Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([Si:11]([CH3:13])([CH3:12])[CH3:14])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: C[Si](C)(C)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Product: C[Si](C)(C)c1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A slurry of 10% wt. palladium on carbon (4.0 g) in IMS (25 mL) was added to a solution of (3-fluoro-4-nitro-phenyl)-trimethylsilane (62.0 g, 0.29 mol) in IMS (250 mL) and the reaction mixture flushed with nitrogen five times then hydrogen three times. The reaction mixture was then stirred under 3 bar pressure of hydrogen at room temperature for 4 hours. The reaction mixture was then purged with nitrogen again before filtering through a pad of Celite® with ethyl acetate washings. The filtrate was concentrated under reduced pressure to give the title compound as a light brown oil (53.0 g, quantitative). 1H NMR (CDCl3) 7.16-7.09 (1H, m), 7.10 (1H, d, J=7.75 Hz), 6.81 (1H, t, J=8.16 Hz), 3.78 (2H, s), 0.26 (9H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15]>>[CH3:15][O:14][CH2:13][CH:12]([NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCC(C)N
Product: COCC(C)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
21 g (0.15 mol) of 1-fluoro-4-nitrobenzene and 42 ml of 2-amino-1-methoxypropane were introduced into a 150 ml three-necked flask. The mixture was stirred for 15 minutes and brought to the boiling point. After reaction for 2 to 3 hours, the reaction medium was poured onto ice. A yellow precipitate formed. This precipitate was filtered off, washed with water, and then successively washed with a minimum amount of ethanol, isopropyl ether, and petroleum ether. 27.8 g of expected product were isolated.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[C:3]=1[O:23][CH3:24].[OH-].[Na+].[CH:27](O)=O>C=O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:27])[CH2:8][CH:7]([C:13]3[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=3)[C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[C:3]=1[O:23][CH3:24]
Reactant: O=CO
Reactant: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccc(SC)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(c(Cl)c1OC)CCN(C)CC2c1ccc(SC)cc1

Procedure:
A solution of 4 g of 6-chloro-7,8-dimethoxy-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give 6-chloro-7,8-dimethoxy-3-methyl-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C2CCOCC2)c1C
Temperature: 80 °C
Yield: 76.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1.0 g, 3.15 mmol) in acetonitrile (15 mL), cesium carbonate (1.97 g, 6.10 mmol) and methyl iodide (2.15 g, 15.27 mmol) were added; resulting solution was heated at 80° C. for 20 h. The solution was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated and the product purified by column chromatography to afford methyl 5-bromo-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzoate (0.82 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCCCBr
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCSc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, butyl bromide and sodium ethylate in ethanol. EI-MS m/e (%): 284 (M+, 48), 283 ([M—H]+, 100), 241 (([M—C3H7]+, 95), 228 (([M—C2H5CH═CH2]+, 92).
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1)NO
Reaction time: 72 h
Yield: 41 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to III (47 mg, 0.11 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5) to furnish IV as a colourless oil (19 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][NH:9][C:8](=[O:11])[CH2:7][C:6]=2[CH:12]=1.C[Al](C)C.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:22]([C:35](OCC)=[O:36])=[CH:21]2>>[O:11]=[C:8]1[CH2:7][C:6]2[CH:12]=[C:2]([NH:1][C:35]([C:22]3[N:23]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[C:24]4[C:20]([CH:21]=3)=[CH:19][C:18]([F:17])=[CH:26][CH:25]=4)=[O:36])[CH:3]=[CH:4][C:5]=2[O:10][NH:9]1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc2c(c1)CC(=O)NO2
Agent: C[Al](C)C
Product: O=C1Cc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2ON1
Yield: 24.6 %

