Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:19](=O)[C:5]2=[CH:6][C:7]3[C:8]([CH3:18])([CH3:17])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[BH4-].[Na+]>C1COCC1.C(O)C.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:19]=1)=[CH:6][C:7]1[C:8]([CH3:18])([CH3:17])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1Cc2cc3c(cc2C1=O)C(C)(C)c1ccccc1-3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=Cc2cc3c(cc2C1)-c1ccccc1C3(C)C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
In a 1000 mL round flask, 2,9,9-trimethyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (50 g, 190.6 mmol) was dissolved THF 400 mL and ethanol 400 mL, and then stirred. Sodium borohydride (NaBH4) (9.4 g, 247.8 mmol) was added to the reaction product in five lots, and then stirred for 12 hours. The resultant mixture, after removal of solvent, was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials. The dried reaction product was dissolved in 320 mL of toluene, and then inputted to a 500 mL round flask. After that, p-toluene sulfonic acid (0.2 g) was inputted thereto, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (150 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, to thereby obtain 42.0 g of 2,9,9-trimethyl-3,9-dihydrocyclopenta[b]fluorene (yield: 89.42%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[O:25][C:22]2=[N:23][CH:24]=1>C1COCC1.CCOC(C)=O>[Br:8][C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:10]=3[Cl:9])[C:14]([OH:16])=[O:15])[CH:20]=2)[O:25][C:26]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
NBS (29.0 mg, 0.163 mmol) was added to a stirring solution of 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (50 mg, 0.136 mmol) in THF (4.5 mL) at room temperature. It was allowed to stir for 1 hour. An additional portion of NBS (29 mg, 0.16 mmol) was added it was allowed to stir for 1 hour after which another portion of NBS (29 mg, 0.16 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 10% NaHSO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-chlorobenzoic acid (57 mg, 0.128 mmol, 94% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48 (1H, d, J=2.14 Hz), 8.19-8.24 (2H, m), 8.17 (1H, d, J=2.14 Hz), 7.99-8.05 (2H, m), 7.79 (1H, d, J=8.24 Hz), 7.46-7.52 (2H, m). LC-MS retention time: 1.29 min; m/z (MH+): 447. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.BrC1C=C2C(I)N(COCCOC)NC2=NC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: COCCOCCl
Reactant: Brc1cnc2[nH]nc(I)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COCCOCN1Nc2ncc(Br)cc2C1I
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCOCn1nc(I)c2cc(Br)cnc21
Reaction time: 4 h
Yield: 47.6 %

Procedure:
To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (470 mg, 1.45 mmol), 60% sodium hydride in mineral oil (104 mg, 4.35 mmol) and tetra-n-butylammonium iodide (134 mg, 0.36 mmol) in DMF (10 mL) was added methoxyethoxymethyl chloride (248 μl, 2.18 mmol) at room temperature and the mixture was stirred for 4 h at the same temperature and subsequently quenched by addition of methanol. The mixture was then distributed between ether and brine and the organic layer dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-bromo-3-iodo-1-(2-methoxy-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (254 mg, 0.69 mmol, 74% yield) as a colorless solid (1:1 mixture with regioisomer 5-bromo-3-iodo-2-(2-methoxy-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine). 