13]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:17][CH2:18][S:19][CH2:20][CH2:21]3)[C:15](=[O:22])[N:14]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]2=[CH:12][CH:13]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccc(Br)cc2C12CCSCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Reaction time: 16 h

Procedure:
Cesium carbonate (610 mg, 1.87 mmol) was added to a solution of 5-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-2(1H)-one from Step C (372 mg, 1.25 mmol) and ethyl bromoacetate (0.166 mL, 1.50 mmol) in DMF (2 mL). After 16 h, H2O (5 mL) was added to the reaction and the resulting precipitate was collected by filtration to give the title compound. MS: m/z=386 (M+1).