Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[N:36]([CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])=[N+:37]=[N-:38].C(N(C(C)C)C(C)C)C>CN(C=O)C.O.[Cu]I>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:38]=[N:37][N:36]([CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:17]=3)=[CH:14][C:13]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]4)=[N:20][CH:19]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cn(C[Si](C)(C)C)nn3)c2s1

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-ethynyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (115 mg, 0.233 mmol), (azidomethyl)trimethylsilane (150 mg, 1.169 mmol), Copper(I)Iodide (8.9 mg, 0.0467 mmol), N-ethyl-N-isopropylpropan-2-amine (30.1 mg, 0.233 mmol) in 2 mL of DMF were stirred at rt for 24 hours. The reaction was diluted with 10 mL of water, filtered and washed with water then dried to yield the desired compound as a beige solid, 95 mg, 65.5 yield %.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Cc2ccc(NC(=O)Nc3cccc([N+](=O)[O-])c3)cc2N1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cccc(NC(=O)Nc2ccc3c(c2)NC(=O)C3)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-(3-nitro-phenyl)-3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-urea (0.23 g, 0.74 mmol) is dissolved in a mixture of DMF-MeOH. To this solution is added Pd/C (10%, wet, 0.10 g). The reaction is placed under a hydrogen balloon and stirred for 20 hours at room temperature. The catalyst is removed and the solvent is evaporated to give 1-(3-amino-phenyl)-3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-urea. LC-MS: 283.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: OC1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.1 g, 3.9 mmol) in 1,2-dichloroethane (20 mL) was added piperidin-4-ol (5.4 mmol), and AcOH (3.9 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (4.6 mmol) was added and the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude reaction was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (0.6 g). MS (Q1) 369 (M)+
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16]([N:26]([CH3:25])[CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1Cl
Reactant: CNCCOc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1N(C)CCOc1ccccc1
Temperature: 70 °C
Yield: 51.7 %

Procedure:
To ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-chlorothiazole-4-carboxylate (7D) (0.15 g, 0.41 mmol) and methyl-(2-phenoxy-ethyl)-amine (1.24 g, 8.1 mmol) was added DMF (10 mL). The reaction mixture was allowed to heat to 70° C. for 48 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 80% EtOAc in hexanes to provide 0.102 g (52%) of the desired product ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20A): LC/MS (APCI): m/z 482.1 (M+H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10](/[CH:15]=[CH:16]/[C:17](OC)=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC.C(OCC)(=O)C>[C:1]1([CH2:7][O:8][C:9]2[C:10]([CH2:15][CH2:16][CH2:17][OH:18])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)/C=C/c1ncccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: OCCCc1ncccc1OCc1ccccc1
Yield: 12.9 %

Procedure:
A solution of (E)-methyl 3-[3-(phenylmethoxy)-2-pyridinyl]-2-propenoate (12.0 g) in dry ether (100 ml) was added to a stirred suspension of lithium aluminium hydride (5 g) in ether (200 ml) under nitrogen. The mixture was heated at reflux overnight and treated successively with water (5 ml), 2N sodium hydroxide (10 ml) and water (100 ml). Ethyl acetate (250 ml) was added and the mixture was filtered. The solution was washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with cyclohexane/ethyl acetate/triethylamine (80:20:1) followed by ethyl acetate/triethylamine (99:1) to give the title compound as a pale orange oil (1.4 g), t.l.c. (ethyl acetate/triethylamine 99:1) Rf 0.21.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH3:7])[CH2:4][O:5][CH3:6].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O>C1(C)C=CC=CC=1>[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[N:2][C:3]([CH3:8])([CH3:7])[CH2:4][O:5][CH3:6]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COCC(C)(C)N
Agent: Cl
Solvent: Cc1ccccc1
Product: COCC(C)(C)N=Cc1ccc(F)cc1F
Yield: 115.8 %

Procedure:
To a solution of the obtained 2-amino-2-methyl-1-methoxypropane hydrochloride (422 mg, 2.08 mmol) in toluene (7 ml) was added 2,4-difluorobenzaldehyde (310 mg, 2.18 mmol) and stirred under reflux using a Dean-Stark trap to remove water for 1 hour. Then triethylamine (1.0 ml) was added to the mixture and stirred for 6 hours. The precipitated hydrochloride was filtered off and the solvent was evaporated to give the crude title compound (547.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:13])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2ccco2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1ccco1)C2
Temperature: 115 °C
Yield: 124.8 %

