Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[CH3:16]CN(CC)CC.C(Cl)(=O)CC>ClCCl>[N+:1]([C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH2:13][CH3:16])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Reactant: CCN(CC)CC
Agent: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Reaction time: 0.08 h

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 209a (200 mg, 1.19 mmol) in dichloromethane (8 mL) was added Et3N (240 mg, 2.38 mmol). After stirring for 5 minutes, a solution of propionyl chloride (121 mg, 1.31 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 265a (260 mg, 98%) as white solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 225.0
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:5]=1[CH3:31])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[C:27]([NH:26][C:24]([NH:23][C:6]1[C:5]([CH3:31])=[C:4]([CH:1]([OH:3])[CH3:2])[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[C:8]=2[C:7]=1[CH3:22])=[O:25])([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(=O)c1c(C)c(NC(=O)NC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(NC(=O)NC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Reaction time: 3 h
Yield: 15.9 %

Procedure:
To a solution of N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(tert-butyl)urea (718 mg, 1.7 mmol) obtained in Example 204 in methanol (10 mL) was added sodium borohydride (64.3 mg, 1.7 mmol) at 0° C., and the resulting mixture was stirred for 3 hours. The reaction solution was diluted with water and the product was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 115 mg (yield: 16%) of the title compound having high polarity of two isomers. Melting point: 212-214° C. (ethyl acetate-hexane).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.I[CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:11]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1)[CH2:12][CH3:13]
Reactant: O=Cc1c[nH]cn1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1cnc(C=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a suspension of NaH (95%, 231 mg, 9.18 mmol) in THF (20 ml) was added 4-imidazole carboxaldehyde (588 mg, 6.12 mmol) under ice cooling. The mixture was refluxed for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and 1-iodopropane (5 ml) was added to the mixture and then refluxed for another 2 hours. The mixture was cooled down to rt and quenched with water. The solution was extracted with EtOAc (2×50 ml), washed with brine, dried over Na2SO4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-10% MeOH in CH2Cl2) to give the title compound (487 mg, 58%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.CCN(CC)CC.N1C=CC=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:19]1([N:8]2[CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:3][C:2]2=[O:1])[CH2:21][CH2:20]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCCN1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCN(C2CC2)C(=O)C1
Temperature: 25 °C

Procedure:
A mixture of benzyl 3-oxo-1,4-diazepane-1-carboxylate (prepared according to Polish J. Chem. 1989, 63, 265-71), cyclopropylboronic acid (6 eq.), Et3N (10 eq.), pyridine (16 eq.) and Cu(OAc)2 (4 eq.) in dry THF (0.24 M) was heated for 10 min. to 140° C. in a microwave oven. After cooling to RT the mixture was filtered through celite, the solvents were removed under reduced pressure and the product was purified by chromatography on silica gel, eluenting with EtOAc/petroleum ether. The product was obtained as a white solid. 1H-NMR (300 MHz, CDCl3) δ: 7.45-7.22 (5H, m), 5.15 (2H, s), 4.22-4.07 (2H, m), 3.70-3.37 (4H, m), 2.75-2.60 (1H, m), 1.90-1.65 (2H, m), 0.85-0.72 (2H, m), 0.60-0.41 (2H, m). MS (ES) C16H20N2O3 requires: 288, found: 289 (M+H)+.
Reaction SMILES: [OH:1][C@@:2]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].Cl.[OH-].[Na+]>CC#N>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C@@H:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)[OH:1]
Reactant: COCCCC[C@@](O)(c1ccccc1Oc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1ccccc1Oc1ccccc1)[C@@H]1CCCNC1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl) pentyl)piperidine-1-carboxylate (1.97 g, 4.19 mmol) in MeCN (100 mL) was added 2 N aq HCl (100 mL) slowly at rt. The resulting solution was stirred at rt until no starting material remained (˜16 h), basified to pH=10 with 10 N aq NaOH, and evaporated under reduced pressure to remove MeCN. The aq layer was extracted with CH2Cl2 (4×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo to afford (S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol (1.56 g, quantitative) as a free amine.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccccc1C(=O)CCCCCBr
Agent: Cl
Product: COc1ccccc1C(=O)CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-methoxyphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-methoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([NH2:15])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:16])[NH:7][S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].[C:17](Cl)(=[O:19])[CH3:18]>>[CH:1]([C:4]1[CH:14]=[C:13]([NH:15][C:17](=[O:19])[CH3:18])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:16])[NH:7][S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)c1cc(N)cc2c1C(=O)NS2(=O)=O
Product: CC(=O)Nc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O