Procedure:
The process is performed according to the method described in Example 6, starting with 0.107 g of 6-amino-3-oxo-2H-benzoxazine (WO 2003/049702), 0.5 ml of trimethylaluminum (2M in toluene) and 0.157 g of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1 of Example 1. 0.053 g of product is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: COCCN
Solvent: O
Product: COCCNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added portionwise, with stirring, to 180 ml of 2-methoxyethylamine, heated to 80° C. After the end of the addition the heating is continued for 2 hours 30 minutes. The reaction mixture is diluted with 180 ml of iced water. The expected product precipitates. It is filtered off, washed with water and dried under vacuum at 60° C. in the presence of phosphorus pentoxide. Recrystallized from 96° ethanol, it melts at 90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:17][CH3:18])[C:11]=1[N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:6]([OH:8])=[O:7].Cl.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:17][CH3:18])[C:11]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1N(C)C(C)=O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(OC)c(N(C)C(C)=O)c(OC)c1
Reaction time: 20 h

Procedure:
A suspension of 35.8 g. of 3,5-dimethoxy-4-(N-methyl-acetamido)-benzoic acid in 500 ml. of absolute methanol was saturated with dry hydrogen chloride, whereby a solution gradually formed. After standing at room temperature for 20 hours, the solution was evaporated to dryness under vacuum. The residue was treated with 200 ml. of ice-water and with a concentrated sodium hydroxide solution until a strongly alkaline reaction was achieved and the resulting emulsion was extracted with two 500 ml. portions of ethyl acetate. The ethyl acetate extracts were washed with two 100 ml. portions of water, combined, dried over magnesium sulfate, filtered and evaporated under vacuum. After recrystallization from ethyl acetate/cyclohexane, the residue yielded 3,5-dimethoxy-4-(N-methylacetamido)-benzoic acid methyl ester having a melting point of 115°-116° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH2:16][C:17]4[S:18][C:19]([C:22]5[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=5)=[CH:20][C:21]=4[C:14]=3[NH:13][N:12]=2)=[CH:7][CH:6]=1.[CH3:29][Si:30]([CH2:33][CH2:34][O:35][CH2:36]Cl)([CH3:32])[CH3:31]>C1COCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH2:16][C:17]4[S:18][C:19]([C:22]5[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=5)=[CH:20][C:21]=4[C:14]=3[N:13]([CH2:36][O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[N:12]=2)=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(N)nc4)cc2-3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(N)nc4)cc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
At 0° C., NaH (60 percent, 0.15 g, 3.0 mmol) was added to a THF solution (15 mL) containing 5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (3.1 g, 2.0 mmol). Then SEM-Cl (90% pure, 0.42 mL, 2 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 5-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (0.7 g, 1.44 mmol) as brown solid in 72% yield.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:18][C:8]([N:5]1[C:4](=[O:19])[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:2]([CH3:1])[O:7][CH2:6]1)([CH3:17])[C:9](=[O:16])[C:10](=[CH:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cccs1)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 31.4 %

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.50 g), 2-thiophenecarboxaldehyde(0.34 g), piperidine(0.43 g) and molecular sieve 4A in toluene was stirred at 80° C. for 7 hrs. The reaction solution was filtered (celite), evaporated and recrystallised (ethanol) to give ethyl 4-methyl-4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo-4H-1,3-oxazin-3-yl)-2-(2-thienylmethylidene)-3-oxo-pentanoate (Compound 206, 0.20 g), NMR 1.23(t,3H) 1.58(s,6H) 1.94(s,3H) 4.29(q,2H) 5.19(s,2H) 7.05(7.20-7.37(6H) 7.48(1H) 8.05(s,1H). By proceeding in a similar manner the following compounds were also obtained:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COCCN(S(F)(F)[F:23])CCOC.[NH4+].[Cl-]>C(Cl)Cl>[F:23][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[CH2:11][O:10][CH2:9]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: OC1(c2cccc(I)c2)COC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: FC1(c2cccc(I)c2)COC1
Reaction time: 1 h

Procedure:
To a solution of 500 mg (1.81 mmol) 3-(3-iodo-phenyl)-oxetan-3-ol in 10.6 mL DCM was added 1.17 mL (2.72 mmol) [bis(2-methoxyethyl)amino]sulfur trifluoride at RT under argon atmosphere. The resulting mixture was stirred for 1 h. The mixture was worked up by adding saturated NH4Cl solution. Phases were separated. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C>[CH2:11]([O:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)[CH3:12]
Reactant: CSc1nccc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc(SC)n1
Temperature: 60 °C
Reaction time: 10 h
Yield: 94.4 %

Procedure:
4-Chloro-2-(methylthio)pyrimidine (3.0 g) was dissolved in ethanol (30 mL), sodium ethoxide (2.54 g) was added, and the mixture was stirred at 60° C. for 10 hr. The reaction mixture was cooled, and the solvent was concentrated under reduced pressure. Water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.0 g) as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Solvent: Cc1ccc(C)cc1
Product: CN1CC(=O)Nc2cccc(Cl)c2C1=O
Temperature: 25 °C

Procedure:
25.0 g 6-chloro-isatoic anhydride (II) and 12.4 g sarcosine were suspended under stirring and argon atmosphere in 100 ml p-xylene and heated at reflux for two hours. The suspension was cooled to room temperature and further stirred 1 hour, then filtered off. The precipitate was washed with 25 ml p-xylene twice and dried at 50° C. under vacuum. The solid so obtained (6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (III)) was digested in 75 ml deionized water at 0° C. for 1 hour, filtered off, washed with 25 ml deionized water and dried under vacuum 18 hours at 80° C. Crude product: 25.2 g as a beige powder. m.p. 230-232° C.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]1.[OH-].[Na+]>C(O)C>[C:14]1([C:17](=[CH:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:18]#[N:19])[CH2:13][CH2:12][CH2:11][CH2:16][CH:15]=1
Reactant: N#CCC1=CCCCC1
Reactant: O=CC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(=CC=Cc1ccccc1)C1=CCCCC1

Procedure:
In a 50 ml 3-necked round bottom flask equipped with a nitrogen inlet, condensor and magnetic stir bar is placed cinnamaldehyde (2.64 g, 0.02 mol), 1-cyclohexenylacetonitrile (2.42 g, 0.02 mol) and sodium hydroxide (0.2 g, 0.005 mol) in absolute ethanol (25 ml). The reaction is stirred at room temperature until completion, during which time the crude product precipitates from solution. The precipitate is filtered, washed with water and dried. Recrystallization from ethanol yields a yellowish solid with maximum absorption at 338 nm and extinction coefficient of 45,825.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([N:16]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[CH2:6]1.CO>C1COCC1>[NH2:1][CH2:2][CH:3]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:26])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: C[C@H](c1ccccc1)N(C(=O)c1ccccc1)C(CC1CCc2ccc(F)cc2C1)C(N)=O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)C(CN)CC1CCc2ccc(F)cc2C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
7 ml (7 mmol) of a molar solution of BH3 /THF are added, dropwise and with vigorous stirring, to a solution, maintained under nitrogen, of 1.20 g (2.70 mmol) of the compound obtained in Step 3 (diastereoisomer 1) in 30 ml of anhydrous THF. The mixture is then heated at 70° C. for 1 hour and is then cooled, treated with 8 ml of CH3OH and stirred at 20° C. for 1 hour. After concentrating in vacuo, the residue is chromatographed on silica, eluting with a solution of CH2Cl2 /CH3OH=95/5, to yield the title compound in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].CCN(CC)CC.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22].Cl>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[S:21]([O:12][C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])(=[O:22])=[O:20]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(Br)c1OS(=O)(=O)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 2-bromo-6-methyl-4-nitrophenol (110.0 g, 0.474 mol) in DCM (950 mL) at −70° C. was added Et3N (62.3 g, 0.616 mol) and Tf2O (147.1 g, 0.521 mol). The resulting solution was stirred at −70° C. for 20 min. TLC showed the reaction was complete. Aqueous HCl (0.5 M, 1 L) was added to quench the reaction. The DCM layers were separated, dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by silica gel column (Petroleum Ether→Petroleum Ether:EtOAc (20:1)) to afford desired 2-Bromo-6-methyl-4-nitrophenyl trifluoromethanesulfonate (146.7 g, 85%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.41 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: CO.[Na].[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5].[F:12][C:13]([F:29])([F:28])[C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)OC1C=C(Br)C=CC=1>N1C=CC=CC=1>[F:12][C:13]([F:29])([F:28])[C:14]1[CH:27]=[C:26]([CH:25]=[CH:16][CH:15]=1)[O:5][C:4]1[CH:6]=[C:7]([OH:8])[CH:9]=[CH:10][CH:11]=1
Reactant: Oc1cccc(O)c1
Reactant: FC(F)(F)c1cccc(Oc2cccc(Br)c2)c1
Agent: [Na]
Solvent: CO
Solvent: c1ccncc1
Product: Oc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Yield: 67.9 %

Procedure:
All apparatus is rigorously dried and flushed with nitrogen before use. The reaction is performed in a 500 mL 3-necked flask equipped with a mechanical stirrer, a reflux condenser topped with a nitrogen inlet tube and a stopper. The flask is charged with methanol (100 mL) and sodium (10.0 g, 0.43 mol). After all of the sodium has been consumed the methanol is distilled from the flask, and the last traces are removed by azeotropic distillation with benzene. Pyridine (250 mL) and resorcinol (35.0 g, 0.32 mol) are added to the reaction mixture, followed by 3-(3-trifluoromethyl phenoxy)bromobenzene (50.0 g, 0.22 mol) and cuprous chloride (20.0 g, 0.20 mol), and the mixture is left to stir at reflux for 24 hours. Capillary GC analysis shows that ca. 87% of the mixture is the desired monoalkylation product, the rest being dialkylation product. The mixture is cooled and filtered with the aid of ether (200 mL). The ethereal phase is washed successively with water (250 mL), 5% HCl (2×250 mL), saturated NaHCO3 (200 mL) and brine (200 mL). Then it is dried with MgSO4, and the solvents are removed on the rotary evaporator to leave 38 g of a dark oily residue. Purification is accomplished by fractional distillation in vacuo. The second fraction (distilling at 132° C. @ 1.5 mm) consisted of pure monoalkylation product (colorless oil, 25.20 g, 44.6% yield). The dialkylation product is not isolated.
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[OH-].[Na+].[C:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:17][CH2:18][C:19]([N:3]2[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=C(O)[C@@H]1CSCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CSCN1C(=O)CCc1ccccc1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of 2.66 g of (R)-(-)-thiazolidine-4-carboxylic acid in 10 ml of a 2N sodium hydroxide aqueous solution were added 5.5 g of 3-phenylpropionyl chloride and 15 ml of a 2N-sodium hydroxide aqueous solution with stirring under cooling at the same time. After adding, the mixture was stirred for 2 hours at room temperature, and then the reaction mixture was washed with diethyl ether. The mixture was acidified by adding hydrochloric acid. The acidic mixture was allowed to stand for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 4.06 g of (R)-(-)-3-(3-phenylpropionyl)thiazolidine-4-carboxylic acid. (yield: 76.5%)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:35]([NH2:37])[CH3:36]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](=[O:16])[NH:37][CH2:35][CH3:36])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: COc1ccc(-c2nn(Cc3ccccc3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Agent: Cl
Product: CCNC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 59 %

Procedure:
Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-one and ethylamine hydrochloride as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 59.0%.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([CH2:20][NH:21][CH2:22][C:23]([CH3:25])=[CH2:24])([OH:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:26](=[O:29])(O)[O-:27].[Na+]>C(#N)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]2([O:19][C:23]([CH3:25])([CH3:24])[CH2:22][N:21]([C:26]([O:27][C:7]([CH3:12])([CH3:8])[CH3:6])=[O:29])[CH2:20]2)[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C([O-])O
Reactant: C=C(C)CNCC1(O)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (12 ml) was added to 1-benzyl-4-((2-methylallylamino)methyl)piperidin-4-ol (Example 271, step a) (2.2 g) and the mixture was allowed to stand for 2 hours at room temperature. The reaction mixture was treated with ice/water (100 mL) followed by solid sodium bicarbonate, portionwise, until the mixture was basic. Acetonitrile (50 mL) was added followed by BOC-anhydride (1.925 g) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was extracted with ethyl acetate (×2) and the combined organics were dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with 1% methanol in dichloromethane switching to 1% methanol in dichloromethane with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.8 g.