Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][C:20](=[O:22])[O:19][CH:18]([C:23]3[N:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[S:26][CH:27]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH-:32].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([N:16]([CH2:21][C:20]([OH:19])=[O:22])[CH2:17][CH:18]([OH:32])[C:23]2[N:24]=[C:25]([C:28]([F:30])([F:29])[F:31])[S:26][CH:27]=2)[CH3:15])=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CC(=O)OC(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)N(CC(=O)O)CC(O)c2csc(C(F)(F)F)n2)cc1
Temperature: 0 °C

Procedure:
1.4 g (0.0031 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-one are dissolved in 10 ml of methanol. 3 ml (0.003 mol) of 1N sodium hydroxide solution are added to this stirred solution at room temperature. After 5 minutes 15 ml of ice-water are added, and the mixture is neutralised with 3 ml of 1N hydrochloric acid. The aqueous phase is extracted by shaking 3× with methylene chloride. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The resulting residue is purified on a silica gel column using methylene chloride methanol =20:1 as eluant. This results, after concentration, in colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl.[Cl-].[NH4+]>[Br:24][C:16]1[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14][N:5]2[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1ccc(-c2nn3c(N4CCOCC4)cc(Cl)nc3c2Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 50.1 %

Procedure:
There was dissolved, in methylene chloride (2 mL), 5-chloro-2-(4-methyl-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (44.4 mg, 0.135 mM), then N-bromo-succinimide (27.1 mg, 0.152 mM) was added to the resulting solution and the mixture was stirred at room temperature for 40 minutes. This reaction liquid was diluted with a saturated aqueous ammonium chloride solution and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus obtain the title compound (27.6 mg, yield: 50%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].O1CCCC1.O.[Li+].[OH-].Cl>CCOCC>[NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: CCOC(=O)C1CCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N[C@@H]1CC(CN2CCC(C(=O)O)CC2)=CC[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of Example 11C (36 mg, 0.088 mmol) in mixture of tetrahydrofuran/H2O (0.3 mL/0.15 mL), LiOH (23 mg, 0.53 mmol) was added at room temperature. The reaction mixture was stirred overnight. It was acidified with 2N HCl in ether until pH=3 and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (25 mg, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.90-8.07 (m, 3H), 7.67 (s, 1H), 7.47-7.58 (m, 2H), 6.01-6.14 (m, 1H), 3.66-3.96 (m, 2H), 2.57-3.04 (m, 4H), 1.65-2.46 (m, 9H). MS (ESI) m/z 383 (M+H)+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(Cl)=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:18])[N:12]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:18])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(CCl)n1
Reactant: CC(C)(C)O
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(CCl)n1
Reaction time: 1 h
Yield: 74 %

Procedure:
5.61 g (75.7 millimoles) of t-butanol and 22 mL of ethyl acetate were added to a reaction system followed by blowing in 3.8 g (38.4 millimoles) of phosgene. A mixed solution containing 1.95 g (13.7 millimoles) of 2-amino-6-chloromethylpyridine, 4.86 g (37.6 millimoles) of N,N-diisopropylethylamine and 19 mL of ethyl acetate were dropped into this solution over the course of 1 hour while holding the internal temperature at −15° C. to −5° C. Following completion of dropping, the solution was stirred for 1 hour. Next, water and 28% sodium hydroxide were sequentially added while holding the internal temperature at 0° C. or lower. After separating the liquid, the aqueous phase was extracted with ethyl acetate. The organic phases were combined and mixed. A portion of the organic phase was sampled and subjected to quantitative analysis by HPLC. The target (6-chloromethyl-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at yield of 74%. The yield of 1,3-bis-(6-chloromethyl-pyridin-2-yl)-urea (urea compound) was 10%.