Procedure:
Reaction of 4-isopropyl-6-aminosaccharin with one molar equivalent of acetyl chloride affords 4-isopropyl-6-acetylaminosaccharin.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9]CO[C:6]=2[C:5]([CH3:12])=[CH:4][CH:3]=1.CC1C=CC(C)=[C:16]([OH:17])C=1O.C(=O)([O-])[O-].[K+].[K+].BrC(Br)C>C(O)CO.CCOCC>[CH3:12][C:5]1[C:6]2[CH2:16][O:17][CH2:9][O:10][C:11]=2[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C)c2c1OCCO2
Reactant: Cc1ccc(C)c(O)c1O
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: OCCO
Product: Cc1ccc(C)c2c1COCO2
Temperature: 120 °C

Procedure:
5,8-Dimethyl-1,4-benzodioxane. To a stirred solution of 3 g of 3,6-dimethylcatechol and 6.15 g of potassium carbonate in 35 mL of ethylene glycol is added 3.74 mL of dibromoethane. A reflux condenser is attached and the mixture heated in an oil bath to 120° C. for 4 hours. The mixture is allowed to cool to room temperature and then is distributed between 100 mL of saturated potassium carbonate solution and 200 mL of ether. The ether layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 2.90 g of 5,8-dimethyl-1,3-benzodioxane as a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.CCCCCCC.C[O:21][C:22]([C:24]1[C:29]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:28][CH:27]=[CH:26][N:25]=1)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:22]([C:24]2[C:29]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:28][CH:27]=[CH:26][N:25]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1nccnc1Nc1cccnc1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Cl)c1)c1nccnc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroaniline (140 mg, 1.1 mmol) was dissolved in 4 mL dioxane and trimethylaluminium-solution 2M in heptane (0.55 mL, 1.1 mmol) was added. The solution was stirred for 1 hr at room temperature and 3-(pyridin-3-ylamino)-pyrazine-2-carboxylic acid methyl ester (127 mg, 0.55 mmol) was added. The reaction mixture was stirred for 2 hrs at 80° C., cooled and quenched with 0.5 mL water. Sodium sulfate was added, stirred for 10 minutes, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:2->0:100 gradient) and the desired product was obtained as a yellow solid (13 mg, 7.2%), MS: m/e=326.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3](C(O)=O)=[N:2]1.C(=O)(O)[O-].[Na+].[I-:18].[Na+].II>ClC(Cl)C.O.ClCCl>[I:18][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[NH:1][N:2]=1
Reactant: [I-]
Reactant: O=C(O)c1n[nH]c2c1CCCC2
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O
Product: Ic1n[nH]c2c1CCCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
To a mixture of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.57 g, 3.43 mmol), and sodium bicarbonate (951 mg, 440 μL, 11.3 mmol) in dichloroethane (5 mL) and water (5 mL) were added in one portion sodium iodide (1.34 g, 8.92 mmol) and iodine (1.13 g, 4.46 mmol) and the mixture heated at to 100° C. (oil bath temperature) with vigorous stirring for 24 h. After cooling to 25° C. the mixture was diluted with dichloromethane, then washed with 10% Na2S2O3 and saturated NaHCO3. The organic phases were combined, dried (MgSO4) and concentrated to an off-white solid which was purified by chromatography (115 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give 3-iodo-4,5,6,7-tetrahydro-1H-indazole (674 mg, 2.72 mmol, 79.2%) as a white solid. MS (M+H)+=249 (>90% purity); 1H NMR (CDCl3) δ: 2.75 (t, J=5.7 Hz, 2H), 2.35 (t, J=5.7 Hz, 2H), 1.61-1.90 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][C@H:12]2[CH2:23][CH2:22][C:21]3[S:20][C:19]4[N:18]=[CH:17][N:16]=[C:15]([O:24][CH:25]5[CH2:30][CH2:29][CH:28]([N:31](C)[C:32](=O)OC(C)(C)C)[CH2:27][CH2:26]5)[C:14]=4[C:13]2=3)=[O:10])=[N:6][CH:7]=1.[ClH:40]>ClCCl>[ClH:40].[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:10])[CH2:11][C@H:12]2[CH2:23][CH2:22][C:21]3[S:20][C:19]4[N:18]=[CH:17][N:16]=[C:15]([O:24][CH:25]5[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]5)[C:14]=4[C:13]2=3)=[N:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25-mL round-bottom flask containing a solution of 36.1 (200 mg, 0.36 mmol, 1.00 equiv) in dichloromethane (15 mL) was added hydrochloric acid (12 M, 2 mL) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum to afford N-(5-fluoropyridin-2-yl)-2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride (130 mg, crude), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>CC(C)=O.CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[OH:23][C@@H:11]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH2:31][CH2:32][CH2:33][C:34]#[N:35])[CH:14]=2)[N:19]=[CH:20][CH:21]=1)[C@@H:10]1[N:5]2[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]2)[CH2:9]1
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Reactant: N#CCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCC#N)cc12
Yield: 94.3 %

