Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]#[C:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[CH3:2].[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[N:42]([C:6]([C:7]3[CH:15]=[CH:14][C:10]5[O:11][CH2:12][O:13][C:9]=5[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1ccc2c(c1)OCO2
Product: CCOC(=O)C=C(c1ccc2c(c1)OCO2)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 39 %

Procedure:
The title compound was synthesized from benzo[1,3]dioxol-5-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (c1), in 39% yield as an E/Z mixture. 1H NMR (CDCl3) δ7.32 (d, 1H, J=7.6 Hz), 7.10–7.04 (m, 2H), 7.00–6.90 (m, 2H), 6.85–6.71 (m, 4H), 6.56–6.49 (m, 1H), 6.10 (s, 0.6H), 6.04 (s, 0.4H), 6.03 (s, 0.8H), 6.00 (s, 1.2H), 4.40–4.35 (m, 2H), 4.13 (q, 0.8H, J=7.1 Hz), 3.98 (q, 1.2H, J=7.1 Hz), 3.76 (t, 2H, J=5.9 Hz), 3.20 (t, 2H, 6.8 Hz), 2.73 (t, 2H, 6.7 Hz), 1.95–1.89 (m, 2H), 1.519 (s, 5.4H), 1.516 (s, 3.6 H), 1.22 (t, 1.2H, J=7.1 Hz), 1.01 (t, 1.8H, J=7.1 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H29N3O5 512.3 (M-Boc +1); found 512.3.
Reaction SMILES: [Cu][C:2]#[N:3].[C:4]([O:7][C@H:8]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20](Cl)=[N:21][C:22]=3[Cl:26])[O:10][C@@H:9]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:6])[CH3:5]>O>[C:4]([O:7][C@H:8]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:2]#[N:3])=[N:21][C:22]=3[Cl:26])[O:10][C@@H:9]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:6])[CH3:5]
Reactant: N#C[Cu]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C

Procedure:
Copper (I) cyanide was added to a solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate (J. Med. Chem., 248, 35, 1992) (22 g, 40 mmol) in N′N′-dimethylformamide (150 ml). The suspension was heated to 100° C. for 2 hours and was then allowed to cool to room temperature. The reaction mixture was poured into water (700 ml) with stirring. The solid was filtered off and stirred in dichloromethane (700 ml) for 30 minutes. The solid was filtered off again and then stirred in dichloromethane (700 ml) for another 30 minutes. The dichloromethane portions were combined and evaporated under reduced pressure to a volume of 500 ml. The dichloromethane was then dried over anhydrous sodium sulphate. The solvent was removed under reduced presure. The residue was redissolved in dichloromethane (300 ml). The solvent was removed under reduced pressure. The residue was then stirred in diethylether (300 ml) for 20 minutes. The solid was filtered off and dried to give the title compound (14.8 g).
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:12][C:11]3[C:13]4[C:18]([C:19](OC)=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:10]=3[CH:9]=[CH:8]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CC[CH2:35][CH2:34]1.C([Mg]Br)=C.Cl>CCOCC>[C:1]1([C:7]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:12][C:11]3[C:13]4[C:18]([C:19]([CH:34]=[CH2:35])=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:10]=3[CH:9]=[CH:8]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1c2c(c3ccccc3c1OC)OC(c1ccccc1)(c1ccccc1)C=C2
Agent: C=C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: C=Cc1c(C(=O)OC)c2c(c3ccccc13)OC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-diphenyl-5-methoxycarbonyl-6-methoxy-2H-naphtho[1,2-b]pyran (4.22 grams) was added to a reaction flask containing tetrahydrofuran (THF) (50 milliliters (mL)). Vinyl magnesium bromide solution (20 mL of 2.0 molar in tetrahydrofuran) was injected slowly into the solution. After stirring at room temperature for two hours, the reaction mixture was poured into a beaker containing a mixture of ice, hydrochloric acid and ether. The ether layer was separated, washed with water twice and dried over anhydrous sodium sulfate. The reaction product was induced to crystallize from an ether/hexane mixture yielding 2.95 grams of 2,2-diphenyl-5-methoxycarbonyl-6-vinyl-2H-naphtho[1,2-b]pyran which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31](O)[CH3:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:57][S:58]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)(=[O:60])=[O:59]>ClCCl.O>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:43]=[CH:44][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[C:11]([C:16]3[C:21]([NH:22][C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:20][CH:19]=[C:18]([CH:31]([N:64]4[CH2:65][CH2:66][N:61]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:62][CH2:63]4)[CH3:32])[CH:17]=3)[N:12]=[C:13]([CH3:15])[N:14]=2)=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Yield: 55 %

