Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].Cl.C1COCC1>O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([N:11]([CH3:10])[CH3:21])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1cccc(C(=O)NNc2ccc(Cl)nn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-chloropyridazin-3-yl)hydrazine, 3-dimethylaminobenzoic acid, WSCD hydrochloride and THF was stirred at room temperature for 2 hours. The reaction solution was combined with water, and the precipitate was collected by filtration, washed with water and isopropyl ether to obtain N′-(6-chloropyridazin-3-yl)-3-dimethylaminobenzohydrazide. To this, ethylene glycol was added and the mixture was stirred at 160° C. for 4 hours. After allowing to cool to room temperature, followed by purification by a standard method, 6-chloro-3-(3-dimethylaminophenyl)-1,2,4-triazolo[4,3-b]pyridazine was obtained. Dat (F:274).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH2:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:69])[CH3:68].Cl>ClCCl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C@@H:2]([C:13](=[O:14])[NH:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:68])[CH3:69])[NH:1][C:16](=[O:17])[O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:5]1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)SSC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 57.3 %

Procedure:
A solution of Fmoc-Trp-OH (5 g, 11.72 mmol) and N-hydroxysuccinimide (1.35 g, 11.72 mmol) in dichloromethane (23 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 2.25 g, 11.72 mmol) was added and the reaction solution was stirred at room temperature for 5.5 hours. The reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (2.05 ml, 11.72 mmol) and H-Cys(StBu)-OH (2.45 g, 11.72 mmol) were added and the reaction solution was stirred at room temperature for 14 hours. Dichloromethane and 1 M hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with 25 wt % brine and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (5S,8R)-5-((1H-indol-3-yl)methyl)-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid (Compound SP602, Fmoc-Trp-Cys(StBu)-OH) (4.15 g, 57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[O:9][N:8]=2)=[CH:3][CH:2]=1.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccncc1)=NO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(C2=NOC3(CCNCC3)C2)ccn1

Procedure:
tert-Butyl 3-(pyridin-4-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (0.48 g, 1.5 mmol) was dissolved in dichloromethane (10 ml) and cooled, and trifluoroacetic acid (1.2 ml, 15 mmol) was added slowly. After refluxing for 2 h, the solvent was removed under vacuum and the residue was co-evaporated with in each case 30 ml of toluene and methanol. Yield: 0.74 g (100%)
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[CH3:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(C)c(F)c1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(C)c(F)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 54 %

Procedure:
3-[(3-Fluoro-4-methylbenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 65-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as white crystals (54% yield); mp 145° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.26 (3H, broad s, CH3), 3.11 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.83 (2H, s, NCH2), 6.99 (2H, m, aromatics), 7.16 (1H, m, aromatic). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.16; H, 5.44; N, 8.88.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:4][S:5]([CH3:8])(=[O:7])=[O:6].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:24]([OH:40])[CH:25]([NH:28][C:29](=[O:39])[CH:30]([NH2:38])[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:24]([OH:40])[CH:25]([NH:28][C:29](=[O:39])[CH:30]([NH:38][C:3](=[N:4][S:5]([CH3:8])(=[O:6])=[O:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:26][CH3:27]
Reactant: COC(=NS(C)(=O)=O)c1ccccc1
Reactant: CCC(NC(=O)C(N)CC1CCCCC1)C(O)c1nc2ccccc2o1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(NC(=O)C(CC1CCCCC1)NC(=NS(C)(=O)=O)c1ccccc1)C(O)c1nc2ccccc2o1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a mixture of N-(methoxy-phenyl-methylene)methansulfonamide (250 mg, 0.616 mmol) and 2-amino-3-cyclohexylpropionic acid [1-(benzoxazol-2-ylhydroxymethyl)-propyl]amide (255 mg, 0.616 mmol) in dry acetonitile (4 mL) at room temperature was added DBU (0.37 mL, 2.46 mmol), and the mixture was stirred at the same temperature overnight. After a removal of the solvent, the reaction mixture was partitioned between ethyl acetate and 1N-HCl solution, washed brine and then water. The organic extracts were dried, concentrated in vacuo, and purified by flash chromatography on silica gel (eluted with EtOAc/hexanes=3/1) to yield 250 mg of N-[1-(benzoxazol-2-yl-hydroxymethyl)propyl]-3-cyclohexyl-2-[(methanesulfonyliminophenylmethyl)amino]-propionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[C:15]([OH:21])[CH:14]=1)(=[O:12])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:31]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:20][O:31]2)=[C:15]([OH:21])[CH:14]=1)(=[O:11])=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1O
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(O)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutyl-4-vinylbenzenesulfonamide (100.8 mg, 0.280 mmol) in dichloromethane (DCM) (20 mL) stirred under nitrogen at 0° C. was added meta-chloroperoxybenzoic acid (mCPBA) (194 mg, 1.122 mmol) portionwise. The reaction mixture was stirred at 0° C. for 30 minutes, then for 72 hours at room temperature. DCM (20 mL) was added to the mixture and the organic phase washed with water (20 mL), dried using a hydrophobic frit and concentrated under a stream of nitrogen to give the crude product, 60 mg, which was used directly in the next step with no further purification. LCMS [LCMS2] Rt 1.42 min, m/z (ES−) 374 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1cccnc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccnc1N(C(=O)c1ccc(Br)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a solution of Preparation 2 (R)-tert-butyl 3-((3-methylpyridin-2-yl)amino)piperidine-1-carboxylate (33.3 g, 114 mmol) and 4-bromobenzoyl chloride (26.3 g, 120 mmol) in dry THF (300 mL) was added 1 M lithium bis(trimethylsilyl)amide (137 mL, 137 mmol) dropwise at 0° C. The reaction mixture was warmed and stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (3×1000 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound as a yellow solid (27 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:37]5[CH:36]=[N:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cnc3sc(-c4ccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c(OC)c4)nn23)cn1
Temperature: 120 °C
Yield: 13.2 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.169 mmol, 1 eq), 2-methoxy-5-pyridineboronic acid (39 mg, 0.253 mmol, 1.5 eq), EtOH (5 ml), Et3N (0.070 ml, 0.507 mmol, 3 eq) and Pd(PPh3)2Cl2 (12 mg, 0.0169 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). The solvents were removed under reduced pressure and the residue was treated with Et2O. The filtrate was evaporated and the residue was purified by HPLC to give the desired product (12 mg; 13%) as a colourless oil. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.30 min, [M+H]+ m/z 538.3; 1H NMR (300 MHz, CD3COCD3) δ 8.87 (m, 1H), 8.28 (dd, J=8.7, 2.5 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.89 (dd, J=8.7, 0.7 Hz, 1H), 4.71 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.75 (m, 2H), 3.32 (m, 2H), 1.98 (m, 2H), 1.70 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Li])CCC.[I:21]I.O>O1CCCC1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([I:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 15.0 grams (0.051 mole) of 3,5-di(trifluoromethyl)phenyl bromide in 45 mL of dry tetrahydrofuran was cooled to below -80° C., and 20.5 mL (0.051 mole) of n-butyllithium (2.5M in hexanes) was added dropwise while maintaining the reaction mixture temperature below -80° C. Upon completion of addition, an additional 50 mL of tetrahydrofuran was added to promote stirring. The reaction mixture was then stirred at -80° C. for an additional one hour. After this time a solution of 13.0 grams (0.051 mole) of iodine in 30 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature below -80° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then poured into 400 mL of water, and the mixture was extracted with one 200 mL portion of diethyl ether. The ether extract was washed with an aqueous solution of 10 % meta-sodium bisulfate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 13.1 grams of 3,5-di(trifluoromethyl)phenyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH:13]=[CH2:14].[N+](=[CH2:17])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[F:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:17][CH2:14]1
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc(C(=O)OCC)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a mixture of ethyl 4-fluoro-3-vinylbenzoate (Preparation 54, 48 g, 0.25 mol, 1 eq) and palladium (II) acetate (2.5 g, 10 mmol, 0.4 eq) in ether (300 mL) was added diazomethane in ether (1.5 mol, 6.0 eq). Then the mixture was stirred at room temperature overnight. The reaction was quenched with a solution of AcOH (75 mL) in water (100 mL). The mixture was filtrated and the filtrate was added saturated solution of sodium carbonate until pH=10. The organic phase was washed with brine (200 mL) and water (200 mL), dried over sodium sulfate and concentrated in vacuo to give title compound as brown liquid (51 g, 0.248 mol, 99.1%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:19]=2)[N:3]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:19]=2)[N:3]=1
Reactant: COc1ccc(Cn2cc(Cn3nc(I)c4c([N+](=O)[O-])cccc43)cn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2cc(Cn3nc(I)c4c(N)cccc43)cn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To 3-iodo-1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)-4-nitro-1H-indazole (1.13 g, 2.31 mmol) in EtOH/H2O (20 mL/5 mL) was added iron (1.29 g, 23.1 mmol) and NH4Cl (0.124 g, 2.31 mmol). The reaction mixture was heated to 80° C. and stirred for 3 hours. The reaction mixture was concentrated, diluted with EtOAc (30 mL) and Et3N (5 mL). The reaction mixture was heated to reflux for 30 minutes and filtered through Celite®, and the filter pad was washed with DCM/MeOH (50 mL, 10:1). The filtrate was concentrated to provide the desired product (0.89 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[Si:43]([O:33][CH2:32][CH2:31][CH2:30][C@@:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.78 mmol), imidazole (142.8 mg, 2.1 mmol), and tert-butylchlorodimethylsilane (350 mg, 2.34 mmol) in CH2Cl2 (20 mL) was stirred overnight. The mixture was washed with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude (R)-6-(3-(tert-butyldimethylsilyloxy)propyl) -6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin -3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (120 mg), which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]([O:28][CH3:29])=[C:9]([NH:11][C:12](=[O:27])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[OH:64][CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]([N:68]3[CH2:69][CH2:70][CH:65]([OH:64])[CH2:66][CH2:67]3)=[O:25])=[CH:16][CH:15]=2)=[O:27])[C:8]([O:28][CH3:29])=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(NC(=O)Nc2ccc(C(=O)O)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(NC(=O)Nc2ccc(C(=O)N3CCC(O)CC3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
85 mg (0.22 mmol) of 4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalene-1-carboxylic acid (Example 17) was dissolved in 1 mL of DMF. To this clear solution was added sequentially, 92 mg (0.294 mmol) of TBTU, and 82 microL (0.59 mmol) of triethylamine. The clear yellow solution was stirred for 5 min, then 33 mg (0.33 mmol) of 4-hydroxypiperidine was added. The reaction was stirred overnight, then concentrated in vacuo. The resulting amber oil was extracted with EtOAc and water, brine, and then dried over magnesium sulfate. Concentration in vacuo provided an amber oil which was purified on silica gel, eluting with with 33% EtOAc-hexane to provide 57 mg (54%) of the title compound as a pale white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=2)[N:3]=1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CC(C)O
Solvent: CCCCO
Product: CCC(CC)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.13 ml of 4-(trifluoromethoxy)-benzenamine in place of the benzylamine. The reaction medium is agitated at ambient temperature then taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for four hours at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:11][OH:12])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][N:11]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: C=Cc1ccccc1
Reactant: Cn1nc(Cl)cc(C=NO)c1=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cn1nc(Cl)cc(C2=NOC(c3ccccc3)C2)c1=O
Temperature: 25 °C
Yield: 54 %

Procedure:
To an ice cold mixture of 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde oxime (300 mg, 1.599 mmol, Preparation #31) and styrene (250 mg, 2.399 mmol, Aldrich) in DCM (15 mL) was added 5% aqueous sodium hypochlorite solution (5 mL, 1.599 mmol). The reaction mixture was warmed to RT over 1 h. The reaction mixture was diluted with dichloromethane (15 mL) and washed with water (10 mL). The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The residue obtained was purified by solvent washings with hexane to afford 6-chloro-2-methyl-4-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyridazin-3(2H)-one 0.250 g (54%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.816 (s, 1H), 7.400-7.327 (m, 5H), 5.807-5.758 (m, 1H) 4.001-3.927 (m, 1H) 3.773 (s, 3H) 3.627-3.558 (m, 1H); MS m/z: 312.2 (M+H)+;
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[O:12]1[C:8]([C:6]2[CH:7]=[C:2]([N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[O:13])[CH:3]=[N:4][CH:5]=2)=[CH:9][N:10]=[CH:11]1
Reactant: Oc1ccccn1
Reactant: Brc1cncc(-c2cnco2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1ccccn1-c1cncc(-c2cnco2)c1
Temperature: 120 °C

Procedure:
To an oven-dried sealed tube containing a solution of 3-bromo-5-oxazol-5-yl-pyridine VIII-a (1.00 g, 4.44 mol) in degassed 1,4-dioxane (20 mL) was added 2-hydroxypyridine (507 mg, 5.33 mmol), K2CO3 (1.23 g, 1.78 mmol), Cut (169 mg, 0.899 mmol) and rac-trans-N,N′-dimethylcyclohexane diamine (280 μL, 1.78 mmol). The tube was flushed with argon and sealed then heated in an oil bath at 120° C. overnight. After cooling to RT, the mixture was filtered and the filter cake washed with 1,4-dioxane. The mixture was evaporated and the residue purified by column chromatography (2% to 5% EtOH in DCM) to give the desired product VIII-b as a beige solid (752 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.80 (dd, J=6.8, 1.6 Hz, 1H), 7.57 (ddd, J=8.8, 6.6, 1.9 Hz, 1H), 6.54 (d, J=9.2 Hz, 1H), 6.39 (t, J=6.7 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].[SH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16]>>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][S:12][CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: C=CCc1cccc(C)c1O
Reactant: OCC(O)CS
Product: Cc1cccc(CCCSCC(O)CO)c1O

Procedure:
In the same manner as in Synthetic example 1, 2-allyl-6-methylphenol and 3-mercapto-1,2-propanediol were reacted to obtain 2-[3-(2,3-dihydroxypropylthio)propyl]-6-methylphenol.