Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][O:15][C:14](=[O:16])[C@@H:13]2[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
In the same manner as described in Reference Example 1-2 but using 500 mg of trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline and 383 mg of p-nitrobenzyl bromide, trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline p-nitrobenzyl ester was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:18]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][Br:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CBr)c1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of (3-tert-butyldimethylsilyloxymethylphenyl)methanol (528 mg) and tetrabromomethane (694 mg) in dichloromethane (10 mL) was added triphenylphosphine (549 mg) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (660 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Yield: 63.4 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.38 g, 17.40 mmol), 5-bromo-2-nitro-pyridine (3.52 g, 17.40 mmol), Cs2CO3 (11.34 g, 34.8 mmol), and Pd(PPh3)2Cl2 (1.27 g, 1.74 mmol) in dioxane (50 mL) was stirred at 85° C. under N2 atmosphere overnight. TLC showed a complete reaction. The solution was poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel (petroleum ether:ethyl acetate, 2:1 eluent) afforded the desired product as yellow solid (3.37 g, 64%). 1H NMR (300 MHz, CDCl3): δ 8.63 (d, J=2.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.93 (dd, J=8.4, 2.4 Hz, 1H), 6.31 (s, 1H), 4.17-4.14 (m, 2H), 3.68 (t, J=5.7 Hz, 1H), 2.57-2.54 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:15]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccccc1-c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1ccccc1-c1ccccc1
Yield: 70.1 %

Procedure:
Under an atmosphere of argon, 2,2′-dibromobiphenyl (9.5 g, 30 mmole), phenylboronic acid (3.7 g, 30 mmole) and tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.87 mmole, 3% Pd) were dissolved into toluene (75 ml). To the obtained solution, an aqueous solution of sodium carbonate (9.7 g, 92 mmole, 3 eq/46 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a dark yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and a colorless oil (6.5 g, 70%) was obtained.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 2.0 g (0.0092 mol) of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone. The resulting solution was added with 1.3 g (0.0123 mol) of anhydrous sodium carbonate and 1.6 g (0.0088 mol) of 4-t-butylbenzyl chloride, and then heated under stirring at 80°~110° C. for two hours. The resulting mixture was cooled to room temperature, and then added with 100 ml of water and stirred. The solid thus precipitated was filtered off, washed with water, dried, and recrystallized from ethanol to obtain 2.9 g of 2 -t-butyl-5-(p-t-butylbenzylthio)-4-chloro-3(2H)-pyridazinone.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:8]([CH2:10][CH3:11])=O)[CH3:7]>>[CH3:7][CH:6]=[C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][CH3:11]
Reactant: CCC(=O)CC
Reactant: C1CCNC1
Product: CC=C(CC)N1CCCC1
Reaction time: 170 h
Yield: 69.3 %