Procedure:
1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (732.1 mg, 1.233 mmol) was dissolved in dichloromethane (22 mL) and the reaction flask was cooled in an ice water bath. The reaction was stirred under nitrogen, and triethylamine (0.77 mL, 5.5 mmol) and methanesulfonylchloride (0.37 mL, 4.8 mmol) were added via syringe. The reaction was stirred at 0° C. under nitrogen for 15 min and then was diluted with dichloromethane (125 mL) and treated with water (20 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dissolved in dichloromethane (13 mL). To this solution were added triethylamine (0.77 ml, 5.5 mmol) and 1-methanesulfonylpiperazine (648 mg, 3.95 mmol). The reaction was stirred under nitrogen at room temperature overnight and then concentrated and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH to elute impurities to 50:1 DCM/MeOH to elute product). The fractions with product were collected, concentrated, and washed with hexanes. The material dried under high vacuum at room temperature to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (501.6 mg,). 1H NMR (CDCl3, 400 MHz) δ 11.63 (s, 1H), 8.70 (d, J=2.54 Hz, 1H), 8.28 (d, J=2.54 Hz, 1H), 8.22 (d, J=2.54 Hz, 1H), 7.92 (dd, J=9.00 Hz, 2.74 Hz, 1H), 7.22 (t, J=9.29 Hz, 4H), 6.86 (dd, J=18.58 Hz, 8.61 Hz, 4H), 6.72 (d, J=8.80 Hz, 1H), 4.93-4.76 (m, 4H), 3.93 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.54 (quartet, J=6.78 Hz, 1H), 3.16 (t, J=4.40 Hz, 4H), 2.68 (s, 3H), 2.61-2.49 (m, 7H), 1.38 (d, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 740 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([C@H:31]2[C:40]3[CH:39]=[C:38]([F:41])[CH:37]=[CH:36][C:35]=3[N:34]([C:42](=[O:54])[C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=3)[C@H:33]3[CH2:55][CH2:56][CH2:57][C@@H:32]23)[C:5](=[O:30])[CH2:6][CH2:7][C:8]([O:10][CH:11]2[O:16][CH:15]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[CH:14]([OH:27])[CH:13]([OH:28])[CH:12]2[OH:29])=[O:9])[CH2:3][CH2:2]1.C1CCC=CC=1>[Pd].C(O)(C)C.C1(OC)CCCC1>[CH:1]1([N:4]([C@H:31]2[C:40]3[CH:39]=[C:38]([F:41])[CH:37]=[CH:36][C:35]=3[N:34]([C:42](=[O:54])[C:43]3[CH:44]=[CH:45][C:46]([O:49][C:50]([F:51])([F:53])[F:52])=[CH:47][CH:48]=3)[C@H:33]3[CH2:55][CH2:56][CH2:57][C@@H:32]23)[C:5](=[O:30])[CH2:6][CH2:7][C:8]([O:10][CH:11]2[O:16][CH:15]([C:17]([OH:19])=[O:18])[CH:14]([OH:27])[CH:13]([OH:28])[CH:12]2[OH:29])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(CCC(=O)N(C1CC1)[C@H]1c2cc(F)ccc2N(C(=O)c2ccc(OC(F)(F)F)cc2)[C@H]2CCC[C@H]21)OC1OC(C(=O)OCc2ccccc2)C(O)C(O)C1O
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1=CCCC=C1
Solvent: COC1CCCC1
Product: O=C(CCC(=O)N(C1CC1)[C@H]1c2cc(F)ccc2N(C(=O)c2ccc(OC(F)(F)F)cc2)[C@H]2CCC[C@H]21)OC1OC(C(=O)O)C(O)C(O)C1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Palladium on carbon (80 mg, 0.752 mmol) was added to a stirred mixture of benzyl 6-((4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (0.23 g, 0.29 mmol) and cyclohexadiene (1.5 mL, 0.293 mmol) in isopropanol (7.5 mL) and cyclopentylmethyl ether (7.50 mL) and the mixture was stirred at 60° C. for 1 h. The mixture was filtered through a Celite® pad and washed with ether/isopropanol (1/1). Solvent was removed to give crude product which was purified using reverse phase HPLC to give 6-((4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 174 (140 mg), [M+H]+=710.1.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4]Cl.[CH3:13][O-:14].[Na+].CCCCCC.C1C=CC=CC=1>CO>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][O:14][CH3:13]
Reactant: Cc1ccc([N+](=O)[O-])cc1CCl
Reactant: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCCCCC
Product: COCc1cc([N+](=O)[O-])ccc1C
Yield: 158.7 %

