Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:58])=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[C@@H:46]([CH3:57])[CH2:45]3)[CH:38]=2)[CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([NH:29][CH2:30][C:31]3[CH:36]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]5[CH2:49][CH2:48][NH:47][C@@H:46]([CH3:57])[CH2:45]5)[CH:38]=4)[C:34]([F:58])=[CH:33][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (88 mg, 0.23 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (107 mg, 0.25 mmol), HBTU (103 mg, 0.27 mmol) and Et3N (0.06 mL, 0.45 mmol) in DCM was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue: LC-MS m/z 785 (M+H)+. The crude residue was dissolved in 25% TFA in DCM (2 mL) and stirred at RT for 2 h. It was purified with a Gilson HPLC (with 0.1% TFA condition), eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]propanediamide as a solid (61 mg, 39%). LC-MS m/z 685 (M+H)+.
Reaction SMILES: C([O:5]CCO)CCC.[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>>[C:9]([OH:14])(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:5])=[O:13]
Reactant: CCCCOCCO
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1ccccc1C(=O)O
Temperature: 130 °C

Procedure:
A reaction flask equipped with a stirrer, thermometer, and nitrogen inlet tube was charged with 93.6 grams of 2-butoxyethanol and 21 grams of phthalic anhydride. The mixture was heated under nitrogen for 30 minutes at 130° C. The butoxyethyl monoester of phthalic acid produced was a light yellow liquid which crystallized upon standing at room temperature for about one week.
Reaction SMILES: [CH2:1]([N:8]([C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C=C)[C:9](=[O:25])[CH:10]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O>C1(C)C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH2:26]([N:8]1[C@H:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][CH2:11][CH:10]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[C:9]1=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=CCC(C(=O)N(Cc1ccccc1)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of N-benzyl-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[(1S)-1-phenylprop-2-en-1-yl]pent-4-enamide (5b) (230 mg) dissolved in Toluene (25 mL) at 80° C. under N2 was added Grubbs catalyst (2nd generation) (22 mg) and the reaction mixture was stirred at 80° C. for 2 h, then cooled to RT. DMSO (0.1 mL) was added to the reaction and the mixture stirred for 1 h, then concentrated. The crude product was directly purified via flash chromatography (gradient—5%, 10%, 15% EtOAc/hexanes) to give a diastereomeric mixture (1.5:1) of the title compound. (168 mg, 78%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[N:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C.C(OCC)(=O)C>[C:17]([N:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[N:3]=[CH:2]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N#CCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 60 h

Procedure:
2.5 g (1H-imidazol-4-yl)-acetonitrile are dissolved in 20 mL DMF. After the addition of 3.6 mL triethylamine and 7.25 g chlorotriphenylmethane the suspension is left for 60 h at RT with stirring. Water and ethyl acetate are added, the organic phase is separated off, dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: C([N:5]([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([NH2:8])=[S:7])(C)(C)C>Cl.CCCCCC.CCOC(C)=O>[CH:9]1([NH:5][C:6]([NH2:8])=[S:7])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)N(C(N)=S)C1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NC(=S)NC1CCCC1
Reaction time: 0.67 h
Yield: 90 %

