Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:18])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH:48][C:49]1([C@@H:53]2[CH2:58][CH2:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:52][NH:51][CH2:50]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:51]1[CH2:52][C:49]([C@@H:53]2[CH2:58][CH2:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])([OH:48])[CH2:50]1)=[O:18]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Reaction time: 0.17 h
Yield: 105 %

Procedure:
3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (200 mg, 0.559 mmol), prepared using procedures similar to those described in WO 2006/045514, was suspended in DMF (7 mL) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol) were added. The mixture was stirred at ambient for 10 minutes and then triethylamine (0.078 mL, 0.559 mmol) was added. After a further 20 minutes, 1,1-dimethylethyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (143 mg, 0.559 mmol), prepared using similar procedures to those described in Example 22(a) and 22(b), and triethylamine (0.16 mL, 1.15 mmol) were added and the mixture was stirred for 15 hours. The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic portion was washed with 5% lithium chloride and twice with saturated sodium bicarbonate, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 60-80% ethyl acetate in hexanes) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (368 mg, 0.587 mmol, 74% yield): 1H NMR (400 MHz, CDCl3): 8.73 (br m, 1H), 8.62 (br s, 1H), 8.14 (d, 1H), 7.47 (dd, 1H), 7.43-7.39 (m, 1H), 7.20-7.12 (m, 2H), 4.38-4.21 (m, 2H), 4.16-4.01 (m, 2H), 4.01-3.88 (m, 1H), 3.44-3.30 (m, 1H), 2.98-2.83 (m, 1H), 2.00-1.88 (m, 1H), 1.71-1.50 (m, 6H), 1.44 (s, 9H); MS (EI) for C25H30FIN4O4: 597 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>O.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:6]([O-:9])=[O:7])[C:13]=1[OH:18]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
A solution of 60 mL of concentrated sulfuric acid diluted with 186 mL of water was cooled to room temperature. Sodium nitrate (79.2 g, 0.93 mol) was added to the solution. 2-Bromo-phenol 1a (60 mL, 0.52 mol) was added dropwise at such a rate that the reaction temperature was kept below 25° C. The reaction mixture was stirred at room temperature for 2 hours. The precipitate was dissolved in 320 mL of ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-6-nitro-phenol 1b (48.2 g, yield 42.8%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][CH2:45][NH2:46]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][CH:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCCC1CCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN1CCCC1CCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine according to conditions described in general procedure C. Mp: 100-101° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.33-2.17 (m, 12 H), 2.88 (s, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 6.17-6.32 (bd, 1 H), 7.02-7.06 (m, 1 H), 7.12 (s, 1 H), 7.27 (d, J=8.7 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.61 (m, 3H), 7.82 (d, J=8.4 Hz, 1 H), 7.99 (d, J=7.7 Hz, 1 H), 8.23 (s, 1 H), 10.46 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(Cl)Cl>[OH:34][C:31]([CH3:32])([CH3:33])[CH2:30][C@@:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:20][C:19](=[O:35])[N:18]([C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:2]3([NH:1][C:45](=[O:47])[CH3:46])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:11][CH:12]=2)[CH3:17])[CH2:23][CH2:22]1
Reactant: C[C@@H](c1ccc(C#CC2(N)CCCCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CCCCC1
Yield: 47.2 %

Procedure:
A vial equipped with a flea stir bar was charged with (S)-3-((S)-1-(4-((1-aminocyclohexyl)ethynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (12 mg, 0.025 mmol), i-Pr2NEt (0.015 mL, 0.08 mmol) and CH2Cl2 (2 mL). Acetic anhydride (0.005 mL, 0.043 mmol) was added. The mixture was stirred overnight at rt and evaporated to dryness. The residue was purified by prep HPLC to afford the title compound (6.1 mg, 47%). LC-MS Method 1 tR=1.65 min, m/z=517, 459; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.30 (m, 1H), 1.51 (d, 3H), 1.65 (m, 6H), 1.87 (m, 2H), 1.99 (s, 3H), 2.14 (m, 3H), 2.21 (s, 2H), 2.35 (m, 1H), 2.78 (m, 1H), 5.65 (q, 1H), 6.88 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]1[O:5][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=1.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>CCOCC>[CH3:21][N:2]([CH2:3][C:4]1[O:5][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:14]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:6]2[O:5][C:4]([CH2:3][N:2]([CH3:1])[CH3:21])=[CH:8][CH:7]=2)=[CH:15][N+:16]([O-:18])=[O:17])=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=1)[CH3:1]
Reactant: NCCCCCCCCCCCCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Solvent: CCOCC
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCNC(=C[N+](=O)[O-])NCCSCc2ccc(CN(C)C)o2)o1
Yield: 77.1 %

Procedure:
A mixture of N,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine (2 g) and 1,12-diaminododecane (0.6 g) was heated at 100° for 3 hours. The oily residue was chromatographed (silica/methanol-0.88 ammonia, 79:1) to give an oil which solidified on trituration with ether giving the title compound (1.77 g) mp. 74°-76°.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)(O)[O-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:23]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To 20 g (152.5 mmol) of 4-hydroxy-L-proline in 35 ml of water was added 36.7 g (436.8 mmol) of sodium bicarbonate and the mixture was cooled to 10° C. before 32.5 g (190.5 mmol) of benzylchloroformate wa added dropwise. The cooling bath was then removed and the mixture was allowed to stir for 24 hours at room temperature. The pH of the reaction was then adjusted to 1 with concentrated HC1 solution and the mixture was extracted with 3 x 100 ml portions of methylene chloride. The organic layers were dried over Na2SO4 and evaporated in vacuum to provide 36.4 g of the product as an oil (90% yield). NMR(CDC13): 7.30 (m,5H, aromatic), 5.12 (m,2H), 4.50 (m,2H), 4.36 (m,2H), 3.6 (m,2H), 2.38 (m,2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:25])[N:3]=1.B([C:29]1[CH:40]=[CH:39][C:32]([CH2:33][C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35])=[CH:31][CH:30]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:35][C@@H:34]([CH2:33][C:32]1[CH:39]=[CH:40][C:29]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:25])[N:3]=2)=[CH:30][CH:31]=1)[C:36]([OH:38])=[O:37]
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)n1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 17.8 %

Procedure:
In a microwave vial, 4-chloro-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (30 mg, 0.081 mmol), 4-borono-L-phenylalanine (20 mg, 0.098 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. Then, 0.3 ml of 1N aqueous sodium carbonate was added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 7.2 mg of (S)-2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.96(m, 3H), 7.61(m, 5H), 6.81(s,1H), 6.77(d, J=6.8 Hz, 1H), 6.74(d, J=4.8 Hz, 1H), 4.27(q, J=5.6 Hz, 1H), 3.36(m, 1H), 3.21(m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C1C(=O)N([I:19])C(=O)C1.C1COCC1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[C:10]([I:19])[C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]ccc2scc(Br)c12
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cc(I)c2scc(Br)c12

Procedure:
The mixture of compound 10 (see Example 4(c)) (1.9 g, 8.3 mmol) and N-iodosuccimide (NIS, 2.2 g, 49.9 mmol) in DMF (25 ml) and THF (20 ml) was stirred for 5 hours at 40° C. The reaction mixture was poured into 10% Na2SO3 and ethyl acetate. The insoluble product was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 3-bromo-7-iodo-5H-thieno[3,2-c]pyridin-4-one (990 mg). The filtrate was collected, dried over Na2SO4, filtered and concentrated in vacuo. The generated precipitate was washed with MeOH to further yield 3-bromo-7-iodo-5H-thieno[3,2-c]pyridin-4-one (1.1 g). 1H NMR (400 MHz, DMSO-d6) ppm 11.75 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([C:11]#[N:12])[CH2:10][CH2:9]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1
Reactant: N#CC1CC1
Reactant: Fc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2cnccn2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