Procedure:
2-Methyl-5-nitrobenzyl chloride (10.2 g) is dissolved in methanol (180 ml). Sodium methoxide (5.4 g) is added and the mixture is refluxed. The reaction is monitored by thin layer chromatography (75:25, hexane:benzene). Additional quantities of sodium methoxide are added and heating continues until the reaction is complete. The reaction mixture is then cooled and filtered. The filtrate is concentrated under vacuum. The residue is dissolved in methylene chloride, washed with water, and the organic layer is then dried over magnesium sulfate. Removal of the drying agent by filtration and concentration of the filtrate under vacuum leaves 15.8 g of solid material which when recrystallized from hexane (150 ml) yields 11.5 g of product as a white solid having a melting point from 45° to 52° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[S:15][C@@H:16]2[C@@H:33]([CH2:34][CH3:35])[C:32](=[O:36])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl.C1COCC1.CCOC(C)=O>[CH3:12][S:13]([C:14]1[S:15][C@@H:16]2[C@@H:33]([CH2:34][CH3:35])[C:32](=[O:36])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)=[O:20])=[O:6]
Reactant: CC[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC)S[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(C)=O)S[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 85% m-chloroperoxy benzoic acid (53 mg, 0.26 mmol) in CH2Cl2 (1 ml) is added dropwise over a few minutes to an ice-cold, stirring solution of p-nitrobenzyl (5R,6S)-2-methylthio-6-ethyl-pen-2-em-3-carboxylate (94 mg, 0.25 mmol) in anhydrous THF (2 ml). The resulting solution is stirred an additional 30 minutes at 0°, then diluted with EtOAc and washed with H2O, 5% aqueous NaHCO3, H2O, and brine. The organic phase is dried with MgSO4, filtered, and evaporated in vacuo to provide the title compound as a mixture of sulfoxide isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH2:6][S:7][CH2:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11].C12CC(CC1)=CC=2.C12CC(CC1)C=C2>[Pd].C1CCCCC=1>[NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][S:7][CH:6]=1
Reactant: COC(=O)C1=C(Nc2ccccc2N)CSC1
Agent: [Pd]
Agent: C1=C2CCC(=C1)C2
Agent: C1=CC2CCC1C2
Solvent: C1=CCCCC1
Product: COC(=O)c1cscc1Nc1ccccc1N
Reaction time: 4 h

Procedure:
Methyl 3-(2-aminoanilino)-2,5-dihydrothiophene-4-carboxylate (2.5 g, 0.001 mol) was added to a flask containing palladium on charcoal catalyst (5%, 200 mg) in cyclohexene (or norbornadiene or norbornylene) (50 ml and the reaction was heated at reflux with stirring for 4 hours, the reaction being followed by t.l.c.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([C:21](=[O:22])[N:20]=[CH:19][N:18]2[CH3:23])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.C(OCC)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH3:23][N:18]1[CH2:19][NH:20][C:21](=[O:22])[C:16]21[CH2:17][NH:14][CH2:15]2
Reactant: CN1C=NC(=O)C12CN(C(c1ccccc1)c1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CN1CNC(=O)C12CNC2

