Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10](O)[CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH2:1]([O:8][CH2:9][C@@H:10]([N:39]1[C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]2[C:35]1=[O:45])[CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC[C@@H](O)COCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCC[C@@H](COCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1-benzyloxy-2-(R)-hydroxy-5-hexene (2.18 g, 10.5 mmol), triphenylphosphine (3.32 g, 12.7 mmol) and phthalimide (1.86 g, 12.7 mmol) was added diisopropyl azodicarboxylate (2.62 ml, 12.7 mmol) at rt, and the resulting mixture was stirred for overnight at rt. The mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with water, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give 1-benzyloxy-2-(S)-phthalimido-5-hexene (2.95 g, 83%) as a colorless oil: 1H-NMR (CDCl3) δ 1.76–1.84 (m, 2 H), 2.06 (dd, J=14.4, 6.8 Hz), 2 H, 2.12–2.22 (m, 1 H), 3.69 (dd, J=10.0, 5.6 Hz, 1 H), 4.00 (t, J=9.6 Hz, 1 H), 4.46 (d, J=12.0 Hz, 1 H), 4.53 (d, J=12.0 Hz, 1 H), 4.51–4.58 (m, 1 H), 4.91–4.99 (series of m, 2 H), 5.72–5.79 (m, 1 H)7.21–7.26 (m, 5 H), 7.71–7.83 (series of m, 2 H); MS (ESI) m/z, 336 (M++H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:31]=[CH:30][C:15]([O:16][S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:36](OC(=O)C)(=[O:38])[CH3:37].O>CCOC(C)=O.CN(C)C1C=CN=CC=1>[C:36]([O:29][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]3[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[O:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:31][CH:30]=2)(=[O:18])=[O:19])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])(=[O:38])[CH3:37]
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(OC(C)=O)c2)cc1
Reaction time: 24 h
Yield: 76 %

Procedure:
At ambient temperature, to a stirred solution containing 4-{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.298 g, 0.602 mmol) and acetic anhydride (1 mL) In EtOAc (2 mL) was added 4-(dimethylamino)pyridine (3.7 mg, 0.0301 mmol). The reaction was refluxed for 72 h. The reaction was cooled to ambient temperature, hydrolyzed with H2O (5 mL) and stirred for 24 h. The reaction was diluted with EtOAc and the organic phase washed sequentially with H2O (2×), brine (2×), dried (MgSO4) and concentrated. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet ether step gradient gave 0.122 g (76%) of the title compound as a yellow solid, mp 54-57° C. 1H NMR consistent. IR (KBr) 3400, 2900, 1700, 1380 and 1190 cm−1. mass spectrum (−ESI) m/z 535 (M−H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>>[CH2:16]([O:18][P:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)(=[O:23])[O:20][CH2:21][CH3:22])[CH3:17]
Reactant: BrCCCCCOCC1CC2C=CC1C2
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCOCC1CC2C=CC1C2)OCC
Temperature: 160 °C

