Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Mg].BrCCBr.[C:17]([O:21][C:22]([N:24]1[CH2:26][CH:25]1[CH3:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C.O.C(OCC)(=O)C>[C:17]([O:21][C:22]([NH:24][CH:25]([CH3:27])[CH2:26][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([F:1])[CH:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1CN1C(=O)OC(C)(C)C
Reactant: Fc1cc(Br)c2occc2c1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
A mixture of 19 gm (88.8 mMol) 5-fluoro-7-bromobenzofuran and 4.7 gm (193.3 mMol) magnesium turnings in 300 mL diethyl ether was stirred at 40° C. while 7.6 mL (88.2 mMol) 1,2-dibromoethane were added dropwise over 15 minutes. Thirty minutes after the addition was complete, the reaction mixture was cooled to −10° C. To this cooled mixture were then added 6.76 gm (32.8 mMol) copper(I) bromide-dimethylsulfide complex all at once followed by the dropwise addition of 13 gm (82.8 mmol) of N-tert-butoxycarbonyl-2-methylaziridine and 20 mL diethyl ether. The resulting mixture was stirred for 2 hours at −10–0° C. The reaction mixture was then diluted 1.5 L ethyl acetate and 150 mL of water. The resulting slurry was filtered through a pad of celite and the celite pad was washed with two 150 ml portions of ethyl acetate. The filtrate was separated and the organic phase was extracted with two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride. The remaining organic phase was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane containing 20% ethyl acetate. This solid was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0–20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from hexane to provide 13.5 gm (56%) of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([NH2:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C([O-])(O)=O.[Na+].O>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:11]([NH:27][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCNc1ccc([N+](=O)[O-])cn1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.5 g (3.2 mmol) of 2-chloro-5-nitropyridine (Fluka, purum), 0.76 g (3.2 mmol) of hexadecylamine (Merck-Schuchard, for synthesis) and 1 g of NaHCO3 are weighed out and suspended in 10 ml of CHCl3 /DMF 1:1 (puriss., for analysis). The suspension is heated to 100° C. (bath temperature) and stirred for 4 hours at this temperature. When the reaction mixture has cooled, water is added and extraction is carried out with diethyl ether. The organic phase is extracted twice with water and dried over Na2SO4. After evaporation of the solvent, the residue is chromatographed on 50 times the amount of silica gel (eluent=hexane/ether 95:5). The slightly yellowish product fraction is concentrated and 1 is recrystallized again from hexane/ether.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccccc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 6.62 (m, 1H), 6.48 (m, 3H), 5.01 (s, 2H), 3.73 (s, 3H), 3.61 (m, 4H), 3.43 (m, 2H), 2.31 (s, 3H) ppm; MS (ES) M+H expected=439.0, found 439.1.
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([Cl:31])[C:12]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH:15]=1)N.[NH2:32][C:33](N)=O.[C-]#N.[Na+].C([O-])(=O)C.[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([Cl:31])[C:12]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH:15]=1)[C:33]#[N:32]
Reactant: COc1ccc(Cc2cc(Sc3c(Cl)cc(N)cc3Cl)ccc2OC)cn1
Reactant: NC(N)=O
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2cc(Sc3c(Cl)cc(C#N)cc3Cl)ccc2OC)cn1