Procedure:
To a solution of 400 mg (1.2 mmol) of 6-hydroxycinchonane (1) in 25 ml of anhydrous acetone (dried and distilled over potassium carbonate) and 5 ml of anhydrous dimethylformamide was added 267 mg (1.93 mmol) of anhydrous potassium carbonate followed by 129 ml (0.87 mmol) of 4-bromobutyronitrile and a catalytic amount (3 mg) of 18-crown-6. The reaction mixture was heated to reflux for 18 h, cooled and filtered. The filtrate was concentrated under reduced pressure and redissolved in 200 ml of chloroform. The organic layer was washed with 2×50 ml of 5% aqueous sodium hydroxide, washed with brine, dried using anhydrous magnesium sulfate and yielded 310 mg (0.82 mmol, 66%) of (9S)-4-[(9-hydroxycinchonan-6'-yl)oxy]butanenitrile (2) as pale yellow solids. MS, IR and NMR data confirmed the identity of the compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C@H:46]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)[CH2:47][C:48]1([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]1>C(Cl)Cl>[C:58]1([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:57]=[CH:56][C:55]([CH2:54][C@@H:46]([NH:45][C:6]([C:5]2[CH:4]=[C:3]([C:9]([OH:11])=[O:10])[NH:2][N:1]=2)=[O:8])[CH2:47][C:48]2([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]2)=[CH:60][CH:59]=1
Reactant: N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1)c1cc(C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
3,5-Pyrazoledicarboxylic acid (35.2 mg, 226 μmol, 1.0 eq.), DIPEA (126 μL) and HATU (85.9 mg, 226 μmol, 1.0 eq.) and DCM (5 mL) were combined and stirred for 5 minutes at room temperature. 1-((R)-2-Amino-3-biphenyl-4-yl-propyl) -cyclopropanecarboxylic acid (86.7 mg, 294 μmol, 2.3 eq,) and DIPEA (0.5 mL) in DCM (5 mL) was added, and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and the product was extracted with DCM, dried and evaporated. The resulting product was combined with AcOH (1.5 mL) and purified with preparative HPLC to yield the title compound (21.4 mg; 93% purity). MS m/z [M+H]+ calc'd for C24H23N3O5, 434.16; Found 433.5.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCO>[N:12]1([C:2]2[CH:7]=[C:6]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1N1CCCCC1
Reaction time: 8 h
Yield: 16.1 %

