Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C.ClCCl>[C:15]1([CH2:14][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccc(O)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: OCc1ccc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(hydroxymethyl)-3-(trifluoromethyl)phenol (for a preparation see Intermediate 17)(3.86 g, 20.1 mmol) in ethanol (80 mL) was added benzyl bromide (2.4 ml, 20.2 mmol, Aldrich) and then 2 M sodium hydroxide (11 ml, 22 mmol). The mixture was stirred at ambient temperature overnight under nitrogen. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (4.68 g);
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12.Cl.O1CCOCC1.[I-:28].[Na+]>O1CCCC1>[I:28][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate (10 g; 32.3 mmol) in tetrahydrofurane (100 ml) at room temperature was slowly added a 4N solution of hydrochloric acid in dioxane (56.5 mL; 226 mmol). The mixture was stirred at 60° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (75 mL), sodium iodide (38.7 g; 258 mmol) was added and the mixture was heated at reflux for 48 h. The volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate and was successively washed with water, a solution of sodium thiosulphate, water and brine. The organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford 10.83 g (71%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[CH2:9]([Br:13])[CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>C(#N)C>[Br-:13].[CH2:9]([N+:6]1[CH:7]=[CH:8][N:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=1)[CH2:10][CH2:11][CH3:12]
Reactant: C=CCn1ccnc1
Reactant: CCCCBr
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=CCn1cc[n+](CCCC)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
1-Allylimidazole (1.0 mL: 0.009 mol) was ice-cooled, and n-butyl bromide (2.97 mL: 0.28 mol) was added thereto dropwise. After the dropwise addition, the temperature was gradually increased to 25° C., and subsequently stirring was carried out continuously for 24 hours. The product was a pale brown viscous liquid. This was added dropwise to 100 mL of toluene, and a viscous liquid that separated out was recovered and dried. The same procedure was repeated once more. The viscous liquid thus obtained was made into an acetonitrile solution, active carbon that had been heated and vacuum-dried was added thereto, and stirring was carried out for about 24 hours. After the acetonitrile was distilled off, the viscous liquid was recovered with dichloromethane, and the solvent was distilled off. The 1-butyl-3-allylimidazolium bromide thus obtained was a liquid at room temperature, the amount collected was 1.93 g (yield; 85%), the glass transition temperature (T.g) was −62.5° C., and the ionic conductivity at 30° C. was 0.533 (mS/cm). The results are given in Table 1. The structure was confirmed by 1H-NMR measurement. The results are shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[S:12]([OH:15])(=[O:14])=[O:13]>O.Cl.C(O)C.[Rh]>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([S:12]([OH:15])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: Cc1cnc2c(S(=O)(=O)O)cccc2c1
Agent: [Rh]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1CNc2c(cccc2S(=O)(=O)O)C1
Temperature: 70 °C
Yield: 68.4 %

Procedure:
20 g (90 mmoles) of 3-methylquinoline-8-sulphonic acid is placed in a mixture of 200 ml of water and 25 ml of 12N hydrochloric acid. 6 g of 5% rhodium on charcoal catalyst is added and the reaction mixture is heated at 70° C. for 16 hours. The catalyst is filtered and washed with hot water and the filtrate is evaporated to provide a residue which is dissolved in 50 ml of ethanol. After evaporation of ethanol the residue is dried over phosphorus pentoxide at 50° C. 14 g of product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:24])([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:26]([O:28]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:26](=[O:28])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:17]2([CH3:24])[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(C)(c1nccn1C)C(c1ccc(F)cc1)N2
Solvent: O
Product: Cn1ccnc1C1(C)c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 67 °C
Reaction time: 10 h
Yield: 14 %

Procedure:
Ethyl 2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (70 mg, 0.18 mmol) was added to hydrazine monohydrate (5 mL) and the mixture was stirred at 67° C. for 10 hr. The resulting mixture was concentrated and purified by prep-HPLC to obtain the title compound as a white solid (9 mg, yield 14%). LC-MS (ESI) m/z: 376 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.79 (s, 3H), 2.57 (s, 3H), 4.50 (s, 1H), 6.68-6.69 (d, J=0.9 Hz, 1H), 6.78-6.82 (m, 2H), 6.84-6.85 (d, J=0.9 Hz, 1H), 7.05-7.09 (m, 2H), 7.16-7.18 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.34 (s, 1H), 7.43-7.45 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.57-7.61 (t, J=7.6 Hz, 1H), 12.30 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][CH:21]([OH:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of 1′-benzyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (3.0 g, 7.8 mmol) and NaBH4 (1.47 g, 38.75 mmol) in MeOH (20 ml) was stirred at RT. After 3 h, the solution was poured into water and the product was extracted with DCM (50 ml). The organic phase was dried over Na2SO4, filtered and evaporated under vacuum to give 1′-benzyl-6-bromo-4-hydroxy-spiro[chromane-2,4′-piperidine] (3.0 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33](=[N:42][C:43]#[N:44])OOC3C=CC=CC=3)[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH3:45][NH:46][CH3:47]>C(O)(C)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33]([N:46]([CH3:47])[CH3:45])=[N:42][C:43]#[N:44])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CNC
Solvent: CC(C)O
Product: CCCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 1c from 4'-[[2-n-propyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol -1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and dimethylamine in boiling isopropanol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[O:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.C1COCC1.[Br-].[Mg+2].[Br-].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Br-].[Mg+2].[Br-]>C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:4]=1)=[O:7]
Reactant: COc1ccccc1
Reactant: CNc1nccc(-c2cccnc2Oc2cc(C(=O)Cl)ccc2C)n1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2cc(C(=O)c3ccccc3OC)ccc2C)n1
Temperature: -78 °C

