Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][C:17](O)=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:17]([CH2:16][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=C(O)CN1CCOCC1
Product: Clc1ccc2[nH]c(CN3CCOCC3)nc2n1

Procedure:
The title compound was prepared as described in Example 23, Step 2 using 6-chloropyridine-2,3-diamine (650 mg, 4.53 mmol) (Example 23, Step 1) and morpholin-4-ylacetic acid (660 mg, 4.53 mmol) as starting materials.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-(2-methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 18.1.1, 38 mg, 0.137 mmol) to give the title compound as an off-white foam. (HPLC: tR 2.58 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.25 (m, 1H), 8.16-8.04 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.45 (m, 1H), 6.99-6.92 (m, 1H), 4.45-4.38 (m, 2H), 3.92 (s, 3H), 3.70-3.64 (m, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]([S:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]([S:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCSc1cc(C#N)c(Cl)cn1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1cc(C#N)c(Oc2ccc(Cl)c(Cl)c2)cn1
Yield: 36.2 %

Procedure:
5-Chloro-2-ethylthio-4-pyridinecarbonitrile (5.4 g) was mixed with 5.4 g of 3,4-dichlorophenol in the presence of 3.7 g of t-BuOK in 30 ml of THF and 30 ml of DMSO. The mixture was heated at boiling temperature for about 70 hours to give 3.2 g (36%) of the desired 5-(3,4-dichlorophenoxy)-2-ethylthio-4-pyridinecarbonitrile, m.p. 79°-81° C.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:41]2[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=2[S:43][C:44]=1[C:45](=[O:47])[CH3:46]>>[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([C:40]4[C:41]5[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=5[S:43][C:44]=4[C:45](=[O:47])[CH3:46])=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)c1sc2ccccc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Product: CC(=O)c1sc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 1-(3-bromobenzo[b]thiophen-2-yl)ethanone were reacted to give 208. LCMS m/z: 536.7 (MH+)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]([C:11]#[N:12])[CH2:9][CH:8]([CH2:13][CH2:14][CH3:15])[CH2:7][C:5]=2[N:6]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[NH:1][C:2]1[S:3][C:4]2[CH:10]([C:11]#[N:12])[CH2:9][CH:8]([CH2:13][CH2:14][CH3:15])[CH2:7][C:5]=2[N:6]=1)[CH3:21]
Reactant: CCCC1Cc2nc(N)sc2C(C#N)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCC1Cc2nc(NC(=O)OCC)sc2C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazole (0.10 mol) dissolved in pyridine (125 ml.) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. Ethyl chloroformate (0.12 mol) is then added dropwise to the reaction mixture with stirring and cooling. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is poured into ice water to form a precipitate. The precipitate is recovered by filtration, is dried and recrystallized to yield the desired product ethyl-N-(5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:4]3[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH2:9][CH3:10])=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCOc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Yield: 98.8 %

