Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.Cl.Cl.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][N:33]=[CH:32]1>O>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)COc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 2.28 g. of phenoxyacetic acid, 2.43 g. of 1,1'-carbonyldiimidazole and 50 ml. of tetrahydrofuran was stirred at room temperature for 2 hours, then 3.0 g. of 1H-imidazole-1-propanamine dihydrochloride was added. The reaction mixture was stirred for 18 hours, then heated at reflux temperature for 5 hours, 5 ml. of water was added, the mixture was heated for 30 minutes and then concentrated to remove the tetrahydrofuran. The residue was treated with methylene chloride and 50 ml. of 1N sodium hydroxide and the layers separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was washed onto a filter with ether, giving the desired product, m.p. 91°-93° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>ClC(Cl)C>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(I)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Clc1ncnc2ccc(I)cc12
Temperature: 90 °C
Yield: 71.4 %

Procedure:
To a cooled (0° C.) suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138 mL, 791 mmol) in dichloroethane (600 mL) was added POCl3 (44.25 mL, 475 mmol). After heating to 90° C. for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73.8 g) collected by filtration. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. The solids (8.3 g) were triturated with isopropanol (450 mL) and cooled in an ice bath before collecting by filtration and drying under high vacuum. The two solids were combined to provide the product (82.1 g, 71%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:27]([O:29]C)=O)=[N:17][C:18]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:11])=[O:10].[NH3:31]>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:27]([NH2:31])=[O:29])=[N:17][C:18]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1

Procedure:
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester (Example 134) (0.05 g) was heated at 60° C. in 7M ammonia in methanol for 4 days. The solution was evaporated to dryness and the product crystallised from methyl acetate. Yield 0.027 g.
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])=[O:13])(=O)C1C=CC=CC=1.[NH3:26]>O.C(OCC)(=O)C>[O:13]=[C:12]([N:26]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])[CH2:11][CH2:10][S:9][S:9][CH2:10][CH2:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])=[O:13]
Reactant: O=C(SCCC(=O)N1c2ccccc2CC1C(=O)O)c1ccccc1
Reactant: N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C1Cc2ccccc2N1C(=O)CCSSCCC(=O)N1c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-[3-(benzoylthio)-1-oxopropyl]-2,3-dihydro-1H-indole-2-carboxylic acid (3.0 g.) and methanolic ammonia (5.5 N solution, 45 ml.) was stirred at room temperature for 2.5 hours, then evaporated under reduced pressure on a rotary evaporator to give a resinous material. The residue was dissolved in water, and the aqueous solution was washed with ethyl acetate three times. The aqueous phase was acidified to pH ca. 2 by dropwise addition of dilute hydrochloric acid, whereby an oil separated. The oil was extracted with ethyl acetate (two times). The combined extract was washed with water, then with saline, and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated on a rotary evaporator under reduced pressure to give an oily residue which was placed under high vacuum to give a solid material. The crude product was dissolved in a small amount of warm ethyl acetate with warming on a steam bath (there was some insoluble solid material which was removed by filtration). The ethyl acetate solution was kept under mild nitrogen stream until a precipitate started to separate. The mixture was chilled in ice, then kept in a refrigerator. The precipitate was collected on a filter and washed with acetonitrile to give 1,1'-dithiobis[3-oxo-1,3-propanediyl]bis[2,3-dihydro-1H-indole-2-carboxylic acid], m.p. 213°-216°.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=2)[O:11][CH2:12][CH2:13][O:14][C:15]2[C:16]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>CCOCC>[N:21]1([C:16]2[C:15]([O:14][CH2:13][CH2:12][O:11][C:10]3[CH:34]=[CH:35][CH:36]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:9]=3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(CN3CCOCC3)c2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1cc(CN2CCOCC2)cc(OCCOc2nccnc2N2CCNCC2)c1
Temperature: 25 °C
Yield: 29 %

Procedure:
The product from step 4 above (54 mg, 0.1 1 mmol) was dissolved in dry ether (20 mL), stirred at room temperature and treated with hydrogen chloride in ether (˜6 M; 5 mL). The resulting white suspension was stirred for 2 h, then quickly filtered off. The hydrochloride salt (hygroscopic), was dissolved in water and neutralized with sodium carbonate. The free base was extracted into dichloromethane. The organic layers were dried magnesium sulfat, filtered, and concentrated in vacuo to furnish 13 mg (29%) of the title product as a pale yellow oil. LS/MS purity 100%. 1H NMR (CDCl3) δ 1.8 (b, 1H); 2.45 (m, 4H); 2.95 (m, 4H); 3.45 (s, 2H); 3.55 (m, 4H); 3.7 (m, 4H); 4.35 (t, 2H); 4.7 (t, 2H); 6.85 (d, 1H); 6.95 (m, 2H); 7.25 (t, 1H); 7.55 (s, 1H); 7.75 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].C(O[C:17](=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=1)C.N12CCCN=C1CCCCC2.C(O)C>CS(C)=O>[CH3:13][S:12][C:6]1[N:7]=[CH:8][C:9]2[CH:10]=[C:18]([C:19]3[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=3)[C:17](=[O:29])[N:3]([CH2:1][CH3:2])[C:4]=2[N:5]=1
Reactant: CCOC(=O)Cc1cc(OC)cc(OC)c1
Reactant: CCNc1nc(SC)ncc1C=O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Temperature: 47.5 °C
Yield: 83.9 %

Procedure:
4.8 Kg of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde and 5.5 Kg of (3,5-dimethoxyphenyl)-acetic acid ethyl ester were dissolved in 10 L of DMSO at room temperature and stirred. 4.4 Kg of 1,8-diazabicyclo[5.4.0]undec-7-ene was added to the reaction mixture. The mixture was heated at about 45-50° C. for at least 3 hours. The reaction was monitored by reverse-phase HPLC. When the reaction was completed, ethyl alcohol (3 L) was added to the reaction vessel, which was cooled to 5-15° C. The yellow product was precipitated and collected by filtration, washed with a mixture of isopropyl alcohol and water (3 L+3 L), and dried in a vacuum tray dryer at about 40-45° C. for at least 12 hours using a house vacuum (˜30 in Hg) to provide 7.3 Kg (84% yield) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one. Proton NMR is consistent with the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[OH:14][C:15]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:11]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccc2[N+](=O)[O-])c1O
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
102 g (2-nitrophenyl)hydrazine and 142 g (Ethoxymethylene)propanedioic acid, diethyl ester are dissolved in 300 ml ethanol and refluxed for 20 hours. After cooling the clear red solution is evaporated and the solvent distilled off. The remaining crystalline residue (168 g) is added to 400 g PPA (polyphosphoric acid) at a temperature of 80° C. The reaction is completed by heating the solution for 10 minutes to 120° C. The solution is then immediately poured on 2 kg ice and stirred for 30 minutes. After filtration the residue is recrystallized from n-propanol to yield 80 g of 5-hydroxy-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester with a melting point of 157°-160° C.; yellow crystals.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28].[Cl:29][CH2:30][C:31](Cl)=[O:32].Cl>>[CH2:1]=[CH:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:31]([CH2:30][Cl:29])=[O:32]
Reactant: O=C(Cl)CCl
Reactant: C=CCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: Cl
Product: C=CCOCCOCCOCCOCCOCCOCCOCCOCCOC(=O)CCl
Temperature: 67 °C
Reaction time: 0.5 h

Procedure:
205.3 g (0.5 mol) of a molar-mass distributed polyether having the average structure CH2═CHCH2(OCH2CH2)8OH were placed under nitrogen at room temperature. Within 30 minutes, 63.4 g (0.55 mol) chloroacetic acid chloride were added dropwise, under intense stirring. During the dropwise addition, the temperature increased to 67° C., and an intensive formation of HCl set in. Upon completion of the dropwise addition, the batch was heated to 120° C. for 40 minutes. Finally all constituents boiling at up to 120° C. and 20 hPa were then removed via distillation. 243.6 g of a yellow, viscous liquid of the composition CH2═CHCH2(OCH2CH2)8OC(O)CH2Cl were obtained. It was determined using gas chromatography that neither chloroacetic acid chloride, chloroacetic acid, nor the OH-terminated oligoethylene glycols are present in the reaction product.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>ClCCl>[C:1]1([S:7]([N:10]2[CH:11]=[CH:12][CH:13]=[C:14]2[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:24])=[CH:16][CH:17]=2)=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cccn2S(=O)(=O)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 168 h
Yield: 70.7 %

Procedure:
To a solution of 1-benzenesulfonyl-1H-pyrrole (284 g, 1.37 mol) in dichloromethane (1.0 L) were added p-toluoyl chloride (318 g, 2.06 mol) and boron trifluoride-diethyl ether (350 g, 2.47 mol) under an atmosphere of nitrogen. The mixture was allowed to stand at room temperature for 7 days. The reaction solution was washed with 1N hydrochloric acid (750 ml) twice, an aqueous 1N sodium hydroxide solution (750 ml) and a saturated aqueous sodium chloride solution (100 ml) in the order, dried and filtered. The filtrate was further concentrated to about 500 ml at atmospheric pressure, followed by addition of hexane (500 ml). Further the solution was concentrated to about 500 ml and cooled to 10° C. The precipitate was filtered, washed with hexane and toluene in the order, and dried to give the subject compound (315 g, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1C(O)=O.ClC(OCC)=O.[N-:21]=[N+]=[N-].[Na+]>CC(C)=O.O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[NH2:21]
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](N)[C@@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 69.3 %

Procedure:
To a solution of trans-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid (1.78 g, 9.4 mmol) in acetone was added water (4 mL) followed, at −5° C., by ethyl chloroformate (0.982 mL, 10.34 mmol). The reaction mixture was stirred for 20 minutes and then a solution of sodium azide (731 mg, 11.28 mmol) in water (8 mL) was added. The resulting mixture was stirred for 45 minutes and then diluted with a 1:1 mixture of water and toluene. The organic layer was separated, dried over Na2SO4, filtered and heated at 100° C. for 1 hour. The solvent was then removed under reduced pressure and an aqueous solution of HCl (8 M, 30 mL) was added, and the resulting mixture was heated at reflux for 45 minutes. The reaction mixture was cooled and an aqueous solution of HCl (10%) was added; the resulting mixture was washed with ethyl ether, then basified by addition of NaOH. The resulting mixture was extracted with ethyl ether, and the combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure to give 1.05 g (70% yield) of trans-2,2-dimethyl-3-phenyl-cyclopropylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13](Cl)(=[O:15])=[O:14])([O-:3])=[O:2].[C:17]1([N:23]2[C:27]([SH:28])=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[C:17]1([N:23]2[C:27]([S:28][S:13]([C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14])=[N:26][N:25]=[N:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Sc1nnnn1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Sc2nnnn2-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
In 100 ml of tetrahydrofuran were dissolved 10 g of 2,4-dinitrophenylsulfonyl chloride and 7.3 g of 1-phenyl-5-mercaptotetrazole and the solution obtiained was cooled to 0° C. Then, 4.1 g of triethylamine was gradually added dropwise to the solution. After one hour, the solvent was distilled off and the residue was crsytallized from a mixture of acetonitrile to provide 6.2 g of the desired product having a melting point of from 128° C. to 130° C.
Reaction SMILES: CN(C[C:5]1[N:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[N:10]=[C:7]2[S:8][CH:9]=1)C.[N+](C1C=CC=CC=1C1N=[C:31]2[N:35]([CH:36]=1)[CH:34]=C(CO)S2)([O-])=O>>[CH3:34][N:35]([CH2:36][C:9]1[S:8][C:7]2=[N:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[CH:12][N:6]2[CH:5]=1)[CH3:31]
Reactant: O=[N+]([O-])c1ccccc1-c1cn2cc(CO)sc2n1
Reactant: CN(C)Cc1csc2nc(-c3ccccc3N)cn12
Product: CN(C)Cc1cn2cc(-c3ccccc3N)nc2s1

Procedure:
Essentially the same procedure used during the preparation of 2-(3-dimethylaminomethyl-imidazo[2,1-b]thiazol-6-yl)-phenylamine was employed, except that [6-(2-nitro-phenyl)-imidazo[2,1-b]thiazol-2-yl]-methanol was used as the starting material.
Reaction SMILES: [C:1]([O:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)(=[O:17])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)=[O:5].OC1CC(C)(C)NC(C)(C)C1.C([O-])(=O)CCCC([O-])=O.[C:49]([O:67][CH:68]1[CH2:73][C:72]([CH3:75])([CH3:74])[N:71](C)[C:70]([CH3:78])([CH3:77])[CH2:69]1)(=[O:66])[CH2:50][CH2:51][C:52](OC1CC(C)(C)N(C)C(C)(C)C1)=O>>[C:1]([O:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)(=[O:17])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:8][C:9]([CH3:16])([CH3:15])[NH:10][C:11]([CH3:14])([CH3:13])[CH2:12]1)=[O:5].[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)(=[O:5])[CH2:52][CH2:51][CH2:50][C:49]([O:67][CH:68]1[CH2:69][C:70]([CH3:77])([CH3:78])[NH:71][C:72]([CH3:74])([CH3:75])[CH2:73]1)=[O:66]
Reactant: CN1C(C)(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Agent: CC1(C)CC(O)CC(C)(C)N1
Agent: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=C([O-])CCCC(=O)[O-]
Product: CC1(C)CC(OC(=O)CCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
The use of di-(2,2,6,6-tetramethyl-4-piperidinyl) succinate as a light stabilizer for synthetic rubber latices containing TiO2 is suggested in Japanese Patent A-84/53545. The compound is mentioned there, but is not described in detail. Both compounds can be prepared process of U.S. application No. 3,840,494 by transesterifying 4-hydroxy-2,2,6,6-tetramethylpiperidine with a dialkyl succinate or glutarate, respectively. The homologous di-(1,2,2,6,6-pentamethyl-4-piperidinyl) succinate is also mentioned in U.S. application No. 3,840,494. Owing to its low melting point, however, this compound is not very suitable for use as a stabilizer for thermoplastic polymers. In contrast, di-(2,2,6,6-tetramethyl-4-piperidinyl) succinate melts at 118° C. and di-(2,2,6,6-tetramethyl-4-piperidinyl) glutarate melts at 83°-84° C., as a result of which dry mixing with the powdered or granulated thermoplastic polymer is possible.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([NH:12][CH2:13][CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>C(Cl)(Cl)Cl>[CH2:5]([NH:12][CH2:13][CH2:14][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCCNCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: ClCCNCc1ccccc1

Procedure:
100 ml. of thionyl chloride are added to a stirred solution of 100 g. of 2-benzylaminoethanol in 500 ml. of chloroform over a period of 20 minutes. The mixture is refluxed for 6 hours. 1350 ml. of ether is added to the cooled chloroform solution and the mixture is stored in the refrigerator overnight. The product, N-benzyl-2-chlorethylamine hydrochloride, is filtered off and crystallized from ethanol-ether; yield 130.9 g., m.p. 192°-194°.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24]1>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:31]3\[C:23](=[O:22])[NH:24][C:25]4[C:30]\3=[CH:29][C:28]([NH:32][C:33](=[O:35])[CH3:34])=[CH:27][CH:26]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(NC(C)=O)cc43)c(C)c2C1=O
Yield: 18.9 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide 30d obtained from step 3 of Example 30 as starting materials to obtain (Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide 51 (12 mg, yield 18.9%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[OH:23])=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH2:42]Cl)[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH2:42][O:23][CH:9]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:14][CH:13]3[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:10]2[CH2:11][CH2:12]3)[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCc1cc(OCc2ccccc2)c2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(O)C(c1ccc(F)cc1)C2
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1cc(OCc3ccccc3)c3ccccc3c1)C(c1ccc(F)cc1)C2

Procedure:
Alkylation of tert-butyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylate with 1-benzyloxy-3-chloromethyl-naphthalene (Example 19) analogously to the procedure described in Example 1 (g) yielded tert-butyl (1RS,2RS,3RS,5SR)-2-(4-benzyloxy-naphthalen-2-yl-methoxy)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless solid; MS: 568 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@@H:12]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([CH:26]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[C:27]2=[O:39])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]2[CH2:16][CH2:15][N:14]([CH:26]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[C:27]3=[O:39])[CH2:13][C:12]2=[O:11])=[CH:19][CH:20]=1
Reactant: COc1ccc([C@H]2CCN(C3CCN(Cc4ccc(C)cc4)C3=O)C[C@@H]2O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CCN(C3CCN(Cc4ccc(C)cc4)C3=O)CC2=O)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
A mixture of DMSO (0.17 mL, 2.46 mmol) and DCM (4 mL) was cooled to −78° C., and oxalyl chloride (0.2 mL, 2.3 mmol) was added dropwise over 2 min. Following the addition, the mixture was stirred at the same temperature for 10 min. To the reaction was then added dropwise (±)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (375 mg, 0.95 mmol, mixture of four diastereomers from step E) in DCM over 5 min. The mixture was stirred for 1 h, and then triethylamine (1 mL, 7.6 mmol) was added and the mixture was stirred for 15 min, slowly warmed to rt, and then extracted with 3×40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under vacuum to yield 345 mg of 4-(4-methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-3-one (as a mixture of 4 diastereomers), which was used directly in the next step. LCMS (method)) RT 1.12 min, m/z 393 (M+H+), 411 (M+H++18), 1.18 min, m/z 393 (M+H+).