Procedure:
The t-butyl-cyclopentylthiourea (3.70 g) was dissolved in concentrated HCl (46 mL). The dark yellow solution was set to a gentle reflux. After 40 min, the reaction mixture was allowed to cool. The volume was concentrated to approx. half under reduced pressure, cooled in ice and basified to pH 9.5 with solid and saturated NaHCO3. The product was extracted into EtOAc (3×), the combined EtOAc extracts were washed with H2O (2×) and brine (1×). The organic layer was dried over anhydrous MgSO4, filtered and evaporated to dryness to obtain the crude N-cyclopentylthiourea as a beige solid (2.46 g crude). Trituration of the crude material in hexane/EtOAc 95/5 provided, after filtration, the N-cyclopentylthiourea as a white solid (2.38; 90% yield).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([CH2:10]C(=O)C)(=O)[CH3:8].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][C:26]3([N:33]([CH3:34])[CH2:32][CH2:31][N:30]4[C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=[C:29]34)[CH2:25][CH2:24]2)=[O:22])=[CH:17][C:16]=1[O:42][CH3:43].BrC(C)=C>Cl[Cu].C1COCC1>[C:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:24][CH2:25][C:26]3([N:33]([CH3:34])[CH2:32][CH2:31][N:30]4[C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=[C:29]34)[CH2:27][CH2:28]2)=[O:22])=[CH:17][C:16]=1[O:42][CH3:43])([CH3:10])=[CH2:8]
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C)ccc1O
Agent: Cl[Cu]
Agent: C=C(C)Br
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C=C(C)Oc1ccc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C)cc1OC
Temperature: 70 °C
Yield: 16 %

Procedure:
A mixture of Cs2CO3 (115 mg, 0.354 mmol), acetylacetone (12 μL, 0.12 mmol), CuCl (5.8 mg, 0.059 mmol) and THF (2.5 mL) in a vial was stirred at room temperature for 5 min before (4-hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (100 mg, 0.236 mmol) then 2-bromoprop-1-ene (27 μL, 0.31 mmol) were added. The vial was capped and heated at 70° C. overnight. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give (4-isopropenyloxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (8.9 mg, 8%). ESI-MS m/z calc. 463.2, found 464.3 (M+1)+; Retention time: 1.47 minutes (3 min run). 1H NMR (400 MHz, CD3CN) δ 7.12 (d, J=1.8 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.01 (dd, J=8.0, 1.8 Hz, 1H), 6.60 (d, J=3.4 Hz, 1H), 6.07 (d, J=3.7 Hz, 1H), 4.42 (s, 1H), 4.12 (dd, J=1.6, 0.9 Hz, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.85 (s, 3H), 3.79 (d, J=1.7 Hz, 1H), 3.67-3.40 (m, 2H), 3.36 (t, J=5.6 Hz, 2H), 3.20 (s, 1H), 2.36 (s, 3H), 2.18 (s, 2H), 2.00 (d, J=0.7 Hz, 3H), 1.83 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][CH2:41][S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:48][C:47]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[O:18][C:44](=[O:45])[C:43]=1[S:42][CH2:41][CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCCc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(2-phenylethoxy)acetophenone (1.21 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 103°-106° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.76 (t, 2 H), 2.97 (t, 2 H), 3.06 (t, 2 H), 4.27 (t, 2 H), 6.67 (s, 1 H), 7.21 (m, 12 H), 7.73 (d, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(C(O)c2cc(F)cc(F)c2)ccc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Yield: 94.3 %

Procedure:
5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile (3.5 g, 13.3 mmol) and sodium iodide (20 g, 133 mmol) are stirred in acetonitrile (50 mL) under nitrogen at 60° C. To the reaction mixture is gradually added chlorotrimethylsilane (17 mL, 134 mmol) over a period of 8 hours. The mixture is diluted with ethyl acetate and washed with water, saturated aquoeus sodium bicarbonate, 10% aquoeus sodium thiosulfate and brine. Purification of the crude by chromatography over silica gel (EtOAc/hexane 5:100) afforded 3.1 g of the title compound (88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl.N1C=CC=N1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]([C:18]3[CH:13]=[CH:14][C:15]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:17]=3)[N:20]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: c1cn[nH]c1
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
3-[4-(Chloro)phenyl]-propane-1,3-dione from Step 1 (18.3 g, 0.1 mol) and 4-sulfonamidophenylhydrazine hydrochloride (22.4 g, 0.1 mol) were dissolved in 150 mL of absolute ethanol and heated to reflux for 16 hours. The solution was cooled to room temperature, diluted with 100 mL of water and let stand, whereupon crystals of pyrazole formed that were isolated by filtration to provide 8.4 g (25%) of a white solid: mp 185-187° C.; 1H NMR (CDCl3/300 MHz) 7.89 (d, J=8.7 Hz, 2H), 7.76 (d, J=1.8 Hz, 1H), 7.43 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 6.53 (d, J=1.8 Hz, 1H), 4.93 (brs, 2H). Anal. Calc'd for C15H12N3SO2Cl: C, 53.97; H, 3.62; N, 12.59. Found: C, 54.08; H, 3.57; N, 12.64.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH2:7]([NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCNCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octylamine (0.35 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-octyl)-(3-(napthalen-2-yloxy)propyl)amine, solid, m.p. 109° C., (yield 0.63 gm, 89%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].[H-].[Na+].[Cl:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl>CN(C=O)C>[Cl:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: ClC/C=C\CCl
Reactant: Cn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C/C=C\CCl)c2ccccc21
Temperature: 40 °C

