Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6][NH2:7])[O:2]1.[CH:16]([C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=1)[O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:15]1[CH2:1][O:2][C:3]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([CH2:4][CH2:5][CH2:6][NH:7][CH2:16][C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[O:14]1
Reactant: CCC(Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Reactant: NCCCC1(c2ccccc2)OCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(Oc1cccc(CNCCCC2(c3ccccc3)OCCO2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
4,4-Ethylenedioxy-4-phenylbutylamine (27.0 mg, 0.13 mmol) was dissolved in chloroform (3 ml) at room temperature, and thereto were added tert-butyl 2-(3-formylphenoxy)butyrate (34.4 g, 0.13 mmol) in a chloroform solution (2 ml) and sodium triacetoxyborohydride (41.4 mg, 0.20 mmol) in sequential order at the same temperature, and thereafter, the mixture was stirred at room temperature for 12 hours. The reaction solution was added to a saturated aqueous sodium hydrogencarbonate solution and thereafter extracted by chloroform. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant substance was purified by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained as a colorless oil (38.5 mg, 64.9%).
Reaction SMILES: [F:1][CH:2]([F:26])[CH2:3][N:4]1[CH2:21][CH:20]([C:22](=O)[C:23]#[CH:24])[O:19][C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5]1.[NH2:27][NH2:28].Cl>C(O)C>[F:1][CH:2]([F:26])[CH2:3][N:4]1[CH2:21][CH:20]([C:22]2[CH:23]=[CH:24][NH:28][N:27]=2)[O:19][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1
Reactant: C#CC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: FC(F)CN1CC(c2cc[nH]n2)OC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 8-(2,2-difluoroethyl)-10-prop-2-ynoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (25 mg, 0.07 mmol), hydrazine (42 μL, 1.34 mmol) and ethanol (0.5 mL) was stirred for 1 hour at room temperature. The solution was concentrated in vacuo to give the crude pyrazole as a yellow oil. HCl (400 μL of 4 M in dioxane, 1.60 mmol) followed by ethanol (0.2 mL) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was concentrated in vacuo to give 8-(2,2-difluoroethyl)-10-(1H-pyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane as a gummy yellow solid. ESI-MS m/z calc. 286.2. Found 287.1 (M+1)+; Retention time: 0.32 minutes (3 min run).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:22](=[O:24])[NH2:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=O)(C)(C)C.[ClH:25].CCOCC>C(OCC)(=O)C>[ClH:25].[NH2:8][C@@H:9]([C:22](=[O:24])[NH2:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NC(=O)[C@H](N)CCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To 3.36 of benzyl t-butyloxycarbonyl-D-isoglutaminate (4, n = 2) there is added 50 ml of a saturated solution of hydrogen chloride in ethyl acetate. The reaction mixture is stored at 22° C for 10 minutes and then 75 ml of ether is added to precipitate the product, which is collected by centrifugation and carefully dried in vacuo to give benzyl D-isoglutaminate hydrochloride (5, n = 2) which is used without further purification in step B of this example.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[C:12]1([C:9]2[C:8]3[CH:18]=[C:4]([CH2:3][C:1]4[NH:21][N:20]=[N:19][N:2]=4)[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc2occ(-c3ccccc3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2coc3ccc(Cc4nnn[nH]4)cc23)cc1

Procedure:
A mixture of 4.6 g. (0.02 mole) of 5-cyanomethyl-3-phenylbenzofuran, 1.5 g. of sodium azide and 1.2 g. of ammonium chloride in 15 ml. of N,N-dimethylformamide is heated at 110° C. for 20 hours. The reaction mixture is poured into 200 ml. of water and stirred. The mixture is extracted with 50 ml. of chloroform. The extracts are washed with water, then dried over magnesium sulfate. Evaporation provides a residue which is recrystallized from ethyl acetate to provide 3-phenyl-5-(1H-tetrazol-5yl)methylbenzofuran.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:8][C:9](=[O:35])[C@@H:10]([C@@H:15]([C:25](=[O:34])[NH:26][O:27]C1CCCCO1)[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:6])=[O:5].O.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CO>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[NH2:1][CH2:2][CH2:3][S:4]([N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:8][C:9](=[O:35])[C@@H:10]([C@@H:15]([C:25](=[O:34])[NH:26][OH:27])[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:5])=[O:6]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.3 %