Procedure:
To a solution of 2-benzhydryl-5-methyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-5A-10a; 189 mg, 0.619 mmol) in methanol (30 ml) was added 1 M HCl in diethyl ether (1.3 ml). After the addition of 20% Pd(OH)2 on carbon (50% water; 95 mg), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 5 hours. The reaction was filtered through a 0.45 μM disk, and then concentrated, in vacuo, to give a solid. Trituration from diethyl ether afforded I-5A-10b (124 mg, 94%) as an off-white solid: +APcI MS (M+1) 142.0; 1H NMR (400 MHz, CD3OD) δ 4.38 (d, J=12.0 Hz, 2H), 4.17 (s, 2H), 4.13 (d, J=12.5 Hz, 2H), 2.71 (s, 3H).
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]([CH:65]3[CH2:67][CH2:66]3)CC3C=CC(OC)=CC=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][C:49]=4[F:54])=[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:84][C@@H:85]([CH3:89])[C:86](O)=[O:87])=O)(C)(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:84][C@H:85]([C:86]([NH:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][CH:65]3[CH2:67][CH2:66]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][C:49]=4[F:54])=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:33][CH2:34]1)=[O:87])[CH3:89]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (62.5 mg, 0.141 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (20 mg, 0.047 mmol), DIEA (0.0062 mL, 0.035 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (17.83 mg, 0.094 mmol) in DMF (1 mL). The clear reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated down, dissolved in CH2Cl2 (0.50 mL) and TFA (0.545 mL, 7.07 mmol) and stirred at rt for 30 min. The reaction mixture was concentrated and purified with HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 6-((trans-4-(L-alanylamino)cyclohexyl)amino)-8-(cyclopropylamino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (10 mg, 42.8%), as a white solid. LC/MS (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). Rt=1.41 (M+H=496.3). 1H NMR (400 MHz, MeOD) δ ppm 8.85 (1H, t, J=6.55 Hz), 8.69 (1H, d, J=3.53 Hz), 8.48 (1H, d, J=6.04 Hz), 8.13 (1H, s), 6.11 (1H, s), 3.97 (1H, d, J=4.28 Hz), 3.87 (1H, q, J=7.13 Hz), 3.72 (1H, br. s.), 2.59 (1H, td, J=6.80, 3.53 Hz), 2.21 (2H, br. s.), 1.99 (2H, br. s.), 1.32-1.62 (7H, m), 0.78-0.96 (2H, m), 0.55-0.76 (2H, m).
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:10])[CH3:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C1(C)C=CC=CC=1>[O:23]=[C:19]([CH3:18])[CH2:20][C:21]([O:10][CH:8]([CH3:9])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: CC(O)CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(C)CN1CCOCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.0 g (34.4 mmol) 1-(4-Morpholinyl)-2-propanol and 35 mg (0.34 mmol) triethylamine are dissolved in 40 ml toluene. At 90° C., 3.76 g (44.77 mmol) diketene are added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling down to room temperature, the mixture is poured into ice-water. The phases are separated and the water phase is extracted two times with toluene. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C:6]1[CH:7]=[C:8]([CH:18]=[O:19])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([CH3:17])([CH3:16])[CH:12]=[CH:11]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:5][C:6]1[CH:7]=[C:8]([CH:18]=[O:19])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([CH3:16])([CH3:17])[CH:12]=[CH:11]2
Reactant: CC1(C)C=Cc2cc(C=O)cc(O)c2O1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C=O)cc2c1OC(C)(C)C=C2

