Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4](F)[CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.CCCCCC.C(OCC)C>[C:31]1([CH2:37][C:38]([NH:40][C:41](=[O:42])[NH:1][C:2]2[CH:29]=[CH:28][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][CH:19]([CH2:22][N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Reaction time: 64.5 h

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (50 mg) was dissolved in N,N-dimethylformamide (1.5 ml) under a nitrogen atmosphere, and then 0.25 M 2-phenylacetyl isocyanate in hexane (1.45 ml) was added, followed by stirring for 64.5 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (3 ml) and hexane (3 ml). The solid was filtered off, and dried under aeration to provide the titled compound (49.1 mg) as white powder.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:13][C:14](Br)=[CH:15][N:16]=1>CN(C=O)C>[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[N:13][C:14]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][N:16]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Oc2ccccc2)nc1C(=O)Nc1ccccc1
Temperature: 100 °C
Yield: 11.8 %

Procedure:
Phenol (62.60 mg, 59.06 μL, 0.6652 mmol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil) (15.96 mg, 17.73 μL, 0.6652 mmol) in anhydrous DMF (1.3 mL) at 0° C. The reaction mixture was stirred until the evolution of H2 ceased. 3-Amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (130 mg, 0.4435 mmol) was added followed by Cu2O (15.87 mg, 0.1109 mmol) and reaction mixture heated to 100° C. overnight. The reaction mixture was cooled to ambient temperature and quenched with crushed ice. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with ammonium hydroxide (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (16 mg, 12% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.15-7.17 (m, 4H), 7.34-7.47 (m, 6H), 7.66-7.68 (m, 2H), 8.24 (s, 1H) and 9.92 (s, 1H) ppm; MS (ES+) 306.99.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][C:31]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])=[O:32].[BH3-]C#N.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:25])([F:26])[F:27])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:28][CH2:29][CH2:30][C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[O:32])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Reactant: NCCC(=O)NS(=O)(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)NS(=O)(=O)c4ccccc4)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(phenylsulfonyl)propanamide (1.19 mmol, 1.5 equiv) were dissolved in anhydrous ethanol. The mixture was stirred at 80° C. for 1 h. Then NaBH3CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80° C. for 16 h. The organic layer was concentrated and purified by preparative thin layer chromatography (mobile phase was methanol:dichloromethane 1:10) to give 3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide as a white solid. 120 mg, white solid, 53%. ESI-MS: 591.0 (M+H)+. HPLC: 98.05%. 1H NMR (400 MHz, DMSO-d6) δ: 8.22˜8.13 (m, 1H), 8.11˜8.04 (m, 2H), 7.79˜7.63 (m, 4H), 7.45˜7.30 (m, 3H), 4.63˜4.49 (m, 1H), 4.27 (s, 2H), 2.99 (t, 2H), 2.32 (t, 2H), 2.19˜2.07 (m, 2H), 1.85˜1.74 (m, 2H), 1.45˜1.30 (m, 2H), 125˜1.12 (m, 2H), 1.10˜0.97 (m, 1H), 0.86 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:6]2=[CH:5][CH:4]=1)=O.CO.CC([O-])=O.[Na+].[NH2:29][OH:30].Cl>O>[OH:30][N:29]=[CH:1][C:3]1[N:8]=[C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:12]3)[C:6]2=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=O)ccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=NO)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
To a stirred solution of tert-butyl 2′-formyl-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-carboxylate (0.5 g, 1.7 mmol, 1 eq.) in mixture of methanol (12 mL):water (12 mL) was added NaOAc (0.28 g, 3.45 mmol, 2 eq.) followed by addition of NH2OH.HCl (0.24 g, 3.45 mmol, 2 eq.) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption starting material, reaction mixture was concentrated under reduced pressure; resulting residue was diluted with water (50 mL) and extracted by ethyl acetate (3×100 mL). Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford title compound as brown solid (0.520 g, 99%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.12 (d, J=9.88 Hz, 2H), 4.34 (d, J=10.12 Hz, 2H), 5.08 (s, 2H), 7.73 (d, J=7.92 Hz, 1H), 7.79 (d, J=7.96 Hz, 1H), 8.21 (s, 1H). LC-MS (m/z): 306.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(Cl)c(Cl)cc21
Reactant: FC(F)(F)c1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(Cl)c(Cl)cc2CCN1c1cnccc1C(F)(F)F
Yield: 8.4 %