Reaction SMILES: O=[C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[NH:3]1.[C:28](OCC)(OCC)(OCC)C.C(Cl)Cl.CO>CCO>[CH3:28][C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: N#Cc1ccn2ncc(-c3ccc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cc1nc2ccc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
To a solution of the compound obtained in example 2 section d (56.4 mg, 0.169 mmol) in EtOH (1.5 mL), PTSA monohydrate (3.21 mg, 0.017 mmol) and triethyl orthoacetate (547 mg, 3.37 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was cromategraphed on a silica gel flash system (ISCO Rf) using CH2Cl2/MeOH mixtures of increasing polarity, a eluent to afford the desired product (15% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1C.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])[CH:19]=1.[CH3:36]N(C)C=O>>[C:32]([O:31][C:29]([N:27]([C:20]1[CH:19]=[C:18]([O:14][C:10]2[C:9]([CH3:15])=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[C:12]([CH3:13])[C:11]=2[CH3:36])[CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[CH3:28])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: COCOc1c(C)cc(O)c(C)c1C
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COCOc1cc(C)c(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Sodium hydride (6.11 g, 55% suspension in mineral oil) was added to a solution of 4-methoxymethoxy-2,3,5-trimethylphenol (27.5 g) in dimethylformamide (300 ml). After stirring the mixture for 1 hour 4chloro-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene (40.1 g) was added in small portions to the mixture and stirred at 120° C. for 2 hours. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=5:1 as the eluant to afford the title compound (57.0 g, Rf=0.55: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=4:1 as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:36])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2F)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2F)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(2-fluorobenzoyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.050 g, 0.12 mmol) and ammonium acetate (0.0936 g, 1.21 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.30 mL, 0.30 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H23ClFN4O (M+H)+: m/z=413.2; Found: 413.2.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[CH:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])[C:13]([C:19]([O:21]C)=O)=C(C)[NH:15][C:16]=2[CH3:17])=[O:10])=[CH:5][CH:4]=1>C(O)C>[CH3:7][O:8][C:9]([CH2:11][C:19](/[CH:13]=[CH:12]/[C:23]1[C:24]([N+:29]([O-:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:21])=[O:10].[F:1][C:2]([F:34])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])=[CH:32][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(C(F)(F)F)cc2)C1c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C(F)(F)F)cc1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-trifluoromethylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-trifluoromethylbenzyl ester of melting point 130° C (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[S:7][CH:6]=1)=[O:4].[CH:14]([NH2:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:16]=[CH:14][O:15][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: NC=O
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Product: COC(=O)c1csc(-c2cocn2)c1
Temperature: 170 °C

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.4 g, 1.52 mmol) was dissolved in formamide (2 mL) and the tube purged with nitrogen and then sealed. The mixture was heated at 170° C. for 20 minutes. The resultant solution was diluted with HCl (1 M) and water and washed with ethyl acetate. The organic phase was evaporated then purified by chromatography on a silica II cartridge, eluting with 2:1 pentane:DCM to neat DCM, to give the side product, 5-oxazol-4-yl-thiophene-3-carboxylic acid methyl ester as white solid (0.049 g). LCMS m/z 251.35 [M+MeCN+H]+ R. T.=3.07 min (Analytical Method 6).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.N1C=CC=CC=1.C[OH:20]>>[C:1]([OH:7])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:20])=[O:6]
Reactant: O=C1CCCC(=O)O1
Reactant: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCC(=O)O
Temperature: 80 °C
Yield: 97.6 %

Procedure:
Glutaric acid-terminated PEG (P8G) was synthesized by dissolving 8-arm PEG-OH (20 g, 7.97 mmol OH or 1 equivalent OH) and glutaric anhydride (4.54 g, 39.84 mmol, or 5 equivalents) in chloroform (2.5 mL chloroform per 1 mmol OH). Pyridine (5 eq) was added dropwise, and the reaction mixture was refluxed at 80° C. for 24 hours under inert air. The product was diluted with MeOH (240 mL or 12 mL MeOH per gram of PEG), precipitated at −20° C. for 1 hour, and centrifuged at −5° C. The supernatant was discarded, and the MeOH wash procedure was repeated twice more. Following diethyl ether precipitations (180 mL or 9 mL ether per gram of PEG), the product was dried under high vacuum overnight to afford a white powder (97.6% yield, 100% conversion). See FIG. 21.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:3]=1[O:4][C:5](=[O:23])[C:6]1[C:15]2=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([CH3:22])=[CH:9][C:10]([CH3:21])([CH3:20])[NH:11]2.CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:26][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:3]=1[O:4][C:5](=[O:23])[C:6]1[C:15]2=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([CH3:22])=[CH:9][C:10]([CH3:20])([CH3:21])[NH:11]2
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1c(O)cccc13
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2c1oc(=O)c1c3c(ccc12)NC(C)(C)C=C3C
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A mixture of 7-Hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-9, 430 mg, 1.40 mmol), methyl iodide (87.2 μL, 1.40 mmol) and potassium carbonate (387 mg, 2.80 mmol) was suspended in anhydrous N,N-dimethylformamide (7 mL) and stirred at 50° C. for 3 hours. After cooling down, the reaction mixture was diluted with ethyl acetate (150 mL). The whole was washed with water (150 mL) and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (384 mg) as a yellow solid. (Yield 85%)
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O.NN>CO.O1CCCC1>[NH2:3][O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (Compound XXIII-1) (13.86 g, 50 mmol) in methanol:tetrahydrofuran (2:3, 150 ml) was added hydrazine monohydrate (7.28 ml, 150 mmol) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (300 ml) and the mixture was washed with sat. NaHCO3 aq. (300 ml). The organic layer was washed with brine (300 ml), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound (6.40 g, 87%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[CH:5][CH:4]=[N:3]1.C1C(=O)N([Br:27])C(=O)C1>C1COCC1>[Br:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1C1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(1-methyl-1H-pyrazol-5-yl)piperidine-1-carboxylate (680 mg, 2.50 mmol) in THF (20 mL) was added NBS (486 mg, 2.80 mmol). The reaction mixture was stirred for 2 h. After concentration, the residue was purified by silica gel chromatography eluting with a 0-50% gradient of EtOAc in petroleum ether to give tert-butyl
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH3:14])=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:29][C:30](OC(C)=O)=[O:31].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[CH2:2][NH:1][C:30](=[O:31])[CH3:29]
Reactant: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)[C@@H](C)c1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of (S)-(5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-phenyl)-methanol (0.0914 g, 0.24 mmol) in CH2Cl2 (3 mL) was added Ac2O (0.0228 mL, 0.24 mmol), Et3N (0.05 mL, 0.36 mmol), and KI (0.0033 g, 0.02 mmol), and stirred at room temperature for 18 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0750 g (64%) of COMPOUND 401 as a white solid. 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.6 Hz), 1.71 (s, 2H), 1.99 (s, 3H), 2.05 (s, 3H), 3.63-3.77 (m, 2H), 3.81-3.96 (m, 2H), 4.02-4.09 (m, 1H), 4.20-4.29 (m, 2H), 4.37 (d, 2H, J=5.4 Hz), 5.76 (s, 1H), 6.87 (s, 1H), 7.04-7.23 (m, 3H), 7.33-7.39 (m, 2H), 7.66 (t, 1H, J=7.5 Hz), 8.38 (d, 2H, J=3.9 Hz), 8.57 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 11.93, 18.45, 23.58, 43.70, 52.43, 53.86, 58.92, 63.32, 122.57, 122.67, 124.03, 127.44, 130.86, 132.10, 132.86, 136.70, 137.05, 138.55, 142.57, 146.56, 148.93, 156.59, 161.08, 170.41. ES-MS m/z 441.4 (M+Na). Anal. Calcd. for C25H30N4O2.0.8CH2Cl2.0.8H2O: C, 63.70; H, 6.55; N, 11.52. Found: C, 63.76; H, 6.56; N, 11.60.