Procedure:
Chloromethyl methyl ether (4 mL, 5 mmol) was added to a solution of 9 (103 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol) in 4 mL of methylene chloride. The reaction mixture was refluxed overnight and concentrated in vacuo. 10 (48 mg, 38%) was purified with ethyl acetate/hexane (1/50). 1H NMR (CDCl3): δ 1.52 (s, 6H), 3.54 (s, 3H), 5.25 (s, 2H), 5.71 (d, J=9.67 Hz, 1H), 6.38 (d, J=9.96 Hz, 1H), 7.26 (d, J=1.76 Hz, 1H), 7.52 (d, J=1.76 Hz, 1H), 9.80 (s, 1H).
Reaction SMILES: C(Br)(Br)(Br)[Br:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16]2)O)=[CH:9][CH:8]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C@@H:35]([C@H:37]2[O:42][CH2:41][CH2:40][N:39]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:38]2)O)=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:2][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)[C@@H:15]1[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16]1.[Br:2][C@H:35]([C:32]1[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=1)[C@H:37]1[O:42][CH2:41][CH2:40][N:39]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:38]1
Reactant: BrC(Br)(Br)Br
Reactant: O[C@@H](c1ccc(Cl)cc1)[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: O[C@H](c1ccc(Cl)cc1)[C@H]1CN(Cc2ccccc2)CCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc([C@@H](Br)[C@@H]2CN(Cc3ccccc3)CCO2)cc1
Product: Clc1ccc([C@H](Br)[C@H]2CN(Cc3ccccc3)CCO2)cc1
Reaction time: 0.5 h

Procedure:
A solution of carbon tetrabromide (2.82 g, 8.5 mmol) in dichloromethane (3 ml) was added dropwise over 10 min to a stirred solution of (R)-[4-chlorophenyl][(2R)-4-benzylmorpholin-2-yl]methanol and (S)-[4-chlorophenyl][(2S)-4-benzylmorpholin-2-yl]methanol (1.80 g, 5.67 mmol) and triphenylphosphine (2.23 g, 8.5 mmol) in dichloromethane (40 ml) at room temperature under nitrogen. After 30 min, the reaction solution was washed with saturated aqueous sodium bicarbonate (50 ml). The dichloromethane layer was dried, filtered and evaporated to a red liquid (8.5 g). Trituration with diethyl ether (20 ml) crystallised triphenylphoshine oxide that was then removed by filtration. The filtrate was evaporated to a yellow oil and was purified by chromatography on silica eluting with ethyl acetate:hexane 20:80 to give a colourless oil of (2R)-2-[(S)-bromo(4-chlorophenyl)methyl]-4-benzylmorpholine and (2S)-2-[(R)-bromo(4-chlorophenyl)methyl]-4-benzylmorpholine (1.17 g) that crystallised to a pink solid on standing.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CC=CCC=1>[Pd].C1COCC1>[OH:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: CCCCCCOc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: CCCCCCOc1ccc(OC(=O)c2ccc(O)cc2)cc1
Temperature: 60 °C

Procedure:
The 4-(hexyloxy)phenyl 4-(benzyloxy)benzoate obtained as described above (5.0 g, 12.4 mmol) and palladium on carbon (2.5 g in the wet state) were placed in a sealed container under a nitrogen atmosphere, and dehydrated THF was slowly added thereto. Then, 28 mL of 1,4-cyclohexadiene was carefully and slowly added thereto dropwise, while heating at 60° C. and stirring. After the addition, the mixture was further stirred for additional 3 hours at 60° C. After the mixture was cooled to room temperature, the mixture was filtered through Celite and the solvents were removed by distillation. Thereby, a white solid compound, 4-(hexyloxy)phenyl 4-hydroxybenzoate (3.8 g) was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[CH:20]1([CH:26]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:1]1([CH:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=CC1CCCCC1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(NC(C1CCCCC1)n1nnc2ccccc21)c1ccc(Cl)cc1

Procedure:
Benzotriazole, 4-chlorobenzamide, cyclohexanecarboxaldehyde, and p-toluenesulfonic acid were processed as in Example 53A to provide the desired product.