Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[C:50]([O:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][C@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[CH:30][CH:29]=[CH:28]3)=[O:20])=[CH:44][CH:45]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 67 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2([C:8]#[N:9])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 4-trifluoromethylbenzyl cyanide (0.92 g, 5.0 mmol) and bis(2-bromoethyl)ether (2.3 mL, 18 mmol) in DMF (10 mL) at room temperature was treated portion wise with sodium hydride (60% in mineral oil, 0.6 g, 15 mmol) over a period of 10 mins followed by stirring at the same temperature for 1 h. The mixture was then stirred at 70° C. for 16 h. Then cooled to room temperature and the reaction mixture was quenched with slow addition of methanol. Water (100 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water and brine and dried over sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography using a gradient of 5% EtOAc in hexanes to 30% EtOAc in hexanes to give the title compound (1.11 g, yield: 87%). 1H NMR (CDCl3 300 MHz): δppm 7.75 (d, 2H), 7.65 (d, 2H), 4.20-4.09 (m, 2H), 4.00-3.85 (m, 2H), 2.27-2.05 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][CH2:12][CH3:13])[CH3:2].O[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].S(=O)(=O)(O)O.O>COCCOC>[CH2:12]([O:11][C:5]1[C:6]([F:10])=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])[CH3:13]
Reactant: CCOc1cccc(F)c1OCC
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=S(=O)(O)O
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Temperature: 25 °C
Yield: 0 %

Procedure:
To a solution of 1,2-diethoxy-3-fluorobenzene (2.28 g, 12.4 mol) and N-(hydroxymethyl)phthalimide (2.41 g, 13.6 mol) in 1,2-dimethoxyethane (8 mL), a solution of sulfuric acid (8 mL) in 1,2-dimethoxyethane (8 mL) was added dropwise on ice, and the mixture was stirred at room temperature for twelve hours. The reaction mixture was poured into water (100 mL), and crystals were filtered. The obtained crystals were recrystallized from acetone and water, and the precipitated crystals were filtered. After the filtrate was concentrated under reduced pressure, the residue was crystallized from acetone to give 0.96 g of the title compound (yield: 23%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:4][N:3]=1.C(SCCSCCSC1N=C2N(N=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=N2)CCCCC>>[CH2:12]([S:11][CH2:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=[N:1]2)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCSCCCSc1nc(N)n[nH]1
Reactant: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Product: CCCCCSCCCSc1nc2nc(C)cc(O)n2n1

Procedure:
Compound 18 was prepared from Compound 9, using a procedure analogous to that described previously for Compound 20. The crude product was recrystallized from ethyl acetate to give a 24% yield of white solid, m.p. 121°-123° C. Analysis: Calculated for C14H22N4OS2 : C, 51.50; H, 6.79; N, 17.16. Found: C, 51.30; H, 6.69; N, 16.97.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11]>O>[OH:11][CH2:10][C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Clc1ccccn1
Solvent: O
Product: OC[C@@H]1CCCN1c1ccccn1
Temperature: 160 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A mixture of 2-chloropyridine (118 g) and L-prolinol (70 g) was heated under nitrogen atmosphere at 160° C. with stirring for 4 h. The mixture was cooled to room temperature and poured into water and the solution was extracted with chloroform repeatedly. The combined organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by column chromatography using 2% MeOH in CHCl3 as eluent to get 67.3 g (54.5%) of the title compound as a syrupy liquid.
Reaction SMILES: C(N1[C@@H](C)CN([C@H]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)C2C=CC=C(O)C=2)[C@H](C)C1)C=C.O.FC(F)(F)C(O)=O>CO.[Pd]>[CH2:28]([N:25]([CH2:26][CH3:27])[C:23](=[O:24])[C:22]1[CH:30]=[CH:31][CH:19]=[CH:20][CH:21]=1)[CH3:29]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@@H]1C
Agent: [Pd]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CC)C(=O)c1ccccc1

Procedure:
(±)-4-((αR*)-α-((2R*,5S*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) -N-N-diethylbenzamide (Example 14) (21.75 g, 0.0499 mol) was dissolved in 330 mL methanol:90 mL water. Trifluoroacetic acid (3.9 mL, 0.0499 mol) was added, followed by 14.5 g of 5% palladium on carbon. The solution was heated at reflux for three days and filtered through Celite. The solvent was removed, and the residue was purified by chromatography on silica gel with ethanol (0-20%) in dichloromethane containing 1% tdethylamine. The solvent was removed, and the residue was redissolved in dichloromethane and washed with water at pH 8. The organic layer was dried over sodium sulfate and concentrated to dryness. The resulting solid was triturated overnight in ethyl acetate. Filtration gave 9.09 g (46%) of (±)-4-((αR*)-α-((2R*, 5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N diethylbenzamide as a tan solid. Calc. for C24H33N3O2 0.5 H2O: C, 71.26; H, 8.47; N, 10.39. Found: C, 71.12; H, 8.47; N, 10.49. NMR (300 MHz, CDCl3): δ0.9 (d, J=6 Hz, 3H),1.2 (d and brtr, 9H); 1.5 (t, J=10 Hz, 1H); 2.2 (br m, 1H); 2.5 (m, 1H); 2.6 (d, J=9 Hz, 1H); 2.8 (m, 2H); 3.1-3.5 (br m, 5.3 (s, 1H); 6.6 (d, J=8 Hz, 1H) 6.7 (d, J=8 Hz, 1H); 6.8 (s, 1H); 7.1 (t, J=8 Hz, 1H); 7.2 and 7.3 (AB q, J=8 Hz, 4H), 9.0 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][OH:16])[CH3:12].[H-].[Na+].O>CN(C=O)C>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzene and 6.0 g (6.8 mL; 51 mMol) of 2-diethylamino-ethanol in 50 mL of DMF at 0° C. is added 2.7 g of NaH portionwise over 2 h. After stirring another hour at rt, the reaction mixture is poured onto 300 mL of water and stirred. After filtering off some crystalline product, the aqeous layers are extracted with ethyl acetate. The combined organic layers are dried and evaporated to obtain diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine. Title compound: ES-MS: 239 [M+H]+; single peak at tR=5.1 min (System 2).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]2[OH:30])=[CH:20][CH:19]=1.C(N(CC)CC)C>>[OH:30][C@@H:25]1[C@@H:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:29][CH2:28][N:27]([CH:2]2[CH2:6][CH2:5][N:4]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[C:3]2=[O:15])[CH2:26]1
Reactant: COc1ccc([C@@H]2CCNC[C@H]2O)cc1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2CCN(C3CCN(Cc4ccc(C)cc4)C3=O)C[C@@H]2O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 450 mg, 1.68 mmol), (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (313 mg, 1.5 mmol) and triethylamine (23 mL, 16.8 mmol) was stirred at 60° C. for 1 h, followed by heating at 85° C. for 1 h, 120° C. for 1 h and at 140° C. for 1 h. The mixture was cooled and then quenched with 40 mL of water and extracted with 3×50 mL of chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via silica gel chromatography (24 g column, gradient of 0-80% ethyl acetate/petroleum ether) to yield 375 mg of (±)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of four diastereomers. LCMS (method F) RT 1.84 min (74% AP), m/z 395.2 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.31-7.41 (m, 8H) 6.86 (d, J=9.07 Hz, 2H) 4.66 (s, 1H) 3.73 (s, 3H) 3.49 (s, 2H) 2.59 (d, J=10.58 Hz, 2H) 2.32-2.47 (m, 3H) 1.89 (td, J=12.65, 4.53 Hz, 2H) 1.56 (d, J=11.71 Hz, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=1.[N+:26]([O-])([OH:28])=[O:27]>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:26]([O-:28])=[O:27])=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:19]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To 85 ml of concentrated sulfuric acid was added 7.0 g of 3-(2,4-difluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-10) at 5° C. Furthermore, 9 ml of 70% nitric acid was added, and the mixture was stirred at 5° to 10° C. for 8 hours. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 7.76 g (yield, 96%) of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-16; m.p., 93.2° C.).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][CH2:23]I>CN(C)C=O.ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][O:1][C:2]2[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCI)cc1OC
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CCOc2cc(C(C)C)ccc(CO)c2=O)cc1OC
Temperature: 80 °C
Yield: 10.8 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (844 mg, 4.35 mmol) in dimethylformamide (5 ml) was stirred while 60% oily sodium hydride (191 mg, 4.78 mg) in small portions were added thereto. Subsequently, 3,4-dimethoxyphenethyl iodide (2.54 mg, 8.70 mmol) was added, then the solution was heated at 80° C. for 7 hours. The solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (3:2)] to give 169 mg of 2-[2-(3,4-dimethoxyphenyl)ethoxy]-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a yellowish brown oil (yield: 11%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:5][CH2:4]1.Cl[Sn]Cl>CCOC(C)=O>[F:34][C:2]([F:1])([F:33])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:7][CH2:8]1
Reactant: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-(4-fluorobenzyl)amino]-4-methylamino-5-nitro-benzoic acid amide (80 mg, 0.166 mmol), SnCl2 (183 mg 0.81 mmol) and 5 mL EtOAc is stirred at reflux for 1 h. The mixture is filtered through a pad of celite and the celite pad is washed with EtOAc. The combined organic phases are dried with Na2SO4, filtered and concentrated. Yield: 68 mg. HPLC Rt=1.35 min (method A). MS m/z: 453 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH:25]([CH2:38][C:39]3([OH:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:26][N:27](C)[C:28](OCC[Si](C)(C)C)=O)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[N+](CC)(CC)(CC)CC.[F-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH:25]([CH2:38][C:39]3([OH:45])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:26][NH:27][CH3:28])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1)[C@@H]1CCCN(C(=O)NC(CN(C)C(=O)OCC[Si](C)(C)C)CC2(O)CCCCC2)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Product: CNCC(CC1(O)CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(F)c2)C1
Temperature: 45 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of (3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-piperidine-1-carboxamide (17.8 mg, mmol) in anhydrous THF (1 mL) was added Et4NF (3 mg). The solution was stirred at 45° C. for 2 h and evaporated under reduced pressure. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide (9.5 mg, 58%) as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.32 (q, 1H), 7.16 (m, 1H), 7.14 (m, 1H), 6.94 (m, 1H), 4.42 and 4.28 (two isomers in a 3:2 ratio, d, 1H), 4.15 (m, 1H), 3.95 and 3.84 (two isomers on 3 to 2 ratio, d, 1H), 3.32 (m, 1H), 3.26 (s, 3H), 3.14 (dd, 1H), 2.95 (m, 1H), 2.70 (s, 3H), 2.60-2.39 (m 3H), 1.94 (t, 2H), 1.79-1.22 (m, 20H), 1.00 (m, 1H); MS m/z 508 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: COc1ccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.93 (M+H+); retention time=0.91 minutes.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.O>C(OCC)C>[CH3:15][S:16]([O:1][CH2:2][CH:3]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C(COS(C)(=O)=O)c1ccc(Cl)cc1
Yield: 79.2 %