Procedure:
In a mixture of ethanol (30 ml) and toluene (90 ml) was dissolved 1-amino-5-(2-furyl)cyclohexen-3-one (1.25 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2.36 g) and granulated potassium hydroxide (390 mg). The mixture was stirred at 115° C. (bath temperature), and to the mixture was added granulated potassium hydroxide (80 mg), 30 minutes later; 1 hour later; and 1.5 hours later; respectively. The reaction solution was stirred at the same temperature for 1 hour. The reaction solution was cooled, and concentrated under reduced pressure, and to the residue was added ethyl acetate (50 ml) and water (15 ml). The mixture was shaken and the separated upper layer was washed with saturated brine. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 7-(2-furyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13]2[C:18]([C:19]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:17][CH:16]=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=2.[H-].[Na+].O>CN(C)C=O>[CH:20]1([C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:26]([O:28][CH3:29])=[O:27])=[CH:14][C:13]=3[N:12]3[C:11]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCCCl)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
To a solution of methyl 2-[2-(2-chloroethoxy)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate (180 mg, 0.44 mmol) in N,N-dimethylformamide (6 ml) was added sodium hydride (20 mg, 0.49 mmol) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue. The precipitated solid was collected by filtration, washed with diisopropyl ether and dried in vacuo to give methyl 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (70 mg, yield 42.3%).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[SH:11][CH2:12][C:13]([OH:15])=O.C[S:17](O)(=O)=O>C1(C)C=CC=CC=1>[CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:12]([S-:11])(=[S:17])[CH2:13][OH:15]
Reactant: CS(=O)(=O)O
Reactant: O=C(O)CS
Agent: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Solvent: Cc1ccccc1
Product: OCC(=S)[S-]

Procedure:
A mixture of isosorbide (60.00 grams, 0.41 moles), mercaptoacetic acid (83.21 grams, 0.90 moles), toluene (300 mL), and methane sulfonic acid (1.00 grams, 10 mmoles) was heated to reflux. Water was separated from the toluene/water azeotrope using a Dean Stark distillation trap. After four hours at reflux, a total of 15 mL of water was collected in the trap. The reaction mixture was cooled and washed with saturated aqueous sodium bicarbonate (2×200 mL) and brine (100 mL). The solution was dried over magnesium sulfate and then concentrated under reduced pressure. The product was a colorless oil. (Yield: 106.10 grams).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH3:12]OS(OC)(=O)=O.ClCCl.C(N(CC)CC)C>O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:12])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a 3-neck 1-liter round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added 2-carboxybenzaldehyde (100.00 g, 0.659 moles), dimethylsulfate (162.8 g 1.291 moles) and 200 ml of dichloromethane under nitrogen. The mixture was heated to reflux and triethylamine (135.89 g, 1.343 moles) was added at such a rate to maintain a brisk reflux. After the addition was complete, the solution was allowed to cool to room temperature and stirred overnight. Water (400 ml) was then added and the layers separated. The aqueous layer was extracted with dichloromethane (1×200 ml) and the combined organic layers washed with saturated sodium bicarbonate solution (1×400 ml), dried over magnesium sulfate and concentrated in vacuo to give a golden oil. Vacuum distillation of this oil gave 88.7 g of the product as a pale yellow oil, bp 95°-98° C./0.4 mm.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=C(C2N(C)N=NN=2)C(O)=O)=CC=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[C:34]([C:38]2[N:39]=[N:40][N:41]([CH3:43])[N:42]=2)[C:35](O)=[O:36])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)=[C:34]([C:38]2[N:39]=[N:40][N:41]([CH3:43])[N:42]=2)[CH:35]=[O:36])=[CH:29][CH:28]=1
Reactant: Cn1nnc(C(C(=O)O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Agent: Cn1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: Cn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1

Procedure:
The general procedure of Steps A, B, and C of Example 6 was repeated, except that the 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoic acid utilized in Step A was replaced by 3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenoic acid [prepared in Example 5] to yield the title compound as a gummy solid in 76% overall yield. MS (CI): m/e=326 for (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([Cl:17])=[O:14])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1nc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1nc(Cl)c(Cl)cc1Cl

Procedure:
To a stirred slurry of 30 g (0.1237 mole) 3,5,6-trichloro-2-pyridyloxyacetic acid in 500 ml methylene chloride, 1 ml N,N-dimethylformamide was added. Then 16.2 g [10 ml (0.136 mole)] thionyl chloride was added dropwise. The mixture was refluxed 31/2 hours. The solvent was stripped in vacuo to give the 3,5,6-trichloro-2-pyridyloxyacetyl chloride as an oil, which was used in step (b) without further isolation.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:20][C:21]1[C:27]([N:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]2)=[CH:26][C:24]([NH2:25])=[C:23]([NH2:38])[CH:22]=1.CC(C)N=C=NC(C)C.C(Cl)Cl.CCO>CN(C=O)C>[Cl:1][C:2]1[C:15]([NH:16][C:17]2[NH:25][C:24]3[CH:26]=[C:27]([N:28]4[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]4)[C:21]([Cl:20])=[CH:22][C:23]=3[N:38]=2)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1cc(Cl)c(N2CCC(C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC(C(F)(F)F)CC4)cc3[nH]2)c1Cl

Procedure:
The title compound was prepared from N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (108 mg, 0.34 mmol), 4-chloro-2-amino-5-(4-trifluoromethyl-piperidin-1-yl)aniline (100 mg, 0.34 mmol), DIC (56 μL) in DMF (2 mL) in analogy to example 5, step (i). Rf(TLC): 0.35 (silica gel, DCM:EtOH 95:5). MS m/z: 576 [M+H]+. HPLC-method G: Rf=1.48 min.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][CH2:16][C@H:17]1[C@H:21]([CH3:22])[O:20]C(C)(C)[N:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:14].C(=O)(O)[O-].[Na+]>CO>[C:28]([O:27][C:25](=[O:26])[NH:18][C@H:17]([C@@H:21]([OH:20])[CH3:22])[CH2:16][O:15][CH2:13][CH3:14])([CH3:29])([CH3:30])[CH3:31]
Reactant: CCOC[C@H]1[C@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC[C@H](NC(=O)OC(C)(C)C)[C@H](C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (130 mL) and p-toluenesulfonic acid monohydrate (134 mg) were added to (4S,5S)-tert-butyl 4-(ethoxymethyl)-2,2,5-trimethyloxazolidine-3-carboxylate obtained in the above-described Step 1 (1.34 g), and the reaction solution was stirred at room temperature overnight. An aqueous sodium bicarbonate solution was added to the reaction solution, and methanol was evaporated under vacuum. Water and ethyl acetate were added, the organic layer was separated, and then washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain tert-butyl((2S,3S)-1-ethoxy-3-hydroxybutan-2-yl)carbamate as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(Cl)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(Cl)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
4-Chloroaniline (0.150 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.115 g, 0.238 mmol, 44%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>C(=O)([O-])O.[Na+]>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After 4.96 g of L-phenylalanine was dissolved in 5% sodium hydrogencarbonate aqueous solution, 3.4 ml of acetic anhydride was dropwise added to the solution over an hour under ice cooling. After completion of the dropwise addition, the mixture was stirred for 2 hours at room temperature. Then 17 ml of hydrochloric acid was added to the reaction mixture to render the system acidic. The precipitated white solid was extracted once with 100 ml of ethyl acetate and twice with 40 ml each of the same solvent. The oily layer was dried over anhydrous sodium sulfate and the solvent was distilled off to give 5.61 g of N-acetyl-L-phenylalanine as white crystalline powders. Yield, 90.3%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:33]3[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@@H]1C
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a flask charged with (2S,4R)-1-acetyl-6-bromo-2-methyl-N-(5-nitro-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 19) (4.1 g, 10.12 mmol), {4-[(methyloxy)carbonyl]phenyl}boronic acid (2.185 g, 12.14 mmol), tetrakis(triphenylphosphine)palladium(0) (1.169 g, 1.012 mmol) and potassium carbonate (4.19 g, 30.4 mmol) was added DME (50 mL) and water (10.0 mL) and the resulting mixture was stirred at 100° C. under nitrogen for 1 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with an EtOAc/hexanes gradient, which gave methyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-nitropyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (4.3 g, 9.34 mmol, 92% yield) as an orange foam, LCMS (HpH, 2 min), Rt=1.13 min, MH+=461.
Reaction SMILES: [NH2:1][Al](C)C.[CH2:5]([C:7]1[NH:8][C:9]([CH2:18][CH3:19])=[CH:10][C:11](=[O:17])[C:12]=1[C:13](OC)=[O:14])[CH3:6].CO>ClCCl>[CH2:5]([C:7]1[NH:8][C:9]([CH2:18][CH3:19])=[CH:10][C:11](=[O:17])[C:12]=1[C:13]([NH2:1])=[O:14])[CH3:6]
Reactant: CCc1cc(=O)c(C(=O)OC)c(CC)[nH]1
Reactant: C[Al](C)N
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(=O)c(C(N)=O)c(CC)[nH]1
Reaction time: 20 h

Procedure:
A 1.3M solution of aminodimethyl aluminium in dichloromethane (obtained as described in Tetrahedron Letters, 1979, 4907) (7.8 ml) was added to a solution of methyl 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxylate (1.05 g in dichloromethane (50 ml) and the solution was left to stand for 20 hours. Methanol (5 ml) was added and the mixture was stirred for 1 hour. The precipitated solid was removed by filtration through a bed of diatomaceous earth. The filtrate was concentrated and the residue purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v), to give 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxamide (0.5 g), m.p. 254° C.; NMR (d6 -DMSO): 1.15-1.25(m,6H), 2.5(q,2H), 3.0(q,2H), 6.1(s,1H), 7.0(br s, 1H), 9.6(br s, 1H), 11.3(br s, 1H).
Reaction SMILES: O([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])C1C=CC=CC=1.[CH3:16][C:17]1(C=O)[C:22]([CH3:23])=[CH:21][CH:20]=[C:19](C2C=CC=CC=2)[CH2:18]1>>[CH3:16][C:17]1[CH:18]=[C:19]([C:15]2[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][CH:14]=2)[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: CC1=CC=C(c2ccccc2)CC1(C)C=O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: Cc1ccc(-c2ccc(C=O)cc2)cc1C

Procedure:
3-phenoxybenzaldehyde for 3,4-dimethylbiphenyl-3-carbaldehyde, the following compounds were generated: