Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:33])[NH:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[C:22]([F:31])=[CH:21][C:20]=1[CH3:32])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:27]1[C:28]([CH3:30])=[CH:29][CH:25]([C:23]2[CH:24]=[C:19]([NH:18][C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:33])[C:20]([CH3:32])=[CH:21][C:22]=2[F:31])[NH:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(-c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)n[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=CC(c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)NN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzylchloroformate (104 mg) was added dropwise to a room temperature solution of [4-fluoro-2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester and DIPEA in CH2Cl2 (2 ml). The mixture was stirred at room temperature for one hour, and then 10% aqueous citric acid solution was added. The organic layer was separated dried (Na2SO4), filtered and concentrated under reduced pressure. “Flash chromatography” of the residue (0 to 20% EtOAc in hexanes) gave 210 mg of 3-(5-tert-Butoxycarbonylamino-2-fluoro-4-methyl-phenyl)-5-methyl-2H-pyrazole-1-carboxylic acid benzyl ester as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[N:14]1([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([CH:31]=O)=[CH:25]3)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:31][C:26]1[NH:27][C:28]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:21][CH2:20][CH2:19][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:30][CH:29]=3)[C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
4-(2-Hydroxy-ethyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=C(\C)/CCC(O)=O.CCCCCC.C(OCC)(=[O:38])C>>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=[O:38]
Reactant: COCCOCOc1c(C/C=C(\C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COCCOCOc1c(CC=O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
By following the procedure of part A and substituting methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro -6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with (E)-6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, there was obtained 2-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 61°-63° C. (hexane-ethyl acetate).
Reaction SMILES: [Br:1]Br.[CH2:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1C=CC=CC=1)[CH2:4]C=C>C(Cl)Cl.O>[Br:1][CH2:11][CH:10]1[O:9][C:8](=[O:17])[NH:7][CH2:3][CH2:4]1
Reactant: C=CCCNC(=O)OCc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: O=C1NCCC(CBr)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (11 g, 68 mmol) was added to a mixture of benzyl but-3-en-1-ylcarbamate (7 g, 34 mmol) in DCM at room temperature under N2. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford 6-(bromomethyl)-1,3-oxazinan-2-one. 1H NMR (400 MHz, CDCl3) δ 6.14 (s, 1H), 4.49-4.45 (m, 1H), 3.59-3.56 (m, 1H), 3.46-3.39 (m, 3H), 2.24-2.20 (m, 1H), 1.95-1.89 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Reactant: COc1ccc(CN)cc1Cl
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C@@H:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][C@H:13]1[OH:24].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][CH2:15][CH2:14][C@@H:13]([OH:24])[C@H:12]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[C:18]=2[CH:19]=1
Reactant: O=C1CCCN1
Reactant: O[C@@H]1CCOc2ccc(Cl)cc2[C@H]1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1CCCN1[C@@H]1c2cc(Cl)ccc2OCC[C@H]1O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
5 ml (5 mmol) of lithium bis-(trimethylsilyl)-amide (1M solution in THF) are added dropwise with stirring to 1.40 g (5 mmol) of trans-5-bromo-7-chloro-4-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin at 0° C. under argon. After stirring for 2 hours, 0.43 g (5 mmol) of 2-pyrrolidinone and subsequently a further 5 ml of lithium bis-(trimethylsilyl)-amide are added, and the mixture is heated at 110° C. for several hours (TLC check). The mixture is poured onto ice-water and extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is triturated with hot methanol/ethyl acetate and filtered off with suction. Crystals of melting point 186°-188° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 28 g of 4-nitrophenol, 36 g of ethyl 2-bromopropionate, 27.6 g of potassium carbonate and 500 ml of butanone was stirred and refluxed for 17 hours. The resulting mixture was diluted with 500 ml of water and extracted with ether. The extract was concentrated in a rotary evaporator and the residue was recrystallized from ether-hexane to give ethyl 2-(4-nitrophenoxy)propionate (1D), as a yellow solid, m.p.: 55-56° C.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:24])[CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)[CH2:11][CH2:12][CH2:13][CH3:14].FC(F)(F)C(O)=O>ClCCl>[OH:7][NH:8][C:9](=[O:24])[CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(Cc1ccc(F)c(C)c1)C(=O)NOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(Cc1ccc(F)c(C)c1)C(=O)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
To a solution of 2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid (tetrahydro-pyran-2-yloxy)-amide (0.0.358 g, 1.062 mmol) in 5 mL of dichloromethane, was added trifluoroacetic acid (5 mL). After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-10% methanol/dichoromethane to give the title compound as an off-white solid (0.059 g, 22% yield). LC-MS: tR=7.1 min; m/z 254 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 0.89 (t, J=6.60 Hz, 3H), 1.27-1.36 (m, 4H), 1.39-1.49 (m, 1H), 1.60-1.67 (m, 1H), 2.23 (d, J=1.50 Hz, 3H), 2.24-2.32 (m, 1H), 2.62 (dd, J=13.50, 5.40 Hz, 1H), 2.79 (dd, J=13.50, 9.60 Hz, 1H), 6.88 (t, J=9.60 Hz, 1H), 6.95-6.96 (m, 1H), 7.01 (t, J=7.50 Hz, 1H).
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)[CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(OC)cc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 138.3 %

Procedure:
Saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to a solution of methyl 4-methoxy-2-trifluoromethylsulfonyloxybenzoate (6.3 g; 0.02 mol) and 4-fluorobenzeneboronic acid (3.36 g; 0.024 mol) in DME (150 ml) at ambient temperature under an argon atmosphere. Tetrakis(triphenylphosphine) palladium (928 mg; 0.8 mmol) was then added and the reaction heated at reflux for 3.5 hours to give a homogeneous solution. After cooling to ambient temperature, the reaction was partitioned between ethyl acetate and water. The organic phase was washed with 2N HCl, water and brine, filtered through 1PS filter paper and the solvent removed in vacuo to give methyl 4-methoxy-2-(4-fluorophenyl)benzoate as a yellow oily solid (7.2 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[CH:12]2.P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:18][CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: COCCOCCOc1ccc2c(=O)[nH]ccc2c1
Reactant: ClP(Cl)Cl
Product: COCCOCCOc1ccc2c(Cl)nccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Phosphorus trichloride (60 mL) and 6-[2-(2-methoxyethoxy)ethoxy]-2H-isoquinolin-1-one (3.38 g, 14.3 mmol) were stirred at reflux under nitrogen atmosphere for 2 h. The reaction solution was cooled to room temperature and concentrated in vacuo until 10 mL remained. The obtained oil was poured onto ice water (80 mL) and stirred for 1 h. The mixture was neutralized with addition of solid potassium carbonate and extracted with methylene chloride (3×80 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulphate, filtered and concentrated. The obtained oil was pre-absorbed on silica gel and purified by flash chromatography (gradient:hexane/ethyl acetate, 6:4→4:6). The appropriate fractions were pooled, concentrated and dried to give 1.24 g (30% yield) of the title compound as a waxy solid. MS (AP+) m/z 282 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)=[O:14]
Reactant: Brc1ccsc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2sccc2Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
Treat a stirred, chilled (0° C.) solution of 3-bromothiophene (20 g, 0.123 mol) and dichloromethane (150 mL) with titanium tetrachloride in dichloromethane (184 mL, 1.0M) at such a rate as to maintain the temperature below 5° C. Add dropwise a solution of 4-methoxybenzoyl chloride (20.9 g, 0.123 mol) and dichloromethane (75 mL) at such a rate as to maintain the temperature below 5° C. Stir one hour at 0–5° C., then quench the reaction by addition of ice (100 mL) and 6N hydrochloric acid at such a rate that the internal temperature remains at or below 10° C. Add more water (100 mL), separate the organic phase, wash with water, dry (Na2SO4), filter and evaporate to an oil which solidifies. Recrystallize the solid from ether to afford the title compound as off-white crystals (19.7 g, 54%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=1.CCN(CC)CC>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:1](=[O:3])[CH3:2])[CH2:13][CH2:12]2)[CH:10]=1
Reactant: CC(=O)Cl
Reactant: Brc1cnn(C2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (312 μl, 4.35 mmol) is added dropwise, under stirring at 0° C., to a solution of 4-(4-Bromo-pyrazol-1-yl)-piperidine (as obtained in preparation 89, 1 g, 4.34 mmol), Et3N (1.824 ml, 13.04 mmol) in CH2Cl2. The cooling bath is then removed and the reaction mixture stirred at RT for an additional 1 h. The mixture is then diluted with de-ionized water and the phases are separated. The organic phase is washed several times with de-ionized water and the aqueous layer re-extracted with CH2Cl2. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as yellow solid, Rt=0.786 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 272 (M+1, 79Br)+
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)N.Cl.[C:18]1([CH2:24][C:25](=O)[CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH3:26][C:25]1[NH:2][C:4]2[C:9]([C:24]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:8][C:7]([C:10]1[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=1)=[CH:6][CH:5]=2
Reactant: NNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1[nH]c2ccc(C3=NNC(=O)CC3)cc2c1-c1ccccc1

Procedure:
4.8 g. (20 mmole) 6-(4-hydrazinophenyl)-2,3,4,5-tetrahydropyridazin-3-one hydrochloride (according to Example 2 (a)) are suspended in 75 ml. 2N hydrochloric acid and 75 ml. ethanol, mixed with 2.8 g. (21 mmole) phenylacetone, stirred for 3 hours at 25° C., filtered off with the suction and the title compound obtained is recrystallised from methanol. Yield 4.85 g. (80% of theory); m.p. 297°-299° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH2:12][CH2:13][O:14][CH3:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([CH2:12][CH2:13][O:14][CH3:15])[N:9]=1
Reactant: COCCc1cnc(C(=O)OC)c(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCc1cnc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-5-(2-methoxy-ethyl)-pyrazine-2-carboxylic acid methyl ester (147 mg, 0.696 mmol) in THF (14 ml) was added 1M NaOH (1.74 ml, 1.74 mmol) and the reaction mixture was stirred at room temperature for 2 h. 1M HCl (1.601 ml, 1.601 mmol) was added to the reaction mixture. The resulting mixture was evaporated and co-evaporated with toluene. The resulting crude material was directly used in the coupling step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])[CH3:30]>C(Cl)Cl>[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:7])[CH2:36][CH2:35]1)=[O:33])[CH3:30]
Reactant: CC1(C(=O)O)CC1
Reactant: CCOC(=O)C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a stirred solution of 1-methyl-cyclopropanecarboxylic acid (14.4 g, 0.144 mol) in 200 mL of CH2Cl2 was added (27.10 g, 0.141 mol) of EDC, (19.10 g, 0.141 g) of HOBt and Et3N (35.93 mL, 0.259 mol). After one hour at RT, was added piperidine-4-carboxylic acid ethyl ester (18.90 g, 0.120 mol). The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1:1) yielded 26.1 g (92%) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:23])=[C:17]([CH2:19][C:20](Cl)=[O:21])[CH:18]=1>C(OCC)(=O)C>[CH2:1]([O:4][C:20](=[O:21])[CH2:19][C:17]1[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[F:23])[CH:2]=[CH2:3]
Reactant: O=C(Cl)Cc1cc(Br)ccc1F
Reactant: C=CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)Cc1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
To a mixture of allyl alcohol (22.1 g, 380.5 mmol) and triethylamine (Et3N) (5.4 ml, 39 mmol) at 0° C. was added over 1 h crude (5-bromo-2-fluoro-phenyl) -acetyl chloride (intermediate B2A) (7.01 g, ca. 26 mmol). Then the reaction was stirred over 1 h from 0° C. to 23° C. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuum left the title compound as a yellow oil (7.290 g, 103%), which was used without further purification. MS (ISP): m/z=280.1 [(M+NH4)+] and 282.1 [(M+2+NH4)+]
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([NH2:15])=[O:14])=[O:7].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:12]([CH:16]=3)[C:13]([NH2:15])=[O:14])=[O:7])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1cc(C(=O)CCCCCl)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(C(=O)CCCCN2CCN(c3ccccc3)CC2)ccc1OCc1ccccc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A mixture of 2 g of 5-(5-chlorovaleryl)-2-benzyloxy-benzamide, 1 g of 1-phenylpiperazine, 0.6 g of sodium carbonate and 10 ml of dimethyl sulfoxide was heated at 90° C. for 6 hours while stirring. After the reaction was finished, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated. The thus produced residue was dissolved in acetone and concentrated hydrochloric acid in an amount of 2 equivalents was added thereto to produce crystals. The crystals were filtered off to obtain 2.3 g of 5-[5-(4-phenyl-1-piperazinyl)valeryl]-2-benzyloxy-benzamide (yield: 