Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=3)[CH2:8][CH2:7][N:6]2[C:21]=1[C:22]([O:24]CC)=[O:23])=[O:2].[OH-].[Na+]>C(O)C>[CH:1]([C:3]1[C:4]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:15][CH:16]([CH3:17])[CH3:18])[CH:13]=3)[CH2:8][CH2:7][N:6]2[C:21]=1[C:22]([OH:24])=[O:23])=[O:2]
Reactant: CCOC(=O)c1c(C=O)c(-c2cccs2)c2n1CCc1cc(OC)c(OC(C)C)cc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(C=O)c(C(=O)O)n1CC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A solution of 815 mg of 15c in 40 ml of ethanol was mixed with 18 ml of 2N NaOH. The mixture was stirred for 1 h at 60° C. The mixture was cooled and concentrated to half its original volume and diluted with 30 ml of water, acidified with 0.5N NaOH and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated to provide 750 mg of 15d as an amorphous material, which was used without further purification in the next step.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CCN(C(C)C)C(C)C>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: Nc1nccs1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(Nc2nccs2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, thiazol-2-ylamine and DIEA to give 2-(thiazol-2-ylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 339 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]Cl)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:28][CH:27]=3)[O:30][C:31]=2[CH3:36])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole (example 123 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>C(Cl)(Cl)Cl>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:25]3[C:24](=[O:26])[C:23]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]4[C:21]3=[O:31])[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Agent: [K]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CN3C(=O)c4ccccc4C3=O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) in chloroform (10 mL) was added potassium phthalimide (556 mg). The mixture was stirred at room temperature overnight and water was added. After separating the organic layer, the aqueous layer was extracted with chloroform. Organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to give the title compound as white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[CH2:13][NH:14]C(=O)OCC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:14][CH2:13][C:12]1[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=1[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccccc1CN

Procedure:
To a solution of 750 mg (1.95 mmol) benzyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}benzylcarbamate in 6.0 mL absolute ethanol was added 150 mg of 10% palladium on carbon catalyst. A balloon of hydrogen was bubbled into the stirring suspension at room temperature over 2 h. The reaction was filtered through celite and the filter pad washed with fresh absolute ethanol (2×). The filtrate was concentrated to dryness in vacuo to give tert-butyl 2-[2-(aminomethyl)phenyl]ethylcarbamate as a colorless oil: 1H NMR (CDCl3, 400 MHz): δ 7.31-7.19 (m, 4H), 5.68 (br s, 1H), 3.90 (s, 2H), 3.41-3.34 (br m, 2H), 2.90-2.83 (br t, 2H, J=6.8 Hz), 1.41 (s, 9H); MS (Electrospray): M+NH=251; TLC Rf=0.24 (160/10/1 of methylene chloride/methanol/concentrated ammonium hydroxide).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC(C)c2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccc(C(=O)O)cc1)c1ccccc1OCc1ccccc1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
Methyl 4-(1-(2-(benzyloxy)phenyl)ethoxy)benzoate (0.5 g, 1.4 mmol) was dissolved in THF (5 ml) and methanol (5 ml). The solution was treated with sodium hydroxide (1N, 6 ml) and the reaction heated at 60° C. for 3 hours. The solvent was removed at reduced pressure and the reaction mixture diluted with water and extracted with ethyl acetate. The aqueous phase was acidified (pH1) with concentrated HCl and extracted with ethyl acetate (3×). The organic phases were combined, dried (MgSO4) and evaporated to give the title compound as a white solid (0.33 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].S(Cl)([Cl:21])=O>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:21])=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To 1.2 g (4.5 mmole) of (-)-2-(4-fluoro-3-trifluoromethylphenoxy)butanoic acid dissolved in 15 ml methylene chloride was added one drop of pyridine and further added dropwise 0.6 g of thionyl chloride. The reaction mixture was further stirred at room temperature for 4 hours and then thionyl chloride and methylene chloride were removed under reduced pressure to obtain 1.2 g of (-)-2-(4-fluoro3-trifluoromethylphenoxy)butanoic acid chloride. The resulting mixture was applied for the next reaction without purification.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@H:14]([CH2:19][O:20][C@@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[C:15]([NH:12][C:9]1[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:16]
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)[C@H](O)CO[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
Trimethylaluminium (2M solution in toluene) (5.98 mL, 11.96 mmol) was added to 5-methylpyrazin-2-amine (1.305 g, 11.96 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (R)-methyl 2-hydroxy-3-((S)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (2 g, 5.98 mmol) in toluene (6 mL) was added and the reaction was allowed to warm to room temperature and then refluxed for 6 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq.) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 mL), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.390 g, 56.5%). 1H NMR (400 MHz, CDCl3) δ 1.04-1.17 (24H, m), 2.54 (3H, s), 3.62-3.67 (3H, m), 3.81-3.85 (1H, m), 4.05-4.09 (1H, m), 4.22 (1H, d), 4.34 (1H, q), 8.13 (1H, d), 9.12 (1H, s), 9.44 (1H, d); m/z (ES+) (M+H)+=412.34; HPLC tR=3.82 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C)C=O>[CH2:16]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:15]=[CH2:14]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC1CCC2(CC1)OCCO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
23.7 g (150 mmole) 1,4-dioxa-spiro[4.5]decan-8-ol were dissolved in 120 ml absolute dimethylformamide under a nitrogen atmosphere. After adding 7.9 g of 50% sodium hydride in mineral oil (165 mmole), the mixture was stirred for 1 hour at 20° C. After adding 14.3 ml allyl bromide (165 mmole), the mixture was heated to 70° C. and stirred for 1 hour. Thereafter it was treated with 160 ml water and was extracted at 10° C.-15° C., three times with ether, once with water and once with saturated sodium chloride solution. After removing the solvent by distillation, 24 g of crude product (81% theoretical) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.12 g, 4.66 mol) in dichloromethane (10 ml), triethylamine (3.88 ml) and acetic anhydride (1.32 ml, 14 mmol) are added at 0° C. The reaction mixture is stirred for overnight, quenched with ice-water and extracted with dichloromethane. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give crude 8-acetyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.34 g).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]12([C:33](Cl)=[O:34])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]12([C:33]([O:1][CH2:2][C@@:3]34[C@@H:20]5[C@H:11]([C@H:12]6[C@@:16]([CH2:18][CH2:19]5)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]6)[CH2:10][CH2:9][C:8]3=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]4)=[O:34])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43COC(=O)C34CC5CC(CC(C5)C3)C4)[C@@H]1CCC2=O