Procedure:
5-[[(5-bromopentyl)oxy]methyl]bicyclo[2.2.1]hept-2-ene 5 (10 g) was added to 50 mL of triethylphosphite and the solution was heated at 160° C. under nitrogen for 20 h. The solution was cooled to room temperature and excess triethylphosphite was removed under reduced pressure. The oily residue was distilled in vacuo to give 6 as a colorless oil, b.p. 145° C., 0.15 Torr. 1H NMR (500 MHz, 25° C., CDCl3): δ (endo isomer, 85%) 6.07-6.05 (m, 1H, olefinic), 5.87-5.85 (m, 1H, olefinic), 4.06-4.00 (m, 4H, POCH2CH3), 3.34-2.94 (m, 6H, CH2), 2.84 (br s, 1H, bridgehead CH), 2.73 (br s, 1H, bridgehead CH), 2.30-2.20 (m, 1H, exo CH), 1.70-1.49 (m, 9H, CH2), 1.27 (t, 6H, POCH2CH3), 0.44-0.41 (m, 1H, endo CH of CH2); (exo isomer, partial) 6.02-6.01 (m, 1H, olefinic), 2.70 (br s, 1H, bridgehead CH). 13C {1H} NMR (125 MHz, 25° C., CDCl3): δ (endo isomer) 137.0 (olefinic CH), 132.5 (olefinic CH), 74.6 (CH—CH2O), 61.4 (d, |2JC-P|=6 Hz, POCH2CH3), 49.4 (CH2 bridge), 44.0 (bridgehead CH), 42.2 (bridgehead CH), 38.9 (CH—CH2O), 29.3 (CH2), 27.4 (CH2), 27.3 (CH2), 25.7 (d, |1JC-P|=140 Hz, CH2P), 22.4 (CH2), 22.3 (CH2), 16.5 (d, |3JC-P|=5.4 Hz, POCH2CH3); (exo isomer, partial) 136.6 (olefinic CH), 75.6 (CH—CH2O), 45.0 (CH), 43.8 (CH), 41.6 (CH), 29.8 (CH2). 31P{1H} NMR (200 MHz, 25° C., CDCl3): δ 32.6
Reaction SMILES: [OH-:1].[K+].C([CH2:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][C:11]2[C:12]([N:23]3[CH2:27][C@H:26]([CH2:28][CH3:29])[O:25]C3=O)=[N:13][C:14](/[N:18]=C/N(C)C)=[N:15][C:16]=2[CH3:17])=[CH:8][CH:7]=1)#N.[CH2:33]([OH:37])CCC>>[NH2:18][C:14]1[N:13]=[C:12]([NH:23][CH2:27][C@@H:26]([OH:25])[CH2:28][CH3:29])[C:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:33]([OH:37])=[O:1])=[CH:32][CH:31]=2)=[C:16]([CH3:17])[N:15]=1
Reactant: CCCCO
Reactant: CC[C@H]1CN(c2nc(/N=C/N(C)C)nc(C)c2Cc2ccc(CC#N)cc2)C(=O)O1
Reactant: [OH-]
Agent: [K+]
Product: CC[C@H](O)CNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1
Temperature: 100 °C

Procedure:
Aq. 5M KOH (1 ml) was added to a stirred solution of the product from step (vi) (136 mg) in butan-1-ol (2 mL). The solution was heated at 100° C. for 15 h and the solvent evaporated under reduced pressure. The residue was diluted with MeOH (2 mL) and the pH adjusted to ˜7 using acetic acid. The solution was purified by RPHPLC to give the subtitle compound as a white solid, 55 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35].[O:46]1[CH2:49][CH:48]([NH2:50])[CH2:47]1.C(N(CC)CC)C>O1CCCC1>[F:30][C:28]([F:31])([F:29])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:50][CH:48]4[CH2:49][O:46][CH2:47]4)=[O:35])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1)([OH:32])[C:24]([F:25])([F:26])[F:27]
Reactant: NC1COC1
Reactant: Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NC1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
(4-Aminophenyl)(1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-yl)methanone (0.367 mmol, 169 mg) and 4-nitrophenyl chloroformate (0.367 mmol, 74.0 mg) were combined in tetrahydrofuran (2 mL) and stirred at room temperature for 1 hour. Oxetan-3-amine (0.734 mmol, 53.7 mg) and triethylamine (1.101 mmol, 111 mg) were added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue purified by basic HPLC to afford the title compound (43 mg). MS (ESI) m/z 560.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][OH:26])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: O=C(C(CO)c1ccccc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1