A mixture of 2-fluoropyrazine (2.0 g, 20.4 mmol, 1 eq) and cyclopropanecarbonitrile (1.5 ml, 20.4 mmol, 1 eq) In a dry flask under an argon atomsphere were dissolved in dry toluene (50 ml). The solution was cooled to 0° C. and potassium bis(trimethylsilyl)amide (0.5 M in toluene, 40.9 ml, 20.45 mmol, 1 eq) was added slowly over 5 min via syringe. The black, opaque reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was diluted with water (200 ml) and ethyl acetate (200 ml), and the layers were separated. The aqueous layer was back extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a black oil. The crude was purified by silica gel (60-120) column chromatography using 20% ethyl acetate in hexane as eulent to give 0.25 g of the product as light a yellow oil. Yield: 0.25 g (8.4%). 1H NMR (400 MHz, CD3OD): δ 1.84-1.86 (m, 4H), 8.51-8.55 (q, 2H), 8.89 (s, 1H). LCMS: (ES+) m/z=146.2 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16](F)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(=O)[NH:27]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.O>[NH2:27][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[C:19]([F:20])=[CH:18][C:17]=1[F:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(F)c(F)cc2F)CC1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(F)cc2F)CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(3,5,6-trifluoro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.59 g, 5 mmol, Example 39a), potassium phthalimide (0.93 g, 5 mmol, Aldrich) in DMF (20 mL) was heated at 140° C. with stirring for 16 h. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted with EtOAc (2×70 mL). The combined organic extracts were dried over Na2SO4, and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 20% EtOAc in hexane to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 315 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].Cl.[NH2:28]O.Cl>CO.CO.O.O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:28][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CCC(C)(C)C)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (549 mg, 1.61 mmol) (from example 95, step 1) in MeOH (1.2 mL) was added to a solution of NaOH (70 mg, 1.75 mmol) in MeOH/H2O (1.3 mL/0.08 mL) at −30° C. After 10 min was added hydroxylaminehydrochloride (223 mg, 3.22 mmol) and NaOH (129 mg, 3.22 mmol) in MeOH (1.6 mL) and H2O (1.6 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (2.4 mL) at 80° C. and heated at 80° C. for 1 h. Concentration of the organic solvent and extraction with DCM (×2), drying using a phase separator and evaporation gave an orange oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 30-60% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (194 mg, 39%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 0.89 (s, 9H), 1.02-1.78 (m, 6H), 1.89-2.03 (m, 2H), 2.83-3.09 (m, 2H), 3.71 (s, 3H), 3.99-4.51 (m, 2H), 5.65 (s, 1H). MS m/z 311 (M+H)+
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14]Cl)[C:7]=2[CH:16]=1)#N.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:25]2[CH2:30][CH2:29]CN[CH2:26]2)[CH:22]=[CH:23][CH:24]=1.[CH:33]([N:36](C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:8]1([CH2:11][CH2:12][CH2:13][CH2:14][N:36]2[CH2:33][CH2:26][CH:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=3)[CH2:30][CH2:29]2)[C:7]2[CH:16]=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc2nnn(CCCCCl)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(C2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
6-cyano-1-(4-chlorobutyl)-1H-benzotriazole (0.06 mol) was dissolved into 150 ml of acetonitrile, 4-(3-(3-trifluoromethylphenyl) piperidine (0.05 mol), diisopropylethylamine (0.2 mol) and potassium iodide (0.05 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, purified, eluted with dichloromethane/methanol mixture to produce 13.5 g N-(4-(1H-benzotriazole-1-yl)butyl)-4-(3-trifluoromethylphenyl)piperidine (I-115) with a yield of 63.1%. ESI-MS [M+H]+: m/z 427.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH2:39][C:40]([NH:1][C:2]2[CH:10]=[C:9]3[C:5](/[C:6](=[C:12](/[NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:22][CH:21]=4)\[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)/[C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: O=C(Cc1ccccc1)Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and phenylacetic acid chloride
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH:13]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:18]2[CH2:19][CH2:20][N:21]([C:2]3[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=3)[CH2:22][CH2:23]2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CC(=O)N(C)c1ccnc(Cl)c1
