Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:5])[CH2:3][OH:4].F[C:7](N(CC)CC)([F:11])[CH:8](F)Cl.[F-].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCO>>[F:11][CH:7]([CH3:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:5][CH2:2][CH2:3][OH:4]
Reactant: CCN(CC)C(F)(F)C(F)Cl
Reactant: CC(Br)CO
Reactant: OCCCCCCCCCCCCCBr
Agent: [F-]
Product: CC(F)CCCCCCCCCCCCCCO

Procedure:
A general procedure for the preparation of penultimate fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 6, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(15-fluoro-hexadecyloxy)propyl cidofovir 42 (15-F-HDP-CDV) and 3-(15-fluoro-hexadecyloxy)propyl (S)-HPMPA 43 (15-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 6, commercially available 2-bromopropanoic acid 35 is reduced to the alcohol with borane:THF complex solution to provide 2-bromo-1-propanol 36. Fluorination of 36 is achieved with 1,1,2-trifluoro-2-chloroethyldiethylamine, a mild and safe reagent to convert 1-hydroxy-2-halogenoalkanes into the corresponding rearranged fluoride 37. Conversion of 37 into a Grignard reagent followed by reaction with 13-bromo-tridecanol in the presence of the catalyst provides 15-fluorohexadecanol 38. Conversion of alcohol 38 into the methanesulfonate derivative, followed by reaction with 1,3-propanediol provides 3-(15-fluorohexadecyloxy)propan-1-ol 39. Reaction of 39 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (40 and 41, respectively) which can then be converted to the desired compounds (42 and 43, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.I(O)(=O)(=O)=[O:29]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:29]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c(SC)cccc32)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c2cccc3S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirring suspension of compound 98 (100 mg, 0.266 mmol) and iron (III) chloride (1.296 mg, 7.99 μmol) in acetonitrile (2 mL) after 5 minutes was added periodic acid (66.8 mg, 0.293 mmol) in one portion. The reaction mixture was left to stir at room temperature overnight then quenched with saturated sodium thiosulfate solution and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and solvent evaporated. Purification via ISCO (0-40% EtOAc/Hexanes; 40 g silica gel column) afforded title compound 99 (60 mg, 57%) as a yellow solid. LRMS (ESI): (calc) 391.09 (found) 392.4 (MH)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[CH3:12][NH:13][CH3:14]>[OH-].[Na+]>[CH3:12][N:13]([CH3:14])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: Nc1ccc(OCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCOc1ccc(N)cc1
Reaction time: 21 h