Procedure:
584 g of pyrrolidine and 126.7 g of diethyl ketone are placed into a pear-shaped flask fitted with a Soxhlet attachment. In the Soxhlet there is contained 200 g of molecular sieve A4. The mixture is boiled for 170 hours at 150° C. bath temperature, and subsequently concentrated in a rotary evaporator. The residue obtained is distilled in a water-jet vacuum. There is obtained 142 g (70% of theory) of N-(3-pent-2-enyl)-pyrrolidine, b.p. 80° C./ 18 Torr. With the use of excess diethyl ketone, it is possible to attain a yield of 94%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a flame dried round bottom flask 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 2.0 g, 7.93 mmol) was dissolved in anhydrous THF (50 ml) and 3,4,5,6,-tetrahydro-2(H)-pyrimidinone (DMPU) (11.5 ml, 95.16 mmol) was added, under argon atmosphere. The reaction was then cooled to -20° C. and a solution of t-butyl magnesium chloride (16 ml, 31.7 mmol) (2M in Et2O) was added dropwise and stirred at -20° C. for 2 h and at ambient temperature for 1 h, under argon atmosphere. The reaction was quenched at 0° C. with saturated ammonium chloride solution (20 ml) and extracted with EtOAc (2×50 ml). The combined extract was washed with water (20 ml), brine (20 ml) and dried over MgSO4. The solvent was evaporated under reduced pressure to afford a yellow oil. To this yellow oil were added MeOH (50 ml) and p-tolylsulfonic acid (100 mg). The resultant reaction solution was heated in an oil bath (60° C.) for 3 h. The reaction was cooled and quenched with water (20 ml), extracted with EtOAc (2×50 ml). The combined extract was washed with saturated NaHCO3 (20 ml), water (20 ml), brine (20 ml), and dried over MgSO4. The solvent was concentrated in vacuo and the title compound was obtained as a colorless oil after purification by flash chromatography (silica, hexane).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCC(CO)CCCCCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(CCCCCCC)COP(=O)(Cl)Cl
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-heptylundecanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was. removed by filtering to obtain 1003.9 grams of a toluene solution of (2-heptylundecyl)dichlorophosphate (34.7% in concentration).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1.O>[OH:2][CH2:1][CH2:3][NH:4][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=1)(=[O:22])=[O:21]
Reactant: NCCO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 3.5 mL (3.54 g, 58 mmol) of ethanolamine in 20 mL of THF and 5 mL of water, was added 10.7 mL of triethylamine. After cooling in an ice bath, 10.53 g (51 mmol) of para-methoxybenzenesulfonyl chloride was slowly added over ten minutes. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and ethyl acetate and water added. The organic layer was separated, washed with 5% KHSO4 and brine, dried over sodium sulfate, filtered and stripped to afford 10.3 g of the desired N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide, m/e=238 (M+Li).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:14][C:15]([OH:17])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18]C(N)=O>>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[C:9](=[O:10])[NH:18][C:15](=[O:17])[CH2:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Reactant: NC(N)=O
Product: CC(C)(C)c1ccc2c(c1)CC(=O)NC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
4-tert-Butyl-2-carboxymethyl-benzoic acid (90 mg, 0.38 mmol) and urea (45 mg, 0.75 mmol) were grinded and mixed in a round bottle flask, then placed into an oil bath, preheated to 145° C. The flask is kept at this temperature for 1 hour before it is cooled to room temperature. Chromatography of the residue afforded the title compound (45 mg, 55%). MS (ESI): 216.1 (M−1)−1.
Reaction SMILES: [CH2:1]([C:3]([N:10]=C=O)([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6])[CH3:2].C(#N)CC.C([Mg]Br)C=C.CCOCC.[NH4+].[Cl-]>CCOCC>[CH2:1]([C:3]([NH2:10])([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6])[CH3:2]
Reactant: C=CCC(CC)(CC=C)N=C=O
Agent: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCC#N
Product: C=CCC(N)(CC)CC=C
Yield: 34 %

Procedure:
1-Ethyl-1-(2-propenyl)-3-butenyl isocyanate: A solution of propionitrile (14.5 g, 264 mmol) in dry Et2O (40 mL) was added dropwise to 1.0M allyl magnesium bromide/Et2O (880 mL). The reaction mixture was mechanically stirred at reflux for 2 h, after which time it was cooled to 0°. A saturated aqueous solution of NH4Cl (320 mL) was added cautiously to the cooled reaction mixture. The organic phase was separated, dried (MgSO4), cooled to 0° and then mixed at the same temperature with 1M HCl/Et2O (200 mL). The resulting solid was collected and dried under reduced pressure (ca 27 g). The latter material dissolved in CH2Cl2 (200 mL). The solution was washed with a 10% (w/v) aqueous solution of Na2CO3 (2×) and then brine, dried (MgSO4) and concentrated to dryness to afford a yellow oil. The oil was distilled (82°-85°/20 Torr) to give 1-ethyl-1-(2-propenyl)-3-butenylamine as a colorless liquid (11.6 g, 34%); 1H NMR(CDCl3), 400 MHz) δ 0.89 (t, J=7 Hz, 3H), 1.39 (q, J=7 Hz, 2H), 2.11 (d, J=7 Hz, 2H), 5.06-5.14 (m, 4H), 5.80-5.89 (m, 2H ).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:10]([Cl:11])=[C:9]([C:12]([OH:14])=O)[S:8][N:7]=1>CN(C)C=O>[Cl:5][C:6]1[C:10]([Cl:11])=[C:9]([C:12]([Cl:3])=[O:14])[S:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1snc(Cl)c1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1snc(Cl)c1Cl
Temperature: 25 °C
Yield: 125.1 %