Procedure:
A solution of 0.25 g of (E)-2′-(2-aminoethanesulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.1 g of p-toluene-sulphonic acid monohydrate. The mixture was stirred for 2.5 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.255 g of (E)-2′-(2-aminoethanesulphonyl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide p-toluene-sulphonate in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.Cl>C1COCC1>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[Cl:1])=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(F)cc1)c1cccnc1Cl
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
2-Chloronicotinic acid (2.5 grams, 15.9 mmol) and 80 ml THF is placed in a 250 ml three neck round bottom flask equipped with mechanical stirring, a thermometer and a rubber septum with a nitrogen inlet. The reaction mixture is cooled to -5° C. and N-methylmorpholine (1.6 grams, 15.9 mmol) added via syringe. Isobutyl chloroformate (2.2 grams, 15.9 mmol) is then added via syringe while maintaining the temperature below 0° C. The reaction is stirred for 30 minutes at -5° C. The p-fluorobenzylamine (2.2 grams, 17.5 mmols) is then added via syringe, keeping the temperature below 0° C. The reaction is allowed to warm to room temperature and stirred for 18 hours, after which 1M HCl (30 ml) is added. This is then extracted with ethyl acetate (2×30 ml), and the combined organics washed with 1M HCl (1×30 ml), 3M NaOH (2×30 ml), H2O (1×50 ml) and brine (1×50 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to a yellow solid. This is triturated with diethyl ether, filtered, washed with fresh diethyl ether and dried in vacuo to yield 3.4 g (80.5%) of the desired chloronicotinamide as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:10][CH3:11])[CH:3]=1.F[C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:18]2[CH:19]=[N:20][CH:21]=[CH:13][C:14]=2[C:15]([OH:17])=[O:16])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CN
Reactant: O=C(O)c1ccncc1F
Product: COc1cc(Cl)ccc1CNc1cnccc1C(=O)O
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 4-chloro-2-methoxy-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 8.10 (s, 1H), 8.00 (br s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.24 (d, 1H, J=8.1 Hz), 7.11 (d, 1H, J=1.9 Hz), 6.96 (dd, 1H, J=8.0, 1.9 Hz), 4.47 (s, 2H), 3.87 (s, 3H). [M+H] calc'd for C14H13ClN2O3, 293, 295. found 293, 295.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:10])#[N:2].C([OH:28])C.OO.[OH-].[Na+]>O>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=1)=[O:10])(=[O:28])[NH2:2]
Reactant: CCO
Reactant: COc1ccc(CC#N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 484 mg of 5-cyanomethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 10 ml of ethanol, 0.6 ml of 30% aqueous hydrogen peroxide and 5 ml of 0.1 mol/l sodium hydroxide, and the mixture was stirred for 1 hour at 50° C. Then, 0.6 ml of 30% aqueous hydrogen peroxide and 5 ml of 0.1 mol/l sodium hydroxide were added again and the mixture was stirred for 30 minutes at 50° C. The reaction mixture was poured into water and extracted with ethyl acetate. After washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence, the organic layer was dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=100:1 to 50:1) to obtain 318 mg of 5-carbamoylmethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH:35]([OH:38])[CH2:36][CH3:37].Cl>CN(C=O)C.O>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:37][CH2:36][CH2:35][OH:38])[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reactant: CCC(O)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reaction time: 0.5 h

Procedure:
77 mg (2.55 retool) of 80% sodium hydride in oil are added to 1 g (2.42 mmol) of methyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in solution in 10 ml of DMF. After 1 h 30 min of stirring, 230 ml (2.42 mmol) of bromopropanol are added to this reaction medium which is left stirring for 12 hours at room temperature, under nitrogen. The reaction medium is poured into water, acidified to pH=1 with concentrated HCl and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica in dichloromethane, and crystallized from the dichloromethane/hexane mixture to give 600 mg (53%) of the expected derivative which melts at 201.9° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[C:39]3[C@H:38]4[CH2:40][C@H:37]4[CH2:36][C:35]=3[C:34]([C:41]([OH:43])=O)=[N:33]2)[CH:27]=1.Cl.[NH2:45][CH:46]([C:51]([F:54])([CH3:53])[CH3:52])[C:47]([O:49][CH3:50])=[O:48]>>[CH3:50][O:49][C:47](=[O:48])[CH:46]([NH:45][C:41]([C:34]1[C:35]2[CH2:36][C@@H:37]3[CH2:40][C@@H:38]3[C:39]=2[N:32]([C:28]2[CH:27]=[C:26]([Cl:25])[CH:31]=[CH:30][N:29]=2)[N:33]=1)=[O:43])[C:51]([F:54])([CH3:53])[CH3:52]
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Reactant: COC(=O)C(N)C(C)(C)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)C(NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21)C(C)(C)F

Procedure:
The title compound was prepared by HATU coupling method using (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and methyl 2-amino-3-fluoro-3-methylbutanoate hydrochloride. LCMS m/z=407.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.42-0.50 (m, 1H), 1.23-1.30 (m, 1H), 1.49 (d, J=21.6 Hz, 3H), 1.57 (d, J=21.0 Hz, 3H), 2.22-2.30 (m, 1H), 2.79-2.85 (m, 1H), 2.87-3.05 (m, 2H), 3.81 (s, 3H), 4.85-4.94 (m, 1H), 7.22 (dd, J=5.4 and 1.8 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].O[NH:13][C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[NH:15]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[O:6][N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[N:13]=1
Reactant: COC(=O)CCCCC(=N)NO
Reactant: COc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CCCCc1noc(-c2ccccc2OC)n1
Yield: 34.4 %

Procedure:
Add 2-methoxybenzoyl chloride (5.20 g, 35 mmol) to a solution of methyl 5-(N-hydroxycarbamimidoyl)pentanoate (5.3 g, 34 mmol) in pyridine (50 mL) under nitrogen at 0° C. and then heat the mixture at reflux for 6 h. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate and wash with 1 N HCl. Wash the combined organic extracts with brine, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:4), to afford methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.4 g, 33% over two steps): 1H NMR (CDCl3) δ1.7-1.85 (m, 2H), 1.85-2.00 (m, 2H), 2.35 (t, 2H), 2.95 (t, 2H), 3.65 (s, 3H), 3.95 (s, 3H), 7.00 (m, 2H), 7.45 (t, 1H), 8.00 (d, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21](=[O:32])[C:22]2[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:24]=1)[CH2:10][CH3:11]>CN(C)C=O>[Br:1][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:9][CH2:10][CH3:11])=[C:14]([C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)[CH:15]=1
Reactant: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 83.6 %

Procedure:
N-Bromosuccinimide (2,6g, 0.016 mol) in dimethylformamide (40 ml) was added dropwise to a stirred solution of 5-(2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 10, 4.0 g, 0.010 mol) in dimethylformamide (40 ml) at room temperature. After 7 hours the solvent was removed by evaporation under vacuum, the residue suspended in saturated aqueous sodium carbonate solution, and the resulting solution extracted with ethyl acetate (3×50 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum. Trituration of the residue with ether, followed by crystallisation from ethyl acetate-hexane, gave the title compound as white crystals (3.39 g, 68%), m.p. 117°-118° C. Found: C,53.15; H,5.03; N,13,78. C18H21BrN4O2 requires C,53,34; N,5.22; N,13.82%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Br)cn1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cn1

Procedure:
Operations similar to those of Production Example 14 were conducted using 5-bromo-2-pyridinecarboxylic acid and 4-fluorophenylboronic acid, to provide the title compound as white solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C@H:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[CH2:3][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S*,4R*)-tert-butyl 3-amino-4-(3-hydroxypropyl)pyrrolidine-1-carboxylate (0.55 g, 2.25 mmol) and p-nitrophenylsulfonyl chloride (0.50 g, 2.25 mmol) and Na2CO3 (0.29 g, 2.70 mmol) in 8 mL THF-water, 3:1, was stirred overnight at room temperature. THF was evaporated, the mixture was diluted with H2O, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1→5% MeOH in CH2Cl2 giving the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][N:14]2C(OC(C)(C)C)=O)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9](=[O:32])[CH:10]2[CH:15]([NH:14][CH2:13][CH2:12][NH:11]2)[C:16]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C2C(=O)N(Cc3ccccc3)C(=O)C21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C2NCCNC2C(=O)N1Cc1ccccc1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of 650 mg (1.5 mmol) of 8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonane-7,9-dione in tetrahydrofuran (10 ml) was added 4N hydrogen chloride solution in ethyl acetate (10 ml) with stirring. After 30 minutes at 50° C., a 2.5N aqueous solution of sodium hydroxide (17 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 85 mg (yield: 24%) of 8-benzyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dione as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])[CH2:4][CH2:3][C:2]1=[O:12].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]([N:1]1[CH:5]([C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7])[CH2:4][CH2:3][C:2]1=[O:12])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)OC(=O)C1CCC(=O)N1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N1C(=O)CCC1C(=O)OC(C)C
Yield: 17.9 %

Procedure:
10.0 g of isopropyl 2-pyrrolidone-5-carboxylate was dissolved in 58.4 g of toluene, and 13.04 g of lauroyl chloride was added thereto. Further, 6.03 g of triethylamine was dropwise added, and reacted under reflux for 2 hours. Toluene was concentrated under reduced pressure, then the reaction mixture was purified through silica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1) to obtain 3.69 g of isopropyl N-lauroyl-2-pyrrolidone-5-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=O)[CH3:8])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][NH2:21].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([CH3:8])[N:20]([C:14]2[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:21]=1)=[O:11])[CH3:2]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2c(Cl)cccc2Cl)n1
Temperature: 80 °C
Yield: 66.7 %

Procedure:
Into a 2000 mL flask was weighed 35.33 g (223.5 mmol) of 2,4-dioxopentanoic acid ethyl ester, 50 g (234.7 mmol) of 2,6 dichlorophenyl hydrazine, 400 mL of acetic acid and 400 mL of ethanol. The resulting solution was heated at 80° C. for 18 h and was then cooled and was washed into a separatory funnel with 1.0 M aq. NaOH and ethyl acetate. The organic layer was separated, washed with sat. aq. NaHCO3, brine, dried over Na2SO4, and was concentrated in vacuo. The residue was recrystallized from EtOH-heptanes to afford 1-(2,6-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (44.6 g, 60%); 1H NMR (400 MHz, DMSO-d6): δ 7.67 (d J=7.67 Hz, 2H), 7.57 (m, 1H), 4.17 (q, J=7.07 Hz 2H), 1.97 (s, 3H); 1.18 (t, J=7.07 Hz 3H), MS (ES): 321 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:14]([NH:21][CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O>[CH2:14]([N:21]([CH2:10][C:9]1[C:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(OC)c1ncccc1C=O
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(OC)c1ncccc1CN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
To a mixture of 2.0 g (11 mmol) of 2-dimethoxymethyl-pyridin-3-carbaldehyde and 1.6 mL (12 mmol) of N-benzyl methyl amine in 30 mL of dichloroethane is added 4.7 g (22 mmol) of sodium triacetoxyborohydride. The reaction is stirred for 18 hours at room temperature. To this mixture is added 20 mL of water. After 1 hour of stirring the pH of the reaction mixture is adjusted to 8.0 with 1N NaOH. The organic layer is separated from the water layer, dried and evaporated to yield 1.9 grams of benzyl-(2-dimethoxymethyl-pyridin-3-ylmethyl)-methyl-amine. 1H NMR (CDCl3) δ8.5 (d, 1H), 7.9 (d, 1H), 7.3 (m, 6H), 5.6 (s, 1H), 3.7 (s, 2H), 3.5 (s, 2H), 3.3 (s, 6H) 2.1 (s, 3H). Mass spectrum: m/e=287.8 (p+1). TLC (1/1 ethyl acetate/hexanes) Rf=0.2.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH:5][CH3:6])=[CH2:3].[CH3:7][CH:8]([CH3:16])/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH3:6][CH:5]1[CH:4]=[C:2]([CH3:3])[CH2:1][CH:9]([CH:8]([CH3:16])[CH3:7])[CH:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/C(C)C
Reactant: C=C(C)C=CC
Product: CCOC(=O)C1C(C)C=C(C)CC1C(C)C

Procedure:
A mixture of 82 g (1.0 mol) of 2-methyl-1,3-pentadiene and 92.3 g (0.65 mol) of ethyl trans-4-methyl-2-pentenoate was heated at 175°-185° C. in an autoclave for 6 hours. After cooling, the reaction mixture was distilled. 57 g were obtained of the desired compound as a mixture of approx. 60% cis-trans- and 40% trans-trans-isomer. b.p.: 90°-91° C./0.7 kPa, NMR (cis-trans-isomer): 0.75 (3H, d, J=7 Hz); 0.8-1.0 (6H, d.d., J=7 Hz); 1.25 (3H, t, J=7 Hz); 1.64 (3H, broad s); 1.5-2.6 (6H); 4.09 (2H, k, J=7 Hz); 5.30 (1H). NMR (trans-trans-isomer): 0.8-1.0 (9H, 3xd, J=7 Hz); 1.27 (3H, t, J=7 Hz); 1.64 (3H, broad s); 1.5-2.6 (6H); 4.13 (2H, m); 5.12 (1H).