Procedure:
11.15 g (0.065 Mol) of 4-(2-Chloro-ethoxy)-phenylamine is suspended in 150 mL (1.18 Mol) of dimethylamine (40% in water; Fluka 38940) and heated under stirring in a steel pressure reactor at 4 bar for 21 h. After cooling the reaction mixture is diluted with 150 mL of 2N NaOH and extracted with ethyl acetate. The combined organic layers are washed with water, dried (Na2SO4), filtered and evaporated under reduced pressure to obtain 4-(2-dimethylamino-ethoxy)-phenylamine. Title compound: ES-MS: 181 [M+H]+; single peak at tR=1.10 min (System 1).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>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]>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[N:26]2[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]2)=[CH:6][CH:7]=1
Reactant: CC1CNCCN1
Reactant: Brc1ccccc1Oc1ccc(-c2ccccc2)cc1
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: CC1CN(c2ccccc2Oc2ccc(-c3ccccc3)cc2)CCN1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-bromo-phenoxy)-biphenyl (0.73 g, 2.25 mmol), rac-2-methylpiperazine (0.285 g, 0.285 mmol), Pd2 dba3 (0.022 g, 1 mol %), rac-binap (0.043 g, 3 mol %) and NaOBut (0.300 g, 3.12 mmol) in dry toluene (15 mL) under argon and stirred at 90° C. overnight. After cooling to room temperature the mixture is filtered and evaporated onto silica gel and and purified by column chromatography eluting with ethyl acetate/heptane 1:2. Yield: 0.264 g (34%). 1H NMR (CDCl3, 500 MHz) 7.55 (m, 2H), 7.49 (m, 2H), 7.38 (m, 2H), 7.27 (m, 1H), 7.10 (m, 1H), 6.90–7.00 (m, 5H), 3.30–3.35 (m, 2H), 2.88 (m, 1H), 2.62–2.80 (m, 3H), 2.30–2.40 (m, 1H) 1.60–2.00 (br, 1H), 0.99 (d, 3H); MS(m/z): 345.1.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:13]([Cl:37])=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[CH:19][CH:18]=[CH:17][CH:16]=2>>[CH2:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([Cl:37])[C:12]=2[N:11]=[CH:1]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCCCNC(=O)OCc1ccccc1
Reactant: CCOC(OCC)OCC
Product: O=C(NCCCn1cnc2c(Cl)nc3ccccc3c21)OCc1ccccc1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
0.52 ml (3.12 mmol) of triethyl ortho-formate was added to 0.12 g (0.312 mmol) of of 3-amino-4-[3-(benzyloxycarbonylamino)propylamino]-2-chloroquinoline. The mixture was heated at 100° C. and stirred for 3.5 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.12 g (0.304 mmol) of 1-[3-(benzyloxycarbonylamino)propyl]-4-chloro-1H-imidazo[4,5-c]-quinoline (shown below) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]([CH2:20][CH2:21][CH3:22])[CH2:8][NH:9][C:10]2[N:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12](C)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:23](=[O:27])([OH:26])([OH:25])[OH:24].[CH:28](O)(C)C>>[P:23]([OH:27])([OH:26])([OH:25])=[O:24].[C:1]1([CH:7]([CH2:20][CH2:21][CH3:22])[CH2:8][NH:9][C:10]2[N:11]=[CH:12][C:13]([CH3:28])([O:17][CH3:18])[CH:14]([CH3:16])[N:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)O
Reactant: CCCC(CNc1nc(C)c(OC)c(C)n1)c1ccccc1
Agent: O=P(O)(O)O
Product: CCCC(CNC1=NC(C)C(C)(OC)C=N1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.09 g of 2-phenylpentylamino-4,6-dimethyl-5-methoxypyrimidine was dissolved in 15 ml isopropylalcohol and cooled to 0° C. Phosphoric acid (85%, 9 g) was added and the mixture stirred at 0° C. for 30 minutes. White solid precipitated and was collected after removal of the isopropylalcohol, washing with pentane and drying in vacuo at 45° C. M.p.: 107°-8° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1)(=[O:16])=[O:15].I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:29]1([CH2:28][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:15])=[O:16])=[CH:22][CH:21]=2)[C:24]([OH:26])=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A solution of diisopropylamine (3.3 mL, 23.5 mmol) in dry tetrahydrofuran (50 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to −78° C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.35 mL, 23.5 mmol). The yellow reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in a small amount of dry tetrahydrofuran. After approximately one-half of the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added, a precipitate formed. Upon further addition of the remaining 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture became thick in nature. After complete addition of the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture was very thick and became difficult to stir. An additional amount of dry tetrahydrofuran (20 mL) was added to the thick reaction mixture, and the reaction mixture was then stirred at −78° C. for 45 min. The reaction mixture was then treated with a solution of iodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (100 mL), and the resulting yellow reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified to pH=2 using concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (1.80 g, 52%) as a white solid: mp 152-154° C.; EI-HRMS m/e calcd for C15H20O4S (M+) 296.1082, found 296.1080.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[C:17]([CH3:27])=[CH:18][C:19]([OH:26])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22].C(OCC)(=O)C>CN(C)C=O.O>[Br:15][C:16]1[C:17]([CH3:27])=[CH:18][C:19]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Potassium carbonate (0.85 g, 6.12 mmol) and benzyl bromide (0.53 ml, 4.49 mmol) were added to a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (1 g, 4.08 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred at room temperature for 72 hours. Ethyl acetate (20 ml) and water (20 ml) were added and the organic layer separated, washed with water (3×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (10% ethyl acetate/hexanes) yielded the title compound as an oil. 1.35 g.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCO)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: OCCCCc1ccc(O)cc1
Temperature: 15 °C
Yield: 86 %