Procedure:
To 4-methyl-3-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-benzoyl chloride (50 mg, 0.14 mmol) in a flame dried, round-bottom flask under nitrogen and cooled to −78° C. was added 4 ml of THF, 2 ml methylene chloride and magnesium-bromide-2-methoxy-benzene in THF (0.3 ml, 0.6 mmol). After addition of the magnesium-bromide, the −78° C. dry ice bath was removed and the reaction allowed to warm to room temperature over 4 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methylene chloride and brine. The organic layers were combined, dried with sodium sulfate and filtered. The solvent was removed under vacuum and the product was purified via preparative HPLC (Gilson). MS m/z=427 [M+H]+. Calc'd for C25H22N4O3: 426.48.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[C-:39]#[N:40].[K+]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:39]#[N:40])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: [C-]#N
Agent: [K+]
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(C#N)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting material: (2R,4 S,4 aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and potassium cyanide.
Reaction SMILES: [C:1]12([C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=4)[NH:15][CH:14]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:1]12([C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:27]5[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=5)[N:20]=4)[NH:15][CH:14]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: O=C(c1c[nH]c2ncc(Br)nc12)C12CC3CC(CC(C3)C1)C2
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C45CC6CC(CC(C6)C4)C5)c3n2)cc(OC)c1OC

Procedure:
Adamantan-1-yl-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from adamantan-1-yl-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone and 3,4,5-trimethoxyphenylboronic acid following general procedures as described in these Examples. MP 267-268° C., M+H=448.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(#N)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:18])[CH2:20][CH2:21]1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), morpholine (313 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into an argon purged vial fitted with a magnetic stirbar. Anhydrous acetonitrile (4 mL) was added, and the yellow suspension stirred in a heating block at a temperature of 65° C. for 18 hours. As starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a separatory funnel. The organic layer was collected, and the aqueous layer extracted twice more with dichloromethane (2×10 mL). The combined organics were washed with brine (15 mL) and dried over sodium sulphate. The solution was decanted and concentrated to afford a yellow oil. The product was purified using flash chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5-5:95-97.5) to afford a yellow oil. Yield: 88 mg yellow oil (77%). 1H-NMR (CDCl3) δ: 8.13 (dd, J=2.7, 9 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 4.04 (t, J=7.5 Hz, 2H), 3.72 (t, J=4.5 Hz, 4H), 3.01 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.46-2.39 (m, 6H), 1.88-1.79 (m, 2H). MS (EI): 319 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:32][O:31][C:27]1[CH:26]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[O:13][N:12]=[C:11]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:23]=[C:22]([O:21][CH3:20])[C:28]=1[O:29][CH3:30]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1nccc(Nc2cc(C3CCCCC3)no2)n1
Product: COc1cc(Nc2nccc(Nc3cc(C4CCCCC4)no3)n2)cc(OC)c1OC

Procedure:
The title compound was prepared by the method described in Example 1 using 2-chloro-N4-(3-cyclohexylisoxazol-5-yl)-4-pyrimidineamine (Step C) and 3,4,5-trimethoxyaniline. MS (MH+)=426.5; Calc'd for C22H27N5O4— 425.49.
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:9][CH:10]=1)[CH2:3][OH:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:12]([NH:11][C:8]1[N:9]=[CH:10][C:5]([C@@H:2]([OH:1])[CH2:3][O:4][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc([C@@H](O)CO)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
A slurry of (R)-N-(5-(1,2-dihydroxy-ethyl)-pyridin-2-yl)-acetamide (prepared as described in Preparation Three, 71.2 g, 362 mmol) in anhydrous pyridine (362 ml) was cooled to 5° C. and treated with p-toluenesulfonyl chloride (69.18 g, 362 mmol) in one portion. The reaction mixture was stirred at 5° C. for 20 minutes, then the cooling bath was removed and the mixture was stirred at ambient temperature for two hours. The mixture was then concentrated, dissolved in 30 ml of methanol, concentrated and dissolved in toluene (300 ml) and concentrated again. The residue was treated again with methanol and toluene, then the residue was dissolved in ethyl acetate and washed sequentially with half-saturated brine, brine and dried over sodium sulfate. The filtrate was evaporated to afford 102.2 g (80%) of the title product as light buff crystals. Recrystallization from ethanol-cyclohexane afforded the title product as colorless crystals. mp 124-126° C. 1H NMR (dmso-d6): δ=10.5 (br, 1H); 8.21 (d, 1H); 7.94 (d, 1H); 7.68 (d, 2H); 7.51 (d of d, 1H); 7.41 (d, 1H); 5.87 (d, 1H); 4.76 (d of d, 1H); 4.05 (d, 2H); 2.41 (s, 3H); 2.10 (s, 3H). MS (CI): m/z=351 (M+H+). Optical Rotation: −36.181° (c=1.19, acetone). Analysis: Calculated for C16H18N2O5S: C, 54.85%; H, 5.18%; N, 7.99%. Found: C, 54.91%; H, 5.34%; N, 8.06%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][CH2:48][CH2:49][OH:50].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][CH2:48][CH2:49][OH:50])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCO)CCC3)cc1
Temperature: 0 °C
Yield: 85.2 %