Procedure:
At room temperature, 146 g (1.23 mol) of thionyl chloride are added dropwise with stirring over a period of 5 minutes to 8.92 g (0.045 mol) of 3,4-dichloro-isothiazole-5-carboxylic acid. Four drops of dimethylformamide are then added and the reaction mixture is heated under reflux for one hour. The reaction mixture is subsequently cooled to room temperature and concentrated under reduced pressure. In this manner, 12.19 g of 3,4-dichloro-isothiazole-5-carbonyl chloride are obtained in the form of an orange oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+].[OH-].[Na+].[OH-].[Na+].O.CO.Cl>CO.O>[C:18]1([CH2:17][NH:6][C@@H:5]([C:4]([OH:3])=[O:9])[CH2:7][OH:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](N)CO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H](CO)NCc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
As per the procedures of WO2005058245, a mixture of D-serine methyl ester hydrochloride (98.84 g, 635.3 mmol) in MeOH (280 mL) was cooled to 10° C. To the mixture was slowly added triethylamine (88.5 mL, 635.0 mmol). The mixture was warmed to room temperature and the resulting solution was cooled to 10° C. To the solution was added benzaldehyde (64 mL, 630.2 mmol), and the solution was stirred for 30 min. To the solution was added sodium borohydride (24.03 g, 635.2 mmol) portionwise over 30 min, and the mixture was stirred for a further 30 min. In a separate flask, MeOH (114 mL) was added to water (170 mL), and to this solution was added a solution of NaOH (77.25 g, 1931 mmol) in water (155 mL). The solution was cooled to 15° C., and the reductive amination mixture was slowly added to the NaOH-water-MeOH solution over 15 min. The solution was stirred and warmed to room temperature over 30 min, and water (170 mL) was added, followed by sufficient 6 N aqueous HCl to adjust the pH to 9.5. The solution was washed with EtOAc (2×60 mL), and sufficient 6 N aqueous HCl was added to adjust the pH to 6.5. The mixture was cooled to 0° C. and held overnight. The resulting solid was collected by vacuum filtration and washed with water (2×200 mL) followed by heptane (2×200 mL). The white solid was dried at 40° C. under high vacuum for 3 days to afford N-(phenylmethyl)-D-serine (79.51 g, 64%). LCMS: (M+H)+: 196.1.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([CH3:13])[CH3:12])C1C=CC=CC=1>[Pd].C(O)C>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]([NH2:10])([CH3:12])[CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C(C)(C)NC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C(C)(C)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Into a round bottom flask, [1-(3-methoxy-phenyl)-1-methyl-ethyl]-carbamic acid benzyl ester (10.0 g, 33.4 mmol), ethanol (200 mL), and 10% Pd/C (1.20 g) were added. The mixture was evacuated under vacuum and charged with hydrogen via balloon (3 times). The reaction was stirred at room temperature overnight under a hydrogen atmosphere via a balloon. The solid was filtered and washed with Ethanol. The solvent was removed under vacuum to give 1-(3-Methoxy-phenyl)-1-methyl-ethylamine as a viscous oil 1-(3-methoxy-phenyl)-1-methyl-ethylamine (4.80 g, 0.0290 mol;) was treated with DMF and N,N-diisopropylethylamine (7.59 mL, 0.0436 mol) acetic acid, bromo-, 1,1-dimethylethyl ester (6.23 g, 0.0320 mol), respectively. The reaction mixture was stirred at 50° C. for 24 hours. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The product was isolate via column chromatography with hexane and EtOAc as eluant (0 to 50%) to afford [1-(3-methoxy-phenyl)-1-methyl-ethylamino]-acetic acid tert-butyl ester as a white solid (5.86 g, 63%). 1H-NMR (CDCl3, 400 MHz): δ 7.22-7.28 (m, 1H), 6.97-7.02 (m, 2H), 6.75-6.80 (m, 1H), 3.80 (s, 3H), 3.06 (s, 2H), 1.44 (s, 6H), 1.42 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[H][H].[CH:10](=[C:17]([CH2:21][OH:22])[C:18]([OH:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.[C].[Pd]>[OH:22][CH2:21][CH:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)C(=Cc1ccccc1)CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C(CO)Cc1ccccc1
Yield: 65.7 %

Procedure:
The product (107.8 g) in Reference Example 3, namely 2-benzylidene-3-hydroxypropionic acid, is dissolved in methanol (500 ml), followed by addition of triethylamine (100 ml; 717 mmol) and 5% palladium-carbon (5.00 g; water content of 52.7%) for catalytic reduction in a hydrogen atmosphere for 50 hours. The reaction solution is filtered through Celite to remove the palladium-carbon. The resulting filtrate is subjected to HPLC analysis, indicating that the filtrate contains the title compound (71.0 g; 394 mmol) (at a yield of 65.7% (on a benzaldehyde basis)). The filtrate is concentrated under reduced pressure, and the resulting residue is dissolved in ethyl acetate (600 ml), followed by addition of water (600 ml) and 37% hydrochloric acid (150 ml) and subsequent agitation, to extract the resulting organic phase. The organic phase is washed with an aqueous mixture solution of water (240 ml) and 37% hydrochloric acid and then with saturated saline (300 ml), and dried over anhydrous sodium sulfate. By filtering off the resulting dried matter, the solution is concentrated under reduced pressure, to give a crude product of the title compound. The crude product is dissolved in ethyl acetate (150 ml) , followed by addition of hexane (450 ml), and the resulting mixture is gradually cooled from 60° C. to 5° C., to precipitate crystal, which is then filtered and dried to recover the title compound (48.45 g at a purity of 96.5%; 295.5 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:18][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1
Reactant: NCC1CCCO1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])ccc1NCC1CCCO1
Temperature: 0 °C

Procedure:
1-Fluoro-2-methyl-4-nitrobenzene (11 g, 70.9 mmoles) is refluxed for 5 hours with 41.5 g (0.41 moles) of tetrahydrofurfurylamine. After that, the reaction product is poured onto 400 g of ice/water and the solid obtained is filtered off. Recrystallization from ethanol/water results in a yellow, grainy dye with a melting point of 56°-58° C.
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[CH:22]1(B(O)O)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]1([C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH2:24][CH2:23]1
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a stirred solution of compound (iii) (3 g, 10.9 mmol) in toluene (75 mL) was added a solution of sodium carbonate (2.29 g, 21.8 mmol) in water (15 mL) and the mixture was purged with nitrogen for 10 min. Cyclopropyl boronic acid (1.4 g, 16.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) were added and the reaction mixture was heated at reflux for 6 h (monitored by TLC). The reaction was then cooled to RT and diluted with EtOAc. The aqueous and organic layers were separated. Concentration of the solvent gave the crude product which was purified by column chromatography to give 5-cyclopropyl-2,4-dinitrobenzaldehyde (iv) (2 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].O.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(F)c(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a cooled (−5° C.) solution of 3,4,5-trifluorobenzaldehyde (7.0 g, 43.75 mmol) in a mixture (50 ml, 9:1) of THF and water NaBH4 (1.662 g, 43.75 mmol) was slowly added in portions over a period of 30 min. The reaction mixture was allowed to attain room temperature over a period of 2 h and carefully poured into ice-cold dil HCl (200 ml, IN). The oily layer was extracted into CH2Cl2 (250 ml) and the organic layer washed with water (200 ml), dried (MgSO4) and evaporated. The crude product (7.08 g, quantitative) obtained was taken forward without further purification.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([O:25]C)[C:12](=[O:24])[N:13]([CH3:23])[C:14]=3[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:9]2=[O:27])=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:25][C:11]1[C:12](=[O:24])[N:13]([CH3:23])[C:14]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])=[C:15]2[C:10]=1[C:9](=[O:27])[NH:8][CH2:17][CH2:16]2
Reactant: COc1ccc(CN2CCc3c(c(OC)c(=O)n(C)c3C(=O)N(C)C)C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)NCC2
Temperature: 110 °C

Procedure:
A solution of 6-(4-methoxybenzyl)-4-methoxy-N,N, 2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.18 g, 0.45 mmol) in toluene (about 3 mL) was treated with p-toluene sulfonic acid (0.34 g, 1.8 mmol). The mixture was heated to 110° C. for 4 hours, then cooled and concentrated under vacuum. The residue was partitioned between water and EtOAc, the aqueous layer concentrated, and the residue purified by reverse phase chromatography to give the title product.