Procedure:
Using an analogous procedure and workup as described for the preparation of Example 1A above, 6,7-dichloro-3,4-dihydroisoquinolin-1(2H)-one (I-55d: 100 mg, 0.463 mmol) was reacted with 3-bromo-4-(trifluoromethyl)pyridine (115 mg, 0.509 mmol), 1,4-dioxane (3 mL), copper iodide (7 mg, 0.046 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (20 mg, 0.1388 mmol) and potassium phosphate (245 mg, 1.157 mmol) in a sealed tube at 120° C. for 16 hours to afford the crude product. Purification by column chromatography on silica gel (20% ethylacetate in hexane) afforded 14 mg of the product (8.3% yield).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[N:12]=[N:11][CH:10]=[C:9]2[O:13][CH2:14][CH2:15][CH2:16][C:8]=12.[BrH:23].C(O)(=O)C>C(O)(=O)C>[BrH:23].[O:13]1[C:9]2=[CH:10][N:11]=[N:12][C:7]([NH2:6])=[C:8]2[CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc(CNc2nncc3c2CCCO3)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Product: Nc1nncc2c1CCCO2
Temperature: 90 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A mixture of N-(2,4-dimethoxybenzyl)-3,4-dihydro-2H-pyrano[2,3-d]pyridazin-5-amine (158, 0.524 mmol) and 30% by weight hydrobromic acid/acetic acid (0.3 mL, 0.4 g, 1.5 mmol) in acetic acid (3 mL) was stirred nearly 2 hours at 90° C. The reaction was then cooled to room temperature and the solvents were removed in vacuo. The dark red solid was washed with diethyl ether and then dried to afford the crude title compound (122 mg) in about 65% purity. MS (ESI) [m/e, (M)+]=151.7. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 8.11 (br s, 2H), 4.36-4.40 (m, 2H), 2.47 (t, J=6.32 Hz, 2H), 1.98-2.06 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][C:60]([OH:62])=[O:61])=[CH:55][CH:54]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:18])[NH:52][C:53]1[CH:54]=[CH:55][C:56]([CH2:59][C:60]([OH:62])=[O:61])=[CH:57][CH:58]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (F.W.=249.27, 1.5 g, 4.0 mmol), HATU (1.6 g, 3.9 mmol), and DIEA (0.7 mL, 4.97 mmol) in DMF (30 mL) was stirred at room temperature for 1 h. (4-Amino-phenyl)-acetic acid (FW=151.17, 0.5 g, 3.31 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered and separated by reverse phase HPLC (0-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1% TFA). The combined fraction was evaporated to furnish the desired product (S)-2-(4-Carboxymethyl-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [OH:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)OC
Product: CCCCCCC(CCCCCCCCCCC(=O)O)OCc1ccccc1

Procedure:
In a similar manner to Example 4-(1), methyl 12-hydroxyoctadecanoate was used instead of ethyl ricinoleate and benzyl bromide was used instead of methyl iodide, the title compound (8-i) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccc(F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A mixture of 4-fluoro-N2-(6-fluoropyridin-3-yl)benzene-1,2-diamine (524 mg, 2.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (493 mg, 2.61 mmol), HOAt (355 mg, 2.61 mmol), 4-methylmorpholine (575 μL, 5.21 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (500 mg, 2.61 mmol) in DCM (20 mL) was stirred at RT for 3 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (973 mg, quantitative). LCMS (Method C): RT 3.25 min [M+H]+ 393.3.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][O:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.NC1C=CC=CN=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[O:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][CH:4]=[CH:5][N:6]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)COC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Agent: Nc1ccccn1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2OCC(=O)Nc2ccccn2)cc1