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (2.19 g) in water (20 ml) was added dropwise to a cooled (10°) solution of 3,5-dichloro-4-(4'methoxy-3'-(6-methoxy-3-pyridylmethyl) phenylthio) aniline (8.94 g) in glacial acetic acid (50 ml) and concentrated sulphuric acid (2.6 ml) with stirring. After 10 minutes urea (1.0 g) was added and this cool solution added from a dropping funnel to a cooled (5°) suspension of cuprous cyanide (19.0 g) and sodium cyanide (10.4 g) in water (260 ml) keeping the temperature of the mixture below 10°. This mixture was stirred vigorously whilst allowing to warm to room temperature and then heated at 60° for 0.5 hour. After cooling chloroform (250 ml) and sodium acetate (10 g) were added. The organic layer was separated and the aqueous re-extracted with chloroform. The combined organic extracts were washed with water (four times), dried over anhydrous magnesium sulphate and evaporated to afford a red solid which was chromatographed on silica gel using ethyl acetate-petroleum spirit (60-80, gradient elution) as eluant. 3,5-Dichloro-4(4'-methoxy-3'-(6-methoxy-3-pyridylmethyl)phenylthio)benzonitrile was obtained as a pale yellow solid (4.20 g, 46%), m.p. 147°-150°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].S(O[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30])(=O)(=O)C>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:18][CH2:19][O:20][C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(OC)c1OCCOS(C)(=O)=O
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(OC)c1OCCOC1CCN(C(C)=O)CC1
Reaction time: 20 h
Yield: 61.8 %

Procedure:
N-Acetyl-4-hydroxypiperidine (4.3 g.) in D.M.F. (50 ml.) was added dropwise to a stirred suspension of sodium hydride (3.0 g., 50% dispersion in mineral oil) in D.M.F. (50 ml.) under an atmosphere of nitrogen. After stirring for 3 hours at room temperature 2-[2,6-dimethoxyphenoxy]ethyl mesylate (9.0 g.) in D.M.F. (50 ml.) was added dropwise and stirring continued for 20 hours at room temperature. The solvent was evaporated in vacuo, the residue taken up in water, extracted with chloroform (3×100 ml.), the organic layer dried (Na2SO4) and the solvent evaporated. Distillation gave N-acetyl-4-(2-[2,6-dimethoxyphenoxy]ethoxy)piperidine (6.0 g.), b.p. 200° C. @ 1 mm.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[OH:8])[OH:6])[NH2:4].CCN=C=NCCCN(C)C.[C:34](O)(=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:34]([NH:4][C@H:3]([C@@H:5]([OH:6])[C@H:7]([OH:8])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][OH:1])(=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@@H](O)[C@H](O)CCCCCCCCCCCCCC
Yield: 66.3 %

Procedure:
To a solution of phytosphingosine (99 mg, 0.31 mmol) in pyridine (3 mL) was added EDCI (128 mg, 0.66 mmol) and DMAP (cat.). Under stirring, stearic acid (90 mg, 0.31 mmol, in 15 mL CH2Cl2) was added dropwise over a period time of 16 h. The reaction was stirred under argon for 24 h at rt. Solvent was evaporated and the residue was applied to silica gel column chromatography (CHCl3:MeOH=88:12, Rf=0.35) to afford 9 as a white powder (120 mg, 68%). 1H NMR (600 MHz, CDCl3:CD3OD=90:10) δ 0.74 (t, J=7.2 Hz, 6H), 1.11-1.64 (m, 52), 1.31-1.58 (m, 4H), 2.07 (d, J=7.8 Hz, 2H), 3.40 (m, 2H), 3.55 (dd, J=11.4, 5.4 Hz, 1H), 3.64 (dd, J=11.4, 3.6 Hz, 2H). 13C NMR (150 MHz, CDCl3:CD3OD=90:10) δ 13.9, 22.6, 25.8, 25.9, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 31.9, 33.1, 36.6, 52.1, 61.2, 72.6, 75.8, 174.7. ESIMS calc'd for C36H73NNaO4 [M+Na]+ 606.54. found: 606.54.
Reaction SMILES: [CH3:1][C:2](O)([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>C(Cl)Cl>[N:20]([C:2]([CH3:14])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[N+:21]=[N-:22]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(O)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C)(Cc1ccc(C(F)(F)F)cc1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
26.3 g of 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-ol was dissolved in 400 mL of methylene chloride, and 25 mL (0.19 mol) of trimethylsilyl azide and 24 mL (0.19 mol) of boron trifluoride diethyl ether complex were added dropwise under cooling with ice. The reaction mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 25.4 g of the desired product.
