Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]2[CH:38]=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:35]=[N:34][C:33]([NH:36][C:37]4[CH:38]=[N:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[CH:32][CH:31]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: FC(F)(F)c1ccc(Nc2ccc(Br)cn2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (1.56 g, 4.1 mmol) and (5-Bromo-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (1.28 g, 4.0 mmol) were dissolved in DME (8 mL) in a pressure vessel, and to the solution was added PdCl2dppf (100 mg, 0.12 mmol) and Na2CO3 (2.0M, 4.0 mL, 8.1 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and stirred at 80° C. for 18 hours. The mixture was partitioned between EtOAc and saturated aqueous NH4Cl, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (10-50%) to obtain the target compound as a solid: 1H NMR (400 MHz, DMSO-d6) ppm 1.25 (br. s., 2 H) 1.42 (s, 9 H) 1.52 (qd, J=12.63, 4.55 Hz, 2 H) 1.77 (m, 2 H) 2.66-2.76 (m, 1 H) 4.09 (m, 2 H) 7.03 (d, J=8.59 Hz, 1 H) 7.34 (d, J=8.34 Hz, 2 H) 7.60 (d, J=8.08 Hz, 2 H) 7.79 (d, J=8.84 Hz, 1 H) 7.99 (dd, J=8.72, 2.65 Hz, 1 H) 8.56 (d, J=2.53 Hz, 1 H) 8.91 (d, J=2.53 Hz, 1 H) 9.87 (s, 1 H); MS (M+H)+ 499.3.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH:3]([CH:22]1[CH2:27][CH2:26][N:25](C(OCC2C=CC=CC=2)=O)[CH2:24][CH2:23]1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.C(O)C>O1CCCC1.[Pd]>[F:39][C:2]([F:1])([F:38])[CH:3]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(C1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(C1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.5 %

Procedure:
Ten percent palladium/carbon (15.0 mg) was suspended in tetrahydrofuran (1.0 mL). To this, a tetrahydrofuran solution (2.0 mL) of N-{3-[2,2,2-trifluoro-1-(1-benzyloxycarbonylpiperidin-4-yl)ethoxy]quinoxalin-2-yl}propane-1-sulfonamide (150 mg, 0.245 mmol) was added and the mixture was stirred under hydrogen stream at room temperature for 3 days. To the reaction mixture, 10% palladium/carbon (15.0 mg) and ethanol (2.0 mL) were added and the mixture was stirred under hydrogen stream at room temperature for 8 hours. The reaction mixture was filtered through Celite and the solvent was evaporated off under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to give Compound 327 (38.7 mg, yield: 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](P(=O)=O)[C:3]=1[OH:11].[P:12](C1C(C)=CC=CC=1O)(=[O:14])=[O:13]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][P:12](=[O:14])=[O:13]
Reactant: Cc1cccc(P(=O)=O)c1O
Reactant: Cc1cccc(O)c1P(=O)=O
Product: Cc1ccccc1OP(=O)=O

Procedure:
The mixing ratio of 2-methyl-6-phosphophenol and its positional isomer, 2-phospho-3-methyl phenol, was 5:3. The mixing ratio was obtained from the integral values of the spectrum of the two compounds using 1H-NMR.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CNCC1CCNC1
Solvent: CC#N
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To 0.80 g (2.8 mmol) of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 0.43 g (2.8 mmol) of 1,8-diazobicyclo [5.4.0]undec-7-ene, was added 0.35 g (3.1 mmol) of N-methyl-3-pyrrolidinemethanamine. The mixture was refluxed for one hour and stirred overnight. The solids were filtered and washed with acetonitrile: ether (1:6) to give 0.81 g of the title compound, mp 265°-267° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=1[CH3:38]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=2[CH3:38])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Cc1ccc([N+](=O)[O-])cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9) (1.80 g, 8.07 mmol) in THF (30 ml) at ambient temperature under nitrogen was added 1.0 M lithium bis(trimethylsilyl)amide in THF (8 mL, 8.00 mmol) and stirred for 20 min. To the solution was added a solution of 2-(bromomethyl)-1-methyl-4-nitrobenzene (1.81 g, 7.87 mmol) in THF (20 ml) and stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (150 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The phases were separated and the aqueous phase washed with ethyl acetate (25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a yellow oil (3.5 g). The residue was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (2.1 g); LCMS (System 4) MH+=373, tRET=2.60 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][NH:16][C:17](=O)[C:18]=3[N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].P(Cl)(Cl)([Cl:23])=O.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[Cl:23][C:17]1[C:18]2[N:19]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH3:1])[CH:3]=3)[CH:11]=[CH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1C
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1C
Yield: 74.5 %

