Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[O:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.ClCCl.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[CH:17]=1)[CH2:13][NH:12][C:4]1[CH:3]=[C:2]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([CH:25]3[CH2:24][CH2:23][O:22][CH2:27][CH2:26]3)=[CH:29][CH:30]=2)[N:7]=[CH:6][C:5]=1[CH2:8][C:9]([NH2:11])=[O:10]
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1cc(F)cc(F)c1
Reactant: Nc1ccc(C2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)Cc1cnc(Nc2ccc(C3CCOCC3)cc2)cc1NCc1cc(F)cc(F)c1
Yield: 16.6 %

Procedure:
29 mg of 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 20) and 35 mg of 4-(tetrahydro-2H-pyran-4-yl)aniline were dissolved in 0.35 mL of 1,4-dioxane, to which 8.0 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane, 17 mg of 1,1′-bis (diphenylphosphino)ferrocene and 12 mg of sodium tert-butoxide were added, and stirred using a microwave reaction apparatus under an argon atmosphere at 100° C. for 1 hour. After cooling, the solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=20:1) to obtain 7 mg (16%) of the title compound as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43].C(=O)(O)[O-].[Na+]>ClCCl>[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:23][CH:24]=1)=[O:43]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2cc(F)ccc12
Yield: 42.6 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-6-fluoro-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (0.5 mL) were dissolved in dichloromethane (15 mL). In an ice bath, dichloromethane solution (10 mL) of 2-naphthoyl chloride (191 mg, 1.0 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 205 mg, at a total yield over two steps of reactions of 42.6%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]2=[O:30])=[C:4]([F:31])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:38](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:38][N:21]1[C:22]([C:26]([F:28])([F:29])[F:27])=[CH:23][C:24](=[O:25])[N:19]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([F:16])([F:17])[F:18])[C:2]([Cl:1])=[CH:3][C:4]=2[F:31])[C:20]1=[O:30]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2C(F)(F)F)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3C(F)(F)F)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 3-[4-chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4,-dione (0.7 g), potassium carbonate (0.27 g) and 2,4-dinitrophenoxyamine (0.39 g) in anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 72 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with hexane:ethyl acetate, 4:1, containing 0.1% of triethylamine. The product (Compound 9-24) was isolated as a pale yellow amorphous solid (0.6 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1cc(C(=O)OC)ccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(C(=O)OC)ccc1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a magnetically stirred solution of 0.405 g (1.94 mmol) of the product of Step D dissolved in 5.0 mL of methylene chloride was added 0.638 g (2.43 mmol) of triphenylphosphine followed by 0.806 g (2.43 mmol) of carbon tetrabromide at room temperature. The reaction mixture was stirred for 30 minutes at room temperature, then the magnetic stir bar was removed and the methylene chloride was evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane, and evaporation of the purified fractions and solvent removal in vacuo afforded 0.496 g (94%) of the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[C:22]2[C:21]3[CH:20]=[C:19]([O:23][CH3:24])[C:18]([O:25][CH3:26])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[NH:12][N:11]=1.BrC1N(C)N=C2C=1C1C=C(OC)C(OC)=CC=1N=C2>CN(C)C=O.C(OCC)(=O)C.O>[Br:9][C:10]1[C:22]2[C:21]3[CH:20]=[C:19]([O:23][CH3:24])[C:18]([O:25][CH3:26])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:1])[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2ncc3[nH]nc(Br)c3c2cc1OC
Agent: COc1cc2ncc3nn(C)c(Br)c3c2cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc2ncc3c(c(Br)nn3C)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (270 mg, 1.95 mmol) and methyl iodide (78 μl, 1.27 mmol) is added at room temperature to a solution of 1-bromo-7,8-dimethoxy-3H-pyrazolo[3,4-c]quinoline (300 mg, 972 μmol) in anhydrous N,N-dimethylformamide (36 ml). The reaction mixture is subsequently stirred at room temperature for 18 h. When the reaction is complete, the mixture is poured into water (150 ml) and diluted with ethyl acetate (150 ml). The phases are separated, and the aqueous phase is extracted a number of times with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered with suction, and the filtrate is evaporated to dryness in vacuo, giving 282 mg (876 μmol) of a mixture of the title compound (Rf=0.45) and 1-bromo-7,8-dimethoxy-2-methyl-2H-pyrazolo[3,4-c]quinoline (Rf=0.55) in the mixing ratio 3:1. For purification, the regioisomer mixture is dissolved in hot ethyl acetate in such a way that a minimal volume of solvent is sufficient for complete dissolution. The solution is subsequently slowly cooled to 0° C., giving a precipitate of pure 1-bromo-7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinoline (125 mg). After filtration with suction, the filtrate (regioisomer mixture about 1:1), evaporated in vacuo, is again dissolved in hot ethyl acetate, and a little cyclohexane is added to the solution. After 24 h, the precipitate obtained is filtered off with suction, giving further 1-bromo-7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]-quinoline (31 mg). The combined crystal batches are dried in a high vacuum, giving the title compound 1-bromo-7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinoline (156 mg, 484 μmol) having a melting point of 235.5° C. MS: 322.0/324.0 (M+H+, monobromo isotope distribution), TLC (HPTLC): Rf=0.45 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: CN1CCNCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN1CCN(c2nccc(-c3ccc(C(=O)NCCc4ccc5[nH]cc(C#N)c5c4)cc3)n2)CC1

Procedure:
Using N-methyl-piperazine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 466 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH3:8][C:9]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH3:8][C:9]1([NH:16][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(N)CCCCCC1
Reactant: O=S1(=O)CCCO1
Solvent: Cc1ccccc1
Product: CC1(NCCCS(=O)(=O)O)CCCCCC1
Temperature: 25 °C

Procedure:
A solution of 1,3-propanesultone (4.3 g, 35 mmol) in toluene (10 mL) was added dropwise to a the crude solution of 1-methyl-1-cycloheptylamine in MTBK (total volume 30 mL). The mixture was heated to reflux for 18 hours then was cooled to room temperature. The solid was collected by suction filtration, rinsed with acetone (2×5 mL). The solid was dried overnight at 45° C. in the vacuum oven. The title compound was obtained as a fine white solid (7.77 g, 31.2 mmol, 80% overall yield). 1H NMR (500 MHz, D2O) δ 1.27 (s, 3H), 1.40-1.60 (m, 8H), 1.71-1.81 (m, 4H), 2.00-2.06 (m, 2H), 2.95 (t, J=6.3 Hz, 2H), 3.13 (t, J=7.1 Hz, 2H); 13C NMR (125 MHz, D2O) δ 22.0, 22.1, 23.3, 29.5, 37.1, 40.0, 48.3, 64.0; ES-MS 250(M+H)
Reaction SMILES: [Na].CCO.[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH2:30][CH3:31])[CH:23]=1>O1CCOCC1>[C:5]([NH:8][C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH2:30][CH3:31])[CH:23]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCc1ccc(CBr)cc1CC
Agent: [Na]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(CC)c(CC)c1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 8.14 g (354 mmol) of sodium was added in batches to 200 mL abs. EtOH and stirred until fully dissolved. 76.9 g (354 mmol) diethyl 2-acetylaminomalonate was then added to this solution, whereupon the sodium salt formed was precipitated. After the addition of 150 mL 1,4-dioxane a solution of 80 g (352 mmol) of 4-bromomethyl-1,2-diethyl-benzene in 500 mL of 1,4-dioxane was added dropwise to this suspension. The reaction solution was kept at 50° C. for 2 hours and then stirred for 16 hours at RT. The solvent was distilled off i. vac., the oily residue was combined with water, while the product was obtained in the form of white crystals. These were suction filtered, washed with water and reacted without any further purification.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](C(OCCC(C)(C)C)=O)[C:14]([C:28]([O-:30])=[O:29])=[CH:13]2)(C)C.Cl.[C:34](O)([C:36](F)(F)F)=O>C1COCC1>[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:28]([O:30][CH2:34][CH3:36])=[O:29])=[CH:13]2
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)CCOC(=O)n1c(C(=O)[O-])cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc21
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCCO)ccc2[nH]1
Temperature: 25 °C
Yield: 107 %