Reaction SMILES: C(OC(OC(P(OOCC)(OOCC)=O)(P(OOCC)(OOCC)=O)CC(O)=O)=O)(C)(C)C.[C:34]([O:38][C:39]([O:41][C:42]([P:57]([O:63][O:64][CH2:65][CH3:66])([O:59][O:60][CH2:61][CH3:62])=[O:58])([P:47]([O:53][O:54][CH2:55][CH3:56])([O:49][O:50][CH2:51][CH3:52])=[O:48])[CH2:43][C:44](Cl)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].[CH3:67][O:68]/[N:69]=[C:70](/[C:74]1[N:75]=[C:76]([NH2:79])[S:77][CH:78]=1)\[C:71]([OH:73])=[O:72]>N1C=CC=CC=1>[CH3:67][O:68]/[N:69]=[C:70](/[C:74]1[N:75]=[C:76]([NH:79][C:44](=[O:45])[CH2:43][C:42]([O:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])([P:57]([O:63][O:64][CH2:65][CH3:66])([O:59][O:60][CH2:61][CH3:62])=[O:58])[P:47]([O:53][O:54][CH2:55][CH3:56])([O:49][O:50][CH2:51][CH3:52])=[O:48])[S:77][CH:78]=1)\[C:71]([OH:73])=[O:72]
Reactant: CCOOP(=O)(OOCC)C(CC(=O)Cl)(OC(=O)OC(C)(C)C)P(=O)(OOCC)OOCC
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CCOOP(=O)(OOCC)C(CC(=O)O)(OC(=O)OC(C)(C)C)P(=O)(OOCC)OOCC
Solvent: c1ccncc1
Product: CCOOP(=O)(OOCC)C(CC(=O)Nc1nc(/C(=N/OC)C(=O)O)cs1)(OC(=O)OC(C)(C)C)P(=O)(OOCC)OOCC

Procedure:
3-Hydroxy-3,3-diphosphonopropanoic acid, tetramethyl ester is converted to 3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)propionic acid and then to 3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)propanoyl chloride. The acid chloride is then added to α-(Z-methoxyimino)-α-(2-aminothiazol-4-yl)-acetic acid and pyridine to form α-(Z-methoxyimino)-α-{2-[3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)-propanoyl-amino]-thiazol-4-yl}-acetic acid. The latter is reacted with oxaloyl chloride to form the acid chloride, α-(Z-methoxyimino)-α-{2-[3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)-propanoyl-amino)-thiazol-4-yl]-acetyl chloride. This acid chloride is reacted with 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and pyridine and gives 7β-{α-(Z-methoxyimino)-α-[2-(3-tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)propanoyl-amino)-thiazol-4-yl]-acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid. Deprotection with trifluoroacetic acid and anisole yields the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:16])[NH:11]2)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH:12]12[CH2:14][CH2:15][CH:9]([NH:8][CH2:13]1)[C:10](=[O:16])[NH:11]2
Reactant: O=C1NC2CCC1N(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1NC2CCC1NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of 5-benzyl-2,5-diazabicyclo[2.2.2]octan-3-one (400 mg) in EtOH (5 mL) was added 20% Pd(OH)2/C (65 mg), followed by stirring at room temperature overnight at normal pressure under a hydrogen atmosphere. The reaction mixture was filtered through Celite and then concentrated under reduced pressure to obtain 2,5-diazabicyclo[2.2.2]octan-3-one (219 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[Cl:28][C:27]1[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ncccc3Cl)cc2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
(S)-tert-Butyl 2-(4-aminophenyl)morpholine-4-carboxylate (120 mg, 0.43 mol), 2,3-dichloropyridine (64 mg, 0.43 mmol) and cesium carbonate (211 mg, 0.647 mmol) were combined with dioxane (2 ml) to give a suspension. The mixture was degassed with argon for 5 min. Xanthphos (15 mg, 0.026 mmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (13 mg, 0.013 mmol) were added. The reaction mixture was capped and stirred at 100° C. for 2 h. The crude reaction mixture was filtered through a syringe filter, concentrated in vacuo and purified by flash chromatography (20 g silica gel, 5 to 20% ethyl acetate in heptane) yielded a light yellow foam (88 mg, 53%); MS (ISP): 390.2 ([{35Cl}M+H]+), 392.2 ([{37Cl}M+H]+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][O:23][CH3:24])C1C=CC=CC=1>C(O)C>[CH3:24][O:23][CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: COCC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CCO
Product: COCC[C@H]1CNCCN1
Temperature: 50 °C
Reaction time: 21 h