Procedure:
To a suspension of 6-(3-methyl-4-methoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)one (1.41 mmole) in toluene (80 ml) was added phosphorus oxychloride (4.23 mmole) and 2,6-lutidine (4.23 mmole). The reaction mixture was refluxed for 16 hours until a black solution was obtained. After evaporation to dryness, the residue was redissolved in ethyl acetate and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography (the mobile phase being a ethylacetate/hexane mixture in a ratio gradually ranging from 2:8 to 3:7), resulting in the pure title compound (300 mg, yield 74%) which was characterized by its mass spectrum as follows: MS (m/z): 287 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])nn1CC(=O)OC(C)(C)C

Procedure:
To a stirring mixture of 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (3.5 gm, 20.5 mmol) dissolved in 150 ml of acetone was added cesium carbonate (8.01 gm, 24.6 mmol) followed by the addition of tert-butyl bromoacetate (3.61 ml). After 5 hours the solids were filtered and the mixture chromatographed on silica gel using 10% ethyl acetate/hexanes as the eluent to obtain 4.16 gm of pure title product. ESI M+1=286.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH2:24])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]([O-])=O.[Na+]>CC(O)=O.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][N:17]4[C:18]5[CH:23]=[CH:22][N:21]=[CH:20][C:19]=5[N:24]=[N:25]4)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cnccc1NCc1nnc2ccc(-c3ccccc3)nn12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-c2ccc3nnc(Cn4nnc5cnccc54)n3n2)cc1
Reaction time: 1 h

Procedure:
To a solution of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0640 g, 0.202 mmol) in HOAc (5 mL) was added sodium nitrite (0.0153 g, 0.222 mmol) in water (2 mL). Stirred for 1 h. Concentrated. Took up in DMSO and purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate and removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=329.2 [M+1]+. Calc'd for C17H12N8: 328.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.O.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1
Reactant: Cc1cc(O)nc(SCc2c(Cl)cccc2[N+](=O)[O-])n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(N)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
To a suspension of the 2-{[(2-chloro-6-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.0 g, 3.20 mmol) in ethanol (30 mL), a water mixture of iron powder (1.07 g, 19.24 mmol) and equivalent NH4Cl (0.741 g, 9.6 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered over Celite and washed with methanol, and the solvent was evaporated. The precipitated solid was filtered off and washed with ether to provide the titled amine (0.316 g, 35% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.42 (s, 2H), 6.01 (bs, 1H), 6.60 (m, 2H), 6.95 (t, J=8.0, 16.1 Hz, 1H); M+ 282.06.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Li+].CC([N-]C(C)C)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].CCCCCC>C1COCC1>[C:1]([C:3]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 39.7 %

Procedure:
A solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.75 g, 3.57 mmol) in THF (25.0 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.8 M in THF, 6.0 mL, 5.35 mmol) and stirred at the same temperature (−78° C.) for 45 min followed by addition of ethyl chloroformate (0.46 g, 4.28 mmol). The temperature of the reaction was slowly raised to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 7% EtOAc:hexane to obtain the product as an orange viscous liquid (0.4 g, 48% yield). MS: 283.14 [M+H]+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([OH:32])[C:24]([OH:33])=[C:23]2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:18][CH:17]=1.[CH2:39]([O:46][CH2:47][CH2:48]O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:39]([O:46][CH2:47][CH2:48][O:33][C:24]1[C:25]([OH:32])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[C:23]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(F)cc1
Reactant: OCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c(OCCOCc2ccccc2)c(C(=O)OCC)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
Diisopropyl azodicarboxylate (317 μL, 1.63 mmol) was added to a solution of diethyl 1-(4-fluorophenyl)-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylate (UL2-003) (500 mg, 1.48 mmol), 2-(benzyloxy)ethanol (232 μL, 1.63 mmol) and triphenylphosphine (428 mg, 1.63 mmol) in DCM (5 ml), at 0° C. The reaction mixture was allowed to warm to RT and stirred for 1 h. The reaction was washed with water (5 mL) and the phases separated using a phase separation cartridge, the organic was concentrated in vacuo to afford a yellow oil. The residue was purified by silica gel chromatography (80 g, 0-25% EtOAc in isohexane) to afford diethyl 3-(2-(benzyloxy)ethoxy)-1-(4-fluorophenyl)-4-hydroxy-1H-pyrrole-2,5-dicarboxylate (22) (122 mg, 17%) as a yellow oil: m/z 472 (M+H)+ (ES+); 470 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.70 (s, 1H), 7.38-7.26 (m, 5H), 7.24-7.12 (m, 4H), 4.54 (s, 2H), 4.27-4.16 (m, 2H), 4.09-3.89 (m, 4H), 3.78-3.71 (m, 2H), 1.01-0.94 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH:6]2C.C[OH:17]>[Ni].C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:17])[CH2:6]2
Reactant: CC1C(=S)Nc2ccc(C(F)(F)F)cc21
Reactant: CO
Agent: [Ni]
Solvent: ClCCl
Product: O=C1Cc2cc(C(F)(F)F)ccc2N1