Procedure:
Dissolve 0.40 g (0.9 m mole) of 8-chloro-11-[1-(2-hydroxy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine (Example 41 of Table 2) in 10 mL of pyridine and stir under nitrogen. Add 0.15 g (1.3 m mole) of methanesulfonyl chloride and stir for 20 hours. Concentrate under vacuo and triturate the residue with ether. Purify the resulting solid by silica gel chromatography using 2% MeOH saturated with ammonia, and 98% CH2 Cl2 as the solvent. The product is obtained as a white solid, mp=110.7°-111.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([CH3:17])[CH:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:30](O)=[O:31]>>[CH:30]([C:4]1[C:5]([CH3:17])=[CH:6][C:7]2[C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][C:11]([CH3:13])([CH3:14])[C:12]=2[C:3]=1[O:2][CH3:1])=[O:31]
Reactant: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Reaction time: 0.5 h

Procedure:
Formylation. 1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (50 g, 0.2155 mol) was added to a stirred mixture of hexamethylenetetramine (31.4 g, 0.224 mol) and trifluoroacetic acid (250 mL) at 35°-40° C., under a nitrogen atmosphere. The stirred reaction mixture was heated to 85°-90° C. and maintained at this temperature for 1.5 h. Trifluoroacetic acid was removed by distillation and the residue was poured onto an ice-water mixture (800 mL). The mixture was then stirred for 0.5 h, neutralized with a 10% sodium carbonate solution, and the product extracted with benzene (2×150 mL). The combined extracts were washed with brine (50 mL) and dried (Na2SO4). The solvent was then removed by distillation and the residue crystallized from hexane to provide 2-formyl-1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (14 g), mp 78° C., GLC purity 100%. 1H-NMR (CDCl3) δ10.39 (1H, s), 6.93 (1H, s), 3.86 (3H, s), 2.49 (3H, s), 1.63 (4H, s), 1.39 (6H, s), 1.37 (6H, s), 13C-NMR (CDCl3) δ192.1 (1C, d), 165.4 (1C, s), 153.5 (1C, s), 138.3 (1C, s), 135.8 (1C, s), 125.8 (2C, s, d), 66.1 (1C, q) 38.1 (1C, t), 35.3 (1C, s), 34.8 (1C, t), 34.3 (1C, s), 31.7 (2C, q), 29.8 (2C, q), 20.8 (1C, q). IR (melt) 1245, 1682 cm-1,MS (m/e) 260 M+, 20.8), 246 (18.7), 245 (100.0), 141 (12.3), 128 (13.2), 115 (13.0).
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:18])[CH:13]([CH3:17])[C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:19]Br.O>C(O)(=O)C>[CH:1]([N:4]([C:12](=[O:18])[CH:13]([CH3:17])[C:14]([CH2:16][Br:19])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)C(C)C(=O)N(c1ccc(Cl)cc1)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)CBr)C(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a reaction flask which contained 71.6 g (0.267 mole) of N-isopropyl-4'-chloro-2-methylacetoacetanilide dissolved in 360 ml of glacial acetic acid, there was added dropwise a solution of 42.7 g (0.267 mole) of bromine in 30 ml of acetic acid. The solution was stirred overnight at ambient temperature. On the following morning, the reaction solution was added to two liters of cold water and the organic material was extracted into toluene. The latter was washed with water and dried over sodium sulfate. After removal of the solvent, there was obtained 86.6 g (97%) of residual oil. N.M.R. (CDCl3) ∂0.9-1.4 (CH3, 9 protons), 3.3-3.6 (CH), 3.9-4.0 (CH2Br), 4.8-5.2 (CH, isopropyl), 7.1-7.6 (aromatic).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][S:5]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:7])=[O:6].[CH3:33][S:34]([O:37]C)(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[S:34]([O-:37])(=[O:36])(=[O:35])[CH3:33].[CH3:1][O:2][CH:3]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][S:5]([CH2:8][CH2:9][N+:10]([CH3:33])([CH3:12])[CH3:11])(=[O:6])=[O:7]
Reactant: COS(C)(=O)=O
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCN(C)C)OC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CC[N+](C)(C)C)OC
Product: CS(=O)(=O)[O-]
Temperature: 70 °C
Reaction time: 5 h
Yield: 70.6 %