Yield: 90.6 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-(2-methoxy-ethyl)-piperazine (2.0 g, 6.2 mmol) in ethanol (15 mL) in a suitable hydrogenation vessel. Add palladium hydroxide (Pearlman's catalyst, 400 mg), purge vessel with nitrogen, then pressure to 60 psi. Heat to 50° C. and stir vigorously for 18-24 hours. Allow the mixture to cool to ambient temperature. Filter off the catalyst and rinse with ethanol (5 mL). Concentrate in vacuo using a 35° C. bath to afford the title compound (0.81 g, 91.1%). 1H NMR (500 MHz, DMSO-d6) δ 1.41 (m, 2H), 2.12 (t, 1H), 2.43 (td, 1H), 2.53 (m, 2H, 1H), 2.63 (d, 1H), 2.72 (m, 2H), 3.19. (s, 3H), 3.34 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][N:7]([C:15]1[CH:20]=[C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])[CH:18]=[C:17]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:35])[CH:16]=1)CCC(OCC)=O)C.[OH-:48].[Na+]>CO>[C:4]([CH2:5][CH2:6][C:16]1[C:17]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:35])=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])=[CH:20][C:15]=1[NH:7][CH2:6][CH2:5][C:4]([OH:3])=[O:47])([OH:3])=[O:48]
Reactant: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CCC(=O)OCC)CCC(=O)OCC)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCNC(=O)c1cc(NCCC(=O)O)c(CCC(=O)O)c(C(=O)NCCCCCCCCCC)c1
Yield: 123 %

Procedure:
A solution of 0.23 g (0.35 mmol) of 3-[[3,5-bis[(decylamino)carbonyl]phenyl](3-ethoxy-3-oxopropyl)amino]propanoic acid ethyl ester and 1.4 ml (1.4 mmol) of 1N NaOH in 10 ml of methanol was stirred at room temperature for 16 hours. The solvent was removed at reduced pressure, the residue was dissolved in water and acidified with 0.2 ml of acetic acid. The precipitate was filtered and recrystallized from acetone-hexane to give 0.13 g (60% yield, mp 139°-141°)of 3-[[(2-carboxyethyl)-3,5-bis[(decylamino)carbonyl]phenyl]amino]propanoicacid.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[C:16](=[O:17])[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)=[C:14]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:13][C:11]3=2)[CH:6]=[N:5]1)#[N:2]>CO>[NH2:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:15]3[C:16](=[O:17])[C:10]4[C:11]([O:13][C:14]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[C:12]3[C:7]([CH:6]=[N:5][N:4]3[CH2:3][C:1]#[N:2])=[CH:8][CH:9]=4)=[CH:23][CH:22]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CC#N)c54)c3=O)cc2)CCC1
Solvent: CO
Product: N#CCn1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 36.3 %

Procedure:
tert-Butyl (1-(4-(1-(cyanomethyl)-6-oxo-8-phenyl-1,6-dihydropyrano[3,2-g]indazol-7-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.037 mmol) was loaded in a 1 g SCX-2 cartridge column preconditioned with methanol (2×1 mL). The compound was loaded to the column using 1 mL of methanol. After 1 h the column was washed with 3×1 mL of methanol. The product was eluted with 7 N ammonia in methanol (2×1 mL). The solvent was evaporated to afford the title compound (6 mg, 49%). Residual starting material was recovered from MeOH washed (10 mg). 1H NMR (500 MHz, MeOD): δ 8.19 (br s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.50-7.47 (m, 2H), 7.40-7.30 (m, 5H), 7.25-7.20 (m, 2H), 5.65 (s, 2H) 5.12 (s, 1H, NH) 2.64-2.56 (m, 4H), 2.30-2.22 (m, 1H), 2.04-1.94 (m, 1H). LCMS (Method J): RT=0.92 min, [M+H]+=448.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18](C3C=CC(C(N4CCNCC4)=O)=CC=3)[CH:19]=2)[CH:3]=1.[CH:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=2)[CH2:39][CH2:38]1)([CH3:36])[CH3:35]>>[CH:34]([N:37]1[CH2:38][CH2:39][N:40]([CH2:43][C:44]2[CH:49]=[C:48]([C:18]3[CH:19]=[C:14]([C:4]4[CH:3]=[C:2]([NH2:1])[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=5)[CH:5]=4)[CH:15]=[N:16][CH:17]=3)[CH:47]=[CH:46][CH:45]=2)[CH2:41][CH2:42]1)([CH3:36])[CH3:35]
Reactant: CC(C)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1
Product: CC(C)N1CCN(Cc2cccc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)c2)CC1

Procedure:
This compound is prepared analogously to [4-(6′-Amino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-piperazin-1-yl-methanone (Example 2.50) by replacing piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 3-((4-isopropylpiperazin-1-yl)methyl)phenylboronic acid (Intermediate B14).