Procedure:
The product from Example 27, Part B (90 mg, 0.3 mmol) and 2-aminopyridine (42 mg, 0.45 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the organic phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained as a white solid by silica gel chromatography (40 mg, 35%). 1H NMR (300 MHz, CDCl3) δ 8.72 (br s, 1H), 8.33 (d, J=4 Hz, 1H), 8.18 (d, J=8 Hz, 1H), 7.72 (m, 1H), 7.23 (d, J=9 Hz, 2H), 7.08 (m, 1H), 6.79 (d, J=9 Hz, 2H), 5.17 (s, 1H), 4.73 (d, J=15 Hz, 1H), 4.23 (d, J=15 Hz, 1H), 3.70 (d, J=15 Hz, 1H), 3.69 (s, 3H), 3.59 (d, J=15 Hz, 1H), 1.87 (s, 6H). MS: m/z (MH+) 382.
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1Cl)[CH2:2][CH2:3][CH3:4].[CH2:16]([Mg]Br)[CH3:17]>[Cl-].[Mn+2].[Cl-]>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[CH2:16][CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCC/N=C/c1c(F)ccc(F)c1Cl
Agent: [Mn+2]
Agent: [Cl-]
Product: CCCC/N=C/c1c(F)ccc(F)c1CC

Procedure:
Butyl-[1-(2-ethyl-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from butyl-[1-(2-chloro-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine, ethylmagnesium bromide and manganese(II) chloride in analogy to Example 194a): brown oil; 1H-NMR (CDCl3): 0.97 (3H, t, CH3), 1.15 (3H, t, CH3), 1.43 (2H, sextet, CH2), 1.70 (2H, quintet, CH2), 2.98 (2H, qd, CH2), 3.66 (2H, t, CH2), 6.87 (1H, td, ArH), 6.99 (1H, td, ArH), 8.52 (1H, s, CH═N).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][C@@H:50]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:51]([NH2:53])=[O:52]>CN(C=O)C>[C:51]([C@@H:50]([NH:49][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)(=[O:52])[NH2:53]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.5 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DMF (3 mL). TBTU (224.14 mg, 0.85 mmol), DIEA (0.31 mL, 2.24 mmol) and (αS)-α-amino-benzeneacetamide (CAN 6485-52-5, 51.2 mg, 0.51 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xbridge-C18, 5 μ, 19×250 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 9.58%) as white solid; LC-MS (UV peak area, ESI) 93.20%, 367.4 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.4 %

Procedure:
A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid tert-butyl ester 31 (1.00 g, 3.78 mmol), potassium carbonate (0.627 g, 4.54 mmol), sodium iodide (0.567 g, 3.78 mmol), and methyl bromoacetate (0.40 mL, 4.21 mmol) in anhydrous DMF (8 mL) was stirred at room temperature for 14 h. The reaction mixture was then diluted with ethyl acetate (100 mL) and hexanes (20 mL), washed with water (20 mL×4) and brine (30 mL), and concentrated under reduced pressure to afford the desired product 32 as a yellow oil (1.28 g, 100% yield) which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H), 1.41-1.65 (m, 4H), 2.49-2.60 (m, 2H), 3.02-3.16 (m, 2H), 3.79 (s, 3H), 4.45 (br s, 1H), 4.59 (s, 2H), 6.79 (d, 2H), 7.05 (d, 2H). m/z (ESI): 338 [C18H27NO5+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:24]([Mg]Br)[CH:25]=[CH2:26].O.C(OCC)(=O)C>O1CCCC1.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:12]1[N:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:13]=1)[CH:25]=[CH2:24]
Reactant: C=CC[Mg]Br
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=CCc1cc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine 1.2 g (3.7 mmol) in tetrahydrofuran (24 ml), tetrakis(triphenylphosphine)palladium (0.21 g, 0.18 mmol) was added. Under cooling with ice water under an argon gas atmosphere, a 1 M solution (11 ml) of allylmagnesium bromide in diethyl ether was added dropwise. After the resulting mixture was stirred at the same temperature for 1 hour, the temperature of the mixture was allowed to rise to room temperature, followed by further stirring for 2 hours. Water-ethyl acetate was added to the reaction mixture, and the thus-obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure and the residue was left over at room temperature for 3 days. The residue was separated and purified by chromatography on a silica gel column [hexane/ethyl acetate (4/1)], whereby the title compound was obtained as a pale brown oil (0.85 g, 69.8%).
Reaction SMILES: Cl[C:2]1[N:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][C:11]=1[OH:12])=[O:5].[OH-].[Na+]>O.[Cu].[Cu](I)I>[O:5]=[C:4]1[C:3]2[C:2](=[N:21][CH:20]=[CH:19][CH:18]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:7][C:6]1=2
Reactant: CC(C(=O)O)c1ccc(O)c(C(=O)c2cccnc2Cl)c1
Agent: I[Cu]I
Agent: [Cu]
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)c1ccc2oc3ncccc3c(=O)c2c1
Yield: 72.7 %