Procedure:
A solution of 1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2 g, 13 mmoles) in DMF (50 ml) was added dropwise and at room temperature to a suspension of 80% sodium hydride (0.4 g, 13 mmoles) in DMF (25 ml). The mixture was heated at 40° C. for 30 minutes and cis-1,4-dichloro-2-butene (2.84 ml, 27 mmoles) in DMF (30 ml) was dropped in 4 hours under stirring. After stirring overnight at room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was evaporated and the crude residue was purified by flash chromatography (hexane-ethyl acetate 55-45) to give 1.4 of the title compound as a thick yellowish oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[N+](C1C=C2CN(C(=O)C)CCN2N=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][O:37][CH3:38]>C(#N)C>[CH3:38][O:37][CH2:36][CH2:35][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Agent: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 80 °C

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (190 mg, 1.13 mmol) 209a in acetonitrile (10 mL) was added K2CO3 (311.9 mg, 2.26 mmol) and 1-bromo-2-methoxyethane (188.3 mg, 1.36 mmol). The reaction mixture was heated at 80° C. for 17 h under microwave irradiation. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 327a as a white solid (230 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 227.0
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([O:18][CH2:19][C:20]#[CH:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([O:18][CH2:19][C:20]#[CH:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCOc1cc(C(=O)OCC)n(-c2ncccc2Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 50 mL flask containing ethyl 1-(3-chloro-2-pyridinyl)-3-(2-propynyloxy)-1H-pyrazole-5-carboxylate (i.e. the product of Step A) (0.45 g, 1.5 mmol) and 10 mL of methanol was added dropwise a mixture of 50% sodium hydroxide (0.7 g, 8.75 mmol) in water (4.0 mL). The mixture was heated to near reflux and then cooled to ambient temperature with stirring continued for 15 minutes. To this mixture was added a solution of 1 N HCl (9.0 mL) and the reaction mixture was concentrated on rotary evaporator to approximately 5 mL to precipitate a solid. The product was isolated via filtration, washed with water, and then air-dried on the filter to afford 0.31 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11]CC1C=CC(O)=C(OC)C=1)=[O:10].C(N)CCCCC>>[C:9]([NH2:11])(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCC(=O)NCc1ccc(O)c(OC)c1
Solvent: CCCCCCN
Product: CCCCCCCCC(N)=O

Procedure:
10 g nonivamide and 5 ml hexylamine was used as the starting material and treated according to the procedure described in example 1 to give compound 6.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1O)[CH:27]=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:20][C@@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:27]=[O:28]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CCCC[C@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Product: CCCC[C@@H](Oc1ccc(C=O)cc1Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 19.5 %