Procedure:
To a solution of 4-(4-methoxyphenyl)butanol (100 g, 0.55 mole) in dichloromethane, cooled to -75° C. in a dry ice-acetone bath, a solution of boron tribromide (278 g; 2.0 mole) was added slowly over one hour. The cooling bath was then removed and the reaction mixture allowed to warm to 15° C. slowly. The reaction was shown to be complete by thin layer chromatography (TLC). The reaction mixture was again cooled in an ice-water bath; 10% sodium hydroxide solution was added until pH of about 9 was obtained. The resulting mixture was then acidified with concentrated HCl to a pH of about 2. The organic layer was separated, the aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 90 g of. crude product. The crude product was purified by dry filtration chromatography using 10% ethyl acetate/dichloromethane as eluent giving an 86% yield of pure 4-(4-hydroxyphenyl)butanol. The 1H NMR was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1.[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41]
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Yield: 51.9 %

Procedure:
A 48 mL sealed tube was charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.150 g, 0.529 mmol), 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.242 g, 0.793 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.0432 g, 0.0529 mmol), cesium carbonate (0.689 g, 2.11 mmol), 1,4-dioxane (3.62 ml, 42.3 mmol), and water (0.905 ml, 50.2 mmol), flushed with argon, sealed, then placed in a 80° C. oil bath for 5 hours. The contents were transferred to a flask and concentrated. The solid was triturated with water to give a red residue, which was purified by MPLC using a 40 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.117 g, 51.9% yield) was isolated as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5](=[O:8])[NH:6][N:7]=1)[CH3:2].Cl[CH:19]([OH:22])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[OH:22][CH2:19][CH2:20][CH2:21][N:6]1[C:5](=[O:8])[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([CH2:1][CH3:2])=[N:7]1
Reactant: CCc1n[nH]c(=O)n1CCOc1ccccc1
Reactant: CCC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1nn(CCCO)c(=O)n1CCOc1ccccc1

Procedure:
The product of Example 5 "5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one" (5.0 g., 23.5 mmol), chloropropanol (2.44 g., 25.8 mmol) and potassium carbonate (9.72 g., 70.4 mmol) in 50 ml. of acetonitrile is heated to reflux for a period of 48 hr. with stirring. Water (50 ml.) is added and the mixture extracted with methylene chloride which is dried over magnesium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one (XIV, Y=H, X1 =0, n=2, R2 =C2H5). Purification is carried out by flash chromatography with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14](OCC)(=[O:17])[CH2:15][CH3:16].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:14](=[O:17])[CH2:15][CH3:16])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CC
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC(=O)C(C#N)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl propanoate (1.61 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxopentanenitrile as a brown oil (0.8 g, 3.4 mmol, 30% yield), MS (EI) for C13H15NO3: 234 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Br[C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.CN1C(=O)CCC1>[CH3:47][O:46][C:43]1[N:42]=[CH:41][C:40]([CH:3]=[CH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:45][CH:44]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(C=CC(=O)OC(C)(C)C)cn1
Temperature: 90 °C
Reaction time: 0.83 h
Yield: 98.4 %

Procedure:
A mixture of tert-butyl acrylate (98%; 137 mL; 916 mmol), triethylamine (100 mL; 720 mmol), tri-O-tolylphosphine (97%; 6.30 g; 20 mmol), Pd(OAc)2 (1.80 g; 8 mmol), and NMP (90 mL) was degassed three times. The mixture was heated to 90° C., and a solution of 2-methoxy-5-bromopyridine 1-2(50.0 g; 266 mmol) and NMP (10 mL) was added via addition funnel over 1 hour, maintaining the reaction temperature at 90° C. The reaction was heated for 12 hours after complete addition. The reaction mixture was cooled down to room temperature after completion of the reaction. To the reaction mixture was added toluene (400 mL), and the resulting solution was then passed through a pad of Solka Flok. The filter cake was washed with toluene (270 mL). The toluene solution was washed with water (3×540 mL). An aqueous solution of sodium hypochlorite (NaClO) (2.5%; 200 mL) was slowly added to the toluene solution keeping the temperature about 30° C. The reaction was aged 50 min with a vigorous stirring. The organic layer was separated, washed with water (540 mL) three times, and followed by saturated aqueous NaCl (270 mL). The organic layer was concentrated to oil. The oil was dissolved in 270 mL hexanes and loaded onto to a silica gel (90 g) pad. The silica gel pad was washed with hexanes (73 mL). The product 1-3was eluted with EtOAc:hexane (1:8; v/v) in about 730 mL. The yellow solution was concentrated to oil (126 g; 49.2 wt %; 98.4% yield). The crude oil was used for the next reaction without further purification. Authentic sample was obtained by further concentration of the oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:25].[I-].N.CCO>>[NH2:25][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(c3cccs3)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccs3)Oc3ccc(Br)cc32)N=C1N
Yield: 27.1 %

Procedure:
A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.047 mmol), NH4I (13.7 mg, 0.094 mmol) in a solution of NH3/EtOH (2 mL, 2 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-methyl-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (5 mg, 20%). 1H-NMR (CDCl3): 2.52 (m, 2H), 3.14 (s, 3H), 6.12 (d, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.14 (d, 1H), 7.43 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[F:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][CH:9]=3)[C:5]([CH3:17])=[CH:4][N:3]=2)[CH:25]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1N
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 5-Fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 54).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.CCN(C(C)C)C(C)C.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:45][NH2:46])C=CC=CC=1>C(Cl)Cl>[SH:45][NH:46][C:20](=[O:21])/[CH:19]=[CH:18]/[C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[N:10][O:9][CH2:8][C:7]2[CH:23]=[CH:24][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: NSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1ccc(C=NOCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C=NOCc2ccc([N+](=O)[O-])cc2)cc1)NS

Procedure:
Compound (2E)-3-{4-[(4-Nitro-benzyloxyimino)-methyl]-phenyl}-N-tritylsulfanyl-acrylamide was obtained (0.050 g, 0.08 mmol, 26% yield) by reaction of intermediate C (2E)-3-[4-({[(4-nitrobenzyl)oxy]imino}-methyl)phenyl]acrylic acid (ST3075, 0.100 g, 0.31 mmol) with SOCl2 (34 μL, 0.46 mmol), DIEA (236 μL, 1.38 mmol) and Triphenylmethanesulfenamide (0.098 g, 0.14 mmol) in anhydrous DCM at room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]Br.S(=O)(=O)(O)O>>[Br:10][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1]
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: Cc1ncc(F)c(Cl)c1Br

Procedure:
4-Chloro-5-fluoro-2-picoline, the product of Exmnple 66, is treated with bromine in fuming sulfuric acid containing 65% sulfur trioxide for 7 hours at 80° C. as described by L. van der Does and H. J. Hertog in Rec Tray Chim 81:864 (1965) to afford the title compound.
Reaction SMILES: C([C:3]([C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH2:7][C:8]([O-:10])=[O:9])C([O-])=O)C.[OH-].[Na+].CCOCC>O>[O:17]=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCCCCC(=O)C(CC)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(=O)CCC(=O)O

Procedure:
The part (a) ester (1.0 g, 3.7 mmol) was treated with a solution of NaOH (1.5 g, 37.5 mmol) in water (15 ml). The heterogeneous mixture was heated under gentle reflux for 9 hours. After cooling, ether (20 ml) was added. The layers were separated. The aqueous layer was washed with ether (10 ml) and then acidified to pH 2 using concentrated HCl. The product was extracted into ether (3×20 ml). The ether extracts were washed with saturated NaCl solution, dried (MgSO4), and freed of solvent in vacuo leaving an oil which gradually solidified (345 mg). This was crystallized from petroleum ether to give title acid (189.9 mg, 30%) as colorless needles, m.p. 64°-66° C.