Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][C@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:13][C@H:12](O)[CH:11]=1)([O-:3])=[O:2].CS(Cl)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C(Cl)Cl.C(OCC)(=O)C.CCCCCCC>[N:26]([C@H:12]1[CH2:13][C@@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:15][C:10]([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11]1)=[N+:27]=[N-:28]
Reactant: O=[N+]([O-])c1cnccc1C1=C[C@@H](O)C[C@@H](C(F)(F)F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1C=C(c2ccncc2[N+](=O)[O-])C[C@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of cis-3-(3-nitropyridin-4-yl)-5-(trifluoromethyl)cyclohex-2-enol (1.0 eq) in DCM (0.14 M) was added TEA (2.5 eq), and followed by MsCl (1.8 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed. The residue was dissolved in DMF (0.19 M), and then the mixture was added sodium azide (1.2 eq). The resulting mixture was stirred at room temperature for 1 hour. Another 1.2 eq of sodium azide was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and heptane, and washed with sat NaCl. The organic was dried over MgSO4, filtered and concentrated. The residue was purified by column (1:1 ethyl acetate and hexanes) to give cis-4-(3-azido-5-(trifluoromethyl)cyclohex-1-enyl)-3-nitropyridine (58%). LC/MS (m/z): MH+=314.1, Rt=0.96 min.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1Br.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.O1CCOCC1.CC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nc(-c2nc(-c3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Under nitrogen atmosphere, a solution of Na2CO3 (220 mg) in water (1.6 ml) was added to a suspension of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (200 mg), phenylboronic acid (158 mg) and tetrakis(triphenylphosphine)palladium (18 mg) in dioxane (6 ml) and the mixture was stirred at 100-105° C. for 2 hours. After addition of water (6 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-(5-amino-3,6-diphenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentanoic acid to yield (3aR,4S,7aR)-4-((S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((S)-2-amino-4,4-dimethyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=5.787 min; HPLC Method I
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:38])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35][OH:36])=[C:19]([Br:37])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)(Cl)[C:41]([N:43]=C=O)=[O:42]>C(Cl)Cl>[Br:37][C:19]1[C:20]([O:33][CH2:34][CH2:35][O:36][C:41](=[O:42])[NH2:43])=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[CH:22]=[C:17]([C:16](=[O:38])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=O)OCCOc1c(Br)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
To a solution of N-(8-phenyl-octyl)-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.463 g, 0.78 mmol, 1 eq) in CH2Cl2 (10 mL) was added trichloroacetyl isocyanate (0.100 mL, 0.84 mmol, 1.1 eq) The reaction was stirred at rt 15 minutes and oven-dried alumina was added. The reaction was stirred overnight at rt and concentrated in vacuo. The residue was purified by flash chromatography (30 to 60% EtOAc:hexane) to afford the title compound (0.308 g, 62%) as a oil. 1H NMR (DMSO-d6) δ 8.56 (bt, 1H); 8.13 (d, 1H); 7.89 (m, 3H); 7.72 (dd, 1H); 7.24 (m, 2H); 7.14 (m, 3H); 6.40 (bs, 2H); 3.90 (dd, 2H); 3.70 (dd, 2H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.25 (m, 4H); 1.27 (m, 8H); IR (KBr) 3330, 2920, 2850, 1720, 1640, 1600, 1550, 1460, 1410, 1330, 1180, 1120 cm−1; mass spectrum [(+)EST], m/z 635/637 (M+H)+; Anal. Calcd. for C31H34BrF3N2O4: C, 58.59; H, 5.39; N, 4.41, Found: C, 57.26; H, 5.46; N, 4.38.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2].[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].C([O-])([O-])=O.[K+].[K+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O.C1COCC1>[C:25]([N:12]1[CH:13]([C:16]([OH:18])=[O:17])[CH2:14][S:15][CH:6]1[C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[C:1]([OH:3])=[O:2])(=[O:27])[CH3:26]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1C(C(=O)O)CSC1c1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
A solution of 6 of 2-carboxybenzaldehyde and 4.8 g of cysteine in 100 ml of water was stirred for 15 minutes. After adding 10 g of K2CO3, the solution was cooled to 0° C. and a solution of 8 g of acetic anhydride in THF was added. After everything had been added, the solution was stirred for a further 15 minutes at 0° C. and then for 1 hour at room temperature. The solution was concentrated under reduced pressure in order to evaporate THF, acidified to pH 1-2 with sulphuric acid and extracted with ethyl acetate. After drying over MgSO4 and evaporation of the solvent, the residue was crystallised from ethyl acetate/diethyl ether. Yield 22%.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([O:35][CH2:36][CH3:37])[CH:34]=1)[O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH2:36]([O:35][C:33]1[CH:34]=[C:15]([CH:16]=[C:17]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH:32]=1)[CH2:14][S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1)[CH3:37]
Reactant: CCOc1cc(CCl)cc(OCc2nc(-c3ccccc3)oc2C)c1
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(CSc2nc(C)c(CC(=O)OC)s2)cc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (455 mg), 4-(3-chloromethyl-5-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (800 mg), potassium carbonate (465 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [2-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-4-methylthiazol-5-yl]acetate (1.02 g, yield 87%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])[C:5]([C:13]#[N:14])=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCOC(C)=O>[C:13]([C:5]1[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[N:7][C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[C:3]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)[N:4]=1)#[N:14]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2Cl)ccc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2cccc(F)c2)ccc1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
A mixture of N′-[6-chloro-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (200 mg), 3-fluorophenylboronic acid (243 mg), tetrakistriphenylphosphine palladium (20.1 mg) and Na2CO3(246 mg) indioxane (10 ml) and water (2 ml) was stirred at 90° C. for 15 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain N′-[3-cyano-6-(3-fluorophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (100 mg) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].Br[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCCc1cc(CO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Yield: 82.6 %

Procedure:
To a solution of 0.484 g (2.91 mmol) of the product of Step F dissolved in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromo-2-phenylacetate, 0.804 g (5.82 mmol) of anhydrous K2CO3 and the mixture was stirred and heated at reflux for 5 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.756 g (83%) of the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-chlorophenylhydrazine hydrochloride (269 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale brown solid (126 mg, 30%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([O:20][CH3:21])=[CH:9][C:10]([C:18]#[N:19])=[C:11]([N:13]=[CH:14][N:15](C)C)[CH:12]=1.C(O)(=O)C.N[C:27]1[CH:31]=[C:30]([CH2:32][C:33]([OH:35])=[O:34])[NH:29][N:28]=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]2[C:10]([C:18]([NH:19][C:27]3[CH:31]=[C:30]([CH2:32][C:33]([OH:35])=[O:34])[NH:29][N:28]=3)=[N:15][CH:14]=[N:13]2)=[CH:9][C:8]=1[O:20][CH3:21]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCCl
Reactant: Nc1cc(CC(=O)O)[nH]n1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCCCCl
Reaction time: 1 h
Yield: 73.9 %

Procedure:
N′-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimidoformamide (464 g, 15 mmol) in acetic acid (13.5 ml, 225 mmol) was reacted with (3-amino-1H-pyrazol-5-yl)acetic acid (2.22 g, 15.8 mmol) at reflux for 1 hour. The mixture was cooled, diluted with ethanol (25 ml) and the resultant precipitate recovered by suction filtration. The solid was stirred in water for 1 hour, collected by suction filtration and dried to yield (3-([7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino)-1H-pyrazol-5-yl)acetic acid (4.5 g, 74% yield):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([C:8]([OH:10])=O)[CH:7]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI.O.CN([CH:26]=[O:27])C>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:27][CH3:26])=[O:10])[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1
Reactant: O=C(O)c1cc(Br)cc(C(=O)O)c1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
5-bromobenzene-1,3-dicarboxylic acid (5 g, 20.4 mmol, 1.0 eq) was dissolved in DMF (150 mL). Cs2CO3 (33.2 g, 102 mmol, 5.0 eq) was added and the reaction stirred for 30 min. MeI (7.2 g, 51 mmol, 2.5 eq) was added dropwise and the solution was stirred at room temperature overnight. Water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a colourless oil (5 g, 90%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:9]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([C:11]4[CH:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:9][C:10]=4[S:32]([CH3:35])(=[O:34])=[O:33])=[O:15])[CH2:17][CH2:18]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2S(C)(=O)=O)CC1
Yield: 84.6 %

Procedure:
Using pyrrolidin-2-one (47 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (239 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 1, the title compound (204 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16]Br)[CH:9]=[N:10]2.[CH3:19][NH:20][CH3:21].C(O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:20]([CH3:21])[CH3:19])[CH:9]=[N:10]2
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(CBr)cc12
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)Cc1c(Cl)ccc2ncc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (3-bromomethyl-6-chloro-quinolin-5-yl)-acetic acid methyl ester (500 mg, 1.52 mmol) in DMF (10 mL) was added a 33% solution of dimethylamine in ethanol (547 μL, 3.04 mmol). The reaction mixture was stirred for 16 h at room temperature, followed by removal of the solvents in vacuo. The residue was purified by flash column chromatography (silica gel, gradient of CH2Cl2/MeOH 100:0 to 90:10) to afford the title compound as a violet solid (424 mg, 1.45 mmol, 95%). %). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=8.89 (d, J=2.0 Hz, 1H), 8.38 (bs, 1H), 8.00 (d, J=9.1 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 4.36 (s, 2H), 3.69 (bs, 2H), 3.63 (s, 3H), 2.24 (bs, 6H). MS (ES+): 293 (M(C15H735ClN2O2)+H)+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH2:7][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCC[C@H](O)CC(=O)OC
Product: CCCCCCCCCCCCC[C@H](O)CC(=O)OCc1ccccc1

Procedure:
(S)-Methyl 3-hydroxyhexadecanoate and benzyl bromide were reacted according to a similar manner to that of Preparation 1 to give (S)-benzyl 3-hydroxyhexadecanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N+:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[O-])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:21])C.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:21])=[CH:4][CH:3]=1
Reactant: [O-][N+](=Cc1ccc(Cl)cc1)CCN1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
4.0 G. of α-(p-chlorophenyl)-N-(2-morpholinoethyl)-nitrone are heated to 90° C. in 15 ml. of glacial acetic acid and 15 ml. of acetic anhydride for 24 hours. The mixture is then cooled to room temperature, poured into 200 ml. of ice-water and rendered basic with 20% sodium hydroxide solution. Thereafter, the mixture is extracted twice with 100 ml. of methylene chloride each time. The methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 0.13 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23](Br)[N:22]=2)=[O:20])=[CH:14][CH:13]=1>CN(C=O)C.CCCCCC.[Cu](Cl)Cl>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:22]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: COc1cc(Br)nc(C(=O)Nc2ccc(C)cc2)c1
Reactant: Cc1cccc(O)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(C)c2)nc(C(=O)Nc2ccc(C)cc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.45 g (0.0019×2.2 mol) of 3-methyl phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.15 g (ca. 60% in mineral oil; 0.0019×2.0 mol) of NaH and then with 0.60 g (0.0019 mol) of N-(4-methylphenyl)-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.19 g (0.0019×1.0 mol) of copper chloride (I), the solution was stirred at about 100° C. for about 4 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH3:22]>C(OC(=O)C)(=O)C>[CH3:21][C:18]1[CH:19]=[CH:20][N:15]=[C:16](/[CH:22]=[CH:11]/[C:10]2[CH:13]=[CH:14][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH:17]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccnc(C)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Temperature: 150 °C
Yield: 45.3 %

Procedure:
A mixture of 4-phenylbenzaldehyde (6.45 g), 2,4-lutidine (7.59 g), and acetic anhydride (10 ml) was heated on a bath at 150° C. for 12 hours and then heated under reflux for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica-gel column chromatography (eluent, hexane:ethyl acetate=9:1 to 5:1) to give 4.35 g of a yellow solid of (E)-4-methyl-2-(4-phenylphenyl)ethenylpyridine.