Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)(Cl)Cl>[CH3:7][C:6]([O:5][C:3](=[O:4])[CH2:2][N:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: C1CNCCNCCNCCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CN1CCNCCNCCNCC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of t-butyl bromoacetate (25.3 g; 130 mmol) in CHCl3 (500 mL) (commercial product) was added dropwise in 7 h to a solution of 1,4,7,10-tetraazacyclododecane (112.3 g; 650 mmol) (commercial product) in CHCl3 (2 L) maintained under nitrogen at room temperature. After 14 h the solution was concentrated to 800 mL, washed with H2O, dried and evaporated to give the desired compound (39 g; 129 mmol). Yield 99%. GC: 92% (area %). K.F.: 0.42%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:16]>[Cu]>[NH2:16][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: [NH4+]
Agent: [Cu]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Temperature: 127.5 °C
Reaction time: 18 h

Procedure:
A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (compound 1.2a), 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at 125-130° C. with stirring for 18 hours. The mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with HCl 1N to pH=2. The obtained solid was washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 214.1 (, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:14][O:15][C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:18][C:16]([O:15][CH3:14])=[O:17]
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1OC
Yield: 99.7 %

Procedure:
A solution of 2-methoxy-4-nitrobenzaldehyde (904 mg, 4.99 mmol) and methyl (triphenylphosphoranylidene) acetate (2.04 g, 5.86 mmol) in CH2Cl2 (25.0 mL) was stirred at 20° C. for 14 h. The solvent was evaporated under reduced pressure and the residue was chromatographed (SiO2 230-400 mesh, 4/1 hexanes/EtOAc) to give the title compound (1.18 g, 4/1 E/Z isomeric mixture, quant.) as a white solid. MS (electrospray, +ions) m/z 238 (M+H).
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6]CC)=O.CO[C:16](OC)([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17].C1(OC2C=CC=CC=2)C=CC=CC=1>O>[CH3:17][C:16]1[N:1]=[CH:2][CH:3]([C:4](=[O:6])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: COC(C)(Cc1ccccc1)OC
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=NC(C)=C(c2ccccc2)C1=O

Procedure:
25 g. of diethyl aminomethylenemalonate, 18 g. of phenylacetone dimethylketal, 300 ml. of dry diphenyl ether and 1.0 g. of TSA.H2O were mixed and heated under a nitrogen atmosphere at 135°-145° C. for three hours. The mixture was then brought to reflux. After 30 minutes the solution was cooled and extracted with 200 ml. of 21/2% aqueous NaOH solution. The basic extracts were acidified yielding a precipitate of ethyl 6-methyl-5-phenyl-4-oxonicotinate. Recrystallization of this material from methylene chloride/ether provided 12.3 g. of white solid, m.p.=178°-180° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][CH:2]=1.[H][H]>CO>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: c1ccc2oc(NCc3ccncc3)nc2c1
Solvent: CO
Product: c1ccc2oc(NCC3CCNCC3)nc2c1

Procedure:
A mixture of 4.5 parts of N-(4-pyridinylmethyl)-2-benzoxazolamine and 120 parts of methanol was hydrogenated at normal pressure at about 50° C. with 2 parts of rhodium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 4.6 parts of N-(4-piperidinylmethyl)-2-benzoxazolamine as an oily residue (intermediate 75).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[CH:19]1([NH:25][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(O)(CNC2CCCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.98 g) was dissolved in acetonitrile (80 mL), and cyclohexylamine (800 mg) and lithium perchlorate (960 mg) were added. The mixture was stirred at 80° C. overnight, and cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using basic silica gel (15% ethyl acetate/hexane to 80% ethyl acetate/hexane) to give the object product (2.39 g, 96%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=O.Cl.[CH2:14]([O:16][NH2:17])[CH3:15]>C(O)C>[CH2:14]([O:16][N:17]=[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)[CH2:2][Br:1])[CH3:15]
Reactant: CCON
Reactant: O=C(CBr)c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCON=C(CBr)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To 3.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone in 25 ml of ethanol, 1.09 g of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 50 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatograph using ethyl acetate-hexane (with a gradient of from 5:95 to 15:85) as the eluent to obtain 3.03 g of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>CO>[CH3:24][N:25]([CH3:27])[CH:26]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][C:3]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:2]=1[F:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1ccccc1SCc1cc(F)ccc1F
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)C(=CN(C)C)c1ccccc1SCc1cc(F)ccc1F

Procedure:
A mixture of methyl [2-(2,5-difluorobenzylthio)phenyl]acetate, (15.6 g), dimethylformamide dimethylacetal (23 ml) and pyridinium tosylate (0.2 g) was heated on an oil bath at 140° with distillation of methanol for 4 hours. Excess dimethylformamide dimethylacetal was evaporated under reduced pressure and the residue purified by silica gel column chromatography to give an oil which was recrystallised from diisopropyl ether to give methyl 3-dimethylamino-2-[2-(2,5-difluorobenzylthio)phenyl]prop-2-enoate, mp 97.5°-99° (compound 1A). A mixture of this product (7.26 g), dissolved in acetone (500 ml) and water (15 ml), and Amberlyst 15 (an acidic ion-exchange resin) was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate evaporated, extracted with ether and the extract worked up to give methyl 3-hydroxy-2-[2-(2,5-difluorobenzylthio) phenyl]prop-2-enoate, as a yellow oil, (compound 1B). This (5.3 g) was dissolved in tetrahydrofuran (70 ml) and sodium hydride (0.495 g of 80% dispersion in oil) was added and the mixture stirred for 30 minutes at room temperature. Methyl iodide (2.34 g) was added and the mixture stirred at room temperature overnight and then heated under reflux for 4 hours. Solvent was evaporated and the resulting oil was partitioned between ethyl acetate/ether and water and the organic phase dried and evaporated. The resulting oil was applied to a silica gel chromatography column and eluted with hexane/ethyl acetate to give crude methyl 3-methoxy-2-[2-(2,5-difluorobenzylthio) phenyl]prop-2-enoate, one fraction as the Z-isomer and another fraction as E-isomer. The Z-isomer (2.6 g) was dissolved in toluene (70 ml) and two drops of concentrated sulphuric acid added. The mixture was heated under reflux for two hours, whereby the Z-isomer was converted to the E-isomer. The mixture was washed with water, dried and evaporated and the resulting oil combined with the previously obtained E-isomer. The combined fractions were further purified by column chromatography to give pure methyl (E)-3-methoxy-2-[2-(2,5-difluorobenzylthio) phenyl]prop-2-enoate, as a light brown oil. (Compound 1C).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([O-:11])[CH:3]=1.[Na+].[C:13]([O-])([O-])=O.[K+].[K+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([O:11][CH3:13])[C:5]([C:9]#[N:10])=[C:6]([CH3:8])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(N)cc([O-])c1C#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(N)nc(C)c1C#N
Reaction time: 216 h

Procedure:
To a mixture of sodium 6-amino-3-cyano-2-methylpyridin-4-olate (500 mg, 2.92 mmol, prepared in analogy to WO2001062233A2 and isolated as sodium salt), and K2CO3 (808 mg, 5.84 mmol) in DMF (1 ml) was added MeI (0.200 ml, 3.21 mmol), and the reaction mixture was stirred at it for 9 d. Saturated NaHCO3 (50 ml) was added and the mixture was extracted with EA (4×20 ml). The combined organic extracts were diluted with additional DCM and MeOH until homogeneous, dried over Na2SO4, filtered and concentrated. The crude product was recrystallized from refluxing MeOH-DCM to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.34 (s, 3H), 3.82 (s, 3H), 5.91 (s, 1H), 6.83 (br, s, 2H); LCMS RtM=1.11 min, [M+H]+=164.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:34]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:30][C:29]1[CH:28]=[CH:27][C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:34]=2)=[CH:25][C:24]=1[NH:23][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:15]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-morpholinobenzamide to give N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamide in 58% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 2.1 (m, 2H), 2.18 (s, 3H), 3.18 (t, 4H), 3.35 (m, 1H), 3.41 (m, 2H), 3.75 (t, 4H), 5.1 (m, 1H), 7.12 (td, 1H), 7.21 (d, 1H), 7.37 (m, 3H), 7.41 (t, 2H), 7.5 (s, 1H), 7.57 (d, 1H), 7.78 (d, 1H), 9.83 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21]C)=O)(=[O:4])=[O:3].C1(OC2C=CC=CC=2)C=CC=CC=1>>[O:21]=[C:19]1[N:10]2[CH:11]=[N:12][C:13]3[CH:14]=[CH:15][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[C:9]2=[N:16][CH:17]=[C:18]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NS(C)(=O)=O)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
A mixture of dimethyl [(6-methanesulfonamido-4-quinazolinylamino)methylene]propanedioate (7.2 g) and diphenyl ether (43 ml) was stirred at 250° C. for 15 minutes and then cooled to ambient temperature to give crystals, which were filtered off and washed with a mixture of chloroform and methanol to give crystalline methyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (4.72 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CCCC3)cc2)cn1
Yield: 11 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using cyclopentylamine instead of cyclopropylmethylamine, to the title compound (14 mg, 11%) which was obtained as an off-white solid. MS: m/e=413.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:12]Br>C(=S)=S>[Br:12][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[OH:9]
Reactant: BrBr
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: S=C=S
Product: Oc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
To a stirred solution of 61.65 gm (0.38 mole) 3-trifluoromethylphenol in 240 mL carbon disulfide were added 19.6 mL (0.38 mole) bromine dropwise. The reaction mixture was stirred at room temperature for about 18 hours and was then partitioned between 200 mL dichloromethane and 100 mL water. The organic phase was washed with 20 mL saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing 40% hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 48.8 gm (53%) of the desired compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=2)O)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:61](=[O:66])([O:63][CH2:64][CH3:65])[NH2:62].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:62][C:61](=[O:66])[O:63][CH2:64][CH3:65])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Reactant: CCOC(N)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
To bis-(4-docosoxy-phenyl)-methanol (28.5 g, 34.2 mmol) were added toluene (350 mL), ethyl carbamate (6.1 g, 68.5 mmol) and methanesulfonic acid (333 μL, 5.14 mmol) and the mixture was stirred at 110° C. for 2 hr. Methanesulfonic acid (333 μL, 5.14 mmol) was added and the mixture was stirred for 30 min. After stirring, the reaction mixture was cooled to room temperature, sodium carbonate (1.1 g, 8.73 mmol) was added and the solvent was evaporated. The residue was crystallized from methanol (400 mL) to give ethyl [bis-(4-docosoxy-phenyl)-methyl]carbamate (32.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[N:11]3[CH2:13][CH2:14][CH2:15][C@@H:16]([NH:17]CCOC)[C@H:10]3[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:26].[CH:27](OCC)=[O:28]>>[Cl:1][C:2]1[C:12]2[N:11]3[CH2:13][CH2:14][CH2:15][C@@H:16]([NH:17][CH:27]=[O:28])[C@H:10]3[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:26]
Reactant: COCCN[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Reactant: CCOC=O
Product: O=CN[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Yield: 30 %

Procedure:
A solution of trans-6,7-dichloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (122 mg, 0.36 mmol) in ethyl formate was stirred overnight at reflux temperature. After removal of the solvent under reduced pressure, the remaining product was purified with preparative LC-MS to give the title compound (40 mg, 30%). Data (m/z)=397 (M+H)+.
Reaction SMILES: [C:1]([C:9]1([CH3:12])[CH2:11][O:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:16])=[O:15].B(F)(F)F.CCOCC.[OH-].[Na+]>O>[C:1]([C:9]1([CH3:12])[CH2:11][O:10][C:14]([CH3:16])([CH3:13])[O:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C(=O)c2ccccc2)CO1
Reactant: CC(C)=O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1(C)OCC(C)(C(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.2 g (0.1 mol) of 2-benzoyl-2-methyloxirane (see Example 1) are dissolved in 35 g (0.6 mol) of acetone, and a solution of 1.42 g (0.01 mol) of boron trifluoride-etherate in 35 g (0.6 mol) of acetone is then added dropwise while the mixture is cooled by means of an ice bath. The mixture is then stirred for 2 hours at room temperature and is then heated under reflux for 5 hours. The reaction solution is cooled, rendered alkaline, with cooling, by means of 50 ml of saturated methanolic sodium hydroxide solution, and diluted with 200 ml of water. The product is extracted with ether. The ether solution is dried with potassium carbonate and concentrated. The residue is distilled in vacuo at 95° C. and 0.5 mbar. The distillate is purified by medium-pressure chromatography, a colourless oil being obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[H][H]>[Ni].CO>[C:27]([O:26][C:24]([NH:23][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:31])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Yield: 92.2 %

Procedure:
Raney nickel 2800 (4.0 g) was added to a degassed solution of the unsaturated ester 43 (4.1 g) in MeOH (150 mL) and the resulting suspension was treated with hydrogen at atmospheric pressure for 18 h. The suspension was filtered over a Celite® bed and concentrated. Flash chromatography (30-50% ethyl acetate in hexane containing 1% acetic acid) of the resulting residue gave the desired saturated ester 44 (3.8 g, 94.5%). 1H NMR (400 MHz, DMSO-d6): 7.54 (d, J=7.6 Hz, 4H), 7.31 (overlapped d, J=8.8 Hz, 2H), 7.29 (overlapped d, J=8.4 Hz, 2H), 4.12 (m, 1H), 3.58 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.65 (t, J 7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH:51]2[CH2:53][O:52]2)=[CH:45][CH:44]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:53][C@H:51]([OH:52])[CH2:50][O:49][C:46]3[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=3)=[CH:24][CH:23]=2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 26.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-ethyl-1-piperidinecarboxamide formate (0.336 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.364 g, 0.90 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.17 g, 0.24 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[C:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].[O-]CC.[K+]>C(OCC)C>[CH2:1]([O:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[C:11]([CH2:19][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
The reaction was carried out in a manner similar to Reference Example 12 b) except for using 14.6 g (46.9 mmol) of 3-benzyloxy-6-trifluoromethyl-2-nitrotoluene, 13.7 g (93.8 mmol) of diethyl oxalate, 7.90 g (93.8 mmol) of potassium ethoxide and 300 ml of diethyl ether. Ethyl (3-benzyloxy-6-trifluoromethyl-2-nitrophenyl)pyruvate was thus obtained in the yield of 10.9 g (56.9%).