Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:10]([O:13]C(=O)C)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)[CH:25]([CH3:27])[CH3:26].[CH3:30]COCC>CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:10]([OH:13])[C@@H:11]([OH:12])[CH:25]([CH3:26])[CH2:27][CH3:30])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[Mg]Cl
Reactant: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCOCC
Solvent: O
Solvent: CO
Product: CCC(C)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound of Step 1 was dissolved to -70° C. this solution was added 13 mL (26 mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and the stirred mixture was allowed to warm to room temperature and stir for 2 hrs. After decomposition with MeOH/H2O the mixture was diluted with ether, washed with saturated NH4Cl solution twice and dried with magnesium sulfate and the solvents evaporated under vacuum. The residue was allowed to stand overnight in 80% NeOH-H2O containing excess ammonium hydroxide. The MeOH was stripped off and the mixture was exracted with ether. These extracts were combined, washed with water, dilute KHSO4, then dried and evaporated to give 2.36 g of a yellow glass which crystallized from 50 mL of pentane on standing overnight. The yellow-white powder obtained was recrystallized from ether-hexane and furnished the title compound (0.41 g) as white, hairy needles, mp 134°-136° C., Rf (ether): single spot, 0.6. By chromatography of the mother liquors and crystallization of the appropriate fractions, an additional 0.22 g of product, mp 138°-139° C., was obtained.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][C:17]=1Cl.[OH2:20]>O1CCCC1>[CH2:7]([O:8][C:15]1[N:14]=[N:13][C:12]([Cl:11])=[CH:17][C:16]=1[O:20][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Phenylmethanol (6.72 g, 62.2 mmol) was added dropwise to a suspension of sodium hydride (60% suspension in mineral oil; 2.486 g, 62.2 mmol) in tetrahydrofuran (total volume: 100 ml) at room temperature. The resulting mixture was stirred for 1 hour and then cooled to 0° C. before 3,4,6-trichloropyridazine (5.7 g, 31.1 mmol) was added portionwise over 10 minutes. The reaction was then allowed to warm to room temperature and stirred for 16 hours before being poured into water and extracted with ethyl acetate (twice). The organic layer was washed with brine, dried (magnesium sulphate) and evaporated. The residue was purified by silica chromatography (eluting with 5-20% ethyl acetate in petrol containing 5% tetrahydrofuran) to yield 3,4-bis(benzyloxy)-6-chloropyridazine (4.0 g, 12.24 mmol, 39.4% yield) as the major product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH2:11]([NH:18][CH2:19][CH2:20][NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH2:11]([NH:18][CH2:19][CH2:20][NH:21][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH3:8])[C:6]=1[CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: NCCNCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nnc(NCCNCc2ccccc2)c1C

Procedure:
Heat a mixture of 3,6-dichloro-4,5-dimethylpyridazine (6.90 g, 39.0 mmol), N-benzylethylenediamine (8.78 g, 58.5 mmol), and diisopropylethylamine (25.2 g, 195 mmol) in DMSO (78 mL) at 120° C. for 3 d. Cool the reaction mixture, pour into H2O, and extract the mixture with Et2O. Wash the organic layer with H2O, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue using flash silica gel chromatography (gradient of 0 to 5% 2 M NH3/MeOH in CH2Cl2) to obtain the title compound as a waxy solid (6.41 g, 57%). ES/MS m/z 291.2 (M+1).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][Mg]Br)=[CH:36][CH:35]=1>C1COCC1>[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:14][CH:15]=2)=[O:9])=[CH:36][CH:35]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: COc1ccc(C[Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cc2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 29.4 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]-methanone (6.0 g, 13.7 mmol) in THF (51 mL) was reacted with a 0.83M THF solution of 4-methoxybenzylmagnesium bromide (19.8 mL, 16.4 mmol) (prepared from 4-methoxybenzylchloride and magnesium turnings in THF) at ambient temperature. Purification by chromatography (silica gel, 1:1 hexane:ethyl acetate, 0.1% ammonium hydroxide) and recrystallization from ethyl acetate gave 2.08 g (29%) of the title compound as tan crystals, mp 126° C.: 1H NMR (300 MHz) δ1.3-1.5 (m, 2H), 1.5-1.7 (m, 4H), 2.4-2.6 (br m, 4H), 2.77 (br m, 2H), 3.73 (s, 3H), 3.83 (s, 3H), 4.08 (s, 2H), 4.23 (br m, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.90 (dd, J=2.5, 8.8 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.9 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.80 (d, J=8.7 Hz, 2H); IR (CHCl3) 1645, 1600 cm-1 ; HRMS (FAB+) m/e calc'd for C31H34NO4S 516.2208 (MH+), found 516.2200; Anal. calc'd. for C31H33 NO4S.0.5H2O: C, 70.95; H, 6.54; N, 2.67. Found: C, 71.17; H, 6.51; N, 2.56.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5](=[O:21])[N:4]([CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[C:3]=1[CH3:33]>C(O)C.[OH-].[Pd+2].[OH-]>[ClH:1].[CH3:33][C:3]1[N:4]([CH2:22][C:23]([OH:25])=[O:24])[C:5](=[O:21])[C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[N:7][CH:2]=1
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCN2C2CCOCC2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(NC[C@H]2CCCN2C2CCOCC2)c(=O)n1CC(=O)O
Product: Cl
Reaction time: 20 h
Yield: 86.2 %

