Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:9]2=O)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:9]2)=[CH:27][CH:28]=1
Reactant: COCCOCCOc1cccc2c1C(=O)N(Cc1ccc(OC)cc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCCOc1cccc2c1CN(Cc1ccc(OC)cc1)C2
Temperature: 60 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
2-(4-Methoxy-benzyl)-4-[2-(2-methoxy-ethoxy)-ethoxy]-isoindole-1,3-dione (149 mg, 0.38 mmol) was treated with a 1M solution of lithium aluminium hydride in THF (5 mL, 5 mmol). The mixture was maintained at r.t. for 4 hours, 60° C. for 1 hour, then r.t. for a further 18 hours. The mixture was then cooled in ice and quenched by the dropwise addition of water (0.2 mL), 2N sodium hydroxide solution (0.4 mL) and water (0.4 mL). Magnesium sulphate was added, followed by ethyl acetate and then the mixture was stirred at r.t. for 15 minutes. The solids were removed by filtration, being well washed with ethyl acetate. Concentration of the filtrate gave a residue which was absorbed onto an SCX cartridge and washed with 5% methanol/dichloromethane then eluted with 10% 1M ammonia in methanol/dichloromethane to afford the title compound (134 mg, 97%). 1H NMR (methanol-d4) 7.43-7.39 (2H, m), 7.27 (1H, t), 6.99-6.96 (2H, m), 6.90 (1H, d), 6.88 (1H, d), 4.33 (2H, s), 4.28 (2H, s), 4.23 (2H, s), 4.18-4.15 (2H, m), 3.85-3.79 (5H, m), 3.67-3.64 (2H, m), 3.54-3.51 (2H, m), 3.33 (3H, s). MS: [M+H]+ 358.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:10]>C(O)C>[OH:10][CH:7]([CH3:8])[CH2:6][CH2:9][C:3]1[CH:8]=[CH:7][C:6]2[C:5](=[CH:9][CH:3]=[CH:4][CH:5]=2)[CH:4]=1
Reactant: O
Reactant: Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
Then, 99 g (0.5 mole) of the compound (XLVII-1) was suspended in 1000 ml of ethanol, 9.5 g (0.25 mole) of sodium borohydride was added thereto, and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction 1500 ml of toluene and 500 ml of water were added thereto to effect extraction, and the organic layer was separated. The organic layer was washed with water and then concentrated to obtain 100 g of 2-(3-hydroxybutyl)naphthalene (XII-2) (yield: 100%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([C:37]#[N:38])[C:28]=1[O:39][CH3:40].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:10][O:11][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[C:29]([C:37]#[N:38])[C:28]=2[O:39][CH3:40])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2ccc(F)c(Cl)c2)CC1
Reactant: COc1c(C#N)cc2ccccc2c1CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C#N)cc2ccccc2c1COCC(c1ccc(F)c(Cl)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
The requisite tert-butyl 4-{1-(3-chloro-4-fluorophenyl)-2-[(3-cyano-2-methoxy-1-naphthyl)methoxy]ethyl}piperazine-1-carboxylate was synthesized using the following method. tert-Butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate (65 mg, 0.18 mmol) was dissolved in THF (1.8 mL). 4-(Iodomethyl)-3-methoxy-2-naphthonitrile (70 mg, 0.22 mmol) was added followed by NaH (9 mg, 0.36 mmol). After reacting at RT overnight, water (60 mL) was added. The mixture was extracted with EtOAc (40 mL). The organic phase was dried over Na2SO4, filtered through a pad of diatomaceous earth and the volatiles removed under reduce pressure. Chromatography of the residue on SiO2 (0-30% EtOAc:hexane) afforded the title compound (99 mg). MS m/z 554.6 (M+H)+. The requisite tert-butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate was synthesized using the following method.
Reaction SMILES: [OH:1][CH:2]([CH:22]=[CH2:23])[CH:3]([NH:9][C:10]([C:12]1[C:13]([C:18]([F:21])([F:20])[F:19])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])[C:4]([O:6]CC)=O.[CH3:24][NH2:25]>CO>[OH:1][CH:2]([CH:22]=[CH2:23])[CH:3]([NH:9][C:10]([C:12]1[C:13]([C:18]([F:19])([F:20])[F:21])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])[C:4](=[O:6])[NH:25][CH3:24]
Reactant: C=CC(O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)OCC
Reactant: CN
Solvent: CO
Product: C=CC(O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)NC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.65 g (4.92 mmol) of ethyl 3-hydroxy-2-[(1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]pent-4-enoate were dissolved in methanol. At 0° C., methylamine gas was introduced for 1 h. After 16 h of stirring at RT, the solvent was removed and the residue was recrystallized from acetone. The precipitate gave 0.65 g of erythro title compound as a colorless powder, the filtrate contained 0.75 g of isomer mixture. Accordingly, the total yield was 1.40 g (89% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15]O)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:31]([CH2:15][C:11]1[CH:12]=[N:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cncc(OCc2ccccc2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
To a stirring solution of 250 mg (1.17 mmol) of (5-(benzyloxy)pyridin-3-yl)methanol in 8 mL of toluene was added 310 μL (1.44 mmol) of DPPA. The mixture was cooled to 0° C. and 210 μL (1.44 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene] (DBU) was added. The ice bath was removed, and stirring was continued with wanning to room temperature. After about 20 h, the solution was diluted with EtOAc, and 1N HCl was added to a pH between 7 and 8. The organic layer was washed with water (2×15 mL) and brine (15 mL) and dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography (56-60% EtOAc/hexanes) to give 181 mg (65% yield) of the azide as a colorless oil.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CCCCCC.[C:33](=[O:35])=[O:34].Cl>C1COCC1>[CH2:1]([O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[C:15]([C:33]([OH:35])=[O:34])=[C:16]([F:19])[C:17]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C=O
Reactant: CCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
36.8 g of the compound (10) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 100 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 26.5 g (76 mmol) of 4-decyloxy-2,3,5,6-tetrafluorobenzoic acid (11).
Reaction SMILES: CS[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14]>[Ni].C(O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[NH2:14]
Reactant: CSCc1cc(C(F)(F)F)ccc1N
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)ccc1N
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Activated Raney nickel (500 g wet paste, ˜50μ) was added portionwise to a solution of 2-[(methylthio)methyl]-4-(trifluoromethyl)benzenamine (55.3 g, 0.25 mole) in 1 L of ethanol over 30 minutes at 25-30° C. The heterogeneous mixture was stirred vigorously for 30 minutes after the addition. The sting was stopped, and the solids were allowed to settle over one hour. The liquid was decanted from the solids and poured through filter paper. The filtrate was evaporated under reduced pressure, and the residue was taken up in dichloromethane. The organic phase was separated from a small volume of water, dried over magnesium sulfate and evaporated under reduced pressure to afford 37.6 g of the title compound as amber oil.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:40]O)[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1>C1(C)C=CC=CC=1>[N:15]([CH2:40][C:33]1[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=[C:31]([O:30][CH3:29])[CH:32]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CO)cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(CN=[N+]=[N-])cc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Diphenylphosphoryl azide (0.316 ml, 0.4 g, 1.46 ml, 1.1 eq) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (0.219 ml, 0.22 g, 1.46 mmol, 1.1 eq) were added to a stirred solution of (3-methoxy-5-nitrophenyl)methanol in 10 ml anhydrous toluene under Ar. After stirring overnight the solvent was removed in vacuo. Purification via flash chromatography yielded 0.278 g (1.34 mmol, 100% yield) of 1-(azidomethyl)-3-methoxy-5-nitrobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([CH3:21])([OH:20])[CH3:19])[N:11]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>ClC(Cl)C.C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[N:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([OH:20])([CH3:21])[CH3:19])[N:11]=1)[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: COc1ccc(Nc2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COc1ccc(N(C(=O)Nc2ccccc2Cl)c2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S)-3-[4-(4-methoxy-phenylamino)pyrimidin-2-ylamino]-2-methyl-butan-2-ol, 2, (129 mg, 0.427 mmol) in dichloroethane (3 mL) is added 2-chlorophenyl isocyanate (57 μL, 0.469 mmol) dropwise via syringe. The reaction is stirred at room temperature for 2 hours. Additional 2-chloroisocyanate (57 μL, 0.469 mmol) is added and the reaction mixture stirred at room temperature for 16 hours after which the reaction mixture is diluted with CH2Cl2 (30 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer is extracted with CH2Cl2 (20 mL) and the combined organic layers washed with water and brine and dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude residue which is purified over silica (5% to 20% Et2O/CH2Cl2 to 10% MeOH/CH2Cl2) to afford the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 13.04 (br s, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.37-7.16 (m, 4H), 7.17 (d, J=8.9 Hz, 2H), 7.02 (d, J=8.9 Hz, 2H), 5.56 (m, 2H), 4.05 (m, 1H), 3.85 (s, 3H), 1.30 (s, 3H), 1.25 (d, J=6.9 Hz, 3H), 1.23 (s, 3H); MS (ESI) m/z 456 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:27]([O:28]C)=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.CCCCCCC.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 5 (0.82 g, 1.9 mmol) in dichloromethane (15 mL) cooled at 0° C. was added a solution of boron tribromide in heptane (1.0 M, 3.8 mL, 3.8 mmol). The reaction was stirred at 25° C. for 30 min and then poured into aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combine organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH:1](=[N:17][NH:18][C:19]([NH2:21])=[NH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: N=C(N)NN
Reactant: CCCCCCCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC=NNC(=N)N

Procedure:
1 mol (170.3 g) of undecanal, 1.1 mol (150 g) of aminoguanidine hydrogen carbonate and 1 g of p-toluenesulphonic acid are mixed with 500 ml of toluene and refluxed with stirring. As soon as 2 mol of water have been separated using the water separator, the mixture is allowed to cool, concentrated by rotary evaporation and the dark red oil is taken up in 250 ml of petroleum ether 40/60°. The precipitate formed is filtered and washed again with petroleum ether. For recrystallisation the precipitate is dissolved in ethyl acetate and mixed with petroleum ether at boiling temperature (boiling range 40 to 60° C.) until beginning to turn cloudy. Fine crystals are obtained, m.p. 101° C. The structure and purity of the compound were confirmed by analytical and spectroscopic data.
Reaction SMILES: Cl[C:2]1(Cl)[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11].O>C(O)(=O)C.[Zn]>[CH2:2]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11]
Reactant: O=C1CC2(CCCCC2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2(CCCCC2)C1
Reaction time: 15 h

Procedure:
According to a literature procedure (Tetrahedron 1993, 49(36), 8159). A mixture of 1,1-dichlorospiro[3.5]nonan-2-one (5.00 g; 24.1 mmol) and zinc dust (4.74 g; 72.4 mmol) was stirred in acetic acid (60 mL) and water (30 mL) for 4 hours. The solution was then stored at −20° C. for 15 hours. The mixture was filtered through Celite®, washing with ether and hexane, and then the filtrate was washed with aqueous sodium hydroxide solution (2N; 4×100 mL). (This resulted in the precipitation of white salts, which needed to be removed by filtration). The organic phase was washed with water (30 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with hexane/ether (10:1) to give the desired product as an almost colorless oil (2.56 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][CH:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([O:26]C)=[CH:24][CH:25]=3)[CH:15]=2)[N:10]=[CH:9]1.I[CH3:33]>C(#N)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][CH:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH3:33])[CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: COc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Reactant: CI
Solvent: CC#N
Product: Cn1cc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)ccc1=O
Temperature: 90 °C

Procedure:
To a solution of rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one (0.025 g, 0.060 mmol) in 1 mL of acetonitrile in a screw capped vial was added iodomethane (0.031 g, 0.22 mmol). The vessel was sealed and heated at 90° C. for 48 h, cooled to rt, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 416.1 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.07-9.05 (m, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.94-7.92 (m, 1H), 7.75-7.72 (m, 2H), 7.45 (d, J=2.5 Hz, 1H), 7.02 (s, 1H), 6.77 (d, J=9.3 Hz, 1H), 4.68 (br s, 1H), 4.27 (s, 2H), 4.01 (br s, 1H), 3.50 (s, 3H), 2.28-1.88 (m, 5H), 1.59-1.44 (m, 3H).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.C[O:22][B:23](OC)[O:24]C>C1COCC1>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([B:23]([OH:24])[OH:22])=[CH:14][CH:15]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
n-BuLi in hexane (2.5M, 625 mmol, 250 ml) is added slowly to a mechanically stirred solution of 4-bromothioanisole (100 g, 492 mmol) in THF (1 ) below −55° C. (internal temp.). After aging at −72° C. for 1 h trimethylborate (73 ml, 1.3 eq.) is added at such a rate to keep the internal temperature below −55° C. After 0.25 h at −78° C. the solution was allowed to warm to 0° C. for 10 min. 2N HCL (500 ml) is added and the solvent is evaporated. Water (500 ml) is added and the product is extracted with EtOAc (1.5 ). The organic layer is dried over Na2SO4, concentrated and the solid is stirred in hexane (500 ml) for 2 h. Filtartion gave 61.9 g (75%) of the desired product. 1H NMR (acetone-d6, 400 MHz) δ7.80 (d, 2H), 7.22 (d, 2H), 7.15 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: ClC1C=C(CC[CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44]C(O)=O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(3,4-dimethoxy-phenyl)-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:33]([NH:35][C@H:36]([P:38](=[O:41])([OH:40])[OH:39])[CH3:37])=[O:34])[CH2:31][OH:32])=[O:28])[CH3:26])=[O:23])C)=O)C1C=CC=CC=1>>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:33]([NH:35][C@H:36]([P:38](=[O:39])([OH:41])[OH:40])[CH3:37])=[O:34])[CH2:31][OH:32])=[O:28])[CH3:26])=[O:23])[CH3:17]
Reactant: C[C@H](NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CNCC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 3(ii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-alanyl-L-seryl)amino]-ethylphosphonic acid there was obtained (1R)-1-(N-sarcosyl-L-alanyl-L-serylamino)-ethylphosphonic acid of melting point 259°-260° C. (decomposition); [α]D20 =-92.3° (c=0.5% in water).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][CH3:16])[CH:14]=2)[C:4]=1[C:17]([O:19][CH3:20])=[O:18])#[N:2].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:7]1[CH:8]=[C:3]([C:1]#[N:2])[C:4]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][CH3:16])[CH:14]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1cc(-c2c(C(=O)OC)c(C#N)cc[n+]2[O-])cn1
Product: CCn1cc(-c2nc(Cl)cc(C#N)c2C(=O)OC)cn1
Yield: 90 %

Procedure:
A solution of 4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)-3-(methoxycarbonyl)pyridine 1-oxide (210 mg, 0.771 mmol) in POCl3 (2 mL) was heated at 80° C. for 3-4 h. The mixture was concentrated and purified by flash chromatography (SiO2, 10-100% EtOAc in Hexane). The fractions were collected and the solvent was removed in vacuo to give the title compound (201 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO>[Br:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Solvent: CO
Product: COC(=O)c1nc(SC)ncc1Br

Procedure:
5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (2 g, 8.03 mmol) was stirred in MeOH (40 mL) at room temperature. To this stirred mixture was added (trimethylsilyl)diazomethane (12.04 mL, 2M, 24-09 mmol). LCMS of aliquot taken immediately after addition indicated there was still unreacted starting acid. Added more (trimethylsilyl)diazomethane (6 mL, 2 M, 12 mmol). LCMS indicated completion of reaction. The reaction was quenched adding about 0.5 mL of TFA into the crude mixture. Volatiles were removed under reduced pressure. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a EtOAc/hexanes gradient mixture (0% to 30%). Related fraction were pooled and evaporated to afford a colorless crystalline solid as the titled compound. LCMS calc.=263.94; found=264.79.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:31]=1)[C:7](=[O:30])[C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[C:9]([CH:11]([N:13]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:12])[N:10]=2.O.NN>CCO>[NH2:13][CH:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:31][N:6]2[C:7](=[O:30])[C:8]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:12]
Reactant: CC(c1nc2ccc(F)cn2c(=O)c1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1nc2ccc(F)cn2c(=O)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(1-(7-fluoro-4-oxo-3-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (0.584 g, 1.409 mmol) in EtOH (28.2 mL) was added hydrazine, monohydrate (0.684 mL, 14.09 mmol), and the mixture was stirred under reflux. After 1 h, the mixture was cooled to rt and the precipitate was filtered and washed with EtOAc (50 mL×2). The filtrate was concd under reduced pressure and then it was redissolved in EtOAc (50 mL) and water (50 mL). The aq layer was extracted with EtOAc (50 mL×1). The combined organic layers were treated with 3N aq HCl (50 mL). The separated aq layer was washed with DCM (50 mL×2) to remove organic impurities, basified to ˜pH 13 with 10N NaOH (80 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO4, filtered, and concd under reduced pressure to give 2-(1-aminoethyl)-7-fluoro-3-(pyridin-2-yl)-4H-pyrido[1,2-a]-pyrimidin-4-one as a yellow syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93-8.98 (1 H, m), 8.65-8.71 (1 H, m), 8.13 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.81-7.93 (2 H, m), 7.59 (1 H, dt, J=7.9, 1.1 Hz), 7.39 (1 H, dd, J=6.3, 4.7 Hz), 3.85 (1 H, q, J=6.7 Hz), 1.23 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=285.1 (M+1).