Product: CC(=O)N(C)c1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of 4 g (22 mmol) N-(2-chloro-pyridin-4-yl)-N-methyl-acetamide and 3.5 g (23 mmol) 1-(cyclopentyl)-piperazine was heated to 120° C. for 24 h. The crude product was purified by flash column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate (0.1% NEt3) to yield after evaporation of the product fractions 3.3 g (50%) of the title compound as light brow oil. MS: (m/e): 303.3 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].CC(O)=O.[CH3:9][C:10]([CH3:21])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]=[CH2:12]>CC(OC(C)=O)=O>[CH3:9][C:10]([CH3:21])([CH:11]=[CH2:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: C=CC(C)(C)CCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=CC(C)(C)CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In a flask, was loaded fuming HNO3 (18.7 mL, 90%, d=1.5), HOAc (18 mL), Ac2O (14 mL), which was allowed to cool back to room temperature before proceeding. This solution was added dropwise to 3,3-dimethyl-5-phenyl-1-pentene (45.8 g, 0.263 mol), which was prepared using the procedure of Reike and coworkers referenced as 12 in the manuscript, in Ac2O (120 mL). The reaction was kept between 0 and −5° C. during the addition. After the addition, the mixture was stirred at 0° C. for 12 h. The reaction mixture was poured into crushed ice (300 g) The product was extracted with ethyl ether (3×200 mL) and the combined organic layers were washed with portions of saturated NaHCO3 (˜300 mL total) until no gas formed on addition of the basic aqueous solution. The organic solution was filtered, and the separated solids were washed with ether (50 mL). The combined aqueous layers were extracted with ether (3×200 mL). The combined ether solutions were dried with MgSO4. The volatiles were removed in vacuo providing the product as a yellow oil in 97% yield (55.95 g) as a mixture of isomers. GC/FID analysis displayed an ortho:para ratio of 49:51. The compound was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:4]1[CH:3]=[C:2]([N:1]=[C:12]=[S:13])[CH:9]=[C:8]([Cl:10])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(Cl)cc(N)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Yield: 71.3 %

Procedure:
A suspension of 4-amino-2,6-dichlorobenzonitrile (500 mg, 2.67 mmol, Eq: 1.00), thiophosgene (1.35 g, 900 μl, 11.7 mmol, Eq: 4.39), triethylamine (875 mg, 1.2 ml, 8.64 mmol, Eq: 3.23) in benzene (30 ml) was heated at reflux overnight. The brown reaction mixture was concentrated and chromatographed (80 g Analogix, 0 to 5% ethyl acetate/hexane) to give 436 mg (71%) of desired product as a light brown solid.
Reaction SMILES: BrC1SC2C(O)=CC(C)=CC=2N=1.C(N(CC)CC)C.[Cl-:20].C(OCC)(=O)C=O.Br[C:29]1[S:30][C:31]2[C:37]([OH:38])=[C:36]([CH:39]([OH:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([CH3:46])=[CH:34][C:32]=2[N:33]=1>ClCCl>[Cl:20][C:29]1[S:30][C:31]2[C:37]([OH:38])=[C:36]([CH:39]([OH:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([CH3:46])=[CH:34][C:32]=2[N:33]=1
Reactant: [Cl-]
Reactant: CCOC(=O)C(O)c1c(C)cc2nc(Br)sc2c1O
Agent: CCOC(=O)C=O
Agent: Cc1cc(O)c2sc(Br)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)c1c(C)cc2nc(Cl)sc2c1O
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-methylbenzo[d]thiazol-7-ol (2.48 g, 10.16 mmol) in dichloromethane (100 mL) at 0° C. was added triethylamine (1.42 mL, 10.16 mmol) to give a clear solution. Titaniuim(IV) chloride (1.0M in CH2Cl2, 10.67 mL, 10.67 mmol) was added slowly to give an orange reaction mixture that was stirred for 30 minutes. A solution of cracked ethyl glyoxalate (1.04 g, 10.16 mmol) in CH2Cl2 (1 mL) was added over 2 minutes and reaction mixture was stirred at room temperature for 2.5 h. Reaction mixture was quenched with Rochelle's salt and stirred at room temperature for 2 h, diluted with CH2Cl2, and aqueous layer extracted with CH2Cl2 (2×). The combined organic layer was dried (MgSO4), filtered and concentrated. Purification by CombiFlash (40 g, 0 to 30% EtOAc/Hex) gave product contaminated with ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate. LCMS-ESI+: calc'd for C12H13ClNO3S: 302.8 (M+H+); Found: 302.1 (M+H+).