Procedure:
To a solution of 5 g of methyl α-(hydroxymethyl)-4-chlorophenylacetate and 3.5 g of methanesulphonyl chloride in 30 ml of anhydrous diethyl ether, cooled at 0° C., a solution of 2.6 g of triethylamine in 10 ml of anhydrous diethyl ether is added dropwise. The temperature is allowed to rise again to room temperature, the reaction mixture is poured into water and is extracted with diethyl ether. The ether solution, washed with water, and dried over Na2SO4, is concentrated under vacuum, to yield 7.2 g of raw product. By crystallization thereof from 5 ml of ethanol, 5.4 g of a white solid product (m.p. 77°-8° C.) is obtained, having the structure indicated in the title of this example.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:13][C:12]=1[OH:25]>N1C=CC=CC=1.O>[OH:25][C:12]1[CH:13]=[C:14]([S:21]([O-:24])(=[O:22])=[O:23])[C:15]2[C:20]([C:11]=1[NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.[NH+:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1c(O)cc(S(=O)(=O)O)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(O)cc(S(=O)(=O)[O-])c2ccccc12)c1ccccc1
Product: c1cc[nH+]cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Benzoyl chloride (1.8 ml) was added portionwise to a vigorously stirred suspension of 2.39 g 4-amino-3-hydroxy-1-napthalenesulfonic acid in a mixture of 50 ml pyridine and 20 ml water with cooling in an ice bath. The mixture was stirred for 2 hours at room temperature. The solid product was collected and washed with 10 ml of ice-cold water. Drying in a vacuum oven gave crude pyridinium 3-hydroxy-4-(N-benzoylamino)-1-naphthalenesulfonate (2.55 g, 60%); an analytical sample was prepared by recrystallization from a mixture of tetrahydrofuran and water (9:1), m.p. 225° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[N:13]1[CH:17]=NC=N1.[CH3:18][O:19][CH2:20]CN>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[NH:13][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCN
Reactant: Nc1nc(-n2cncn2)c2cc(Br)ccc2n1
Product: COCCNc1nc(N)nc2ccc(Br)cc12

Procedure:
The title compound was synthesized by a method analogous to example 23 using 6-Bromo-4-[1,2,4]triazol-1-yl-quinazolin-2-ylamine and 2-methoxyethylamine. The product was characterized as follows: MS (m/z) 297[M+H]+; HPLC Rt=1.05 minutes (Method B).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[N:7]=[C:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:9]2[O:10][CH:11]([NH2:17])[C:12](=[O:16])[NH:13][C:14]=2[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:3]([CH2:2][N:13]1[C:12](=[O:16])[CH:11]([NH2:17])[O:10][C:9]2[C:8]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:7][C:6]([CH3:5])=[N:15][C:14]1=2)#[N:4]
Reactant: Cc1nc(CCN2CCOCC2)c2c(n1)NC(=O)C(N)O2
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1nc(CCN2CCOCC2)c2c(n1)N(CC#N)C(=O)C(N)O2
Yield: 91.3 %

Procedure:
0.25 g of chloroacetonitrile dissolved in 50 ml of methyl ethyl ketone is dropped within 15 minutes to a suspension containing 0.88 g of 2-methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one base (e.g. prepared as described in Example 23) and 0.5 g of anhydrous potassium carbonate in 15 ml of methyl ethyl ketone under boiling and stirring. The mixture is further boiled under stirring for 8 hours, the precipitate is filtered as hot and washed with methyl ethyl ketone. The filtrate is evaporated and the residue is triturated with diisopropyl ether. After filtering, the solid is washed with diisopropyl ether and dried to give 0.91 g (91%) of the product, m.p.: 126°-128° C.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]([CH2:8][NH:9][C:10](=[O:18])[O:11][CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16])=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:3]([CH2:4][O:5][C:6]([CH2:8][NH:9][C:10](=[O:18])[O:11][CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16])=[O:7])=[O:2]
Reactant: CCC(=O)OCOC(=O)NCC(=O)OCC(OC)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)OCOC(=O)NCC(=O)OCC=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 55 (268 mg, 0.91 mmol) was dissolved in 10 mL of CH2Cl2 and 5 mL of TFA (containing 5% H2O) was added. The mixture was stirred for 30 min at room temperature. The solution was then concentrated to dryness in vacuo to give the product 56 that was used immediately for the next step. 1H NMR (400 MHz, CDCl3) δ 1.15 (t, J=7.43 Hz, 3H), 2.40 (q, J=7.43 Hz, 2H), 4.16 (d, J=5.47 Hz, 2H), 4.78 (s, 2H), 5.75 (s, 2H), 6.30 (bs, 1H), 9.60 (s, 1H).
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])(=[O:8])[O:5]CC)C.C[Si](I)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:18])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3CP(=O)(OCC)OCC)cc2)cc1
Agent: C[Si](C)(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3CP(=O)(O)O)cc2)cc1

Procedure:
{2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-benzyl}-phosphonic acid diethylester is dissolved in CH2Cl2 and and the mixture obtained is treated with trimethylsilyl iodide at 0°. The mixture obtained is stirred at 0° for several hours and diluted with toluene. From the mixture obtained solvent is evaporated. The evaporation residue obtained is dissolved in 1N NaOH solution, washed with EtOAc, HCl is added, precipitation occurs and the precipitate obtained is collected. {2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-benzyl}-phosphonic acid is obtained.