Procedure:
2.5 g of 2-[3-(2-chloronicotinoyl)-4-hydroxyphenyl]propionic acid and 0.7 g of sodium hydroxide are dissolved in 10 ml of water. Catalytic amounts of powdered copper and copper iodide are added to the solution, and the mixture is stirred under reflux for 2 hours. After cooling, the reaction mixture is diluted with water, and filtered with suction. The filtrate is made acid with hydrochloric acid, and the resulting crystals are filtered off and recrystallized from aqueous dioxane to give 1.6 g of 2-(5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid melting at 193.5°-194.5°C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:15]([C:16]([C:23]4[CH:28]=[CH:27][C:26]([O:29]C)=[C:25]([N+:31]([O-:33])=[O:32])[CH:24]=4)=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][C:4]=1[N+:34]([O-:36])=[O:35]>CC(=O)CC.Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:22]3[C:17]([C:16]([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([N+:31]([O-:33])=[O:32])[CH:24]=4)=[C:15]4[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:5][C:4]=1[N+:34]([O-:36])=[O:35]
Reactant: COc1ccc(-c2c3ccccc3c(-c3ccc(OC)c([N+](=O)[O-])c3)c3ccccc23)cc1[N+](=O)[O-]
Agent: Br
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cc(-c2c3ccccc3c(-c3ccc(O)c([N+](=O)[O-])c3)c3ccccc23)ccc1O

Procedure:
19.2 g (0.04 mol) of 9,10-bis(4-methoxy-3-nitrophenyl)-anthracene in a mixture of 200 ml of butanone and 200 ml of concentrated HBr are refluxed for 24 h while stirring. After the end of the reaction, the suspension is evaporated down to half its volume in a rotary evaporator and the product is filtered off with suction. Recrystallization from toluene is then effected.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[P:10](Cl)(Cl)(Cl)=[O:11]>CC(C1C=CC(OP(OC2C=CC=CC=2)(OC2C=CC=CC=2)=O)=CC=1)C.CC(C1C=CC=C(OP(OC2C=CC=CC=2)(OC2C=CC=CC=2)=O)C=1)C.CC(C1C(OP(OC2C=CC=CC=2)(OC2C=CC=CC=2)=O)=CC=CC=1)C>[CH2:4]1[O:5][P:10]2([O:7][CH2:6][C:3]1([CH2:8][OH:9])[CH2:2][O:1]2)=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCC(CO)(CO)CO
Agent: CC(C)c1ccc(OP(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Agent: CC(C)c1cccc(OP(=O)(Oc2ccccc2)Oc2ccccc2)c1
Agent: CC(C)c1ccccc1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: O=P12OCC(CO)(CO1)CO2
Temperature: 100 °C
Yield: 75 %

Procedure:
In a 250 mL four-necked reaction flask fitted with a mechanical stirrer, pot thermometer, addition funnel, and condenser with gas outlet were placed 42.5 g (0.313 mole) of pentaerythritol and 150 mL of PHOSFLEX 41P brand of isopropylated triphenyl phosphate under nitrogen. The mixture was stirred and heated at 95° C. as 49.2 g (0.321 mole) of phosphorus oxychloride was added dropwise over five hours. The resulting white slurry was heated to 100° C. with a nitrogen gas sparge for eight hours to remove HCl. The mixture was cooled to 50° C. and filtered. The solid was washed three times with 40 mL of hexane and dried at 100° C./2 mm Hg for sixteen hours to give 42.3 g (71.2% yield) of crude pentaerythritol phosphate alcohol (2,6,7-trioxa- 1-phosphabicyclo [2.2.2]octane-4-methanol-1-oxide). The product had a 31P NMR resonance at -6.0 ppm in d6 -DMSO.