Procedure:
5-Bromo-2-propoxy-3H-imidazole-4-carbaldehyde (2.1 g, 8.8 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (3.2 g, 8.8 mmol) and potassium carbonate (3.6 g, 26.4 mmol) were dissolved in DMF (100 mL). The solution was stirred until the reaction was complete, as determined by HPLC. The mixture was extracted with EtOAc (200 mL), washed with saturated aqueous NaCl (4×100 mL), dried over MgSO4, evacuated to dryness, and purified by flash chromatography (EtOAc/hexanes) to yield compound A (4.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: CN(C)CCCl
Product: CN(C)CCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 95 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32 mmol) and BnBr (6.6 g, 38 mmol) in CH3CN (100 mL) was added K2CO3 (8.8 g, 64 mmol). The mixture was heated at reflux for 2 hours. The resulting mixture was poured into water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1) to give 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1 H), 7.73 (dd, J=2.0, 8.4 Hz, 1 H), 7.47-7.34 (m, 5 H), 7.08 (d, J=8.8 Hz, 1 H), 4.26 (s, 2 H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[C@@H:7]([O:28][CH2:29][CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16]/[CH:17]=[C:18](/[CH3:27])\[C:19]#CC2C=CC=CC=2)=[CH:11][CH:10]=1)C.[CH2:32](O)[CH3:33]>>[C:8]1([C:33]2[CH:32]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:10][C:19](/[C:18](/[CH3:27])=[CH:17]/[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][C@H:7]([O:28][CH2:29][CH3:30])[C:6]([OH:5])=[O:31])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/C)C#Cc2ccccc2)cc1)OCC
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Sodium hydroxide (1N, 1.25 mL, 1.25 mmol) was added to a solution of (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester (example 3) (0.246 g, 0.627 mmol) in ethanol (20 mL) and the mixture stirred at 70° C. for 2.5 h. After cooling to room temperature the resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was collected, acidified with 1N hydrochloric acid (5 mL) and extracted into ethyl acetate (100 mL). The organic phase was washed with brine, dried (Na2SO4) and evaporated to give (E)-(S)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionic acid as an oil; 0.150 g (66%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1Br.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)noc2N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 52 mg, 1.3 mmol) in dry dimethylformamide (2.0 ml) was added 4-methoxyphenol (0.15 g, 1.2 mmol). After stirring the solution at room temperature of 10 min, 5-amino-4-bromo-3-methylisoxazole (0.20 g, 1.1 mmol) was added, followed by bis(triphenylphosphine)palladium(11) chloride (79 mg, 0.11 mmol). The mixture was heated to 50° C. for 2.5 h and then cooled to room temperature. The dark brown reaction mixture was worked up with ethyl acetate and 5% NaOH. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using 20% ethyl acetate in hexanes as eluent to give 0.13 g (51% yield) of 5-amino-4-(4-methoxyphenoxy)-3-methylisoxazole.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:20]([NH2:22])=[O:21])[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1.C(N(C(C)C)C(C)C)C.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>C(Cl)Cl>[OH:19][CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([C:20]([NH2:22])=[O:21])[CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][CH2:6][C:5]1[CH:23]=[CH:24][CH:25]=[C:3]([NH:2][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)[CH:4]=1
Reactant: NC(=O)c1cc(CO)cc2c(NCc3cccc(N)c3)ncnc12
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cc(CO)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
The reaction mixture of 4-[(3-aminobenzyl)amino]-6-(hydroxymethyl)quinazoline-8-carboxamide hydrochloride (20 mg; 0.06 mmol; 1.00 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.03 ml; 0.17 mmol; 3.00 eq.) in DCM was added 4-methoxybenzoyl chloride (11 mg; 0.06 mmol; 1.10 eq.). The reaction mixture was stirred at RT for 1 hr. Purified by HPLC, to get the title compound (18 mg, yield 71%) MS (M+1) 458.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O>C1CCCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:27])=[O:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1
Reactant: CC(C)=O
Reactant: OCc1cc(F)c(-c2ccc(OCc3ccccc3)cc2)c(F)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(O)c1cc(F)c(-c2ccc(OCc3ccccc3)cc2)c(F)c1

Procedure:
An oxidation was carried out with 107 mg of the product of Stage B, with Jones' reagent under the conditions as described in Example 2, Stage C to obtain 86 mg of the expected product with a Rf=0.06 cyclohexane/ethyl acetate 7/3).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH2:18]([C:22](N(OC)C)=[O:23])[CH2:19][CH2:20][CH3:21]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:22](=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CCCCC(=O)N(C)OC
Agent: [Li]CCCC
Product: CCCCC(=O)c1ccc(OC)cc1C(=O)O

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with butyl-N-methoxy-N-methylcarboxamide. It is used in crude form in the following reaction.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:8][N:9]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:3). The fractions containing 1-(2-phenylmorpholin-4-yl)butan-1-one are collected and the solvent is removed in vacuo to give 378 mg of colorless oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:2]1.[CH3:13][C:14]1[N:15]=[C:16]([NH2:25])[S:17][C:18]=1[CH2:19][CH2:20][O:21][N+:22]([O-:24])=[O:23]>>[CH3:13][C:14]1[N:15]=[C:16]([NH:25][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH:3]2[CH2:4][CH2:5][S:1][S:2]2)[S:17][C:18]=1[CH2:19][CH2:20][O:21][N+:22]([O-:24])=[O:23]
Reactant: O=C(O)CCCCC1CCSS1
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: Cc1nc(NC(=O)CCCCC2CCSS2)sc1CCO[N+](=O)[O-]
Yield: 51 %

Procedure:
Pet-151 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 5-[1,2]Dithiolan-3-yl-pentanoic acid (DL-Lipoic acid) and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 51% as a pale yellow liquid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:26](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:25][O:24][C:22]([C:16]1([N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH3:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)OC)CCCCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}-amino)cyclohexanecarboxylate (4.5 g.,12.3 mmol), anhydrous potassium carbonate (20.0 g, excess) and methyl iodide (2 g, 14.08 mmol) was refluxed in acetone for sixteen hours. The reaction mixture was then cooled to room temperature and filtered. The acetone layer was concentrated and extracted with chloroform. The chloroform layer was washed well with water, dried over anhydrous MgSO4, filtered and concentrated to provide methyl1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylate as a yellow oil. Yield: 4.6 g (quantitative) Electrospray Mass Spec 380 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[C:8]([O:9][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccnc1C#N
Temperature: 0 °C
Yield: 98.9 %

Procedure:
2-Cyano-3-hydroxypyridine (5.00 g) is dissolved in acetone (50 ml), and thereto are added methyl bromoacetate (7.0 g) and potassium carbonate (6.3 g). The mixture is heated under reflux for 1.5 hours. After allowing to cool, ice-water is poured to the reaction solution and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diethyl ether/n-hexane and the solid is collected by filtration to give the title compound (7.91 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1>C(O)C>[CH2:1]([N:8]([CH2:15][C:16]1([OH:14])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: CC(C)(CO)NCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN(Cc2ccccc2)C(C)(C)CO)CC1
Temperature: 100 °C
Yield: 59.9 %

Procedure:
2-(Benzylamino)-2-methyl-propan-1-ol hydrochloride (539 mg, 2.50 mmol) was treated with aqueous sodium hydroxide (50 mL of 2 M, 100 mmol), then diethyl ether (50 mL) was added to the solution and stirred for 3 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the 2-(benzylamino)-2-methyl-propan-1-ol free base as a white powder. The 2-(benzylamino)-2-methyl-propan-1-ol (2.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.344 mmol) were dissolved in ethanol (2 mL) and the reaction mixture was heated in a sealed tube at 100° C. for 48 h. The ethanol was evaporated and the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes) to provide tert-butyl 4-((benzyl(1-hydroxy-2-methylpropan-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylate as white powder (551 mg, 60%). ESI-MS m/z calc. 392.5. Found 373.3 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.43 (s, 1H), 3.91 (s, 2H), 3.62 (s, 2H), 3.22 (d, J=4.8 Hz, 2H), 2.97 (s, 2H), 2.58 (s, 2H), 1.44-1.27 (m, 13H), 0.88 (s, 6H).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:8]2[CH:12]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([CH2:13][CH:14]([CH3:15])[CH3:16])[S:10][C:9]=2[CH2:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(CC(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(CC(C)C)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 76.5 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-({cyclohexyl[2-ethyl-5-(2-methylpropyl)thiophen-3-yl]methyl}amino)benzoic acid (250 mg) synthesized in Example 83 (1) and ethyl 3-(methylamino)propanoate (98.5 mg) to give the title compound (232 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:20]([N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCCCNCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
3-Fluoro-4-hydroxyphenylacetic acid (170 mg, 0.999 mmol) dissolved in DMF (3 ml) was cooled in an ice-bath N-Hexylbenzylamine (201 mg, 1.049 mmol) was added and then TBTU (337 mg, 1.049 mmol) followed by DIPEA (407 mg, 3.147 mmol). The mixture was stirred at room temperature overnight and evaporated. Sodium hydrogencarbonate aqueous solution (sat.) was added into the residue. The mixture was then extracted with ethyl acetate (×2). The extracts were combined and washed with water and brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/15 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 265 mg the desired product, yield 77%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[F:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:35]4[CH2:36][CH2:37][C@H:33]([F:32])[CH2:34]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: F[C@@H]1CCNC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc(CN4CC[C@H](F)C4)cc3)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (R)-3-fluoropyrrolidine (121 mg; 0.97 mmol) to give Example 167 as a white solid. 1H NMR: (CDCl3, 400 MHz) 8.72 (2H, dd, J=4.6, 1.6 Hz), 8.05 (2H, d, J=8.0 Hz), 7.63-7.52 (2H, m), 7.47 (2H, d, J=8.0 Hz), 7.40-7.33 (3H, m), 7.19 (1H, t, J=9.1 Hz), 5.25-5.11 (1H, m), 3.72 (2H, s), 2.92-2.69 (3H, m), 2.53-2.45 (1H, m), 2.24-1.99 (2H, m). LC/MS (Method C): 486 (M+HPLC (Method I) Rt 14.98 min (Purity: 95.7%).