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C@@H:10]([OH:21])[CH2:11][S:12]([CH2:15][C:16](OCC)=[O:17])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(Cl)(Cl)Cl.CO>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C@@H:10]([OH:21])[CH2:11][S:12]([CH2:15][C:16]([NH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:17])(=[O:14])=[O:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)CS(=O)(=O)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CS(=O)(=O)CC(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.98 g (4.7 mmole) of ethyl 2-[[(2R,3S) 3-(t butoxycarbonylamino)-4-cyclohexyl-2-hydroxy-1-butyl]sulfonyl]acetate and 2.3 ml of 4-(2-aminoethyl)morpholine was stirred under N2 at room temperature for 2 days. The light amber syrup was dissolved in 75 ml of ethyl acetate and washed with 3×30 ml of saturated aqueous NH4Cl followed by 30 ml of H2O. The ethyl acetate fraction was dried over Na2SO4, filtered, and concentrated. Further drying in vacuo (oil pump) gave 2.19 g (92%) of a nearly colorless, stiff foam or glass. Structure and purity were confirmed by 300 MHz NMR (CDCl3), mass spectrum, and TLC (9:1 CHCl3 --MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:19][CH2:18][C@@:10]3([NH:14]C(=O)N(C)[C:11]3=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[O:22]1CCOCC1.Cl>O.C(O)(=O)C>[NH2:14][C@:10]1([C:11]([OH:22])=[O:17])[CH2:18][CH2:19][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C1COCCO1
Reactant: CN1C(=O)N[C@@]2(CC[C@H](c3ccc(Br)cc3)C2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N[C@]1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a slurry of (5R,7S)-7-(4-bromo-phenyl)-3-methyl-1,3-diaza-spiro[4.4]nonane-2,4-dione (79 g, 0.24 mol) in water (1 L) was added 2 M aqueous NaOH (1 L, 2 mol) and dioxane (200 mL). The resulting mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with water (2 L) and acidified with concentrated HCl until a precipitate began to form (about pH 7). Acetic acid (about 20 mL) was added, producing a thick precipitate. The white precipitate was collected and washed with water (2×1 L) and EtOAc (1 L). The filter cake was suspended in toluene (1 L) and concentrated in vacuo at 45° C. This process was repeated once more. The white precipitate was dried to a constant weight under vacuum to give (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid (65 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][NH:8][C:9]([NH2:11])=[O:10])([O-:3])=[O:2].C([O:22][CH:23](O)[C:24](OCC1C=CC=CC=1)=[O:25])C1C=CC=CC=1>C(O)(=O)C>[OH:25][CH:24]1[N:8]([CH2:7][C:6]2[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:9](=[O:10])[NH:11][C:23]1=[O:22]
Reactant: NC(=O)NCc1cccc([N+](=O)[O-])c1
Reactant: O=C(OCc1ccccc1)C(O)OCc1ccccc1
Solvent: CC(=O)O
Product: O=C1NC(=O)N(Cc2cccc([N+](=O)[O-])c2)C1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
N-(3-Nitrobenzyl)urea (78 g) was dissolved in 500 mL of 80% acetic acid, 120 g of benzyl 2-benzyloxy-2-hydroxyacetate was added thereto at 80° C. and the mixture was stirred at 80° C. for two hours. The mixture was concentrated in vacuo and the solvent was evaporated therefrom by means of an azeotropic distillation with toluene. The residue was purified by a silica gel column and recrystallized from a mixed solvent of ethyl acetate and hexane to give 49 g of 5-hydroxy-1-(3-nitrobenzyl)-2,4-dioxoimidazolidine.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=2[OH:12])[CH:5]=[CH:4][CH2:3]1.[H][H]>O.[Ni]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=2[OH:12])[CH2:5][CH2:4][CH2:3]1
Reactant: CCCc1ccc2c(c1O)N(C)CC=C2
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Product: CCCc1ccc2c(c1O)N(C)CCC2
Yield: 36 %

Procedure:
Into a stainless steel autoclave, one introduces 37.3 g of paratoluenesulfonate of N-methyl-7-propyl-8-hydroxyquinoline (0.1 mole) in 120 ml of water, and 5 g of Raney nickel. The hydrogenation is carried out under an 80 kg/cm2 hydrogen pressure. After absorption of the hydrogen, one cools and filters off the catalyst; one neutralizes the filtrate with an ammonia solution, resulting in the formation of a grayish-white precipitate that one separates and distills under high vacuum. One collects 8 g of a colorless liquid that distills at 180°-110°C under a 0.5 mm Hg pressure. One obtains a yield of 36%.