1H-NMR (500 MHz, d6-DMSO) isomer A (50%) S8.75 (d, 1H), 8.29 (d, 1H), 5.78 (s, 1H), 3.61-3.63 (m, 2H), 3.37-3.39 (m, 2H), 3.17 (s, 3H); isomer B (50%) δ 8.74 (d, 1H), 8.28 (d, 1H), 5.77 (s, 1H), 3.61-3.63 (m, 2H), 3.37-3.39 (m, 2H), 3.16 (s, 3H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(N(C1C=CC(Cl)=CN=1)S(C(F)(F)F)(=O)=O)(=O)=O.[CH2:47]([O:49][C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)=[O:51])[CH3:48].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(#N)C>[C:11]([O:10][C:8]([N:4]1[CH2:3][C:2]([C:55]2[CH:56]=[CH:57][C:52]([C:50]([O:49][CH2:47][CH3:48])=[O:51])=[CH:53][CH:54]=2)=[CH:7][CH2:6][CH2:5]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C2=CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (−78° C.) solution of tert-butyl 3-oxopiperidine-1-carboxylate (5.00 grams, 25.1 mmol) in anhydrous THF (40 mL) was added lithium bis(trimethylsilyl)amide (28.9 mL, 1.0 M in THF, 28.9 mmol) dropwise. After 90 min, a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]5-chloropyridine (10.35 g, 26.3 mmol) in THF (20 mL) was added, and the resulting mixture was allowed to warm slowly to ambient temperature overnight, at which point it was quenched by pouring into sat aq NaHCO3. The mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting enol triflate was filtered though silica gel, concentrated in vacuo, and used without further purification. To a flask containing the unpurified enol triflate were added 4-ethoxycarbonylphenylboronic acid (6.33 g, 32.6 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (890 mg, 1.26 mmol). Acetonitrile (90 mL) and sodium carbonate (63 mL, 1.0 M aqueous, 63.0 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 3 h, then was allowed to cool to room temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc) provided the title compound: LCMS m/z 276.0 [M-tBu]+; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.34-6.32 (m, 1H), 4.37 (q, J=7.0 Hz, 2H), 4.30-4.24 (br m, 2H), 3.58-3.54 (m, 2H), 2.34 (br m, 2H), 1.50 (s, 9H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[O:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(N(CC)CC)C.C(OCC)C.[Cu]I.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>[CH2:9]([O:13][C:20](=[O:16])[C:19]1[CH:3]=[CH:1][C:2]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:17][CH:18]=1)[CH3:8]
Reactant: C1CCOC1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 13, 0.23 g, 1.1 mmol) and ethyl-4-iodo benzoate (Reagent A, 0.36 g, 1.3 mmol) in triethyl amine (7 mL) and anhydrous tetrahydrofuran (3 mL) was treated with copper(I)iodide (0.114 g, 0.6 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 0.33 mmol) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to a brown oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 6-7% ethyl acetate in hexane as the eluent to afford the title compound (0.29 g, 72%) as a pale brown solid.
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[CH2:5]1[S:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH2:13]C(NCCCCCC(ON2C(=O)C(S([O-])(=O)=O)CC2=O)=O)=O)[C@H:7]2[NH:36][C:37]([NH:39][C@@H:6]12)=[O:38].[Na+]>O>[OH:2][C:1]([CH2:13][CH2:12][CH2:11][CH2:10][C@H:8]1[C@@H:7]2[C@@H:6]([NH:39][C:37]([NH:36]2)=[O:38])[CH2:5][S:9]1)=[O:4]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)[O-])C1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
About 2.0 mg of DBP is buffer exchanged with 20 mM bicarbonate at pH 9.6 three times to give a final volume of 1.0 mL. Two aliquots of sulfo-NHS-LC-biotin (Pierce) are dissolved in water to give a 1 mg/mL solution just prior to addition. The first aliquot (10 uL) is added and the reaction is maintained at room temperature for 5 minutes. The second aliquot (10 uL) is added and the reaction proceeds for an additional 4 minutes. The unreacted biotin is removed by size exclusion chromatography using SEPHADEX G-25 and 100 mM PBS, pH 7.4 as the mobile phase.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([NH2:27])=[N:22][N:23]2[CH3:26])=[CH:19][CH:18]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[Br:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([NH:27][C:2]3[CH:3]=[C:4]([C:8]4([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]4)[CH:5]=[CH:6][CH:7]=3)=[N:22][N:23]2[CH3:26])=[CH:19][CH:18]=1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Reactant: Cn1nc(N)c2ccc(Br)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(Nc2cccc(C3(C)COCC(=O)N3)c2)c2ccc(Br)cc21
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 5-(3-bromo-phenyl)-5-methyl-morpholin-3-one [Example 1, step f)] (CAS registry 1262858-67-2) (138.5 mg, 0.513 mmol), 6-bromo-1-methyl-1H-indazol-3-ylamine (CAS registry 1214899-85-0) (116 mg, 0.513 mmol), X-phos (78 mg, 0.164 mmol) and K3PO4 (218 mg, 1.025 mmol) in toluene (2.5 ml) and water (0.250 ml) was degassed with argon (5 min), then Pd2(dba)3 (37.6 mg, 0.041 mmol) was added and the reaction mixture was stirred at 120° C. for 20 h. The reaction mixture was diluted with water, sat. aq. NaHCO3 soln. and EtOAc. The layers were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude product was purified by RP-HPLC (Waters SunFire C18 column, 5 μM, 19×150 mm, gradient 10 to 70% ACN+0.1% TFA) to yield the title compound as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:37]1[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1cc(I)cc[nH]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 1. LC-MS Method 1tR=1.23 min, m/z=389, 447 (M+1); 1H NMR (CD3OD) 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)C(C)C)(C)C.[Br:23][C:24]1[CH:28]=[N:27][N:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]([CH3:44])([N+:41]([O-])=O)[CH3:40])[NH2:33].C(O)(=O)C.[OH-].[NH4+]>ClCCl.[Zn]>[NH2:41][C:39]([CH3:44])([CH3:40])[CH2:38][O:37][C:36]1[CH:35]=[CH:34][C:32]([NH:33][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:31][C:30]=1[C:25]1[N:26]([CH3:29])[N:27]=[CH:28][C:24]=1[Br:23]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 3-trifluoromethylbenzoyl chloride (17 μl, 0.11 mmol), N,N-diisopropylethylamine (21 μl, 0.12 mmol) and 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (37 mg, 0.10 mmol) in 0.5 mL of dichloromethane was stirred at room temperature. After 1 h the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was taken up in methanol (0.4 mL), acetic acid (114 μl, 2.0 mmol) was added followed by zinc dust (65 mg, 1.0 mmol) and the mixture was stirred at room temperature. After 1 h the mixture was made strongly basic with conc. ammonium hydroxide, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative LCMS and lyophilized to afford the product (46 mg, 74%) as a TFA-salt. LCMS m/z (%)=513.5 (M+H 81Br 71.7%), 511.3 (M+H 79Br 82.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 3 H), 1.18 (s, 3 H), 3.67 (s, 3 H), 3.84 (d, J=9.60 Hz, 1 H), 4.00 (d, J=9.85 Hz, 1 H), 7.31 (d, J=9.09 Hz, 1 H), 7.67 (s, 1 H), 7.70 (d, J=2.78 Hz, 1 H), 7.80 (t, J=7.71 Hz, 1 H), 7.86-7.94 (m, 3 H), 7.94-8.01 (m, 2 H), 8.26 (d, J=8.08 Hz, 1 H), 8.29 (s, 1 H), 10.57 (s, 1 H).
Reaction SMILES: [Br:1]CCCC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1.Cl[CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>>[Br:1][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(C#CCCCCl)cc1
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C#CCCCBr)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 40, using Intermediate 41 as a substrate. ES/MS calcd. for C11H11BrNO2+ 268.0. Found m/z=268.1 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH:12](C)[CH3:13]>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][NH2:12]
Reactant: CNC
Reactant: C=CCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)CN
Reaction time: 20 h

Procedure:
20g of 1-undecene and 10g of (CH3)2NH are reacted in accordance with the method of example 3 with Zr (Me2N4) (1g) in 50ml of toluene. After 20 hours at 200° C., (N-methyl, N-2 methylundecylamine) is obtained, and is separated by chromatography on an Al2O3 column.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:20][CH:21]([OH:29])[C:22]2[CH:23]=[CH:24][C:25](Cl)=[N:26][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:20][CH:21]([OH:29])[C:22]2[CH:27]=[N:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(Cl)nc2)cc1OC
Agent: [Ni]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2cccnc2)cc1OC

Procedure:
A solution of N-[1-(3,4-dimethoxyphenyl)-2-phenylethyl]-2-hydroxy-2-(2-chloropyrid-5-yl)-ethylamine (100 mg, 0.26 mmol) in ethanol (7 mL) with 5N sodium hydroxide (0.1 mL, 0.5 mmol) is degassed with argon prior to addition of Ni(R) (100 mg). The mixture is hydrogenated at 40 Psi for overnight and then the catalyst is filtered through Celite and washed with a small amount of ethanol. Evaporation of the filtrate gives the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[CH2:16][CH2:17][OH:18].C(N(CC)CC)C.ClCCl.CO>C(#N)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:16][CH2:17][OH:18])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: OCCBr
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Temperature: 50 °C
Yield: 66.1 %

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (5 g, 25 mmol), 2-bromoethanol (1.77 mL, 25 mmol) and triethylamine (3.86 mL, 27.5 mmol) in acetonitrile (20 mL) was heated in a sealed tube at 50° C. for 16 hours. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate (300 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (100 mL). The aqueous phase was back-extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (4:1) gave 4.04 g (66% yield) of product as a colorless solid, mp 66° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C

Procedure:
A solution of 7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyrdine-6-carboxylic acid ethyl ester (10) (750 mg, 1.87 mmol), Cs2CO3 (1.83 g, 5.63 mmol), 4-fluoro benzyl bromide (0.276 mL, 2.24 mmol) in dry NMP was heated overnight at 90° C. The solution was poured into ice water and the solids formed were filtered, washed by cold water, and dried. The crude product was purified by reverse phase flash chromatography in combiflash eluting with water/acetonitrile gradient. Yield 240 mg (25%). 1H-NMR (DMSO-d6) δ 1.27 (t, J=6.8 Hz, 3H), 3.36 (m, 4H), 3.82 (m, 4H), 4.26 (q, J=6.8 Hz, 2H), 5.35 (s, 2H), 6.65 (m, 1H), 7.06 (dd, J=0.8, 3.6 Hz, 1H), 7.16 (m, 2H), 7.32 (m, 3H), 7.87 (m, 1H), 8.03 (d, J=5.6 Hz, 1H); EIMS m/z 510 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].[C:22]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CCCCCC>[C:16]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:22]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:17]
Reactant: O=C1CCCCC1
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: N#CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
p-Benzyloxyphenyl acetonitrile (100 g) and methanol (300 ml) was charged into flask Subsequently the reaction mixture was cooled to 0-5° C. and 10% aqueous solution of sodium hydroxide (180 g) and PEG-400 (10 ml) were added. The reaction mixture was then stirred for 30 min. and cyclohexanone (64 g) was added dropwise at 0-5° C. Subsequently, the reaction mass temperature was raised to 25-27° C. and stirred for 15 hours. After completion of the reaction hexane (600 ml) was added, the reaction mixture filtered, washed with hexane (100 ml) followed by DM water to obtain 120 g (83.9%) of the 1-[cyano(p-benzyloxyphenyl)methyl]cyclohexanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][C:16]1[O:22]C(C)(C)O[C:18](=[O:19])[CH:17]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:18]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])(=[O:19])[CH2:17][C:16]([CH3:15])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCN1C(=O)c2ccccc2C1=O
Yield: 76.4 %

Procedure:
A solution of 10.0 g (52.3 mmol) of N-(2-hydroxyethyl)phthalimide, 8.84 ml (67.7 mmol) of 2,2,6-trimethyl-1,3-dioxen-4-one, and 10 mg of p toluenesulfonic acid in 50 ml of toluene is heated at reflux under N2 for 4 hr. The solvent is removed under vacuum and the dark-colored residue is flash chromatographed on silica gel (1:1 hexane-EtOAc). The resulting product is recrystallized from EtOAc to give 11.0 g of 2-phthalimidoethyl acetoacetate.