Procedure:
A mixture of 4.0 g. of 5-trifluoromethyl-3-methylthio-oxindole, 20 g. of Raney Nickel and 100 ml. of methanol is refluxed for 4 days, cooled, treated with methylene chloride, filtered to remove the Raney Nickel and the filtrate concentrated in vacuo to obtain 5-trifluoromethyl-oxindole, m.p. 188°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:37]/[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2csc(N3CCOCC3)n2)c(OC)c1)OCC
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a mixture of 3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), tetraethyl methylenediphosphonate (0.25 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.36 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 93-94° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH3:8][C:9]([S:14][CH3:15])([CH3:13])[C:10](Cl)=[O:11].Cl>C(=O)([O-])[O-].[K+].[K+]>[CH3:8][C:9]([S:14][CH3:15])([CH3:13])[C:10]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4])=[O:11]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CSC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSC(C)(C)C(=O)N[C@@H](CS)C(=O)O
Temperature: 0 °C
Yield: 89.2 %

Procedure:
L-Cysteine (7.1 g) is dissolved in 88 ml of 2 M potassium carbonate and 7.5 g of 2-methyl-2-(methylthio)propanoyl chloride [b.p. 78° C. (37 mmHg)] is added dropwise while stirring under a nitrogen atmosphere at 0° C. After the addition, the mixture is stirred overnight at room temperature. The mixture is acidified with hydrochloric acid and the obtained crystals are separated by filtration and dried to yield 10.4 g (89.8%) of the titled compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][C:19]=1[CH3:20])[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:18][C:19]=1[CH3:20])[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A solution of KOH (141 mg, 2.52 mmol) in ethanol (2 mL) was added to a solution 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.1 g, 2.29 mmol) in ethanol (10 mL) and methylene chloride (4 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in water. Ethyl acetate was added and the organic layer was washed with 0.5 M HCl, water, brine and dried. After filtration and concentration under reduced pressure gave crude 2-(6-[N,N-bis(tert-butoxycarbonyl)-amino]-4-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>C(O)(C)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cccc(Cl)c1
Yield: 76 %

Procedure:
Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 40 ml of isopropanol for 8 hours, 2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 121° C is obtained. Yield: 76% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:18]=[CH:17][N:16]=[C:15](C=O)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BH4-].[Na+].C[OH:24]>>[OH:24][C:15]1[CH:14]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]=[CH:17][N:16]=1
Reactant: CO
Reactant: COc1cc(-c2cc(C=O)ncn2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(-c2cc(O)ncn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3,4,5-Trimethoxyphenyl)pyrimidine-4-carboaldehyde (364 mg) was dissolved in methanol (50 mL), and to the solution sodium borohydride (25 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([Br:13])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.C([Li])CCC>O>[Br:13][C:5]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:2][S:3][CH:4]=1
Reactant: CCCCCCc1c(Br)sc(Br)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1cscc1Br
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Compound 51 (70 g, 0.173 mol) was mixed with dry THF (400 mL). To this mixture, n-butyllithium (138 mL, 2.5M in hexane, 0.345 mol) was added dropwise at −78° C. under argon. The resulting mixture was stirred for 10 minutes, then water (30 mL) was added to quench the reaction. The THF was evaporated and the organic was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), water (70 mL) and dried over MgSO4. After evaporation of the solvent, the resulting crude product was purified by vacuum distillation (72-74° C. at 0.17 mbar) to yield 52 (35.3 g, 82.6% yield). GC/MS: 246 g/mol (M-1). 1H NMR (CD2Cl2): δ 7.22 (s, 1H), 6.96 (s, 1H), 2.57 (t, 2H), 1.61 (m, 2H), 1.32 (m, 6H), 0.88 (t, 3H). 13C NMR: 141.92, 122.87, 120.95, 112.89, 31.88, 30.07, 29.53, 29.20, 22.88, 14.14.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>>[CH:1](=[N:13][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)N
Product: CC(C)(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
530.85 g (5.00 mol) of benzaldehyde was placed into a 2000 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel. Subsequently, 367.50 g (5.02 mol) of t-butyl amine was dropped into the flask in a water bath, while maintaining the solution temperature at 25° C. After the completion of the dropping, the mixture was reacted while stirring at 25° C. for 15 hours. After the completion of the reaction, the reaction mixture was subjected to separation, and the organic layer obtained was refluxed under reduced pressure (25° C., 13.3 Pa) for 2 hours, to provide 788.91 g of N-benzylidene-t-butyl amine. (Isolation yield; 98%)