Procedure:
A mixture of benzyl 2-[3-chloro-2-methyl-6-oxo-5-({[(2R)-1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinyl]methyl}amino)-1(6H)-pyrazinyl]acetate (preparation 158) (970 mg, 2.04 mmol) and palladium hydroxide (80 mg) in ethanol (8 ml) was hydrogenated at 15 psi and room temperature for 20 hrs. The reaction mixture was filtered through Whatman® fibre, and the filtrate evaporated under reduced pressure to give the desired compound, (680 mg, 95%). LRMS: m/z=351 (M+1)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:32]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[N:31]=[CH:30][CH:29]=1)CCC>>[CH3:11][C:9]1[N:10]=[C:5]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:3]([CH3:22])[C:2]([C:28]3[N:32]([C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[N:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[N:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Product: Cc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1

Procedure:
The title compound was prepared from 6-bromo-2,7-dimethyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 7, 100 mg, 0.27 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 186 mg, 0.405 mmol) using a similar method to that used in Example 1 (Step 4) (91 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]Br)=[CH:45][CH:44]=1>CN(C=O)C.CC(OC)(C)C>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: BrCCc1ccccc1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
To a stirred solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.4 mmol) in dry DMF (5 mL) was added K2CO3 (168 mg, 1.22 mmol) and 2-phenethyl bromide (90 mg, 0.48 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was then cooled to 0° C., diluted with MTBE and quenched with water. The layers were separated and the aqueous layer was extracted with MTBE (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude material was purified by flash chromatography (gradient from 10% to 50% EtOAc/hexanes) to provide the title compound (175 mg, 72%). 1H NMR (CDCl3) 8.65 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0, 2.0 Hz, 1H), 7.53 (s, 1H), 7.36-7.34 (m, 3H), 7.25-7.17 (m, 5H), 6.90 (d, J=8.0 Hz, 1H), 6.81-6.79 (m, 2H), 5.14 (s, 2H), 3.99 (s, 3H), 3.97-3.95 (m, 2H), 3.67 (t, J=7.2 Hz, 2H), 3.50 (br s, 2H), 2.76 (t, J=7.2 Hz, 2H), 1.70-1.60 (m, 4H), 1.40-1.20 (m, 4H), 0.98-0.84 (m, 6H); MS(ESI+) m/z 596.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([CH:21]=O)=[N:9]1.[CH3:23][NH2:24].CO.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([CH2:21][NH:24][CH3:23])=[N:9]1
Reactant: Cc1ccc(Sc2cc(C=O)nn2-c2ccccc2Cl)nc1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(Sc2ccc(C)cn2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(5-methylpyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (422 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.3 mL) and methanol (4 mL) at 0° C. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), sodium borohydride (60 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 433 mg, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].O>S1(=O)(=O)CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccnc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A mixture of 2-chloro-4-methoxypyrimidine (29 g) and 1-(5-nitro-2-pyridinyl)piperazine (35 g) in tetrahydrothiophene 1,1-dioxide (50 ml) was stirred at 130° C. for 1 hour. The mixture was poured into sodium carbonate and water, stirred for 30 minutes and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. The residue was triturated in diisopropyl ether, yielding 23 g (43%) of 4-methoxy-2-[4-(5-nitro-2-pyridinyl)-1-piperazinyl]pyrimidine (interm. 10).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[S:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C(O)(=O)C.N1CCCCC1>C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:21]=[C:37]4[S:33][C:34](=[O:39])[NH:35][C:36]4=[O:38])=[CH:23][CH:24]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C4SC(=O)NC4=O)cc3)nc12
Temperature: 80 °C
Yield: 77 %

Procedure:
To a 35 ml reaction vial 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl amino)benzaldehyde (0.200 g, 0.0004 mole) and thiazolidine-2,4-dione (0.155 g, 0.0105 mole) were taken in ethanol (10 ml). Piperidine acetate (3.3M solution in water) (3 ml) was added at RT. The reaction mixture was heated to 80° C. for 16 hrs. After completion of the reaction, ethanol was evaporated under reduced pressure and diluted with EtOAc. Organic layer was washed with water, dried over Na2SO4 and evaporated to get crude product which was purified using column purification by eluting the compound with 10-20% EtOAc in Hexanes to yield 0.170 g of 5-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][NH2:10]>C1COCC1>[Br:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Clc1ncccc1Br
Solvent: C1CCOC1
Product: NNc1ncccc1Br
Reaction time: 16 h

Procedure:
To 3-bromo-2-chloropyridine (1-3) (12.5 g, 65 mmol) in THF (100 mL) was added hydrazine (10.4 g, 10.2 mL, 325 mmol). The mixture was heated to reflux and stirred vigorously for 16 h. An additional portion of hydrazine (5.1 g, 5.0 mL, 159 mmol) was added and the reaction was heated for another 24 h. After cooling, the mixture was concentrated in vacuo, suspended in water (50 mL), and extracted with EtOAc (1×350 mL, 1×50 mL). Combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (1-4) was used in the subsequent step without further purification. LC/MS: m/z (M+H)=187.9.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#N)=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O.C(=O)([O-])[O-:21].[K+].[K+].S(=O)(=O)(O)O>CO.C(O)=O>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2=[CH:16][C:15]([O:19][C:10]2=[O:21])=[O:18])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=CC(=O)O
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: O=C1C=C(c2ccc(C(F)(F)F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
4-Trifluoromethylphenylacetonitrile (38.9 g, 210 mmol) was dissolved in dry methanol under nitrogen. Glyoxylic acid monohydrate (29 g, 315 mmol) was added followed by potassium carbonate (74 g, 535 mmol) and the resulting mixture was stirred for 15 hours at room temperature. The resulting solid was filtered, washed with dichloromethane and dried on the sinter to yield an off white solid which was added at room temperature to a solution of conc. sulfuric acid (30 ml) and formic acid (400 ml). The resulting mixture was then heated with stirring at 110° C. for 3 hours, allowed to cool to room temperature and concentrated under vacuum to ⅔ of the initial volume. It was then poured ice-water (1000 ml) and the resulting solid was filtered off, washed with water and dried on the sinter to yield 35 g of 3-(4-trifluoromethylphenyl)maleic anhydride as an off white solid. The crude anhydride (35 g) was suspended in water (290 ml) and glacial acetic acid (145 ml) was added followed by a solution of hydrazine hydrate (7 ml, 144 mmol) in water (21 ml). After thorough mixing conc. sulfuric acid was added in small portions with external water cooling and the mixture was heated while stirring at 125° C. for 3 hours. After cooling to room temperature the solid was filtered off, washed with water until the pH was neutral and dried on the sinter to yield a grey solid. Phosphorous oxychloride (200 ml, 2.1 mol) was added to the solid and the mixture was heated at 120° C. for 2 hours. After cooling to room temperature the homogeneous dark solution was concentrated under reduced pressure to half of its original volume and poured into water (800 ml) while stirring vigorously. The resulting solid was filtered off, washed with water and dried on the sinter to yield a grey solid which was recrystallised from toluene/iso-hexane (1:1) to yield the title compound as a yellow solid (8.2 g, 13%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]([NH2:20])=[O:19])=[CH:4][CH:3]=1.[Cl:27][CH2:28][C:29]([NH:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[ClH:27].[ClH:27].[NH2:20][C:18]([CH:13]1[N:12]([CH2:11][CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16][N:15]([CH2:28][C:29]([NH:31][C:32]2[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=2[Cl:38])=[O:30])[CH2:14]1)=[O:19]
Reactant: O=C(CCl)Nc1c(Cl)cccc1Cl
Reactant: NC(=O)C1CNCCN1CCCC(c1ccc(F)cc1)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: NC(=O)C1CN(CC(=O)Nc2c(Cl)cccc2Cl)CCN1CCCC(c1ccc(F)cc1)c1cccnc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 32.2 %

Procedure:
A mixture of 1-[4-(4-fluorophenyl)-4-(3-pyridinyl)butyl]-2-piperazinecarboxamide (6.75 g), 2-chloro-N-(2,6-dichlorophenyl)acetamide (5.24 g), sodium carbonate (3.16 g) and DMF (143 ml) was stirred for 4 hours at 70° C. The reaction mixture was evaporated and water was added to the residue. After extraction with DCM, the combined organic layers were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent:CHCl3/CH3OH 95/5). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and DIPE and converted into the hydrochloride salt. The salt was filtered off and dried, yielding 2.23 g of 3-(amino-carbonyl)-N-(2,6-dichloro-phenyl)-4-[4-(4-fluorophenyl)-4-(3-pyridinyl)-butyl]-1-piperazineacetamide dihydrochloride.monohydrate (compound 14, mp. 226.3° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:5][S:6]([CH2:9][C:10](O)=O)(=[O:8])=[O:7].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:21]=1C=O.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[CH:21]=[C:20]([O:19][CH3:18])[C:27]=1/[CH:10]=[CH:9]/[S:6]([CH2:5][C:4]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:2]([OH:1])[CH:3]=1)(=[O:8])=[O:7]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1O
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(O)c2)c(OC)c1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A mixture of the 2-((3-hydroxy-4-methoxybenzyl)sulfonyl)acetic acid (1.9 g, 7.3 mmol, 1 eq), 2,4,6-trimethoxybenzaldehyde (1.58 g, 8.0 mmol, 1.1 eq.), benzoic acid (134 mg, 0.15 eq.) and piperidine (81 mg, 0.13 eq.) in toluene (50 mL) was heated at reflux temperature for 2-3 h with continuous removal of water using a Dean-Stark trap. When the reaction was complete by TLC analysis, the reaction mixture was cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate solution (50 mL), dilute hydrochloric acid (50 mL), and water (50 mL) and dried (sodium sulfate). Volatile components were removed in vacuo to yield the crude product, which was purified by recrystallization from isopropanol to yield 1.8 g (62.5%) of the desired (E)-5-((2,4,6-trimethoxystyryl-sulfonyl)methyl)-2-methoxyphenol.
Reaction SMILES: C(O[CH:5]([CH:19]([CH3:21])[CH3:20])[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([F:18])=[CH:10][CH:9]=1)=[O:7])(=O)C.Cl.OC(C(C)C)C(C1C2C(=CC=CC=2)C(F)=CC=1)=O.OC(C1C2C(=CC=CC=2)C(F)=CC=1)C(=O)C(C)C.[N:59]#[C:60][NH2:61]>C(O)C>[NH2:61][C:60]1[O:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)=[C:5]([CH:19]([CH3:21])[CH3:20])[N:59]=1
Reactant: CC(=O)OC(C(=O)c1ccc(F)c2ccccc12)C(C)C
Reactant: N#CN
Agent: CC(C)C(=O)C(O)c1ccc(F)c2ccccc12
Agent: CC(C)C(O)C(=O)c1ccc(F)c2ccccc12
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(N)oc1-c1ccc(F)c2ccccc12
Temperature: 110 °C
Yield: 6 %

Procedure:
A mixture of 2-acetoxy-3-methyl-1-(4′-fluoronaphth-1-yl)butan-1-one (4.8 g), IMS (100 ml) and hydrochloric acid (1M; 70 ml) were boiled under reflux for 4 hours. The mixture was cooled, evaporated in vacuo and partitioned between dichloromethane and brine. The organic layer was separated, dried with sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography in 66-100% dichloromethane in petroleum ether to afford a mixture of 2-hydroxy-3-methyl-1-(4′-fluoronaphth-1-yl)butan-1-one and 1-hydroxy-3-methyl-l-(4′-fluoronaphth-1-yl)butan-2-one (3.2 g). Cyanamide (0.65 g) and anhydrous ethanol (10 ml) were added and the resulting mixture was boiled under reflux for 48 hours. After cooling the volatiles were removed in vacuo and the residue heated at 110° C. for a further 48 hours. The mixture was cooled, triturated with chloroform (100 ml) and filtered. The filtrate was washed with water, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (0.25 g; m.p. 141° C., softens from 125° C.) was obtained following silica gel column chromatography of the residue in 50% ethyl acetate in petroleum ether.