Procedure:
A solution of 22 g of 19-hydroxyandrost-4-ene-3,17-dione, 18 g of 1-adamantanecarboxylic acid chloride, and 29 ml of pyridine in 2.2 liters of toluene is refluxed overnight. The reaction mixture is cooled, and the toluene layer is washed with water, dried over magnesium sulfate and filtered then the solvent is removed. The resulting residue is crystallized from methanol to give 19-(1-adamantanylcarbonyloxy)androst-4-ene-3,17-dione, M.P. 161°-163° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH3:13].[OH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH2:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[C:19]1[CH:20]=[C:15]([OH:14])[CH:16]=[CH:17][CH:18]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cnc2c(Cl)cccc2c1Br
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 4-bromo-8-chloro-3-methyl-quinoline and 3-hydroxyphenyl boronic acid according to the procedure of Example 1. MS (ES) m/z 343.9.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[CH3:16][O:17][CH2:18][CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([O:5][CH2:19][CH2:18][O:17][CH3:16])=[O:4]
Reactant: CCCCCCCCCCC(O)C(=O)O
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC(O)C(=O)OCCOC

Procedure:
The alpha-hydroxylauric acid prepared in the foregoing manner was converted to the 2-methoxyethyl ester by refluxing a 5:1 molar ratio of 2-methoxyethanol with the acid in toluene solvent in the presence of a catalytic amount (0.3%) of p-toluenesulfonic acid. The reaction vessel was fitted with a moisture trap to remove H2O as it forms during the esterification. After water evolution was complete, the reaction mixture was water-washed and refined with 5% KOH/70:30 water:alcohol. The product was water-washed a second time, and the solvent was evaporated to yield 2-methoxyethyl alpha-hydroxylaurate.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O>O1CCCC1>[Br:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Solvent: C1CCOC1
Product: CCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Yield: 85.2 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (980 mg, 3.92 mmol) [prepared in Example 98] and N-bromosuccinimide (697 mg, 3.92 mmol) in tetrahydrofuran (19.6 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 10-40% EtOAC in hexanes) yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (1.1 g, 3.34 mmol, 85% yield) as a yellow oil: LCMS (ES) m/e 329, 331 (M, M+2)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CC1c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 1 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford 2-(3-bromophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=O)[CH2:6][CH2:5]1.[C:15]1(C)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:4]12[CH2:3][CH2:2][C:7]([C:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:12])([CH2:6][CH2:5]1)[CH2:8][CH2:9]2
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Temperature: -15 °C
Yield: 57 %