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]([CH3:35])=[CH2:34]>C1COCC1.C(OCC)(=O)C>[C:8]1([C:7](=[N:6][CH:5]([CH2:34][C:33]([CH3:35])=[CH2:32])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)CC(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of N-(diphenylmethylene)glycine ethyl ester (available from Aldrich Chemical Co., Milwaukee, Wis.) (50.0 g, 187 mmol) in dry THF (200 mL) at −78° C. under argon was added a 1.0 M solution of lithium bis(trimethylsilyl)amide (Li HMDS; 210 mL, 0.2 mol) in THF over a period of 45 min (“1.A, Scheme A). After 0.5 hour at −78° C., 3-bromo-2-methylpropene (18.91 mL, 187 mmol) was added dropwise to the orange-yellow suspension. After the addition was complete, the reaction mixture was stirred for an additional 0.5 hour at 0° C. and then allowed to warm to room temperature. After 1 hour the reaction mixture was concentrated under reduced pressure to give an orange-colored oil. The crude material was dissolved in ethyl acetate (EA) (600 mL), washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to give the desired compound (60 g, 99%), which was used for the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][CH:7]([CH3:14])[CH2:6]1)=[O:3].[N:15]1C=CC=[CH:17][CH:16]=1.C(N)C.Cl>C1(C)C=CC=CC=1.O>[CH:11]([C@@H:10]1[CH2:9][CH2:8][C@@H:7]([CH3:14])[CH2:6][C@H:5]1[O:4][C:2](=[O:3])[NH:15][CH2:16][CH3:17])([CH3:13])[CH3:12]
Reactant: c1ccncc1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Agent: CCN
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCNC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
58.7 g of menthyl chloroformate (80% in toluene) were added to a mixture of 16.6 g of pyridine and 150 mL ethylamine (2M solution in THF) in 100 mL toluene at 0° C. over a period of 30 minutes. After stirring for 12 hours at room temperature, 100 mL of 2M HCl and subsequently 50 mL water were added, the phases separated and the water phase discarded. After washing with saturated NaHCO3-solution and water the organic phase was dried and evaporated to yield 47.1 g of crude product which was recrystallized from 82.4 g n-heptane to give 24.4 g of the analytically pure product as white crystals.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:16])[CH2:7][CH:8]=[CH:9][C:10]([CH3:15])=[CH:11][C:12]([OH:14])=O.[CH2:19]([Li])[CH3:20].[Cl-].[NH4+]>C1C=CC=CC=1.CCOCC>[OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:16])[CH2:7][CH:8]=[CH:9][C:10]([CH3:15])=[CH:11][C:12](=[O:14])[CH2:19][CH3:20]
Reactant: CC(C=CCC(C)CCCC(C)(C)O)=CC(=O)O
Reactant: [Li]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.35 g. of 11-hydroxy-3,7,11-trimethyldodeca-2,4-dienoic acid in 50 ml. ether at -20°C under nitrogen is added dropwise 59.1 ml. of a 0.67 molar solution of ethyllithium in benzene. The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction mixture is then taken up in a mixture of ether and saturated aqueous ammonium chloride. The organic layer is separated, is washed with saturated aqueous ammonium chloride, 5% aqueous sodium bicarbonate, water, and saturated sodium chloride, is dried over calcium sulfate, and the solvent is removed to yield 13-hydroxy-5,9,13-trimethyltetradeca-4,6-dien-3-one which is purified by preparative thin layer chromatography (50% ether/hexane).
Reaction SMILES: [Mg:1].C(Br)C.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[CH2:9]Cl.[Cl-:15]>O1CCCC1>[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[CH2:9][Mg:1][Cl:15]
Reactant: [Cl-]
Reactant: [Mg]
Reactant: Cc1cc(C)cc(CCl)c1
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1cc(C)cc(C[Mg]Cl)c1
Temperature: 50 °C

Procedure:
To a mixture of 12.8 g magnesium turnings in 100 ml of anhydrous THF (tetrahydrofuran) was added under nitrogen atmosphere 0.3 ml ethyl bromide as starter reagent and the reaction was heated to 50° C. A solution of 67.8 g 3,5-dimethylbenzyl chloride in 450 ml of anhydrous THF was added slowly so that the reaction proceeded without violent reaction but with clear consumption. After the addition of the total amount of chloride, the solution was heated at 50° C. overnight. This resulted in a clear, greenish solution of 3,5-dimethylbenzyl magnesium chloride. This solution was used for the next step.