Procedure:
A solution of 1-(1,1-dimethylethyl)2-ethyl 5-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H-indole-1,2-dicarboxylate (0.389 g, 0.840 mmol) in THF (4 mL) was treated with 1N HCl (0.840 mL, 0.840 mmol) and the reaction mixture was stirred for several hours at room temp. TLC showed consumption of the starting material and 2 product spots. Solvents were evaporated and the residue dissolved in DCM (4 mL) and TFA (0.25 mL, 3.24 mmol) was added. TLC showed a single product spot. The solvents were evaporated to afford the title compound (0.224 g, 96%) as a grey solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 10.74 (br. s., 1H), 7.41 (d, 1H), 7.32 (s, 1H), 7.12 (d, 1H), 7.06 (d, 1H), 6.94 (dd, 1H), 4.32 (q, 2H), 4.05 (t, 2H), 3.88 (t, 2H), 1.32 (t, 3H). LCMS: m/z 204.2 (M-45).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][NH2:14]>C1COCC1>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:14][CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: C1CCOC1
Product: CNc1nc(OC)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 154a from 2-chloro-6-methoxy-3-nitropyridine and 2 N methylamine (solution in THF) in THF
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)SC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:24]([NH2:26])[CH3:25]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)[NH:26][CH2:24][CH3:25])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CSC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCCC2
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 4.05 g 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-methylsulfanyl-methylene]-benzenesulfonamide in 30 mL MeOH was added 7.86 mL of a 70% aqueous solution of ethylamine. The mixture was stirred for 1 h. at room temperature and evaporated to dryness. The residue was dissolved in a minimal amount of DCM and triturated with MTBE. The precipitate was filtered off and dried in vacuo, and subsequently recrystallized from n-butyl acetate to give 2.40 g (67%) of 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-benzenesulfonamide as an off-white microcrystalline material after drying in vacuo at 80° C.; m.p. 141-142° C. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.22 Hz, 3H), 1.47-1.89 (m, 8H), 3.35-3.57 (m, 2H), 3.79 (s, 2H), 4.02 (br.s., 2H), 6.65 (d, J=8.73 Hz, 2H), 6.78 (s, 1H), 6.91 (br. s., 1H), 7.70 (d, J=8.73 Hz, 2H).
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].C(N1CCCC1=O)=C.[C:17]([O:22][CH2:23][CH2:24]OC(=O)C(C)=C)(=[O:21])[C:18](C)=C.C(N1CCCC1=O)=C.C(OCCCCCCCCCCCC)(=O)C(C)=C>C1CCCCC1.C(OOC(=O)CCCCCCCCCCC)(=O)CCCCCCCCCCC>[CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].[C:17]([O:22][CH:23]=[CH2:24])(=[O:21])[CH3:18]
Reactant: C=C(C)C(=O)OCCOC(=O)C(=C)C
Agent: C=C(C)C(=O)OCCCCCCCCCCCC
Agent: C=CN1CCCC1=O
Agent: CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC
Solvent: C1CCCCC1
Product: C=COC(C)=O

Procedure:
An uncrosslinked vinylpyrrolidone (VP) homopolymer, a crosslinked 98/2 weight ratio vinylpyrrolidone/ethylene glycol dimethacrylate (VP/EGDM)copolymer, an uncrosslinked 70/30 weight ratio vinylpyrrolidone/lauryl methacrylate (VP/LM) copolymer and an uncrosslinked 79/21 weight ratio vinylpyrrolidone/vinyl acetate (VP/VA) copolymer were prepared by solution polymerization in cyclohexane using lauroyl peroxide as catalyst. The viscous reaction mixture was cast on a polytetrafluoroethylene sheet and the solvent was permitted to evaporate. The resultant thin film was dried at 60° C. in a forced air oven, washed free of residual monomer, if any, with petroleum ether and redried in vacuo at 60° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1>C1COCC1>[Br:28][C:12]1[N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:8])=[O:7])[CH:13]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccn(CC2CCCCC2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc(Br)n(CC2CCCCC2)c1
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a stirred mixture of compound 27e (280 mg, 0.94 mmol) in dry THF (3 mL) was added NBS (200 mg, 1.13 mmol) at −78° C. and the solution was stirred at this temperature for 30 min, quenched with water and extracted with EA twice. The combined organic layers were washed with water (3×) and brine, concentrated and purified by CC (PE/EA=5/1) to give compound 27f (300 mg, 85%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 65.2 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-cyano phenoxy)-nicotinic acid 1.25 g (3.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.65 g, 3.5 mmol) were used to afford 1.2 g of the required product. Percentage purity (LCMS): 95.6%, (M+1)=525.2 (with BOC). 1H NMR (DMSO-d6): δ 1.40 (9H, s), 3.30 (2H, m), 3.42 (4H, m), 3.61 (2H, m), 6.98 (1H, d), 7.35 (4H, m), 7.82 (4H, dd), 8.02 (2H, d).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[C:30]([CH2:29][CH2:28][C:27](=[O:33])[O:23][CH2:22][C:20](=[O:21])[C@:19]1([OH:24])[C@:15]2([CH3:25])[C@H:16]([C@H:11]3[C@H:12]([C@H:13]([OH:26])[CH2:14]2)[C@:2]2([CH3:1])[C:8](=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)[CH2:9][CH2:10]3)[CH2:17][CH2:18]1)([OH:32])=[O:31]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)COC(=O)CCC(=O)O

