Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.C1COCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:46]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Temperature: 62.5 °C
Reaction time: 48 h
Yield: 44.2 %

Procedure:
To a solution of N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (33 mmol, 15 g) in toluene (100 mL, stored over 4 A molecular sieves) and freshly distilled THF (50 mL) was added Lawesson's reagent (33 mmol, 13.35 g, 1.0 equiv.) at room temperature. The solution was heated to 60-65° C. and was stirred for 48 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and was poured into saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×150 mL). An oil formed in the aqueous layer, which was separated, diluted with water and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate solution (200 mL), with brine (300 mL), dried (MgSO4), filtered and the solution was concentrated in vacuo. The residual light brown syrup was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1) to obtain 6.87 g (44%) of N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxo-methyl]-4-nitro-L-phenylalanine methyl ester as a fluffy yellow solid. HRMS: Obs. mass, 493.1438. Calcd. mass, 493.1443 (M+Na).
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7](B(O)O)[CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(OCC)(=O)C.C(COC)OC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1B(O)O
Reactant: Fc1ccc(I)cc1
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
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To water (2 mL) and dimethoxyethane (20 mL), 5-chloro-2-nitrophenylboronic acid (3.27 g, 16.4 mmol), 1-fluoro-4-iodobenzene (3.65 g, 16.4 mmol), tetrakis(triphenylphosphine)palladium (0.95 g, 0.82 mmol) and potassium carbonate (6.81 g, 49.3 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at 60° C. for 2 hours. After the reaction, the reaction mixture was cooled to room temperature and ethyl acetate (30 mL) was added. After the organic phase was washed with water (30 mL) and saturated brine (20 mL), it was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give 5-chloro-4′-fluoro-2-nitrobiphenyl as a crude product. The obtained compound was used for the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:58]>CO>[ClH:58].[OH:8][C@@H:7]1[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4][C@@H:3]1[CH2:2][NH:1][CH2:35][C:33]1[CH:32]=[CH:31][C:28]2[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=2[N:34]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ccc(=O)n(CCN3C[C@H](CN)[C@H](O)C3)c2c1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CNCc4ccc5c(n4)NC(=O)CO5)[C@H](O)C3)c2c1
Product: Cl
Reaction time: 18 h
Yield: 40 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-(methyloxy)-2(1H)-quinolinone (116 mg, 0.365 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (72 mg, 0.402 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (243 mg, 1.1 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and purified to obtain the free base of the title compound as a pale yellow oil (91 mg, 40%) after column chromatography (90:10:1:DCM:MeOH:NH4OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[C:15]([C:16]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+].[ClH:33]>C(O)(C)C.O.CN(C)C=O>[ClH:33].[CH3:26][C:25]([CH3:27])=[CH:24][CH2:23][N:19]1[CH2:20][CH2:21][C:16]2([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[O:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]1
Reactant: CC(C)=CCBr
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COc1cccc2c1Oc1ccccc1C21CCN(CC=C(C)C)CC1

Procedure:
A mixture of 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.), 1-bromo-3-methylbut-2-ene (1.15 g.), sodium bicarbonate (0.59 g.) and dimethylformamide (20 ml.) is heated under reflux for 4 hours. The mixture is cooled, poured into water and extracted with chloroform. The chloroform extract is washed with water, dried with MgSO4 and evaporated to give a gummy residue. The residue is dissolved in isopropanol and treated with ethereal hydrochloric acid. The residue is recrystallised from isopropanol-ether to give 1'-(3-methylbut-2-enyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 247°-249° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5](=C)[CH2:4][O:3]1.C1C[O:20]CC1>>[CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5](=[O:20])[CH2:4][O:3]1
Reactant: C=C1COC(C)CN(C(=O)OC(C)(C)C)C1
Reactant: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CC(=O)CO1
Temperature: 30 °C
Reaction time: 5 h
Yield: 78.48 %

Procedure:
To a mixture of tert-butyl 2-methyl-6-methylene-1,4-oxazepane-4-carboxylate (2.40 g, 10.56 mmol, 1.00 eq) in THF (50.00 mL), was added NaIO4 (4.97 g, 23.23 mmol, 2.20 eq) and K2OSO4 (401.83 mg, 2.11 mmol, 0.20 eq) in one portion at 30° C. under N2. The mixture was stirred at 30° C. for 5 hours. TLC showed the reaction was completed. The mixture was poured into saturated NaSO3 (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with saturated brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=8/1) to afford tert-butyl 2-methyl-6-oxo-1,4-oxazepane-4-carboxylate (1.90 g, 8.29 mmol, 78.48% yield) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:18][N:19]([CH3:32])[C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH:23]2[CH2:22][CH2:21][C:20]([N:19]([CH3:32])[CH3:18])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCCCC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2[nH]cc(C3CCN(C4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-methoxy-3-piperidine-4-yl-1H-indole (461 mg, 2 mmole) and 4-dimethylamino-4-phenylcyclohexane (435 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (40 ml). Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg, 2.8 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (20 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The non-polar diastereoisomer was obtained as a colourless oil in a yield of 590 mg (68%) and the polar diastereoisomer was obtained as a colourless oil in a yield of 170 mg (20%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:10]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:13]=1)#N.[Cl-].[NH4+].[O:34]1CCCC1>O.C(OCC)(=O)C>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[S:23][C:14]1[CH:13]=[C:12]([C:10](=[O:34])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:21][C:15]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: C1CCOC1
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Sc1ccc(F)cc1F
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)Cc2ccccc2)cc1Sc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Benzyl chloride (1.92 ml) was added dropwise to a mixture of magnesium (357 mg) in tetrahydrofuran (15 ml) at 40° C. The mixture was stirred at room temperature for 40 minutes. To the resulting solution was added a solution of 4'-cyano-2'-(2,4-difluorophenylthio)methanesulfonanilide (1 g) in tetrahydrofuran (15 ml) dropwise at room temperature. The reaction mixture was stirred for 1 hour and hydrolyzed with cold ammonium chloride solution. Ethyl acetate (30 ml) and water (30 ml) were added. The organic layer was separated, shaken with diluted hydrochloric acid, dried, and evaporated. The residual oil (2.2 g) was purified by column chromatography on silica gel (40 g) eluting with a mixture of toluene and ethyl acetate (40:1) followed by recrystallization from ethanol to give pale brown crystals of 2'-(2,4-difluorophenylthio)-4'-(phenylacetyl)methanesulfonanilide (0.52 g).
Reaction SMILES: Cl[C:2]([F:6])=[C:3]([F:5])[F:4].[Li]CCCC.[O:12]1[C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[Cl-:22].[NH4+]>CCCCCC.C(OCC)C.O1CCCC1>[Cl:22][C:3]([F:5])([F:4])[C:2](=[C:19]1[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1)[F:6]
Reactant: [Cl-]
Reactant: FC(F)=C(F)Cl
Reactant: C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: FC(=C1CCC2(CC1)OCCO2)C(F)(F)Cl
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
At −100° C., 17.2 g of chlorotrifluoroethylene were condensed into 120 ml of tetrahydrofuran and 80 ml of diethyl ether. Over a period of 30 minutes, 84 ml of a 16 molar solution of n-BuLi in hexane were added dropwise at a temperature between −90° C. and −100° C. 18.8 g of 1,4-dioxaspiro[4.5]decane were added and the mixture was stirred at −60° C. for 1 h. The reaction solution was poured into aqueous ammonium chloride and extracted with diethyl ether and the combined organic phases were dried over magnesium sulfate and concentrated. The residue was taken up in 200 ml of pyrimidine and, at −30° C., mixed with 71 g of thionyl chloride. The reaction solution was slowly warmed to 0° C. and stirred for another 1.5 hours at this temperature. The reaction solution was poured onto ice and extracted with methylene chloride and the organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel (petroleum ether:ethyl acetate 4:1), to give the title product as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([NH:16]C(=O)OC(C)(C)C)[S:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]=[C:14]([NH2:16])[S:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc(S(C)(=O)=O)cc2)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nsc(N)n2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 3-(4-(methylsulfonyl)phenyl)-1,2,4-thiadiazol-5-ylcarbamate (1.57 g, 4.42 mmol) in DCM (20 mL) was added anisol (0.50 mL) and TFA (10 mL). The reaction mixture was stirred at room temperature for 6 h and concentrated. The solid was suspended in saturated NaHCO3 (˜200 mL) and stirred for 30 min. The solid was collected by filtration, washed with water (˜500 mL) followed by hexanes (˜50 mL), and dried under high vacuum to give 3-(4-(methylsulfonyl)phenyl)-1,2,4-thiadiazol-5-amine.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][N:7]=1.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:2][C:3]1[N:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)Cn1ccnc1CO
Reactant: O=S(Cl)Cl
Product: CC(C)Cn1ccnc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 2-hydroxymethyl-1-isobutylimidazole (2.40 g) was added thionyl chloride (24 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from methanol-ethyl acetate, to give 2-chloromethyl-1-isobutylimidazole hydrochloride (2.17 g) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH:11]2[CH2:18][CH2:17][CH2:16]NC(=O)[CH2:12]2)=O)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)([O-])O.[Na+].[N:40]1[CH:45]=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]2[S:22][C:12]3[NH:40][CH2:45][CH2:16][CH2:17][CH2:18][C:11]=3[N:10]=2)=[CH:19][CH:20]=1
Reactant: c1ccncc1
Reactant: O=C(C=Cc1ccc(Cl)cc1)NC1CCCNC(=O)C1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(C=Cc2nc3c(s2)NCCCC3)cc1

Procedure:
3-(4-Chlorocinnamoyl)amino-ε-caprolactam (11.0 g) and phosphorus pentasulfide (8.37 g) were added to 500 ml of pyridine, and the whole was refluxed for 1.5 hrs. After cooling, the reaction mixture was added to a sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel, and recrystallized from cyclohexane to give the title compound as crystals, m.p. 188°-189° (yield 6.28 g, 57% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH3:2].C(O)[C:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1.Cl.O1CCOCC1>>[CH2:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[C:2]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NN(Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCc1ccccc1)c1cc(O)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.9 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (1.5 g, 3.3 mmol) was dissolved in benzyl alcohol (20 mL, 100 mmol) and 4 M HCl in dioxane (10 mL, 40 mmol) was added. The mixture was stirred at room temperature for 6 hours. The mixture was evaporated under reduced pressure and purified (Interchim C18 reverse phase chromatography column, 30-95% MeCN in water with 0.05% TFA). The clean fractions were combined, lyophilized and purified to yield the title compound (688 mg; purity 98%). MS m/z [M+H]+ calc'd for C27H24ClN3O6, 522.14. found 522.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[S:14][C:15]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:16]=2[N:17]=1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[CH3:27][O:26][C:19]1[C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:15]2[S:14][C:13]([CH:12]=[O:11])=[N:17][C:16]=2[CH:18]=1
Reactant: COc1cc2nc(CO)sc2c(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nc(C=O)sc2c(OC)c1OC
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.78 mL) was dissolved in dichloromethane (10 mL), DMSO (1.49 mL) was added dropwise at −78° C., and the mixture was stirred for 30 minutes. After a solution of 2-hydroxymethyl-5,6,7-trimethoxy-benzothiazole (1.53 g) in dichloromethane (10 mL) was added dropwise at −78° C. to the mixture, stirring was conducted for 1 hour, triethylamine (6.46 mL) was added, and the resultant mixture was warmed to room temperature. After an aqueous solution of ammonium chloride was added to the mixture, extraction was conducted with dichloromethane. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]([CH3:15])([CH3:14])[CH2:5][NH:6][CH2:7][C:8]([N+:11]([O-])=O)([CH3:10])[CH3:9])([O-])=O.[H][H]>[Ni].C(O)C>[NH2:11][C:8]([CH3:10])([CH3:9])[CH2:7][NH:6][CH2:5][C:4]([NH2:1])([CH3:14])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)(CNCC(C)(C)[N+](=O)[O-])[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(N)CNCC(C)(C)N
Yield: 52 %

Procedure:
Into a 2 L pressure reactor, 21.17 g (0.0965 mol) of compound III was placed along with 600 mL of ethanol (90%). Approximately 3 g of Raney Nickel was added and the bomb was pressurized to 90 PSI with hydrogen (99.9%). The solution was stirred and intermittently repressurized with hydrogen. Over the course of 5 days, 105 PSI (0.406 mol) of hydrogen were consumed. The bomb was then depressurized and the solution filtered through celite to remove the catalyst. The filtrate was evaporated under vacuum to remove all solvent and then was vacuum distilled at room temperature and a pressure of 50 mtorr. Purified product weighed 8.031 g, giving a yield of 52%. Purity was checked by NMR, with a singlet at 2.26 ppm and a singlet at 0.96 ppm.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(=O)[nH]1
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from the above described 6-ethyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (4.6 g, 17.2 mmol) and phosphoryl chloride (7.85 mL, 86.1 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a light yellow solid (2.2 g, 44%). MS (ISP) 286.1 [(M+H)+] and 288.0 [(M+2+H)+].
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1C(O)=O>C1(C)C=CC=CC=1>[N:13]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: O=C(O)C1CCCCN1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CCCCN3C2C1

Procedure:
17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 13 g (0.1 mol) of piperidine-2-carboxylic acid in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[CH:22]=4)[NH:17]3)=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([OH:30])=[O:29])[CH:22]=4)[NH:17]3)=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3=CCCCC3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)C2=CCCCC2)cc1
Yield: 47.5 %

Procedure:
A mixture of methyl 2-(4-(cyclohex-1-enecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (217 mg, 0.52 mmol) in methanol (3 mL) and water (1.5 mL) was treated with a solution of sodium hydroxide (353 mg, 2.63 mmol) in water (1.5 mL) was heated to reflux until the completion of the reaction (monitored by Thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 100 mg of 2-(4-(cyclohex-1-enecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid Yield: 53%. MS (ESI+APCI) M+1=405.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[CH2:14](Cl)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: ClCC=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OC/C=C/c2ccccc2)c(C)c(C)c1NC=O
Yield: 44 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and cinnamyl chloride, the title compound was synthesized according to Reference Example 17b. Yield: 44%. Melting point: 197-199° C. (Ethyl acetate-hexane)
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O.O>C(O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[CH:14]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccccn1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A mixture of 25.2 g. of sodium bicarbonate, 12.3 g. of 2-aminopyridine and 30 g. of α-bromo-p-methoxyacetophenone in 100 ml. of water and 550 ml. of absolute ethanol is heated at reflux temperatures for 1.5 hrs. The reaction mixture is concentrated under reduced pressure to a yellow solid, which is partitioned between chloroform and water. The organic layer is separated, dried over sodium sulfate. Removal of the chloroform in vacuo leaves the crude intermediate as a yellow solid. Recrystallization from ethanol-water give 15.2 g. of the desired material, m.p. 131°-134° C.