Procedure:
To a solution of 2,4-difluoronitrobenzene (2.09 g, 13.1 mmol) in EtOH (10 mL) at ambient temperature was added piperidine (3.35 g, 39.4 mmol) dropwise. The reaction was allowed to stir overnight and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (2×100 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (10% EtOAc-hexane) afforded 610 mg (16%) of 2,4-dipiperidinylnitrobenzene as an oil. 2,4-dipiperidinylnitrobenzene (273 mg, 0.94 mmol) was then stirred in the presence of 168 mg of 5% Pd—C in 10 mL of MeOH under H2 for 2 h. The reaction was filtered through Celite and concentrated in vacuo to afford 230 mg of 2,4-dipiperidinylaminobenzene (94%) as an oil. Using a procedure similar to Example 4, step (c), 2,4-dipiperidinylaminobenzene (100 mg, 0.38 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (73 mg, 0.46 mmol) in the presence of DIEA (145 μL, 0.83 mmol) to afford 90 mg 62%) of the title compound as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C22H26N4O2, 379.2 (M+H), found 379.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][C:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)(O)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[Cl:27][C:22]1[CH:21]=[C:20]([C:16]2[CH2:17][CH2:18][C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:14][CH:15]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1ccc(Cl)c(Cl)c1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Clc1ccc(C2=CCC3(CCNCC3)CC2)cc1Cl
Yield: 104.9 %

Procedure:
9-(3,4-Dichloro-phenyl)-9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (547 mg, 1.32 mmol) was dissolved in trifluoroacetic acid (25 mL) and heated to reflux over night. Ethyl acetate was added and the reaction mixture was basified with sodium hydroxide (2 N). The aqueous phase was extracted three times with ethyl acetate and the combined organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated to give 410 mg (100%) of 9-(3,4-dichloro-phenyl)-3-aza-spiro[5.5]undec-8-ene as a white gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:33][C:25]1[C:26]([C:30]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[O:31])=[C:27]([CH3:29])[NH:28][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])(=[O:11])=[O:12])=[CH:21][CH:20]=2
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCN(C)CC3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), 1-methyl-piperazine (1.2 eq.), HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (0.2 M) was stirred at rt for overnight. The reaction was concentrated, diluted with DCM, washed with water, dried and concentrated. The residue was triturated with ethyl ether to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[N:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=[O:24])=[CH:17][CH:16]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:22]([CH2:23][OH:24])=[CH:25][CH:26]=[CH:27][N:28]=2)=[CH:17][CH:16]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a mixture of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinaldehyde (2.16 g), tetrahydrofuran (30 ml) and ethanol (30 mL) was added sodium borohydride (0.20 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, and dried with air to give crystals (2.12 g, 97%) of [2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 111-112° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:17])[CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][CH2:5][C:6]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([OH:17])[CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)(CCN=[N+]=[N-])c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(O)(CCN)c1ccccc1

Procedure:
A solution of 1-azido-5-{[tert-butyl(dimethyl)silyl]oxy}-3-phenylpentan-3-ol (1.19, 3.3 mmol) in 30 mL EtOAc was stirred for 2 h under 40 psi of H2 gas in the presence of catalytic 10% Pd/C. After filtration through celite, the reaction mixture was evaporated to give 1-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-3-phenylpentan-3-ol in quantitative yield as a clear oil that was used without further purification. ESI-MS 310 (M+H), 332 (M+Na).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].I[CH3:12]>CN(C=O)C.CCOC(C)=O>[CH3:12][O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 0° C. solution of methyl 2-hydroxyisobutyrate (2 g, 16.93 mmol) in DMF (20 mL) was treated with NaH (60% in mineral oil, 0.813 g, 20.33 mmol), stirred for 0.5 h at 0° C., treated with iodomethane (1.269 mL, 20.29 mmol), allowed to warm to RT and stirred overnight. The mixture was diluted with EtOAc, quenched with cold satd. NH4Cl, extracted with EtOAc (3×) and the combined organics were washed with satd. NaHCO3, 10% LiCl, then brine, dried over Na2SO4 and concentrated to dryness to afford methyl 2-methoxy-2-methylpropanoate (2.08 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 3.64 (s, 3H), 3.11 (s, 3H), 1.30 (s, 6H).