Procedure:
Prepared according to the procedure used to prepare Intermediate 103 starting from (1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (196 mg, 0.63 mmol) and 3-chloro-4-hydroxybenzaldehyde (141, 0.90 mmol) to afford the title compound (55 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24]>>[C:25]1([CH:23]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH3:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(Br)c1ccccc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(c1ccccc1)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 137 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (1-bromoethyl)benzene and conditions outlined in procedure V. LCMS: 406 [M+H]; Rt=0.96 min.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]1([CH3:41])[CH3:40]>ClCCl>[CH3:40][C:25]1([CH3:41])[C:24](=[O:23])[CH2:28][CH2:27][CH:26]1[NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)C(O)CCC1NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)C(=O)CCC1NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Dess-Martin periodinane (9.49 g, 22.39 mmol) was added to a solution of cis/trans mixture of benzyl 3-hydroxy-2,2-dimethylcyclopentylcarbamate (3.93 g, 14.92 mmol, from Step 1 of Intermediate 21) in dichloromethane (150 mL) at room temperature. After 2 h at room temperature, the mixture was filtered to remove the precipitate. The filtrate was washed with 10% aqueous sodium thiosulfate (10 mL), saturated sodium bicarbonate (20 mL), brine (20 mL), dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 10 to 50% ethyl acetate in hexanes, gave benzyl 2,2-dimethyl-3-oxocyclopentylcarbamate (3.20 g, 82% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.30-7.74 (5 H, m), 4.97-5.33 (2 H, m), 4.60-4.93 (1 H, m), 2.17-2.42 (2 H, m), 1.47-1.82 (2 H, m), 1.12 (3 H, s), 0.91 (3 H, s); MS (ES+) m/z: 262.3 (M+H); HPLC retention time: 2.643 min (analytical HPLC Method A).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>C(Cl)Cl.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15]3[C:16](=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:1](=[O:5])[C:2]2=[O:3])=[CH:12][CH:13]=1
Reactant: Fc1ccc(Nc2ccc(F)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C1C(=O)N(c2ccc(F)cc2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (9.62 ml, 0.11 mole) was dissolved in 45 ml CH2Cl2. A solution of di-(4-fluorophenyl)amine (19.7 g, 0.096 mole) in 145 ml CH2Cl2 was added over 15 minutes; the temperature rose from 23° to 28°. After stirring 1 hour, AlCl3 (40.8 g) was added portionwise over 15 minutes; the temperature rose from 20° to 30°, and was kept less than 30° by cooling.. After stirring for 10 minutes, the reaction mixture was added to 250 ml ethyl acetate and 500 ml ice and water (the temperature rose to 30° C.). The aqueous layer was washed 2×250 ml ethyl acetate The organic layers were combined, back-washed 1×400 ml H2O, dried over MgSO4, evaporated to solids and triturated with 100 ml 1:1 ether:hexane to recover title product, 19.9 g, m.p. 180°-190°, tlc Rf 0.55 (1:1 ether;hexane)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:13](=O)[C@H:12]2[N:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[C:16](=O)[C@@H:7]1[CH2:8][CH:9]=[CH:10][CH2:11]2.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH2:13][C@H:12]2[N:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[CH2:16][C@@H:7]1[CH2:8][CH:9]=[CH:10][CH2:11]2
Reactant: COc1ccc(CN2C(=O)[C@@H]3CC=CC[C@H]2C(=O)N3c2ccc3ccccc3c2)c(OC)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: COc1ccc(CN2C(=O)[C@@H]3C/C=C\C[C@H]2C(=O)N3c2ccc3ccccc3c2)c(OC)c1
Agent: COc1ccc(CN2C[C@@H]3C/C=C\C[C@H]2CN3c2ccc3ccccc3c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@@H]3CC=CC[C@H]2CN3c2ccc3ccccc3c2)c(OC)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Z-(1S,6S)-7-(2,4-Dimethoxy-benzyl)-9-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (102 mg, 0.023 mmol), THF (1 mL) and DiBAl-H (6 mL, 6 mmol, [1M]) were placed in a μW tube under argon vent then heated to 130° C. for 900 sec. The reaction was quenched with Rochelle's solution and diethyl ether and the resulting mixture stirred overnight. The organic layer was separated and dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a crude oil, which was purified via reverse chromatography (20% CH3CN/water to 100% water) to yield the title compound as a residue.