Procedure:
In 10 ml of chloroform are dissolved 0.48 g of 2-[(2-methoxy-3-octadecyloxypropyl)sulfonyl]ethyldimethylamine and 1 g of methyl methanesulfonate and the solution is stirred at 70° C. for 5 hours. Then the reaction mixture is concentrated under reduced pressure and the residue is crystallized from chloroform and ether to give 417 mg of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:43][C:44]1[CH:45]=[C:46]([CH:63]=[CH:64][CH:65]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([C:54]2[NH:58][CH:57]=[C:56]([C:59]([O:61][CH3:62])=[O:60])[CH:55]=2)[CH:49]=1.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:45]=[C:46]([CH:63]=[CH:64][CH:65]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([C:54]2[NH:58][CH:57]=[C:56]([C:59]([O:61][CH3:62])=[O:60])[CH:55]=2)[CH:49]=1)=[O:9]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(N)c3)ccn2)c1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methyl-2-furoic acid (490 mg, 3.88 mmol), HATU (1.71 g, 4.5 mmol) and N,N-diisopropylethylamine (1.0 g, 7.8 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of methyl 5-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (1.0 g, 3.24 mmol). The mixture was stirred at 50° C. for 2 hours and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate as white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH3:15])=[O:5].C1(=O)[NH:20]C(=O)C2=CC=CC=C12.[K].O.NN.Cl>O.C(O)(=O)C.CN(C)C=O>[NH2:20][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH3:15])=[O:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCc1cccc(C)c1NC(=O)CCBr
Agent: Cl
Agent: NN
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NC(=O)CCN

Procedure:
The 3-bromo-2'-ethyl-6'-methylpropionanilide (13.5 g, 0.0500 mole) described above, potassium phthalimide (10.2 g, 0.0551 mole), and dimethylformamide (50 ml) were stirred under reflux for two hours. A mixture of glacial acetic acid (20 ml) and water (50 ml) was added with continued stirring until the mixture reached room temperature. The solid phthalimide derivative was filtered off, washed with water, and dried. The yield: 13.8 g (82.1%), m.p.: 208°-209.5° C. This product (13.8 g, 0.041 mole) was suspended in 250 ml alcohol and an amount of 85% hydrazine hydrate (4.0 ml) was added. The mixture was refluxed with stirring for two hours. Concentrated hydrochloric acid (8 ml) was added and the stirring was continued until the mixture reached room temperature. The solid was filtered off, was washed with some 95% ethanol, and was discarded. The solvents were evaporated from the filtrate and the residue was dissolved in water, was filtered, and made basic with 7 M sodium hydroxide, and was extracted exhaustively with methylene chloride. The extracts were dried (K2CO3), were filtered, and gaseous hydrogen chloride was fed into the solution. The salt that was formed was filtered off, was washed with methylene chloride, and was dried (9.5 g), and was recrystallized from alcohol-ether. Yield of 3-amino-2'-ethyl-6'-methylpropionanilide: 7.35 g, m.p.: 215.5°-216° C. Calcd. for C12H19ClN2O: C 59.4, H 7.89, Cl 14.6, N 11.5. Found: C 59.3, H 7.80, Cl 14.6, N 11.7.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(O)(O)(=O)=O.[NH2:20]O>>[OH:1][NH:20][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h
Yield: 1678 %

