Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.C(O[C:10]([N:12](C)[C@@H:13]([CH2:17][CH2:18][CH:19]=[CH2:20])[C:14]([OH:16])=[O:15])=O)(C)(C)C.[CH3:22]O>>[ClH:3].[CH3:10][NH:12][C@@H:13]([CH2:17][CH2:18][CH:19]=[CH2:20])[C:14]([O:16][CH3:22])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: C=CCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: C=CCC[C@H](NC)C(=O)OC
Product: Cl
Temperature: 25 °C

Procedure:
Step K (2): Thionyl chloride (1.22 mL, 16.9 mmol) was added to a round bottom flask charged with a solution of (S)-2-(tert-butoxycarbonyl(methyl)amino)hex-5-enoic acid (2.06 g, 8.47 mmol) from Step K (1) in MeOH at 0° C. After complete addition, heated at reflux for 2 h. Cooled to rt, concentrated in vacuo, and removed residuals on high vacuum overnight. This afforded 1.64 g (quantitative yield) of the title compound as an off-white solid. LC-MS (M+H)+=158.3; 1H NMR (500 MHz, CDCl3) δ ppm 2.09-2.27 (m, 3H) 2.29-2.43 (m, 1H) 2.71-2.81 (m, 3H) 3.77-3.88 (m, 3H) 5.04 (d, J=10.07 Hz, 1H) 5.12 (d, J=17.09 Hz, 1H) 5.68-5.82 (m, 1H) 9.59-9.72 (br s, 1H) 9.99-10.12 (br s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:30]Br>C(O)(=O)C>[CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[C:10]([Br:30])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1cc(OCc2cccc(Cl)c2)cc(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(OCc2cccc(Cl)c2)c(Br)c(=O)n1Cc1ccccc1
Reaction time: 1 h

Procedure:
The product of example 38 (SC-83316), 1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.91 mmol, 310 Mg), acetic acid (20 mL), and sodium acetate (0.91 mmol, 80 Mg) were stirred at room temperature when bromine (0.91 mmol, 145 Mg) was added. After stirring for one hour, the mixture was concentrated, dissolved in ethyl acetate, and washed successively with saturated aqueous sodium bicarbonate solution, brine, and water. After drying over magnesium sulfate and concentrating, the product was recrystallized from tetrahydrofuran/hexanes to yield a white solid. (240 Mg, 63%): 1H NMR (DMSO-d6/300 MHz) 7.6-7.0 (m, 10H), 6.5 (s, 1H), 5.33 (s, 2H), 5.33 (s, 2H), 2.3 (s, 3H). ES HRMS m/z 420.019 (M+H, C20H17NO2BrCl requires 420.019).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([CH2:11][OH:12])[CH3:10].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]([NH:8][CH:9]([CH3:10])[CH2:11][OH:12])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
31.3 ml of triethylamine were added to a solution of 16.9 g of DL-alaninol in 100 ml of anhydrous tetrahydrofuran, after which 100 g of benzyloxycarbonyl chloride (as a 30% to 35% w/v solution in toluene) were added dropwise, whilst ice-cooling. The reaction mixture was then stirred at room temperature overnight. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 18.07 g of the title compound, melting at 52.2° C. to 56.6° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[C:4]([I:25])[C:3]=1[OH:26].[CH3:27]I>>[CH3:27][O:26][C:3]1[C:2]([I:1])=[CH:7][C:6]([C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][C:4]=1[I:25]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(I)c(O)c(I)c1
Reactant: CI
Product: COc1c(I)cc(C(=O)NCCCCCCCCc2ccccc2)cc1I

Procedure:
The title compound was prepared as a solid (0.691 g, 94%) from 2,6-diiodo-4-(8-phenyl-octylcarbamoyl)phenol using methyl iodide and a procedure similar to step 4 of Example 93; 1H NMR (DMSO-d6) δ 1.19–1.34 (m, 8H), 1.41–1.61 (m, 4H), 2.48–2.59 (m, 2H), 3.21 (dd, J=6.4, 14.1 Hz, 2H), 3.78 (s, 3H), 7.10–7.21 (m, 3H), 7.21–7.31 (m 2H), 8.28 (s, 2H), 8.53 (t, J=5.6 Hz, 1H); mass spectrum [(+) ESI], m/z 592 (M+H)+, 614 (M+Na)+.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.OC(C)(C)[C:22]#[N:23]>C1COCC1>[NH2:5][CH:16]([C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:22]#[N:23]
Reactant: CC(C)(O)C#N
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC(N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium bis(trimethylsilyl)amide (42.7 mL) was added to 4-chlorobenzaldehyde (5 g) in THF (100 mL) at −40° C. under nitrogen. The resulting solution was warmed to room temperature and stirred for 4 hours. α-Hydroxyisobutyronitrile (acetone cyanohydrin, 6.50 mL) was then added, and the reaction mixture was stirred at 25° C. for a further 12 hours, then quenched with saturated NaHCO3 (50 mL), extracted with EtOAc (3×100 mL), the organic layer was dried over MgSO4, filtered and evaporated. The crude material was then purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-amino-2-(4-chlorophenyl)acetonitrile as a colourless oil, which solidified on standing to give a white solid (3.40 g, 57.4%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].C([C@H:21]1[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C:22]1([CH3:31])[C:28]([OH:30])=[O:29])C=C.N1C=C[CH:35]=[CH:34][CH:33]=1>>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]\[C:11]([O:27][CH:25]2[CH2:26][CH2:21][C:22]([CH3:31])([C:28]([O:30][CH2:35][CH:34]=[CH2:33])=[O:29])[CH2:23][CH2:24]2)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: C=CC[C@H]1C[C@@H](O)CCC1(C)C(=O)O
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Product: C=CCOC(=O)C1(C)CCC(OC(=O)/C=C\c2ccc(OC(C)=O)c(OC)c2)CC1

Procedure:
2.3 g of 4-acetoxy-3-methoxycinnamoyl chloride, disclosed in the literature [K. Freudenberg and R. Dillenburg, Chem. Ber., 84, 67-70 (1951), was added to a solution of 1.8 g of allyl cis-4-hydroxy-1-methyl-1-cyclohexanecarboxylic acid (Example 7) in 70 ml of pyridine. The resultant solution was reacted at room temperature for 18 hours. After reaction, the solvent was removed in vacuo. To the residue, 150 ml of 2N hydrochloric acid was added. The resultant solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with 2N hydrochloric acid, once with an aqueous sodium hydrogencarbonate solution and once with an aqueous sodium chloride solution, and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The resultant oily substance was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 1.6 g of allyl cis-4--(4-acetoxy-3-methoxycinnamoyloxy)-1-methyl-1-cyclohexanecarboxylate (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.[OH-].[K+]>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: O=Cc1cccs1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(N)c2nc(-c3cccs3)nn2c1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 1.114 g (6.66 mmol) 5,6-diamino-nicotinic acid methyl ester in 40 ml dioxane was treated with 1.578 g (7.33 mmol) O-mesitylenesulfonylhydroxylamine (prepared from ethyl-o-mesitylenesulfonylacetohydroxamate and HClO4 (70%)) for 1 h at room temperature. 0.897 g (8 mmol) thiophene-2-carboxaldehyde and molecular sieves 4 Å was added and heated to 100° C. for 4 h before addition of 1.6 ml 5M KOH in methanol. The mixture was heated to 70° C. for 2 h and stirred at room temperature for 14 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane to yield after evaporation 0.88 g (48%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:17]O>>[CH3:17][O:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Br:1]
Reactant: CO
Reactant: OC(c1ccccc1)c1ccccc1Br
Agent: Cl
Product: COC(c1ccccc1)c1ccccc1Br

Procedure:
A solution of 152 g. of 2-bromobenzhydrol, 1 liter of methanol, and 45 ml. of conc. hydrochloric acid is heated under reflux for 24 hours, cooled, stirred with 100 g. of potassium carbonate, filtered, and distilled to provide 2-bromobenzhydryl methyl ether, b.p. 126°-128° (0.7 mm.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][NH:16][CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>CN1CCCC1=O>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][N:16]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CNCC4C3)cc12
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(S(C)(=O)=O)CC4C3)cc12
Reaction time: 3 h

Procedure:
To a solution of Example 282A in 1-methyl-2-pyrrolidinone (2 mL) was added triethylamine (0.177 mL, 1.267 mmol) and methanesulfonyl chloride (0.033 mL, 0.422 mmol) and the mixture was stirred for 3 hours. The mixture was treated with water and stirred for 10 minutes and the precipitate was filtered, washed with water, and vacuum oven-dried. The solid was suspended in 1 mL methanol and treated with 1 mL 2M hydrogen chloride in ether. The suspension was diluted with 4 mL ether, stirred for 10 minutes, filtered, washed with ether, and vacuum oven-dried to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, Methanol-d4) δ 2.63-2.76 (m, 1H), 2.85 (s, 3H), 3.00-3.13 (m, 1H), 3.11-3.24 (m, 2H), 3.37-3.54 (m, 3H), 3.68-3.77 (m, 1H), 3.80 (s, 3H), 6.39-6.48 (m, 2H), 7.20-7.29 (m, 2H), 7.28-7.37 (m, 1H), 8.43 (d, J=3.9 Hz, 1H). MS (ESI+) m/z 446.2 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O.[Cl-].[Na+].O>[OH:1][N:2]=[C:3]([C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1)[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1
Reactant: COCCNc1nonc1C(Cl)=NO
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride (1.3 g, 5.0 mmol) [made according to Example 1, steps A through E] was stirred in water (10 mL) and warmed to 60° C. for 5 minutes. 3-(trifluoromethyl)aniline [Aldrich, product # A41801] (880 mg, 5.5 mmol) was added in one portion and the reaction stirred for 15 minutes. While remaining at 60° C., a solution of sodium bicarbonate (630 mg, 7.5 mmol) in water (10 mL) was added dropwise over 5 minutes. The reaction was stirred at 60° C. for an additional 50 minutes, and then allowed to cool to room temperature. Ethyl acetate (20 mL) and brine (30 mL) were added to the flask and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to give the desired product as an orange solid (1.4 g, 80%). LCMS calculated for C13H15F3N5O3 (M+H)+: m/z=346.1. 1H NMR (400 MHz, CD3OD): δ 7.36 (t, J=8.2 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 3.60 (t, J=5.2 Hz, 2H), 3.46 (t, J=5.2 Hz, 2H), 3.38 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[ClH:17].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:24]COCCO>>[ClH:17].[C:1]1([N:7]2[CH:11]=[C:10]([C:12](=[O:14])[CH2:13][CH2:24][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnn(-c2ccccc2)c1
Reactant: C1COCCN1
Reactant: CCOCCO
Agent: C=O
Agent: Cl
Product: O=C(CCN1CCOCC1)c1cnn(-c2ccccc2)c1
Temperature: 5 °C

Procedure:
1-Phenyl-4-acetyl pyrazole (17.9 g) was mixed with paraformaldehyde (3.2 g), morpholine hydrochloride (11.71 g) and cellosolve (37 ml). The mixture was refluxed for 30 minutes and then cooled to 5° C. The white coloured Mannich Base was filted and washed with ethyl alcohol (100 ml) and acetone (50 ml). The white solid was dried at 70° C. to give 1-phenyl-4-(β-morpholinopropionyl)-pyrazole hydrochloride ##STR33## m.p. 212°-214° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:18]=[CH:19][S:20][C:3]1=2.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][C:4]3[CH:18]=[CH:19][S:20][C:3]=3[C:2](=[O:1])[C:8]=2[CH:9]=1)(=[O:24])=[O:23]
Reactant: O=C1c2cc(CCCCO)ccc2OCc2ccsc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A chilled stirring solution of 9.5 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol in 200 ml of sieve dried pyridine was treated dropwise with 3.80 g of methanesulfonyl chloride and the addition funnel was rinsed with a few ml of methylene chloride. The stirring solution was allowed to equilibrate to room temperature overnight with the bath in place. The resulting solution was poured into 750 ml of water and was allowed to stand for 15 min. The solids were collected by filtration, and dried in vacuo overnight at 42°0 C. Concentration of the mother liquor produced additional solids which were combined with the first crop and dried to give a total of 9.09 g of crude material. A 2.0 g portion of the product was recrystallized from hexane/ethyl acetate to give 1.3 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol methanesulfonate, m.p. 97°-98° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[N+:5]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O-:7])=[O:6].BrC1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(O)C>[CH:2]([C:3]1[CH:31]=[CH:30][C:27](/[CH:28]=[CH:12]/[C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:22][CH:21]=2)=[CH:26][CH:25]=1)=[O:1]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC[O-]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: [Na+]
Solvent: CCO
Product: O=Cc1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium ethoxide in ethanol (0.23 g Na in 10 mL ethanol) was added to a solution containing diethyl p-nitrobenzyl-phosphonate (2.73 g, 0.01 mole), 4-bromobenzaldehyde (1.85 g, 0.01 mole) and ethanol (50 mL) at 0° C. The mixture was warmed to room temperature and stirred overnight. The product was filtered, washed with ethanol and vacuum-dried overnight to give trans-4-formyl-4'-nitrostilbene (2.826 g, 0.0093 mole, 93%, m.p. 251°-219° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:12]=2[NH:11][C:10]1=[O:24].[H-].[Na+].[CH3:27][CH2:28][N:29]([CH2:32][CH2:33]Cl)[CH2:30][CH3:31].Cl.[C:36](=[O:39])(O)[O-:37].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:21][C:20]([F:23])([F:22])[C:36]([OH:37])=[O:39].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[C:14]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:16]([C:18]([NH2:19])=[O:37])=[CH:17][C:12]=2[N:11]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:10]1=[O:24]
Reactant: O=C([O-])O
Reactant: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1Cl
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(-c2ccc(Cl)cc2Cl)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
1-(2,4-Dichlorophenyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (0.1541 g) was dissolved in N,N-dimethylformamide (5 ml), and to the solution was added sodium hydride (21.5 mg). The mixture was stirred at room temperature for 5 minutes. To the mixture were added 2-chlorotriethylamine hydrochloride (92.6 mg) and triethylamine (0.087 ml), and the mixture was stirred at 60-70° C. for 15 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was dissolved in 2-methyl-2-propanol (10 ml) and heated at 50° C. To the solution was added powdered potassium hydroxide (0.5810 g), and the mixture was stirred for 1 hour. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by HPLC using condition 1 to give the title compound (88.3 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23]O)=[N:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])=[N:21][CH:22]=1
Reactant: OCc1ccc(Br)cn1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccc(Br)cn1)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.1 %

Procedure:
To a stirred solution of 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1, 110 mg) in tetrahydrofuran (2.5 mL) were added (5-bromo-pyridin-2-yl)-methanol (CAS [88139-91-7], 92 mg), triphenylphosphine (129 mg) and diethyl azodicarboxylate (88 mg). The mixture was stirred for 48 h at r.t. The solvent was evaporated under reduced pressure and the product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give N-(5-bromo-pyridin-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide (106 mg) as a colorless oil. MS: 417.2 ([M+H]+)
Reaction SMILES: N1CCOCC1.C(=O)([O-])[O-].[K+].[K+].C(=O)CC.[CH2:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:18]=[CH2:19]>CS(C)=O>[O:23]1[CH2:24][CH2:25][N:20]([CH:17]=[CH:18][CH3:19])[CH2:21][CH2:22]1
Reactant: C=CCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCN1
Solvent: CCC=O
Solvent: CS(C)=O
Product: CC=CN1CCOCC1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A 500 ml 4-neck flask was equipped with a stirrer, thermometer, addition funnel and condenser. To the flask was charged 191.7 g (2.2 m) of morpholine and 138.2 g (1 m) of potassium carbonate (anhydrous) and the mixture was stirred and cooled to -5° C. with an ice-salt bath. To the flask was added 58 g (1 m) of propionaldehyde over a period of 55 minutes at a pot temperature of -5° C. The temperature was then allowed to rise to 25° to 27° C. and the reaction was continued for 2 hours at 25° C. The product was filtered and the filter cake washed with four 15 ml washes of toluene. The fitrate was heated under vacuum while morpholine was stripped using a 1 foot Vigreux column. This treatment was carried out at an oil bath temperature of 85° to 112° C., a pot temperature of 70° to 90° C., a vapor temperature of 41° to 58° C. and at a pressure of approximately 35 to 40 mm of Hg. The vacuum stripping was carried out until 133.3 g of product was obtained as a residue. GLC and GC/MS established that the predominant product was 4-(2-propenyl)morpholine. 13C NMR in d6 -DMSO (in δ units): 15.2 (CH3); 95.1 (CH3 --CH)=; 140.8 (--CH=CH--); 49.4 (--N(--CH2 --)2); and 66.1 (O(--CH2 --)2).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][C:6](=[N:8][CH2:9][C:10]([CH3:12])=[CH2:11])[CH2:5][C:4]([CH3:14])([CH3:13])[NH:3]1.CC([O-])(C)C.[K+].CS(C)=O>C1(C)C=CC=CC=1>[CH3:13][C:4]1([CH3:14])[CH2:5][C:6](=[N:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:7][C:2]([CH3:15])([CH3:1])[NH:3]1
Reactant: C=C(C)CN=C1CC(C)(C)NC(C)(C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)=CN=C1CC(C)(C)NC(C)(C)C1
Temperature: 50 °C
Yield: 84.2 %

Procedure:
162.5 g of the N-(2,2,6,6-tetramethyl-4-piperidylidene)-2-methylallylamine are dissolved in 162 ml of toluene in a 500 ml three-necked flask with reflux condenser, and 4.86 g of potassium tert-butylate are added. To the reaction mixture are then added, with stirring, 50 ml of dimethyl sulfoxide, and stirring is maintained at 50° C. for 8 hours. The organic phase is afterwards extracted with 100 ml of distilled water, and the organic part, after separation of the solvent, is distilled to yield 136.9 g of N-(2,2,6,6-tetramethyl-4-piperidylidene)-2-methyl-1-amino-1-propene as a colourless liquid, b.p. 56° C. at 40 Pa (82% of theory).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl.[CH3:6][O:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[C-:15]#[N:16].[K+]>CO.O.C(OCC)C>[CH:1]1([NH:4][C:11]2([C:15]#[N:16])[CH2:12][CH2:13][N:8]([O:7][CH3:6])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: NC1CC1
Reactant: CON1CCC(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CON1CCC(C#N)(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopropylamine (1.4 ml, 1.14 g, 20.0 mmol) in methanol (20 ml) at 0° C. was added 1N hydrochloric acid (20 ml, 20.0 mmol) dropwise and the mixture was stirred at room temperature for 30 minutes. 1-Methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (2.58 g, 20.0 mmol), followed 10 minutes later by potassium cyanide (1.3 g, 20.0 mmol) in water (10 ml) were then added dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred overnight, diluted with water and diethyl ether, the layers separated and the aqueous phase thoroughly extracted with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Yield: 3.19 g of 4-cyclopropylamino-1-methoxy-piperidine-4-carbonitrile (title compound P5.2) as an oil. This material was used without further purification in the next step.