Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:19]([NH:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>C(Cl)(Cl)Cl>[Cl-:1].[C:19]([NH:22][C:23]1[CH:28]=[CH:27][N+:26]([CH2:2][C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ccncc1
Reactant: O=C(CCl)Nc1ccccc1Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc[n+](CC(=O)Nc2ccccc2Nc2ccccc2)cc1
Product: [Cl-]
Reaction time: 8 h

Procedure:
Dissolved in 30 ml of chloroform are 6.2 g of 2-chloro-N-[2-(phenylamino)phenyl]acetamide and 5.0 g of 4-acetylaminopyridine, and the solution is left on standing overnight. After completion of the reaction, the reaction mixture is held at 5° C. to 10° C., and left on standing at the same temperature for 5 hours. The precipitates, which separate out, are recovered by filtration and recrystallized from ethanol to give the desired compound of 4-acetylamino-1-[2-oxo-2-[[2-(phenylamino)phenyl]amino]ethyl]pyridinium chloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(CCCCO)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCCCN1CCCc2ccccc21

Procedure:
The 1-(5-hydroxypentanoyl)-1,2,3,4-tetrahydroquinoline (2.0 g) was refluxed for 8 hours in ether (250 ml) containing lithium aluminium hydride (1.0 g). The solution was cooled, water was added, and the ethereal solution was extracted with dilute hydrochloric acid. The extract was basified with sodium hydroxide and extracted with ether. The ethereal solution was dried and evaporated to afford the title compound as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH:10]2[CH:15]3[O:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[O:19][CH:14]3[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[CH3:24][I:25]>>[I-:25].[CH2:13]1[CH:14]2[CH:15]([O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[O:19]2)[CH:10]([O:9][CH2:8][CH2:7][N+:4]2([CH3:24])[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:11][CH2:12]1
Reactant: CI
Reactant: c1ccc2c(c1)OC1CCCC(OCCN3CCOCC3)C1O2
Product: C[N+]1(CCOC2CCCC3Oc4ccccc4OC23)CCOCC1
Product: [I-]
Yield: 64.7 %

Procedure:
In an analogous manner as described in Example 8 but starting with 600 g (1.88 moles) of the compound of Example 3 and 537.4 g (3.76 moles) of methyliodide, there were obtained 561 g of the title-compound with melting point 162° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3](O)([CH2:5][CH2:6][C:7]([CH3:10])(O)[CH3:8])[CH3:4].C(Cl)[Cl:13]>>[Cl:1][C:3]([CH3:4])([CH2:5][CH2:6][C:7]([Cl:13])([CH3:10])[CH3:8])[CH3:2]
Reactant: CC(C)(O)CCC(C)(C)O
Reactant: Cl
Reactant: ClCCl
Product: CC(C)(Cl)CCC(C)(C)Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 2 L three neck round bottom flask fit with an overhead stirrer, thermometer, and nitrogen inlet was charged with 1.2 L concentrated HCl. The HCl was stirred land chilled in an ice/salt bath to 0° C. Gradually, 150 g of 2,5-dimethyl-2,5-hexanediol (Aldrich) was added to the HCl. The reaction mixture was initially a milky white slurry which gradually thickened and the ice bath was removed to allow the reaction to warm to 10 C. The solids were isolated by filtration, dissolved in methylene chloride (500 mL) and washed repeatedly with water until neutral to pH paper. The organics were dried over anhydrous magnesium sulfate and left in the refrigerator overnight. The resulting mixture stripped on the rotary evaporator to yield)of white crystalline 2,5-dichloro-2,5-dimethylhexane (152 g, 94% pure by GC). 1HNMR (CDCl3, 500 MHz) δ1.95 (s, 4H); 1.60 (s, 12H).
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].CON(C)[C:23](=[O:25])[CH3:24]>>[CH:17]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C:7]1[C:12]([C:23](=[O:25])[CH3:24])=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][N:8]=1)=[O:6])([CH3:19])[CH3:18]
Reactant: CON(C)C(C)=O
Reactant: CC(C)N(C(=O)c1ccc(C(F)(F)F)cn1)C(C)C
Product: CC(=O)c1cc(C(F)(F)F)cnc1C(=O)N(C(C)C)C(C)C

Procedure:
Prepared in analogy to Example A17(b) from 5-Trifluoromethyl-pyridine-2-carboxylic acid diisopropylamide (CAS: 765298-31-5) and N-methoxy-N-methylacetamide instead of dimethylformamide. Orange solid. MS (m/e): 317.1 ([M+H]+, 100%)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([O:45]CC)=[O:44])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:16][C:15]1[C:10]2[N:9]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[N:8]=[C:7]([C:37]3[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([OH:45])=[O:44])=[CH:39][CH:38]=3)[C:11]=2[C:12]([O:17][CH3:18])=[N:13][CH:14]=1
Reactant: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1ccc(OCC(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate obtained in Step A of Example 152 (250 mg) in DMF (3 mL)/water (0.3 mL) were added ethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (241 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (23 mg) and cesium carbonate (367 mg). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate, and neutralized 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (166 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:47]=[CH:46][C:13]([C:14]2[C:19]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:30]5N(CC)[C:33]6[CH:37]=[CH:38][C:39]([C:41]([OH:43])=[O:42])=[CH:40][C:32]=6[N:31]=5)[CH:26]=4)[N:21]=3)=[CH:18][C:17]([O:44][CH3:45])=[CH:16][CH:15]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:8]1[C:33]2[CH:37]=[CH:38][C:39]([C:41]([OH:43])=[O:42])=[CH:40][C:32]=2[N:31]=[C:30]1[C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:19]1[C:14]([C:13]3[CH:46]=[CH:47][C:10]([Cl:9])=[CH:11][CH:12]=3)=[CH:15][CH:16]=[C:17]([O:44][CH3:45])[CH:18]=1)[CH:29]=[CH:28]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: NCc1ccccc1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4Cc4ccccc4)ccc3n2)c1

Procedure:
The title compound was prepared from resin 534a and benzylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:10])=[O:11]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 3-(2,5-dichlorophenylsulfonyloxy)-5-methylphenol (642 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl) dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (700 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.56 (s, 2H), 6.63 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.82 (m, 2H), 2.26 (s, 3H), 2.00 (m, 2H), 1.58 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20](Cl)=[O:21])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].O>CCCCC>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:20](=[O:21])[C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=2[F:12])[CH2:23][CH2:24]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Solvent: O
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a slurry of 6.6 g of aluminum chloride and 20 ml of 1,3-difluorobenzene was added, with stirring at ambient temperature, 5.0 g of N-acetylisonipecotyl chloride. The reaction mixture was heated under reflux for 11/2 hrs and then poured onto 100 ml of ice and water. The mixture was extracted with chloroform. The chloroform fractions were combined, washed with water and dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate gave an oil. Trituration of the oil with pentane gave 4.65 g (65.9%) of product, mp, 100°-102°.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]#[N:33])[CH:30]=2)[NH:25][CH:24]=1.C(N(CC)CC)C.C(N(C(C)C)C(C)C)C>C(#N)C>[ClH:18].[ClH:18].[O:1]=[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]#[N:33])[CH:30]=4)[NH:25][CH:24]=3)[CH2:10][CH2:9]2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: O=c1cc(N2CCNCC2)c2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cl
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4cc(=O)oc5ccccc45)CC3)c2c1
Reaction time: 8 h

Procedure:
0.79 g (0.003 mol) of 4-(2-oxo-2H-1-benzopyran-4-yl)piperazine [obtainable, for example, by reaction of N,N-bis(2-chloroethyl) amine with 4-amino-2-oxo-2H-1-benzopyran] and 0.80 g (0.003 mol) of 3-(4-chloro-butyl)-5-cyanoindole [which can be prepared by reduction of 3-(4-chlorobutanoyl) indole-5-carbonitrile] are dissolved in 100 ml of acetonitrile, 0.50 ml (0.004 mol) of triethylamine and 1.20 ml (0.007 mol) of ethyldiisopropylamine are added, and the mixture is stirred overnight on a steam bath. After customary working up, 3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinyl]butyl}indole-5-carbonitrile, dihydrochloride, m.p. 284-285°, is obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[C:8]([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].[F-:13].[Cs+].Br[CH2:16][CH2:17][CH2:18][CH3:19]>COCCOCCOC>[C:3]([CH2:16][CH2:17][CH2:18][CH3:19])([C:8]([F:13])([F:9])[F:10])([C:4]([F:7])([F:6])[F:5])[C:2]([F:11])([F:12])[F:1].[F:13][F:1]
Reactant: [F-]
Reactant: FC(F)=C(C(F)(F)F)C(F)(F)F
Reactant: CCCCBr
Agent: [Cs+]
Solvent: COCCOCCOC
Product: CCCCC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Product: FF
Temperature: 50 °C

Procedure:
6.3 mL (10 g; 50 mmoles) perfluoroisobutylene (CAUTION! highly toxic) were condensed into a heterogeneous mixture of 7.6 g (50 mmoles) cesium fluoride stirring in 20 mL of dry diglyme. A yellow color developed within the reaction mixture, attributed to carbanion formation. After 2 hours of mild heating (about 50° C.) and stirring, 6.9 g (50 mmoles) 1-bromobutane were added. Upon this addition of alkyl halide, much milky precipitate was observed. The reaction was allowed to stir several hours (about 4 hours), then the low boiling product was isolated by attaching a condenser to the reaction set-up and heating to 150° C. Thus 9.8 g of a clear, colorless liquid were distilled from the crude reaction mixture. Further purification by fractional distillation yielded 8.0 g (58% overall yield) of liquid with a boiling point of 108° C. Confirmation of structure (CF3)3CCH2CH2CH2CH3, was provided by proton and fluorine-19 NMR with supporting data from the chemical literature (Knunyants, I. L., Yakobson, G. G., Synthesis of Fluoroorganic Compounds, Springer-Verlag, N.Y., 1985).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[CH:6][CH:5]=[CH:4][C:3]=1[S:15]([NH:18][C@@H:19]([CH2:23][C:24]1[CH:28]=[C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:26][N:25]=1)[C:20]([OH:22])=O)(=[O:17])=[O:16].[NH:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([C:20](=[O:22])[C@@H:19]([NH:18][S:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])[C:2]=2[Cl:1])(=[O:17])=[O:16])[CH2:23][C:24]2[CH:28]=[C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[O:26][N:25]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCCNCC1
Reactant: O=C(O)[C@H](Cc1cc(-c2ccc(Cl)s2)on1)NS(=O)(=O)c1cccc(N2CCOCC2=O)c1Cl
Product: O=C([C@H](Cc1cc(-c2ccc(Cl)s2)on1)NS(=O)(=O)c1cccc(N2CCOCC2=O)c1Cl)N1CCCCCC1

Procedure:
Intermediate 12 (300 mg, 0.55 mmol) and azepane (54 mg, 0.55 mmol) were coupled using the procedure described in example 1; 1.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26].O>O1CCCC1>[C:11]([C:10]1[C:14]([CH3:15])=[C:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[C:25](=[O:26])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)C(=NNc1cccc(Cl)c1)C(C)=O
Reactant: O=C(Cl)Cc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(-c2cccs2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Pentan-2,3,4-trione 3-(3-chlorophenylhydrazone) (2.39 g) was added to a suspension of 66% sodium hydride (0.77 g) in anhydrous tetrahydrofuran (40 ml) under ice cooling, followed by stirring at room temperature for 30 minutes. Then, a solution of 2-thiopheneacetyl chloride (1.77 g) in anhydrous tetrahydrofuran (10 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), and the resulting crude crystals were washed with hexane to obtain 6-acetyl-2-(3-chlorophenyl)-5-methyl-4-(2-thienyl)-3(2H)-pyridazinone (2.19 g) (Compound No. 1-97).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH3:31])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH3:31])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 69.3 %

Procedure:
Using isothiazolidine 1,1-dioxide (53 mg) and (5-bromopyridin-2-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (170 mg) described in Preparation Example 138 and by the reaction and treatment in the same manner as in Example 1, the title compound (130 mg) was obtained.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]([CH3:21])[CH2:7][C@H:8]([CH3:20])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.[NH4+]>C1COCC1>[NH2:17][C:13]1[CH:12]=[C:11]([C@@:9]([OH:10])([CH2:1][CH3:2])[C@@H:8]([CH3:20])[CH2:7][N:6]([CH3:21])[CH3:5])[CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](CN(C)C)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC[C@](O)(c1cccc(N)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
726 ml of ethylmagnesium bromide (1M in THF; 0.726 mol) are added under a nitrogen flow into a 2-liter four-neck flask, provided with mechanical stirrer, thermometer and dropping funnel. A solution of (S)-3-(dimethylamino)-2-methyl-1-(3-nitro-phenyl)-propan-1-one (50 g, 0.242 mol) in 50 ml of THF are dripped maintaining the temperature between 15-30° C. The reaction is stirred at room temperature for 3 hours. It is cooled to about 10° C. and toluene (200 ml) and slowly a 20% ammonium hydrogen sulphate solution (200 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The organic phase is concentrated under vacuum almost to oily residue. Then toluene (200 ml), 30% sodium metabisulfite solution (300 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is washed 2 times with 200 ml of toluene. The organic phases are eliminated while Cert-butylmethylether (200 ml) is added to the aqueous phase. The pH of the mixture is brought to 11-12 with 28% sodium hydroxide. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is eliminated while the organic phase is concentrated under vacuum to oily residue which solidifies by cooling. 35 g of a yellowish solid with a 95% HPLC purity are obtained.
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4]/[C:5](/[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])=[CH:6]\[C:7]([O:9]CC)=O.C(OCCCC)(=O)C.C[Si]([N:34]=[C:35]=[S:36])(C)C.[OH-].[Na+]>CO.O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:5]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:35](=[S:36])[NH:34][C:7](=[O:9])[CH:6]=2)[CH:17]=1
Reactant: CCOC(=O)/C=C(\NCC(N)=O)c1cc(Cl)ccc1OC
Reactant: C[Si](C)(C)N=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCCCOC(C)=O
Product: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(=S)n1CC(N)=O
Temperature: 30 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
A reaction vessel equipped with an efficient stirrer was charged with (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (15 g, 50.2 mmol), butyl acetate (150 mL) and trimethylsilyl isothiocyanate (160.7 mmole, 21.1 g, 22.7 mL) and the mixture was heated to reflux. After 15 hours, the mixture was cooled to 30° C. and treated with 1 N aqueous sodium hydroxide (112.5 mL, 112.5 mmoles). After 30 min, the organic layer was separated and extracted with another portion of 1 N sodium hydroxide (37.5 mL, 37.5 mmoles). The combined aqueous phases were extracted twice with dichloromethane (2×45 mL), filtered, and treated with 6N HCl until a pH of 2.5 was achieved. After stirring for 1 hour, the resulting solid was isolated by vacuum filtration, resuspended in 100 mL of a 1:1 methanol-water solution, heated with stirring at 50° C. for 2 hours, and cooled to room temperature before collecting the solid by vacuum filtration, pulling dry and drying in a vacuum oven (20 mm Hg, 50° C.) for 12 hours to afford 8.7 g of the desired product as a tan solid.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]>C(Cl)(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]=[CH:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCC(O)C=C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: C=CCCCC(=O)C=C
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.6 %

Procedure:
In 100 cc of carbon tetrachloride is dissolved 3.1 g of 1,7-octadien-3-ol, followed by addition of 10 g of activated manganese dioxide. The mixture is stirred at room temperature for 4 days. The reaction mixture is filtered and the solvent is distilled off under a reduced pressure of 20-30 mm Hg. As a fraction at 30°-32° C./4 mm Hg, there is obtained 2 g of 1,7-octadien-3-one. The above fraction is identified to be 1,7-octadien-3-one by the following analyses.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:9]([O:13][C:14](=[O:30])[NH:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([CH2:21][OH:22])[C:17]([F:20])([F:19])[F:18])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][O:22][CH2:21][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([NH:15][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:30])[C:17]([F:18])([F:19])[F:20])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cccc(Br)c1)C(F)(F)F
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)COCC(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)(F)F

Procedure:
With the use of a syringe pump a solution of 1.87 ml (15.17 mmol) ethyl diazoacetate in 8 ml DCM were added to a stirred solution of 2.01 g (5.23 mmol) [1-(3-bromo-phenyl)-2,2,2-trifluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester and 46 mg (0.105 mmol) Rh2 (OAc)2 in 34 ml DCM over a period of 3.5 h. After 30 min the mixture was evaporated and chromatographed on silica gel (c-hexane/0-20% TBME) to give the desired product contaminated with a diazo ester oligomer.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C@H:17]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][NH:19][CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.O>C(OCC)C>[CH2:23]([O:22][C@H:21]1[C@H:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:18][N:19]([Cl:1])[CH2:20]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(CO[C@@H]2CNC[C@H]2OCc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: ClN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-Chlorosuccinimide (7.05 g, 52.6 mmol) was added to a solution of (3R,4R)-3,4-dibenzyloxypyrrolidine (15 g, 52.8 mmol) in diethyl ether (300 ml). The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Addition of toluene (250 ml) and water (200 ml), washing of the organic phase with 2 M sodium thiosufate (200 ml) and water (200 ml), drying with magnesium sulphate gave a solution of (3R,4R)-3,4-dibenzyloxy-1-chloropyrrolidine in toluene. The compound is unstable and was used without further purification.