Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[I-].[K+].[F:9][CH:10]([F:28])[O:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1([CH2:26]Br)[O:23][CH:22]([CH2:24][CH3:25])[CH2:21][O:20]1.O>CN(C)C=O>[F:28][CH:10]([F:9])[O:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1([CH2:26][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[O:23][CH:22]([CH2:24][CH3:25])[CH2:21][O:20]1
Reactant: CCC1COC(CBr)(c2ccc(Cl)cc2OC(F)F)O1
Reactant: c1nc[nH]n1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1COC(Cn2cncn2)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C

Procedure:
5.9 parts of 1,2,4-triazole sodium salt, a catalytic amount of potassium iodide and 12 parts of the 2-(2'-difluoromethoxy-4'-chlorophenyl)-2-bromomethyl-4-ethyl-1,3-dioxolane prepared in (b) are stirred in 100 ml of dimethylformamide for 16 hours at a bath temperature of 130° C. The reaction mixture is cooled to room temperature, poured into 500 ml of water and extracted with 2×300 ml of diethyl ether. The combined organic phases are washed with 2×200 ml of water, dried over sodium sulfate, filtered, and the solvent is removed by evaporation. The oily residue is chromatographed through a 50 cm column of silica gel with a 1:1 mixture of methylene chloride/diethyl ether as eluant. The eluant is removed by evaporation to give a yellow oil with a refractive index nD27 : 1.5132.
Reaction SMILES: C(N(CC)[C:4]1[CH:9]=CC=C[CH:5]=1)C.[Cl:12][C:13]1[CH:18]=[C:17]([O:19]CC#C)[C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1.[F-].[Cs+]>O>[Cl:12][C:13]1[C:18]2[CH:5]=[C:4]([CH3:9])[O:19][C:17]=2[C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1
Reactant: CCN(CC)c1ccccc1
Reactant: C#CCOc1cc(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 185 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
100 ml of N,N-diethylaniline was added to 5.2 g (14 mmol) of 3-(4-chloro-2-fluoro-6-propargyloxyphenyl)-1-methyl-6-trifluoromethyluracil and 6.4 g (42 mmol) of cesium fluoride, followed by stirring at 180 to 190° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.4 g (yield: 26.9%) of the desired product as white powder. Melting point: 196-197° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33](I)[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33]([C:4]#[C:3][CH:2]([CH3:5])[CH3:1])[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 209a, 3-methyl-1-butyne (0.22 g, 3.2 mmol) was used in place of 3,3-dimethyl-1-butyne to react with racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) prepared in Example 190c, CuI (3 mg), triethylamine (0.97 g, 9.6 mmol), and dichlorobis(triphenylphosphine)palladium (11.2 mg, 0.016 mmol) in anhydrous N,N-dimethylformamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-methyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (Yield 50 mg, 28%)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[N:24]([CH:2]=2)[CH:23]=[CH:22][S:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reactant: Nc1nccs1
Solvent: CCO
Product: COc1cc(-c2cn3ccsc3n2)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (520 mg, 1.7 mmol) and 2-aminothiazole (170 mg, 1.7 mmol) in ethanol (10 mL) was heated to reflux for 12 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with a solution of saturated aqueous sodium bicarbonate (25 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to MeOH:EtOAc (1:19) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[2,1-b][1,3]thiazole.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:19][C:18]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:20]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:19][C:18]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:17][N:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cnc(N2CCC(CN)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Reaction time: 3.5 h
Yield: 85.3 %

Procedure:
A solution of 0.612 g (1.17 mmol) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl]-carbamic acid tert-butyl ester in a mixture of methylene chloride (2 mL) and trifluoroacetic acid (2 mL) is stirred for 3.5 hours in a capped flask. The reaction mixture is concentrated under reduced pressure, diluted with water, and washed with diethyl ether. The pH of the aqueous phase is adjusted to alkaline with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The combined organic phase is washed with an aqueous solution of sodium carbonate followed by water then dried over anhydrous sodium sulfate and filtered to remove the drying agent. The aqueous phase is re-extracted with a 1:1 mixture of n-butanol:ethyl acetate followed by n-butanol. The organic phases from these extractions are washed with an aqueous solution of sodium carbonate followed by water. The organic phase is then concentrated under reduced pressure co-evaporating with toluene. The residue is dissolved in a mixture of methanol:methylene chloride, dried over anhydrous sodium sulfate and combined with the previous organic washings. The combined organic phase is concentrated under reduced pressure to give 0.422 g (85.0%) of N-(4-aminomethyl-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide as a resin.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[O:24])[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(fur-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.96 min, MH− 376. NMR: δH [2H6]-DMSO 9.99, (1H, s), 9.10, (1H, s), 8.83, (1H, t), 8.38, (1H, s), 8.30, (1H, d), 7.80, (2H, s), 7.75, (1H, d), 7.66, (1H, d), 7.30, (1H, d), 3.20, (2H, t), 2.31, (3H, s), 1.06, (1H, m), 0.46, (2H, m), 0.27, (2H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])[CH3:9]>C(Cl)Cl>[N:22]1([CH2:21][CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([C:8](=[O:10])[CH3:9])[CH2:12][CH2:13]3)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(=O)N1CCc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(CCN3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Trifluoroacetic acid (4.08 mL, 53.08 mmol) was added to a solution of tert-butyl 4-(2-(1-acetylindolin-5-yl)ethyl)piperazine-1-carboxylate (0.793 g, 2.12 mmol) in dry DCM and the reaction was stirred at room temperature for 60 min. The mixture was evaporated and the crude mixture was made basic with 10% NaOH aq. The aq phase was extracted with DCM (3×), dried (Na2SO4), filtered and evaporated to give 0.590 g of the product. This product was taken to the next step assuming quantitative yield without further purification. MS (ES+) m/z 274.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[N:3]1.S(Cl)(Cl)=O.[Cl:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:17][C:18]1[C:23]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:9])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)O
Reactant: Nc1cccnc1Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O=S(Cl)Cl
Product: Cn1ncc([N+](=O)[O-])c1C(=O)Nc1cccnc1Cl

Procedure:
Prepared analogously to Example A(a) from 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid, thionyl chloride, and 2-chloro-3-aminopyridine in hexamethylphosphoric acid triamide.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O>CCO.N1CCCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=[C:2]1[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10]
Reactant: O=C1CC(=O)c2ccccc21
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccc(Cl)c(Cl)c2)C(=O)c2ccccc21
Yield: 85 %

Procedure:
To a solution of indan-1,3-dione (1a) (960 mg, 6.6 mmol) in EtOH (8.2 mL) was added 3,4-dichlorobenzaldehyde (1b) (1.3 g, 7.2 mmol) followed by piperidine (3 drops). The reaction mixture was heated to reflux for 30 min. After cooling, the reaction was diluted with EtOH (8 mL) and the precipitate was filtered. The resulting solid was triturated twice with EtOH and dried under high vacuum to give 2-(3,4-dichloro-benzylidene)-indane-1,3-dione (1c) (1.7 g, 82% yield).
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:18]2[CH2:19][CH2:20][O:21][CH:16]([CH2:15][NH:14][C:3]([NH:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C#N)=C(NC)SC
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Product: CCOC(=O)C(C#N)=C(NC)NCC1CN(Cc2ccc(F)cc2)CCO1
Yield: 53 %

Procedure:
This compound was synthesized as a yellow oily substance from ethyl 3-methylamino-3-methylthio-2-cyanoacrylate and 2-aminomethyl-4-(p-fluorobenzyl)morpholine according to the same procedure as in Example 8. Yield=53%.
Reaction SMILES: [CH:1]1[C:6]([I:7])=[C:5]([N+:8]([O-])=O)[CH:4]=[C:3]2[N:11]=[C:12]([Cl:14])[NH:13][C:2]=12>CCO.[Ni]>[NH2:8][C:5]1[C:6]([I:7])=[CH:1][C:2]2[NH:13][C:12]([Cl:14])=[N:11][C:3]=2[CH:4]=1
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1I
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2nc(Cl)[nH]c2cc1I
Reaction time: 7 h
Yield: 61.8 %

Procedure:
A mixture of 0.339 g (1.048 mmol) of 26 and 0.090 g (wet) of Ra-Ni in 10 mL of EtOH was hydrogenated at room temperature, 50 psi of H2 for 7 h. The reaction mixture was filtered and the filtrate was evaporated. The residue was chromatographed on a silica column (2×6 cm, eluted successively with 1%, 2%, 3% MeOH/CHCl3). Evaporation of fractions 11-17 (20 mL per fraction) gave 0.190 g (62%) of 26a as a foam. An analytical sample (a yellowish crystalline compound) was obtained by recrystallization from MeOH. MP:>200° C. (dec). MS: (El) m/e 292.9202 (100%, M+ =292.9217). 1H NMR (DMSO-d6): d 12.80 (br s, 1, 1-NH), 7.75 (s, 1, 4-H), 6.87 (s, 1, 7-H), 5.03 (s, 2, 6-NH2). Anal. Calcd. for C7H5CllN3 : C, 28.65; H, 1.72; N, 14.32. Found: C, 28.84; H, 1.66; N, 14.17.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Cl-].[CH:16](=[N+:23]([CH3:25])[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:16]([N:23]([CH3:25])[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Cl-]
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1H-indole-2-carboxylic acid ethyl ester and benzylidene-dimethyl-ammonium chloride. For characterization, an ESI-MS was recorded:
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:15]([N:6]1[CH:7]=[C:2]([I:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]1=[O:8])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-iodo-4-methyl-3-nitro-2-pyridone (8.0 g, 28.6 mmol) and sodium hydride (1.03 g, 43 mmol) in DMF (150 mL) was stirred at rt for 1 hour. n-Hexyl bromide (8.03 mL, 57.2 mmol) was added, and the mixture was stirred for 24 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed, dried, filtered and evaporated. Chromatography of a portion of the residue over silica gel (20% petroleum ether/methylene chloride) gave 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[S:30]([O:11][CH2:10][CH2:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
The reaction is performed under dry conditions. 30.0 g of 1,1,2-triphenyl-1-butene-4-ol are dissolved in 100 ml of dry pyridine. Then with stirring and cooling the mixture on ice, 57.0 g of 4-toluenesulfonic acid chloride in 50 ml of dry pyridine are added dropwise to the mixture. The mixture is stirred for 6 h at 0° C. Then 250 ml of ice-cold water and 750 ml of cold 2M hydrochloric acid are added. The precipitate is collected by filtration and washed with water. Finally the product is recrystallized from ethanol. The yield is 36.8 g (81%) of a product having m.p. 137°-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([CH:22]([O:26][C:27](=[O:29])[CH3:28])[C:23](=O)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([CH:22]([O:26][C:27](=[O:29])[CH3:28])[CH:23]([NH:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)OC(Cc1ccccc1)C(C)=O
Product: CC(=O)OC(Cc1ccccc1)C(C)Nc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and acetic acid 1-benzyl-2-oxo-propyl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=O.[CH2:18]([CH2:20][NH2:21])[OH:19]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([NH:21][CH2:20][CH2:18][OH:19])=[O:6]
Reactant: NCCO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCO
Yield: 94 %

Procedure:
The procedure of Example 1 was repeated except that 4.7 g of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid and 1.8 ml of ethanolamine were used as starting materials. 5.2 g (yield 94%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][CH2:23][CH3:24])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH2:17][CH3:18])=[C:12]([CH2:19][CH3:20])[N:11]=2)[CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][CH2:23][CH3:24])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH2:17][CH3:18])=[C:12]([CH2:19][CH3:20])[N:11]=2)[CH:9]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1-c1nc(CC)c(CC)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Yield: 108.8 %

Procedure:
The compound (16.5 g, 50 mmol) of example 41 was dissolved in methanol, added with 0.4 g 10% Pd/C, and hydrogenized at the normal temperature and pressure. When hydrogen was not absorbed by the reaction mixture any more, the reaction was quenched and Pd/C was filtered off. The filtrate was concentrated to a small volume, and fed with HCl gas to generate a white solid. The obtained solid was filtered and dried to give the hydrochlorate of the title compound (16.4 g. yield: 97%). 1H NMR 1H NMR (CDCl3) δ: 7.68 (1H, d), 7.43 (1H, dd), 7.24 (1H, d), 4.04 (2H, t), 2.57 (2H, q), 2.46 (2H, q), 1.75 (2H, m), 1.19 (3H, t), 1.04 (3H, t), 0.96 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([CH2:18][CH:17]=[CH2:16])[C:8]1[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cccnc1Cl
Temperature: 60 °C
Yield: 97.3 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (7 g, 30.7 mmol), allyl bromide (5.26 g, 40.8 mmol) and cesium carbonate (20.8 g, 63.8 mmol) in DMF (280 mL) is heated at 60° C. for 1 h. The reaction is quenched with water, extracted with EtOAC. The organic layer is dried (Na2SO4), filtered and concentrated to afford allyl-(2-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (8.03 g, 98%), which is sued in the next step with no further purification.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=1
Reactant: ClCCN1CCCC1
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1cnn(CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60% paraffin oil dispersion, 0.507 g, 21.13 mmol) was added portionwise to a solution of 4-iodopyrazole in DMF at 0° C. The reaction mixture was stirred for 1 hour, treated with solution of 1-(2-chloroethyl)pyrrolidine (1.40 g, 10.56 mmol) in DMF, slowly warmed to RT and stirred for additional 16 hours. The reaction mixture was cooled to 0° C. and ice cold water was added, followed by extraction with EtOAc (2×40 mL). The combined organics were washed with water (3×40 mL), brine solution (40 ml), dried (Na2SO4), filtered, and concentrated to obtain 4-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole, which was used as is for subsequent reactions without further purification; 1H-NMR (400 MHz, CHCl3): 7.60 (1H, s), 7.52 (1H, s), 7.49 (1H, s), 4.25 (2H, t), 2.95 (2H, s), 2.57 (4H, m), 1.79 (4H, m); ES-MS: 292.0 (M+H).
Reaction SMILES: [CH2:1]([C@H:8]1[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>O1CCCC1>[O:24]=[C:21]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([CH3:13])([CH3:14])[O:11][C:10]1=[O:15])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: CC1(C)OC(=O)N[C@H]1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC(C)(C)[C@@H]1Cc1ccccc1
Yield: 85.4 %

Procedure:
Reaction of the auxiliary (10) (0.8 g, 3.90 mmol) in solution in tetrahydrofuran (27 ml) at -78° C. with butyllithium (1.3M, 3.03 ml, 3.94 mmol) and propionyl chloride (0.373 ml, 4.29 mmol) for 30 minutes and then at room temperature overnight with work-up and recrystallisation from pentane gave the title compound (20) as a solid (0.870 g, 85%); mp 61° C.; νmax (CHCl3) 1773 and 1702 cm-1 ; [α]D25 (c 1 in CHCl3)=-42.5; (Found: C, 69.06; H, 7.43; N, 5.21. C15H19NO3 requires C, 68.94; H, 7.33; N, 5.36%); δH (CDCl3 ; 200 MHz) 1.13 (3H, t, J=7.36, CH2CH3), 1.35 (3H, s, C(CH3)2), 1.36 (3H, s, C(CH3)2), 2.81-2.98 (2H, m, CH2Ph and CH2CH3), 3.14 (1H, dd, J=4.0 and 14.4, CH2Ph), 4.50 (1H, dd, J=4.0 and 9.6, CHCH2), 7.18-7.34 (5H, m, ArCH); δC (125 MHz; CDCl3) 8.20 (CH3), 22.15 (CH3), 28.43 (CH3), 29.23 (CH2), 35.24 (CH2), 63.46 (CH), 82.20 (C), 126.96 (CH), 128.82 (CH), 129.26 (CH), 137.26 (C), 152.93 (CO), 174.53 (CO); m/z (CI+, NH3) 262 (M+ +1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.ClC(OCC)=O.C(N(CC)CC)C.[N:27]1([CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:42][CH:41]=1)=[O:7]
Reactant: NCc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2ccc(OCCN3CCCC3)cc2)c(OC)c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a cooled suspension of 1.82 g of 2,4-dimethoxybenzoic acid in 10 ml of tetrahydrofuran was added 1.09 g of ethyl chloroformate and 1.01 g of triethylamine. After stirring for 15 minutes, to the mixture was added a solution of 2.00 g of 4-[2-(1-pyrrolidinyl)ethoxy]benzylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 15 minutes and the solvent was evaporated. To the residue was added 10% hydrochloric acid, and the solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give 3.31 g of the title compound as a colorless oil.