Procedure:
A solution of 3.60 g of 11-epi-cortisol and 1.00 g of succinic anhydride in 45 ml of pyridine was stirred for 4 days at room temperatures The reaction was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was partitioned with sodium bicarbonate. The aqueous layer was washed with methylene chloride. The aqueous layer was acidified with 10% aqueous U HCl and was extracted with chloroform. The organic phase was concentrated. The residue was chromatographed on RP2 silica gel (20% ethyl acetate/methylene chloride) to yield the product which was crystallized from hot ethyl acetate to yield 2.00 g of the white, solid product, mp 208-209. Anal. Calcd for C25H34O8. Calcd/Found: C, 64.92/64.24; H, 7.41/7.08
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[OH-].[K+]>O.C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:20][CH2:19]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)C1CCc2cc(OCc3ccccc3)ccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid benzyl ester (30) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h, cooled to room temperature, and quenched with hydrochloric acid (5%), the resulting white solid was filtered, washed with water, and dried under vacuum to give 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (31) as a white solid (95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([CH3:16])([CH2:14][OH:15])[CH2:12]O.C(C=P(CCCC)(CCCC)CCCC)#N.O.O.[Sn](Cl)Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:11]1([CH3:16])[CH2:14][O:15][CH2:12]1)[NH2:8]
Reactant: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1Br
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: Cl[Sn]Cl
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2ccc(N)cc2Br)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (0.145 g, 0.500 mmol) was dissolved in 2.5 mL of anhydrous benzene. Cyanomethylenetributylphosphorane (CMBP) (0.181 g, 0.750 mmol) was then added and the solution was allowed to stir at room temperature for 72 hours. The mixture was evaporated to dryness and then re-dissolved in 4 mL of EtOH. Tin(II) chloride dihydrate (0.564 g, 2.50 mmol) was then added and the resulting solution was heated at 70° C. for 1 hour. The mixture was cooled to room temperature and then quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were evaporated to dryness and purified by preparative LC/MS to yield 3-bromo-4-(3-methyloxetan-3-yl)aniline as a pale yellow oil (0.032 g, 32%) 1H NMR (400 MHz, CD3CN) δ 7.13 (dd, J=0.7, 1.8 Hz, 1H), 6.94-6.88 (m, 2H), 6.75 (br s, 2H), 4.98 (d, J=5.6 Hz, 2H), 4.51 (d, J=6.1 Hz, 2H), 1.74 (s, 3H). ESI-MS m/z calc. 241.0, found; 242.1 (M+1)+ Retention time 0.53 minutes.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[CH:13][C:12]=3[N:21]=[C:9]2[CH2:8][O:7][CH2:6]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:3][CH2:4][C@@H:5]2[N:10]3[C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=[CH:13][C:12]=4[N:21]=[C:9]3[CH2:8][O:7][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OC[C@H]1COCc2nc3cnc4ccccc4c3n21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 98.5 %

Procedure:
A 100-mL, round-bottomed flask, under an atmosphere of N2, was charged with sodium hydride (60% oil dispersion, 72 mg, 1.78 mmol). The sodium hydride was washed with 3 portions of hexanes to remove the oil and then 20 mL of anhydrous THF was added. The reaction mixture was cooled to 0° C. and (11S)-11-hydroxymethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (413 mg, 1.62 mmol) was added. After stirring for 75 minutes, 4-fluorobenzyl bromide (215 μL, 1.78 mmol) was added. The reaction was allowed to warm to ambient temperature overnight. After 20 hours the reaction mixture was treated with 20 mL of saturated NaHCO3 solution and 20 mL of ethyl acetate and the layers were separated. The organic portion was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduce pressure to give (11S)-11-{[(4-fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (580 mg) as a light-yellow, glassy solid.