Reaction SMILES: [CH2:1]([S:7][CH:8]=[CH:9][CH2:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(C(C)C)CC)(C)C.[CH3:21][OH:22]>CCCCCC>[CH3:21][O:22][CH2:10][CH:9]=[CH:8][S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CO
Reactant: CCCCCCSC=CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CCCCCCSC=CCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hexylthio-2-propenyl chloride is added to a solution of diisopropyl ethyl amine (3.68 g, 28.5 mmol) in 20 ml of methanol. The mixture is stirred overnight at RT. It is then diluted with hexane, washed with water and with brine and is stripped. The crude product is purified by prep. TLC to give 3-methoxy-1-hexylthio-1-propene.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([OH:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:19]([O:23]C(=O)CBr)(C)(C)[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH:1]1[C:11]2[CH:10]([O:12][CH2:20][CH2:19][OH:23])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1c2ccccc2COc2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCOC1c2ccccc2COc2ccccc21
Temperature: 35 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
6,11-Dihydrodibenzo[b,e]oxepin-11-ol (1.06 g, 5 mmol) was dissolved in dry THF (25 mL) at 0° C. Sodium hydride (0.24 g of 50% mineral oil dispersion, 5 mmol) was added portionwise at 0° C. and then refluxed for 30 min. tert-Butylbromoacetate (980 mg, 5.0 mmol) in dry THF (10 mL) was added over a period of 20 and the mixture stirred at 35° C. for 16 h. The reaction mixture was quenched with water at 0° C. and the product extracted with ether. The combined extracts were dried (MgSO4), and concentrated in vacuo. The product was redissolved in ether and added dropwise to an ether (15 mL) suspension of lithium aluminium hydride (190 mg, 5.0 mmol). The reaction was stirred 48 h at room temperature, quenched with water, cooled, and filtered through Decalit. The ether solution was washed with saturated NaCl, dried, and purified by chromatography eluting with ethyl acetate/dichloromethan (1:10) to give 267 mg (21%) of 2-(6,11-dihydrodibenzo[b,e]oxepin-11-yloxy)-ethanol.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]1([CH2:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F-].[K+]>CS(C)=O>[CH2:18]([NH:19][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1cnc2ccc(NCc3ccccc3)nn12
Temperature: 130 °C
Reaction time: 24 h

Procedure:
3-Bromo-6-chloroimidazo[1,2-b]pyridazine (20.0 g), phenylmethanamine (11.3 ml), and potassium fluoride (12.0 g) were dissolved in dimethyl sulfoxide (400 ml), and the solution was stirred at 130° C. for 24 hours. After standing to cool to room temperature, the reaction solution was poured into ice water (2.0 L). The resulting solid was collected by filtration and dried under reduced pressure. The obtained solid was dissolved in hot ethyl acetate, and the insoluble matter was filtered under heating. After distilling off the solvent, the solid was recrystallized from ethyl acetate to obtain the title compound (21.0 g).