Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[C:3]1([S:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH2:26][CH2:27][O:28][S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[CH:23]=3)[NH:18][N:17]=2)(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:39](=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:39][N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)(=[O:30])=[O:31])=[CH:21][CH:20]=2)[C:16]([S:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)(=[O:14])=[O:15])=[N:17]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyliodide (0.06 mL, 0.96 mmol) was added to a chilled mixture of toluene -4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.401 g, 0.767 mmol) and cesium carbonate (0.29 g, 0.89 mmol) in acetone (10 mL). The reaction mixture was stirred at ambient temperature under nitrogen for 3 hours. It was then partitioned in ethyl acetate and water. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 25-40% ethyl acetate in hexane, 100% chloroform and 1% methanol in chloroform. Drying at 65° C. in vacuo for yielded toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester as a buff foam (0.224 g, 54.4%). 1HNMR (400 MHz, DMSO-d6): δ8.27 (d, 1H, J=8.54 Hz), 8.55 (dd, 1H, J=7.42 Hz and 1.16 Hz), 8.30 (d, 1H, J=8.35 Hz), 8.05-8.07 (m, 1H), 7.72-7.76 (m, 3H), 7.60-7.70 (m, 3H), 7.31 (d, 2H, J=8.01 Hz), 7.18 (d, 1H, J=2.20 Hz), 7.00-7.03 (m, 1H), 4.35-4.37 (m, 2H), 4.22-4.24 (m, 2H), 4.07 (s, 3H), 2.28 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]([CH3:20])([C:18]#[CH:19])[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[C:19]#[C:18][C:13]([CH3:20])([CH3:12])[C:14]([O:16][CH3:17])=[O:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC(C)(C)C(=O)OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(C)(C)C#Cc1cc([N+](=O)[O-])ccc1N
Temperature: 70 °C
Reaction time: 24 h
Yield: 8.6 %

Procedure:
To a deoxygenated solution of compound 2-bromo-4-nitroaniline (9.43 g, 43.7 mmol), methyl 2,2-dimethylbut-3-ynoate (5.00 g, 39.7 mmol), CuI (754 mg, 3.97 mmol) and triethylamine (8.03 g, 79.4 mmol) in toluene/H2O (100/30 mL) was added Pd(PPh3)4 (6.17 g, 3.97 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 h. After cooling, the solid was filtered off and washed with EtOAc (50 mL×3). The organic layer was separated and the aqueous phase was washed with EtOAc (50 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to obtain methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (900 mg, 9%). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=2.8 Hz, 1H), 8.01 (dd, J=2.8, 9.2 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 5.10 (brs, 2H), 3.80 (s, 3H), 1.60 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][N:19]([CH2:2][CH:3]([C:5]2[CH:14]=[CH:13][C:8]3[NH:9][C:10](=[O:12])[O:11][C:7]=3[CH:6]=2)[OH:4])[CH2:18][CH2:17]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(CCl)c1ccc2[nH]c(=O)oc2c1
Product: O=c1[nH]c2ccc(C(O)CN3CCC(O)(c4ccccc4)CC3)cc2o1
Yield: 25 %

Procedure:
By the procedures of Examples 8 and 2, 6-(2-chloroacetyl)-2(1H)-benzoxazolone and 4-hydroxy-4-phenyl-piperidine were converted to present title product in 25% yield after recrystallization from ethanol/ether; m.p. 175°-177° C. NMR (methanol-d4) 7.51 (dd, J=1.5, 8.5 Hz, 2H), 7.35-7.29 (m, 3H), 7.24-7.19 (m, 2H), 7.05 (d, J=8 Hz, 1H), 4.94-4.90 (m, 1H--becomes dd J=3, 8.5 Hz with D2O wash), 2.96-2.90 (m, 2H), 2.80-2.57 (m, 4H), 2.19 (dq, J=4.5, 13 Hz, 2H), 1.74 (br d, J=14.5 Hz, 2H). IR(KBr) 3320, 3115, 2920, 2830, 1785, 1750.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)=[O:17])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 85.6 %