Procedure:
A solution of 2.08 g (3.37 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)], and 1.41 g (10.14 mmol, 3.0 equiv.) of 3-bromo-1-propanol in 10 ml of toluene and 0.1 ml of N-methyl-pyrrolidone was treated with 1.44 g (10.14 mmol, 3.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was refluxed for 24 h under an inert atmosphere. Subsequently, the reaction mixture was poured into 200 ml of an ice/water mixture and extracted three times with 150 ml of ethyl acetate. The combined organic phases were washed five times with 20 ml of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 1:1 mixture of hexane and ethyl acetate as the eluent and yielded 1.94 g (2.87 mmol, 85.2% of theory) of (3R,4R)-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 675 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N+:22]([O-:24])=[O:23])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.C1C[O:35][CH2:34][CH2:33]1.C(Cl)(=O)C>C(OCC)(=O)C>[C:34]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:12]=[C:11]1[N+:22]([O-:24])=[O:23])(=[O:35])[CH3:33]
Reactant: C1CCOC1
Reactant: COc1ccc(-c2nc([N+](=O)[O-])[nH]c2-c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: COc1ccc(-c2nc([N+](=O)[O-])n(C(C)=O)c2-c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3.0 g, 9.22 mmole) and triethylamine (7 ml., 51 mmole) in 30 ml. THF at 0° C. under N2 was dropwise added a solution of acetyl chloride (1.3 ml., 18.4 mmole) in 5 ml. THF. After 2 hours at 0° C., the reaction mixture was diluted with ethyl acetate washed with 1N HCl, saturated aqueous NaHCO3 and brine, dried and concentrated on a rotary evaporator. Crystallization from ether gave approximately 600 mg. of starting material. HPLC of the mother liquor and crystallization from ether gave 1-acetyl 4,5-bis(4-methoxyphenyl)-2-nitroimidazole, mp. 146°-151° C. H-NMR indicates purity >95%. H-NMR: 2.41δ (s, 3H), 3.8δ (s, 3H), 6.73-7.56 δ(2AB quartets, J=9Hz, 8H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1B(O)O.CCN(C(C)C)C(C)C>C(O)C.C1(C)C=CC=CC=1.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>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1F
Reactant: OB(O)c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2c(F)cccc2F)ccc1F
Temperature: 120 °C
Yield: 88 %

Procedure:
To a solution of 6-bromo-3-fluoro-2-methylpyridine (1.0 equiv.) in ethanol and toluene (1:1, 0.2 M) was added 2,6-difluorophenylboronic acid, DIEA (5 equiv.) and Pd(PPh3)4 (0.2 equiv.). The reaction was heated in the microwave at 120° C. for 30 min. The solution was filtered and rinsed with ethyl acetate. The volatiles were removed in vacuo and the crude was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (2.5-20% ethyl acetate). Upon concentration of the pure fractions, 6-(2,6-difluorophenyl)-3-fluoro-2-methylpyridine was isolated in 88% yield. LC/MS=224.1 (M+H), Rt=0.87 min.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([Cl:27])[C:23]=1[O:24][CH2:25][CH3:26])[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:20])[CH:11]=1)=[O:8]>O.C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([Cl:27])[C:23]=1[O:24][CH2:25][CH3:26])[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:20])[CH:11]=1)=[O:8]
Reactant: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)OC)c(C)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)O)c(C)c2)cc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 22.5 %

Procedure:
Lithium hydroxide (60 mg, 2.51 mmol) in water (1 mL) was added dropwise to a stirring solution of methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3) (267 mg, 56%) (240 mg, 0.628 mmol) in THF (5 mL) and the resulting yellow solution was stirred for 5 days at RT. The solvent was evaporated in vacuo and dissolved in water (5 mL), then acidified with 2 M HCl. The resultant mixture was extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and filtered and pre-adsorbed on silica. Silica gel chromatography (40 g, 0-10% IPA in DCM) provided 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-019) (52 mg, 22%): m/z 366 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.66 (1H, s), 10.49 (1H, s), 8.08 (2H, s), 7.87 (1H, d), 7.71 (1H, dd), 7.68 (1H, d), 4.14 (2H, q), 2.54 (3H, s), 1.40 (2H, t).