Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](=O)[N:20]([CH3:22])[CH3:21])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:22][N:20]([CH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([CH2:8][NH:7][CH3:6])=[CH:10][CH:11]=[CH:12]2)[CH3:21]
Reactant: CN(C)C(=O)c1ccc2c(CNC(=O)OC(C)(C)C)cccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cccc2cc(CN(C)C)ccc12

Procedure:
To a room temperature solution of (6-dimethylcarbamoyl-naphthalen-1-ylmethyl)-carbamic acid tert-butyl ester, 8, (20.45 g, 62.4 mmol) in anhydrous THF (300 mL) is added 1 M LAH in THF (125 mL, 2 eq.). After the addition is complete the resulting solution is heated at reflux for 3 hours. The reaction solution is then cooled in an ice bath and quenched by the addition of water (2.7 mL). The resulting mixture is dried over MgSO4. The solid is removed by filtration and the filtrate concentrated in vacuo to afford 14.25 g of the desired product as a colorless oil. LRMS: 229.05 (M+1).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])[C:12]1=[O:26].O>C(O)(=O)C>[Cl:4][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:9]1[CH:27]=[CH:28][C:29]([Cl:30])=[C:7]([Cl:6])[CH:8]=1)[C:12](=[O:26])[C:13]12[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
Sulphuryl chloride (2.74 g.) was added to a stirred suspension of 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (3.0 g.) in acetic acid (50 ml.). The mixture was stirred at 60° C. for 5 hours, cooled to ambient temperature and then stirred at this temperature for 16 hours. The mixture was then poured into water (250 ml.). The white solid which formed was collected by filtration, washed with water, air dried and recrystallised from 2-propanol to give 5'-chloro-1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.9 g.), m.p. 268°-270° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([OH:31])[C:29]#[CH:30]>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:30]#[C:29][CH2:28][OH:31])=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCO)ccc12

Procedure:
7-(3-hydroxy-prop-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 58% overall yield using the method described in example 23A, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 2-propyn-1-ol.
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24](C(OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][C:12]=2[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cc2ccccc2)ccc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(Cc3ccccc3)ccc2o1

Procedure:
6.9 g of 1A was dissolved in 130 ml of 2-butanone. The solution was heated to reflux and 8.1 g of potassium carbonate was added. Then 7.8 g of diethyl bromomalonate was added, drop-by-drop over a 10-minute period. The mixture was stirred at reflux for 58 hours, then was cooled and filtered. The filtrate was concentrated under reduced pressure to leave an oil, which was poured into water. The mixture was extracted with ether. The extract was washed with 5% sodium hydroxide solution, then with water, dried (MgSO4), and concentrated under reduced pressure. The residue was recrystallized from methanol and dried over P2O5 to give 1, mp: 78°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][F:11].Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:25][CH2:26]1
Reactant: ClCCN1CCOCC1
Reactant: CCC1SC(=O)NN=C1c1ccc(OCF)c(OC)c1
Product: CCC1SC(=O)N(CCN2CCOCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
In analogy to Example 4, by reacting 5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-2-morpholinoethane, 2-morpholinoethyl-5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[C:11]([F:16])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccccc1F
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].P(Br)(Br)[Br:18].C(=O)([O-])O.[Na+].O>ClCCl>[Br:18][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1CBr
Temperature: 5 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
1.3 g of tert-butyl (2-hydroxymethylphenyl)carbamate were dissolved in 20 ml of dichloromethane; at 5° C., a solution of 630 mg of phosphorus tribromide in 5 ml of DCM was then added dropwise. The reaction mixture was subsequently stirred at 5° C. for 2 h. For workup, the mixture was admixed cautiously with solid sodium hydrogencarbonate and 1 ml of water, stirred at 5° C. for 30 min, filtered through a cartridge and concentrated under reduced pressure. tert-Butyl (2-bromomethylphenyl)carbamate was obtained in a 67% yield. 1H NMR: 8.71, s, 1H, 7.45, d, 1H, 7.42, d, 1H, 7.3, t, 1H, 7.1, t, 1H; 4.78, 2, 2H, 1.45, s, 9H.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:20][C:21]([OH:23])=[O:22].[H][H]>[C].[Pd].CO>[CH3:13][O:12][C:8]1[C:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6]2[C:11]([CH:2]=[C:3]([NH:20][C:21]([OH:23])=[O:22])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CCCCCOc1c(OC)ccc2c(Cl)c(NC(=O)O)cnc12
Agent: [Pd]
Solvent: CO
Product: CCCCCOc1c(OC)ccc2cc(NC(=O)O)cnc12
Yield: 78.6 %

Procedure:
4-Chloro-7-methoxy-8-pentyloxyquinoline-3-carbamic acid (101 mg, 0.312 mmol) and methanol (10 ml) were mixed, and 10% palladium-carbon catalyst (30 mg) was added to this solution. The mixture was stirred at room temperature for 5 hours in a stream of hydrogen. The palladium-carbon catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=10/1-6/4) to give 7-methoxy-8-pentyloxyquinoline-3-carbamic acid (74.6 mg, 83%) as yellow crystals.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[NH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: NN1CCCCC1
Solvent: O
Product: C=CCNc1nc(NN2CCCCC2)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A mixture of 200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.86 g (18.53 mmol) of 1-aminopiperidine was stirred at room temperature for 2 hours. Water was added to the reaction solution followed by extraction with ethyl acetate, washing brine, and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 100 mg (40.3%) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:18]([C:21]2[CH:22]=[CH:23][C:24](O)=[C:25]([CH:30]=2)[C:26]([O:28][CH3:29])=[O:27])(=[O:20])=[O:19])=[CH:13][CH:12]=1)[CH3:10].C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:32][CH:33]([CH3:34])[CH3:35])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[C:25]([CH:30]=2)[C:26]([O:28][CH3:29])=[O:27])(=[O:20])=[O:19])=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)c(C(=O)OC)c2)cc1
Reactant: OCC1CCOCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(C(=O)OC)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (74.2 mg, 0.639 mmol) and methyl 5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-hydroxybenzoate (500 mg, 1.277 mmol) in toluene (0.5 mL) at room temperature, was added a solution of 2-(tributylphosphoranylidene)acetonitrile (339 mg, 1.405 mmol) in toluene (0.5 mL) in one charge. The reaction mixture was stirred vigorously for 1 hour, then left to stand overnight. Additional 2-(tributylphosphoranylidene)acetonitrile (339 mg, 1.405 mmol) and (tetrahydro-2H-pyran-4-yl)methanol (74.2 mg, 0.639 mmol) were added and the reaction mixture stirred for an additional 8 hours. The solvent was evaporated in vacuo to give the crude product, which was purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane) to give the title compound as an orange gum, 109.6 mg. LCMS [LCMS1] Rt 1.37 min, m/z (ES+) 490 (M+H).
Reaction SMILES: [C:1]([C:9]1([OH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH:21]1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:21][O:16][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:18])=[O:17]
Reactant: O=C(O)C1CCCCC1(O)C(=O)c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCCCC1(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
9.93 g (0.04 mol) of 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid prepared according to the method of example 1 and 1.4 g of methanol (0.044 mol) are dissolved in 200 ml of dichloromethane. 9.91 g (0.044 mol) dicyclohexylcarbodiimide are added to the solution and the resulting suspension is stirred for 3 hours at room temperature. After this time, no more carboxylic acid is detected by TLC analysis. The reaction mixture is filtered and the solid dicyclohexylurethane is washed with dichloromethane. The organic solution is washed with sodium bicarbonate and water, dried over MgSO2 and evaporated in vacuum. The residual crude product is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1) to give 7.03 g (71%) 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid methyl ester as a viscous resin.
Reaction SMILES: [CH2:1]([C:3]1(O)[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1](=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)[CH3:2]
Reactant: CCC1(O)CC2CCC1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC=C1CC2CCC1C2
Yield: 78.9 %

Procedure:
In 600 ml of benzene was dissolved 125.0 g of 2-ethylbicyclo[2.2.1]heptan-2-ol in endo-form. To the solution was added 8.5 g of p-toluenesulfonic acid monohydrate. This reaction mixture was heated, agitated under reflux for 6 hours while removing water, and subjected to conventional post-treatment. The resulting oily substance was purified by silica gel column chromatography, obtaining 85.9 g of 2-ethylidenebicyclo[2.2.1]heptane. The yield was 78.8%.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1ccc2ncc(I)n2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ncc(-c3ccccn3)n2c1
Yield: 75.4 %

Procedure:
A mixture of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate (1.00 g, 3.30 mmol), 2-(tri-n-butylstannyl)pyridine (2.44 mg, 6.62 mmol), tetrakis(triphenylphosphine)palladium(0) (381 mg, 0.33 mmol) and toluene (50 mL) was heated under reflux overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=4/1-1/1) to give the title compound (630 mg, yield 75%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH3:14])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 4-bromobenzoyl chloride (2.00 g, 9.11 mmol) and dimethyl amine hydrochloride (892 mg, 10.90 mmol) in 20 mL of CH2Cl2 was added triethylamine (3.81 mL, 27.30 mmol). The mixture was stirred at room temperature for 2 h, quenched with water, extracted with 3×CHCl3, dried with Na2SO4, concentrated and purified by Biotage column chromatography with 1-4% MeOH in 1:1 EtOAc/CH2Cl2 to give a white solid (1.73 g, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.48-7.65 (m, 2 H) 7.20-7.37 (m, 2 H) 3.05 (d, J=50.78 Hz, 6 H); LCMS for C9H10BrNO m/z 228.00 and 230.00 (M+H)+
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[C:10](=[O:32])[N:11]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)(=O)C.[OH-].[Na+]>C(O)C>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=1)[CH2:17][N:11]1[C:10](=[O:32])[C:9]2[C:8]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:7][C:6]([CH2:5][OH:4])=[N:16][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: CC(=O)OCc1cc(-c2ccccc2)c2c(n1)OCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2c(-c3ccccc3)cc(CO)nc2OCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A mixture of 8-acetoxymethyl-4-(3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine (Example 37) (4,51 g), ethanol (50 ml), and 4N-NaOH (50 ml) was stirred for 1.5 hours at room temperature. After evaporation of the solvent, water was added to the residue. The pH of the mixture was adjusted to ca.8 using dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the entitled compound as colorless crystals (4.10 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].N[CH2:7][C@@H:8]1CC[CH2:10][N:9]1CC>>[CH3:1][N:2]([CH2:7][CH2:8][NH:9][CH3:10])[CH2:3][CH2:4][OH:5]
Reactant: CCN1CCC[C@H]1CN
Reactant: CNCCO
Product: CNCCN(C)CCO

Procedure:
By using 2-(methylamino)ethanol (867.5 mg) as a starting material, the title compound (740 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C[O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1)=[O:29]>>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:28]([OH:27])=[O:29])=[N:31][CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccc(B(O)O)cn1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Product: Cc1cc(C(=O)CC(c2cccc(-c3ccc(C(=O)O)nc3)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 6, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 2-(methylcarboxy)pyridine-5-boronic acid (4 h at 80° C., 40 h at rt) was prepared the title compound as an off-white semisolid, MS (ESI−): m/z=435.2 ([M−H]−, 1Br).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30]>C(Cl)Cl>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: OCCCSc1ccncc1
Reactant: NCc1cccs1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1csc(CNCCCSc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 290.9 %

Procedure:
In 200 ml of methylene chloride were dissolved 10.34 g (61.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 10.2 ml (73.3 mmol) of triethylamine, methanesulfonyl chloride [5.7 ml (73.3 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. To 8.05 g of the residue was added 3.3 ml (3.25 mmol) 2-thiophenemethylamine. The mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 2.5 g of the desired compound (yield: 29.1%, yellow oil).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][NH:26][CH2:25][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1)[CH3:15].C(N(CC)CC)C>ClCCl>[CH2:14]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:27][N:26]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH2:25][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)=[CH:20][CH:21]=1)[CH3:15]
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.93 g (9.57 mmol) of 4-nitrophenyl chloroformate were added slowly to 2.5 g (9.57 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate, the compound from Example 17A, and 1.94 g (19.1 mmol) of triethylamine in 292 ml of dichloromethane. The mixture was stirred at RT for 2 h. For workup, the reaction mixture was washed first with saturated aqueous sodium hydrogencarbonate solution, then with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of preparative HPLC. Yield: 2.66 g (64% of theory)
Reaction SMILES: [CH2:1]([CH:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2I)[N:10]([CH3:24])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].O>CN(C=O)C.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.[Cu]I>[CH2:1]([CH:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH:16]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]([CH3:24])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN1C(=O)C(Cc2ccccc2I)N(C)C(=O)C1Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C(C#C[Si](C)(C)C)c2ccccc2)N(C)C(=O)C1Cc1ccccc1
Yield: 22.8 %

Procedure:
Under argon, 3-benzyl-6-(2-iodobenzyl)-1,4-dimethylpiperazine-2,5-dione (polar isomer from 1.5, 100 mg, 0.22 mmol) was stirred together with diisopropylamide (0.5 ml), trimethylsilylacetylene (40 mg, 0.4 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol) and CuI (10 mg, 0.05 mmol) in DMF (abs., 5 ml) at 80° C. for 12 h. After cooling and addition of H2O, the mixture was extracted with methyl tert-butyl ether and the organic phases were dried and concentrated. Purification by column chromatography gave 21 mg (23%) of the target compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>N1C=CC=CC=1>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromophenol (20 g) in dry pyridine (75 ml) was cooled to 0° C. and heptanoyl chloride (18.79 ml) was added dropwise. The mixture was stirred at room temperature for 21/2 hours. Water (10 ml) was added to dissolve the precipitate and the mixture then evaporated under reduced pressure. The residue was dissolved in diethyl ether, washed with water, hydrochloric acid, water, aqueous saturated sodium hydrogen carbonate, water, dried and evaporated under reduced pressure to give 4-bromophenyl heptanoate.