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-glutamine (8.0 g) and 1-benzylpiperazine (5.7 g) were condensed to obtain a colorless crystal 1-(N-tert-butoxycarbonyl-L-glutaminyl)-4-benzylpiperazine (11.2 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[C:7]2/[C:8](=[O:22])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:10](=[O:12])[CH2:11]/2)=[CH:2]1.C(N(CC)CC)C.[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33]>ClCCl>[O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[C:7]2/[C:8](=[O:22])[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[C:10]([O:12][C:32](=[O:33])[C:31]([CH3:36])([CH3:35])[CH3:30])[CH2:11]/2)=[CH:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)C/C(=C\c3ccoc3)C2=O)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)C/C(=C\c3ccoc3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[1-furan-3-yl-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (50 mg) in dichloromethane (2 ml) is added triethylamine (118 μl), followed by trimethylacetyl chloride (105 μl) and the resulting suspension allowed to stir at room temperature for 3 hours. The crude reaction mixture is then purified by automated flash chromatography to give 2,2-dimethyl-propionic acid 4-[1-furan-3-yl-meth-(E)-ylidene]-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:3]=2)[CH:13]=[CH:12][N:11]=1
Reactant: C1CCNC1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cncc(Br)c2)n1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cncc(N3CCCC3)c2)n1
Temperature: 160 °C

Procedure:
(2-Meth yl-5-nitro-phenyl)-[4-(5-pyrrolidin-1-yl-pyridin-3-yl)-pyrimidin-2-yl]-amine 9 is prepared by mixing 8 (0.40 g, 1.04 mmol), pyrrolidine (3.12 mmol), K3PO4 (0.44 g, 2.08 mmol), CuI (38.5 mg, 0.10 mmol) and L-proline amino acid (48.1 mg, 0.21 mmol) in DMSO (8 ml) and heating at 160° C. in a microwave oven for 20 min. The cooled mixture is partitioned between water and ethyl acetate. The organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is dissolved in DMSO (4 mL) and purified with HPLC to afford pure product 9. 1H NMR (400 MHz, d-CDCl3) δ 9.23 (d, J=2.4 Hz, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.58 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.90 (dd, J=8.4, 2.4 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 3.43-3.48 (m, 4H), 2.49 (s, 3H), 2.12-2.16 (m, 4H). LC/MS (m/z) (M+1)+: 377.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of 1-methylpiperazine (1 g, 8.771 mmol, 1.0 eq) in DMF were added K2CO3 (265 m g, 21.927 mmol, 2.5 eq) and ethyl 2-bromoacetate (167 mg, 13.15 mmol, 1.5 eq). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 76.4% yield. (1.3 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-].[Li+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([O:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a solution of 0.200 g (0.535 mmol) of the product of Step 1 in 12 mL of ethyl acetate is added 0.716 g (5.35 mmol) of lithium iodide and the resulting mixture is heated to reflux for 24 h. An additional 0.716 g (5.35 mmol) of lithium iodide is then added and the reaction mixture is heated to reflux for an additional 6 h. The reaction is then let cool to room temperature and washed with 5% HCl solution, sodium thiosulfate solution, and brine. The organics are then dried over MgSO4, filtered and concentrated in vacuo to afford 0.123 g (64%) of 2-({[4-(2-butynyloxy)phenyl]sulfonyl}oxy)-3-methylbenzoic acid as a white solid pure enough for use in the next step. Electrospray Mass Spec: 358.8 (M−H)−
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([N:55](CC3C=CC(OC)=CC=3)[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:87][C@@H:88]([CH3:92])[C:89](O)=[O:90])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:87][C@H:88]([C:89]([NH:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:33][CH2:34]1)=[O:90])[CH3:92]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (68.4 mg, 0.155 mmol) was added to a solution of 62B (30.0 mg, 0.052 mmol), DIEA (0.036 mL, 0.206 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (19.52 mg, 0.103 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min, and then concentrated to dryness. TFA (0.238 mL, 3.09 mmol) was added and the reaction solution was stirred at 70° C. for 1 h. The resulting mixture was concentrated and then diluted with MeOH and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 90% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to afford 6-((trans-4-(L-alanylamino)cyclohexyl)amino)-N-(2-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (13.7 mg, 0.026 mmol, 49.9% yield) as white solid. HPLC Rt=1.618 minutes (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). [M+H]=533.17.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[N:5]([CH3:7])[CH3:6].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH2:12][CH3:13].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(N(C)C2C=CC=CC=2)C=1P(C1CCCCC1)C1CCCCC1>[CH3:6][N:5]([C:4]1[CH:3]=[C:2]([CH:12]([CH3:13])[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:10]=[CH:9][CH:8]=1)[CH3:7]