Procedure:
Ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (199 g, for example, as prepared by Example 1) in water (800 ml) was added to toluene (2000 ml) and potassium carbonate (118 g) in water (800 ml) and rinsed in with water (400 ml). The mixture was stirred until a biphasic solution was obtained. The aqueous layer was separated and extracted with toluene (3000 ml). The combined organic layers were concentrated to 4000 ml by vacuum distillation. This solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C. Acetic acid (178 ml) was added, the mixture concentrated to 4000 ml by vacuum distillation and added to an 18% w/w aqueous potassium carbonate solution (2432 g). The layers were separated, the organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml) added. The solution was cooled to −15° C. and 2M phenyl lithium in dibutyl ether (800 ml) added. Water (2000 ml) and n-butanol (700 ml) were added and the mixture heated to 75° C. The aqueous layer was removed and the organic layer washed with water (1000 ml). Toluene (1000 ml) was added and mixture distilled until 3000 ml of solvent had been removed, then cooled to 20° C. and stirred overnight. The product was filtered, washed with toluene (2×200 ml) and dried under vacuum at 40° C. to give a white solid (131 g, 57%). EI-MS m/z 294 (M+H+) Rt (3.6 min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)(=O)C.[O:16]=[CH:17][C:18](=[CH2:20])[CH3:19]>C1COCC1>[CH3:19][CH:18]([CH2:20][N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH:17]=[O:16]
Reactant: C=C(C)C=O
Reactant: c1cncc(-c2c[nH]cn2)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C=O)Cn1cnc(-c2cccnc2)c1

Procedure:
To a solution of 4-pyridin-3-yl-imidazole (8.5 g) in THF (293 mL) was added acetic acid (16.8 mL) and methacrolein (9.7 mL) and the resulting solution was heated under gentle reflux for 24 hours. Another 9.7 mL methacrolein was added and the solution was heated under reflux for another 24 hours. THF was then removed in vacuo and the residue was purified on a Flash 75 long column eluting with MeOH—CH2Cl2 to give the title compound as slightly yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCO)CCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (10.5 g, 47.6 mmol) in anhydrous methylene chloride (25 mL) was added dropwise with stirring to a 0° C. solution of diethanolamine (5.00 g, 47.6 mmol) and triethylamine (4.92 g, 47.6 mmol) in anhydrous methylene chloride (50 mL). Reaction stirred three hours at 0° C. and then overnight at room temperature. Reaction mixture concentrated under reduced pressure. Residue dissolved in ethyl acetate, washed with 1 N NaOH, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with ethyl acetate to afford the title compound. MS (ESI) m/z 291 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)nc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(6-aminopyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (180 mg, 0.482 mmol) in MeOH (10 mL) under N2 atmosphere was added Pd—C (103 mg, 0.096 mmol). The reaction mixture was stirred at room temperature under H2 balloon. After 2 h, the reaction mixture was filtered through Celite pad, washed with methanol and evaporated to provide desired product, which proceeded for next step without purification (150 mg, 71%). LCMS (m/z): 264.2 (MH+), 0.565 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=[O:9].[Cl-].[NH4+]>O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: ONc1ccccc1Cl
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
A suspension of 2-chloronitrobenzene (50 g, 0.318 mol) and ammonium chloride (16.9 g, 0.318 mmol ) in 636 mL of water was warmed to 65° C. To the mixture was added in portions zinc (60 g, 0.955 mol) over 20 min, and the temperature was kept at 70° C.˜75° C. After stirring for 10 min, TLC showed the reaction was completed. The mixture was filtered and washed with water (˜70° C.). To the filtrate was added NaCl, then cooled to −10° C. After 1 h, the mixture was filtered and washed with pertrolume, and then dried to afford the desired hydroxylamine as a white solid (35 g, 76.9%), which was used to next step without purification. 1HNMR (400 MHz, DMSO): δ 8.36 (s, 2 H), 7.16 (m, 2 H), 6.79 (m, 2 H).