Procedure:
Sodium hydroxide (40% aqueous solution, 12.9 g, 0.129 mol) was added over 20 minutes to a stirred mixture of diethyl maleate (17.3 g, 0.1 mol) and hydroxylamine sulfate (25% aqueous, 39.0 g, 0.059 mol) during which the reaction temperature rose from 28° C. to 53° C. The reaction mixture was stirred for 30 minutes under nitrogen. The mixture was transferred to separating funnel, methylene chloride was added (50 ml), the organic layer was collected and concentrated to give diethyl N-hydroxyaspartate (18.5 g, 0.99 mol, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][NH:9][CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16].[CH:17](=O)[CH2:18][CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:17][CH2:18][CH3:19])[CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16]
Reactant: CCC=O
Reactant: Nc1c(Cl)cc2c(c1Cl)CCC1CNCC21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN1CC2CCc3c(cc(Cl)c(N)c3Cl)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
6,8-Dichloro-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-7-ylamine (275 mg, 1.07 mmol) and propionaldehyde (81 μl, 1.12 mmol) were dissolved in tetrahydrofuran (25 ml). Acetic acid (90 μl, 1.6 mmol) and sodium trisacetoxyborohydride (340 mg, 1.6 mmol) were sequentially added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was dissolved in a 1 M NaOH solution (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted once more with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield the pure product (295 mg, 92%).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4]O.O=S(Cl)[Cl:14]>C(Cl)Cl>[Cl:14][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)c1ccccc1
Solvent: ClCCl
Product: CN(CCCl)c1ccccc1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
In a mixture of compound 2a (1.25 g, 8.3 mmol) and CH2Cl2 (50 mL), SOCl2 (1.2 mls, 16.5 mmol) was added dropwise over 20 min. During addition the solution turned from colorless to yellow. After the addition was complete, the mixture was heated to reflux for one hour. After cooling to room temperature, the mixture was quenched carefully with cold, saturated aqueous K2CO3 (50 mL). The mixture was then extracted with CH2Cl2, and the combined organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound 2b (0.55 g, 3.2 mmol, 39.3% yield) as a yellow oil. HRMS (ESI, positive) m/z calcd. for C9H13ClN [M+H]+: 170.07310, found: 170.07309. 1H NMR (400 MHz, Chloroform-d) δ 7.24 (dd, J=8.8, 7.3 Hz, 2H), 6.73 (m, J=14.2, 7.6 Hz, 3H), 3.71-3.56 (m, 4H), 3.00 (s, 3H).
Reaction SMILES: [N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH:29]C(=O)OC(C)(C)C)[N:16]=[N:17][C:18]=3[C:19](=[O:21])[NH2:20])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH2:29])[N:16]=[N:17][C:18]=3[C:19]([NH2:20])=[O:21])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3nccn3)n2)c(C(N)=O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(-n2nccn2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(5-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (79 mg, 160 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (364 mg, 246 μL, 3.19 mmol) and the mixture stirred at room temperature for 16 h. The mixture was diluted with dichloromethane and 1 N NaOH (2 mL), and then washed with NaHCO3 and brine. The organic layer was dried over MgSO4, then filtered and concentrated in vacuo. The mixture was dissolved in ethanol and concentrated (3×). The residue obtained was triturated with ether and finally filtered to give 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-((1R,2S)-2-aminocyclohexylamino)pyridazine-3-carboxamide (5 mg, 10.8 μmol, 7%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 8.46 (s, 1H), 8.38 (s, 2H), 7.99 (t, J=8.1 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.94 (s., 1H), 1.35-1.85 (m, 8H), 1.46 (m, 2H); MS (EI/CI) m/z: 395.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[C:7]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8]1.Cl>CO.C(O)(C)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc(CC2CCNCC2)cc1OC
Yield: 98.2 %

Procedure:
4-(3,4-Dimethoxyphenylmethyl)piperidine is prepared by hydrogenation at 20° C., under two atmospheres, in the presence of palladium hydroxide (0.042 g), of 4-(3,4-dimethoxybenzylidene)-1-phenylmethylpiperidine (0.42 g) in methanol (100 cc), to which a 5N solution of hydrochloric acid in isopropanol (0.26 cc) has been added. After filtration and evaporation of the solvent under reduced pressure, 4-(3,4-dimethoxyphenylmethyl)-piperidine (0.3 g) is isolated in the form of a white solid whose melting point is 76° C.