Reactant: CCC(=O)c1ccccc1
Reactant: CN(C)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: CC(C(=O)c1ccccc1)c1cccc(N(C)C)c1
Yield: 79.2 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are 3-chloro-N,N-dimethylaniline (155.9 mg, 1.0 mmol), propiophenone (160.9 mg, 1.2 mmol), palladium acetate (6.7 mg, 0.030 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyl(dicyclohexyl)phosphine (18.4 mg, 0.045 mmol), t-BuONa (116.1 mg, 1.2 mmol) in 3 mL dry toluene at 110° C. for 11.5 h. 2-[3′-(N, N-dimethylamino)phenyl]-1-phenyl-1-propanone (200.7 mg) was obtained with a yield of 79% as liquid. 1H NMR (300 MHz, CDCl3) δ 8.03-7.97 (m, 2H, ArH), 7.52-7.44 (m, 1H, ArH), 7.43-7.35 (m, 2H, ArH), 7.20-7.11 (m, 1H, ArH), 6.65-6.55 (m, 3H, ArH), 4.19 (s, 2H, CH2), 2.87 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 197.7, 150.6, 136.4, 135.1, 132.8, 129.1, 128.5, 128.4, 117.4, 113.1, 110.9, 45.9, 40.3; IR (neat) v (cm−1) 3056, 2891, 2804, 1679, 1601, 1579, 1501, 1447, 1354, 1330, 1276, 1205, 1180, 1155, 1062; MS (70 eV, EI) m/z (%): 240 (M++1, 10.27), 239 (M+, 54.99), 105 (100); HRMS calcd for C16H17NO (M+): 239.1310. Found: 239.1309.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH2:22]([O:29][CH2:30]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][CH2:30][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Reactant: ClCOCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12COCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of LDA (531 mL, 0.109M, 58.1 mmol) at −78° C. was added a solution of Intermediate 85a (10.0 g, 41.2 mmol) in THF (200 mL) over 30 min maintaining the temperature below −70° C. The mixture was stirred at −78° C. for 2 h, then a solution of benzyloxymethyl chloride (11.6 g, 74.1 mmol) in THF (50 mL) added, maintaining the temperature below −70° C. The mixture was allowed to warm to −30° C. over 3 h before being quenched with dropwise addition of water (300 mL). The aqueous was extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-60% diethyl ether in cyclohexane, to give the title compound as a clear oil (6.39 g, 42%). 1H NMR (400 MHz, CDCl3): 1.63-1.77 (1H, m), 1.94-2.04 (1H, m), 2.08-2.17 (1H, m), 2.26-2.36 (1H, m), 3.22-3.29 (1H, m), 3.30-3.38 (1H, m), 3.74, (2H, s), 4.62 (2H, s), 4.99 (1H, s), 7.26-7.37 (5H, m).
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:3].[CH3:13][O:14][N:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:13][O:14][N:15]1[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12]
Reactant: C=C(C)C1CCCCCCC1=O
Reactant: CCCCCC=NOC
Agent: CCCCCC1C/C(C)=C/CCCCCCC(=O)N1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCCC1CC(C)=CCCCCCCC(=O)N1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
An argon flushed three-necked flask which was cooled by an ice-water bath was charged with 2-(prop-1-en-2-yl)cyclooctanone (1.50 g, 9.02 mmol), hexanal O-methyl oxime (1.56 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml). The mixture was stirred for 2 days at room temperature. The completion of reaction was checked by GC analysis of reaction aliquots quenched with a solution of saturated NaHCO3 in water. The reaction mixture was quenched with sat. aqueous NaHCO3 solution (50 mL). The organic phase was separated and the aqueous layer was extracted with MTBE three times. The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated in vacuo. The crude product was purified by distillation to give the title product as a yellow oily liquid (2.38 g, 89%). E isomers>98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18]Br)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:20]#[N:21].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:20]#[N:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CBr)cc2C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CC#N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 21.76 mmol of tert-butyl-7-(bromomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 80 ml DMF were added at 0° C. 65.3 mmol sodium cyanide in small portions. The mixture was stirred at room temperature for 2 h. Brine solution was added to the mixture and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and filtered. Evaporation of the solvent gave 5.6 g of a brown oil. The material was purified by flash chromatography to yield 1.63 g of a pale yellow solid (27.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccnc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to a solution of 276 mg (0.855 mmol) of 3-[5-methyl-3-(3-pyridinylsulfonyloxy)phenoxy]propanol, as prepared in the preceding step, in anhydrous dichloromethane (2 mL) containing 450 μL (2.58 mmol) of N,N-diisopropylethylamine and 92 μL (1.19 mmol) of anhydrous dimethyl sulfoxide was added 204 mg (1.28 mmol) of sulfur trioxide pyridine complex. The reaction mixture was stirred at 0° C. for 30 min, diluted with 20 mL of toluene, and concentrated to an oil which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=[O:10].B.C1COCC1.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccccc1Br
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromophenylacetic acid (3.96 g, 18.42 mmol) in 60 mL of anhydrous THF was added slowly at room temperature 24.0 mL (23.95 mmol) of a 1 M solution BH3/THF. After finishing the addition of BH3/THF, the solution was stirred at room temperature for 1 h and then heated at 100° C. for 2 h. After this time, the solution was cooled to room temperature, and a mixture of THF and water (20 mL) was added. Potassium carbonate was then added, along with 60 mL of ether. The organic layer was separated from the mixture, and this layer was washed with water (60 mL), aqueous NaHCO3 (60 mL), and brine (60 mL) before it was dried over magnesium sulfate, filtered, and concentrated to give the crude product. This crude product was purified by silica gel flash chromatography eluting with hexanes and a 5 to 10% gradient of ethyl acetate to give 3.47 g (94%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.57 (d, 1H, J=7.8 Hz), 7.31-7.21 (m, 2H), 7.14-7.08 (m, 1H), 3.90 (app. t, 2H, J=6.6, 6.9 Hz), 3.05 (app. t, 2H, J=6.6 Hz), 1.51 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ 137.76, 132.95, 131.25, 128.19, 127.44, 124.67, 62.04, 39.30. Anal. Calc'd. for C8H9BrO: C, 47.79; H, 4.51. Found: C, 47.75; H, 4.50.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([N:17]=[C:18]=[O:19])[CH:2]=1.[CH2:20]([CH:22]([NH:25][OH:26])[CH2:23][CH3:24])[CH3:21]>O1CCCC1>[CH2:7]([C:6]1[CH:5]=[CH:4][C:3]([NH:17][C:18](=[O:19])[N:25]([OH:26])[CH:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[CH:2][CH:1]=1)[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:16])[N:25]([CH:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[OH:26])=[CH:10][CH:9]=1
Reactant: CCC(CC)NO
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)N(O)C(=O)Nc1ccc(Cc2ccc(NC(=O)N(O)C(CC)CC)cc2)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A solution of 4,4'-methylenebis(phenylisocyanate) (1.5 g, 6.0 mmol) and tetrahydrofuran (75 ml) was charged with N-(1-ethylpropyl)hydroxylamine (1.5 g, 14.5 mmol) and maintained at ambient temperature for 16 hr. The solvent was removed in vacuo to provide the crude product as a white solid. Recrystallization from ethyl acetate.backslash.hexanes provided 1.0 g of the desired product as a white powder: MP: 196.0-198.0° C. (decomp); 1H NMR (300 MHz, DMSO): δ 9.16 (s, 2H), 8.78 (s, 2H), 7.50 (d, J=8.5 Hz, 4H), 7.05 (d, J=8.5 Hz, 4H), 3.96-3.87 (m 2H), 3.77 (s, 2H), 1.59-1.31 (m, 8H), 0.85-0.80 (t, J=7.3 Hz, 12H); 13C NMR (75 MHz, DMSO): δ 157.7, 137.4, 134.9, 128.2, 119.1, 59.6, 24.5, 11.0; IR (KBr): 3395, 3147, 2966, 2931, 2875, 1641, 1590, 1528, 1461, 1413, 1328, 1312, 1225, 1150, 815, 761 cm-1 ; MS (FAB): m/e 457.2804 (457.2815 calc'd for C25H37N4O4, M+H); Anal. calc'd for C25H36N4O4 : C, 65.76; H, 7.95; N, 12.27. Found: C, 65.53; H, 7.87; N, 12.11.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:22][C:23](O)=[O:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: CCNCc1ccccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(6-amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine