Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][C:18](=[O:20])[CH3:19])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[S:7][CH:8]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][NH2:35])=[S:33])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[C:18]([O:17][C:5]1[C:4]([C:1](=[N:35][NH:34][C:32](=[S:33])[NH:31][C:29]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([Cl:21])[CH:30]=2)[CH3:2])=[CH:8][S:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)(=[O:20])[CH3:19]
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(Cl)c(Cl)c1
Product: CC(=O)Oc1c(C(C)=NNC(=S)Nc2ccc(C(=O)O)c(Cl)c2)csc1-c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from acetic acid 4-acetyl-2-(3,4-dichlorophenyl)thiophen-3-yl ester (39.5 mg, 0.12 mmol) and 2-chloro-4-(hydrazinecarbothioamido)benzoic acid (40.5 mg, 0.132 mmol) following the procedure described in the synthetic example 185.
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].Br[C:7]1[CH:8]=[C:9]([CH2:14][OH:15])[CH:10]=[C:11]([F:13])[CH:12]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:13][C:11]1[CH:10]=[C:9]([CH2:14][OH:15])[CH:8]=[C:7]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:12]=1
Reactant: CS(=O)[O-]
Reactant: OCc1cc(F)cc(Br)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(F)cc(CO)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 48.2 %

Procedure:
Methanesulphinic acid sodium salt (748 mg, 7.33 mmol) was added to (3-bromo-5-fluorophenyl)methanol (501 mg, 2.44 mmol) and copper(I) iodide (0.248 mL, 7.33 mmol) in DMSO (12 mL) under nitrogen. The resulting mixture was stirred at 90° C. for 3 days. The reaction mixture was diluted with EtOAc (300 mL), then filtered. The filtrate was washed sequentially with water (200 mL) and saturated brine (2×200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford [3-fluoro-5-(methylsulfonyl)phenyl]methanol (240 mg, 48.1%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([CH:10]=[CH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:12][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: ClCc1coc(C=Cc2ccc(Cl)c(Cl)c2)n1

Procedure:
2.3 g (10.6 mmol) 3-(3,4-Dichloro-phenyl)-acrylamide, 4.73 g (37,2 mmol) 1,3-dichloro acetone and 15.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by flash column chromatography (heptane/ethyl acetate 2:1). Yield: 2.88 g (94%) 4-Chloromethyl-2-[2-(3,4-dichloro-phenyl)-vinyl]-oxazole as tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH2:22])=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH:22][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:24][CH:25]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(COc2cn(C)c3c(C(N)=O)cccc3c2=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cn(C)c3c(C(=O)NCCN4CCCC4)cccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carboxamide (1.09 g, 3.22 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.193 g, 4.83 mmol) and the mixture was stirred at room temperature for 1 h. Then the mixture of 1-(2-chloroethyl)pyrrolidine, Hydrochloride (0.548 g, 3.22 mmol) and triethylamine (0.494 mL, 3.54 mmol) in N,N-dimethylformamide (30.0 mL) was added in one portion. The resulting mixture was stirred at 50° C. for 3.5 h. Extra NaH (0.15 eq) was added, the mixture was stirred at 50° C. for another 0.5 h. The solvent was removed in vacuo, and the residue was partitioned between water (50 mL) and dichloromethane (50 mL), and extracted with DCM for three times. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The light yellow residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with [CH2Cl2/MeOH/NH4OH (80:20:2)]/CH2Cl2 (0-50%) to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-8-carboxamide (0.3 g, 0.689 mmol, 21.38% yield) as a light brown oil. LCMS: (M+H)+: 436.3.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([F:18])([F:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:22]=1>>[F:17][C:8]1([F:18])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:30]#[C:29][C@@:27]([OH:31])([C:23]3[N:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH3:28])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(F)F
Reactant: C#C[C@@](C)(O)c1cccnn1
Product: C[C@@](O)(C#Cc1ccc2c(c1)-n1nc(C(N)=O)cc1C(F)(F)CO2)c1cccnn1

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,4-difluoro-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(pyridazin-3-yl)but-3-yn-2-ol to give a mixture of titled compound after purification by prep HPLC.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20]Cl)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1c(NC(C)=O)c(OCCCl)c(OC)c2occc12
Solvent: Cc1ccccc1
Product: COc1c(NC(C)=O)c(OCCN2CCN(C)CC2)c(OC)c2occc12

Procedure:
A solution of 15.5 g (0.05 mole) of 5-acetamido 6-(2-chloro ethoxy) 4,7dimethoxy benzofuran prepared in the preceding example and 15 g (0.15 mole) of N-methyl piperazine was brought to reflux for 8 hours in 100 ml of toluene. It was filtered and the filtrate evaporated under vacum the residue was taken up again in alcohol and hydrochloric alcohol was added. It was filtered and recrystallized in absolute alcohol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[N:19]=[C:18]([CH:30]([CH3:32])[CH3:31])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:30]([CH3:32])[CH3:31])=[N:19][N:20]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2nc3ccccc3s2)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2nc3ccccc3s2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (86.5 g, 486 mmol) was added in portions to the pyrazole (164 g, 486 mmol, Step A) in DMF (1l) at 0° C. under an atmosphere of N2. This mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was poured into H2O (1 l) and the resulting precipitate was collected and washed with water. The product was dried overnight to give 184.1 g (91%), mp 146°-147° C. (hexanes).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:30]([C:31](Cl)=O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[C:30]([C:31]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccnc2Cl)n1
Temperature: 150 °C
Yield: 34.2 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-3-pyridinecarbonyl chloride (0.186 g, 1.10 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.047 g (40% yield) of pure product: MS (ES) m/z 445 (M+).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][CH2:16][CH2:17]I.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCI
Reactant: NCCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCCCN)c1ccccn1
Yield: 66.9 %

Procedure:
Sodium hydride (1.1 g) was dissolved in DMSO (20 ml) at 70°-75° C. under nitrogen. The solution was cooled and a solution of 2-(4-aminobutylamino)pyridine (6.9 g) in DMSO (20 ml) added at room temperature. N-Propyl iodide (7.81 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 25°-35° C. After a further 15 min. water (200 ml) was added and the mixture was extracted with ether. The ether extract was washed with hydrochloric acid (2N) and the aqueous layer made alkaline to pH 6. After extracting with chloroform, the pH of the aqueous layer was raised to pH 14 and extracted with ether. The ether extracts were washed with 0.1N sodium hydroxide, dried (K2CO3) and the ether evaporated to give 2-[N-(4-aminobutyl)-N-propylamino]pyridine (5.79 g) as an oil which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[OH:4][CH2:3][CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:14])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C(N)CO)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: Cc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(C(F)(F)F)cc4)n3)cc2)cc1

Procedure:
The title compound was prepared with 2-amino-2-(p-tolyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.39 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.76 (t, J=8.5 Hz, 2H), 6.63-6.49 (m, 7H), 5.12-5.00 (m, 1H), 3.56-3.08 (m, 2H), 1.73 (s, 3H); ESIMS m/z 498 ([M+H]+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][NH:10]2)=[CH:6][CH:5]=1.I[CH3:20].O>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][N:10]2[CH3:20])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCOC(=O)Cc1n[nH]c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1nn(C)c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Sodium hydride (24 mg, 0.602 mmol, 60% in oil) was added to ethyl (6-chloro-1H-indazol-3-yl)acetate (Preparation 168, 120 mg, 0.502 mmol) in THF (4 mL) at 0° C. and the mixture was stirred for 30 minutes. Then iodomethane (0.09 mL, 1.508 mmol) was added. The mixture was stirred at room temperature for 30 mins then water (4 mL) was added. The mixture was evaporated in vacuo and the aqueous residue was acidified with aqueous HCl (6 M). This was extracted with ethyl acetate (10 mL) and the organic phase was dried over sodium sulphate and evaporated in vacuo to afford the title compound as a white solid in 100% yield, 150 mg.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([Pb+3])[CH:19]=1.[CH:23]12[CH2:30][CH:27]([CH2:28][CH2:29]1)[C:26](=[O:31])[CH2:25][C:24]2=[O:32].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([CH:25]2[C:26](=[O:31])[CH:27]3[CH2:30][CH:23]([CH2:29][CH2:28]3)[C:24]2=[O:32])[CH:19]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution of 5-bromo-2-ethylphenyllead triacetate (16.34 g, 28.80 mmol) in chloroform (160 ml) is added bicyclo[3.2.1]octane-2,4-dione (3.61 g, 26.10 mmol) and 4-dimethylaminopyridine (16.63 g, 131 mmol), and the reaction mixture is stirred at room temperature for 5 minutes. Next toluene (40 ml) is added, and the mixture is stirred at 80° C. for 1 hour (pre-heated oil bath). The reaction mixture is allowed to cool to room temperature, quenched with 1M hydrochloric acid, and the organic phase separated. The aqueous phase is further washed with dichloromethane (×2), and again the phases are separated. All organics are combined then evaporated under reduced pressure to give a crude oil, which is purified by flash column chromatography on silica gel (30% to 50% ethyl acetate/iso-hexane eluant ratio, then 10% methanol/dichloromethane eluant ratio). The resulting gum is then recrystalised from dichloromethane/hexane to afford 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (4.62 g, 55%) as a cream coloured solid.
Reaction SMILES: S[C@:2]1([OH:33])[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:23])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:22])[CH2:17]CC(O)C)[CH2:3]1.C(O)(=O)C>CC(N(C)C)=O>[CH3:22][CH:16]([CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:24]2([CH3:32])[C@H:8]([C@H:7]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C:4]([CH2:3][C@H:2]([CH2:30][CH2:29]2)[OH:33])=[CH:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:23])[CH3:17]
Reactant: CC(O)CCC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@](O)(S)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -2 °C
Reaction time: 1 h
Yield: 325.8 %

Procedure:
The bromobutylated Tecothane (1.14 g, containing approximately 0.5 mmol of 4-bromobutyl groups) described above was dissolved in DMAc (20 ml) under argon and cooled to −2° C. A solution of 3-mercapto-2-hydroxypropyl-cholesterol (0.495 g, 1.04 mmol) in DMAc (8 ml) was added and a freshly prepared 0.12 M DMAc-solution of (Bu4N)2B4O7 (5 ml, 6 mmol) was also added. The mixture was stirred at −1 to 1° C. for one hour and acidified with acetic acid (0.12 ml, 2 mmol). The reaction solution was then filtered and the polymer was precipitated with methanol (150 ml). The precipitate was washed with methanol alternating with 2-propanol and stirred consequently with large amounts of 2-propanol, methanol, and water and dried under 0.05 mm Hg conditions. The procedure yielded 1.31 g of cholesterol-modified Tecothane. 1H NMR analysis of this polymer (DMF-d7) indicated covalent attachment of cholesterol to 20% of the urethane segments via noncleavable sulfide bonds (see FIG. 2) corresponding to approximately 0.4 mmol of pendant cholesterol moieties per gram of polymer.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]=[O:11].S(OC)(O[CH3:16])(=O)=O.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:16][O:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COc1c(C=O)cccc1C=O
Temperature: 75 °C
Yield: 54 %

Procedure:
2-Hydroxy-1,3-benzenedicarboxaldehyde (1.05 g, 7 mmol), dimethyl sulfate (1.06 g, 8.4 mmol), and 55 mL of acetonitrile were charged into a 1-necked flask equipped with a mechanical stirrer. 1.45 g (10.5 mmol) of potassium carbonate was added at room temperature under nitrogen. The mixture was stirred at 75° C. until GC-MS indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether, washed with NaCl/H2O, and dried over MgSO4. The ether was evaporated off. The crude product was recrystallized from diethyl ether. Pale yellow solid (0.62 g, 54% yield) was obtained. 1H NMR in CDCl3 was consistent with the proposed structure. 1H NMR (CDCl3): δ 10.4 (2H), 8.1 (2H), 7.4 (1H), 4.1 (3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[Br-:15].[Br-:16].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2]>CO.C(Cl)Cl>[Br:15][C:6]1[C:5]([C:11]([F:12])([F:13])[F:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([Br:16])[C:7]=1[OH:10]
Reactant: [Br-]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(O)c(Br)c1C(F)(F)F
Yield: 15.5 %

Procedure:
2-Nitro-5-hydroxybenzotrifluoride (2.0 g, 9.7 mmol) was dissolved in a mixture of MeOH and CH2Cl2 (80 mL, 1:1) at 0° C. Benzyltrimethylammoniumtribromide (7.53 g, 19.3 mmol) and CaCO3 (2.0 g, 19.3 mmol) was added. The reaction mixture was heated at reflux for three days. The reaction was deemed complete by HPLC and LC/MS analysis and quenched by the addition of 1N HCl. The reaction mixture was washed with brine, dried with MgSO4 and purified on column (silica gel, with gradient elution of CHCl3/MeOH). This gave to 550 mg (16%) of 2,6-dibromo-3-trifluoromethyl-4-nitrophenol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]=[N:12][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([CH2:19][CH2:20][CH3:21])[N:12]=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCBr
Reactant: O=c1nn[nH]n1-c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of 1-(4-nitrophenyl)-5-tetrazolone (6 g) in anhydrous N,N-dimethylformamide (30 mL) was added powdered 85% potassium hydroxide (1.9 g) and 1-bromopropane (3.9 g). The mixture was stirred at 55° C. for 2 hours and then poured into 300 mL of water. The biphasic mixture was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate:hexane) to afford 7.2 g of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 8.32 (ABq, JAB =9.6 Hz, 4 H), 4.02 (t, J=7.2 Hz, 2 H), 1.93 (m, 2 H), 1.03 (t, J=7.5 Hz, 3 H); MS (CI) m/z 250 (MH+); Rf =0.6 (25% ethyl acetate/hexane).
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH2:21].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O>[O:26]1[CH2:27][CH2:28][N:23]([CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[NH2:21])[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: Nc1ccc(C(=O)OCCCCl)c(N)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C(=O)OCCCN2CCOCC2)c(N)c1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of 35 ml of toluene, 4.6 g of (3-chloropropyl)-2,4-diaminobenzoate and 3.5 g of morpholine was refluxed for 10 hrs, cooled to room temperature, and poured into 70 ml of water with stirring. The precipitate was filtered, washed with hexane and dried. Recrystallization from toluene gave 2.6 g (3-morpholinopropyl)-2,4-diaminobenzoate, a white solid, mp 96° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si:29]([CH3:32])([CH3:31])[CH3:30])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cc2cc(Br)cnc2n1S(=O)(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a well stirred solution of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (6.0 g, 17.8 mmol) in dry THF (60 mL) was added LDA (2M in THF; 16.0 mL, 32 mmol) at −78° C. slowly over 15 min. The reaction mixture was stirred at −70° C. for 1 h and then cooled back to −78° C. Chlorotrimethylsilane (4.1 mL, 32 mmol) was added slowly, and the reaction mixture was allowed to warm to ambient temperature over 4 h (TLC monitoring: 20% ethyl acetate in hexanes). Solvent was removed under reduced pressure keeping temperature below 40° C. to give a residue. It was extracted with ethyl acetate (2×50 mL) and washed with water (40 mL), followed by brine (10 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield a brown solid which was purified by column chromatography using 10% ethyl acetate in hexanes to yield the title compound as a white solid (4.8 g, 66%). 1H NMR (CDCl3, 300 MHz): δ=0.51 (s, 9H), 6.72 (s, 1H), 7.47-4.59 (m, 3H), 7.91 (d, J=2.1 Hz, 1H), 8.09-8.12 (m, 2H), 8.37 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25]N=[C:23](OC)[CH:22]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:30]1SN=C(C2C=CN=C(Cl)C=2)N=1.BrCCC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:30]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2nsc(Cl)n2)ccn1
Reactant: COc1cc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)ccn1
Agent: BrCCc1ccccc1
Product: Clc1cc(-c2nsc(N3CCN(CCc4ccccc4)CC3)n2)ccn1

Procedure:
In analogy to the procedure described for the synthesis of 3-(2-chloropyridin-4-yl)-5-(4-(2-(2-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-1,2,4-thiadiazole (Example 168), the tile compound was prepared from 5-chloro-3-(2-chloropyridin-4-yl)-1,2,4-thiadiazole and (2-bromoethyl)benzene.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4](=[O:5])[CH2:12][CH3:13]
Reactant: CON(C)C(=O)[C@H]1CCCO1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)[C@H]1CCCO1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of (R)—N-methoxy-N-methyltetrahydrofuran-2-carboxamide (20.15 g, 1 equiv) in THF (250 ml) was added ethyl magnesium bromide (44.3 ml of a 3M solution in THF, 1.05 equiv) The reaction was stirred at −78° C. for 1 h and then quenched with saturated NH4Cl solution. EtOAc was added and the organic portion was separated and washed further with saturated NH4Cl solution, dried (MgSO4) and concentrated in vacuo to afford the title compound; NMR (CDCl3) 1.05 (3H, t, CH3), 1.9 (3H, m), 2.2 (1H, m, CH), 2.6 (2H, m, CH2), 3.95 (2H, CH2O), 4.3 (1H, m, CHO).