Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[CH3:12].[Br:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[BrH:13].[OH:1][CH2:2][C:3]1[N:11]=[C:6]2[N:7]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[CH3:12]
Reactant: Cc1c(CO)[nH]c2ncccc12
Reactant: BrCCc1ccccc1
Solvent: CC#N
Product: Br
Product: Cc1c2cccn(CCc3ccccc3)c-2nc1CO

Procedure:
A solution of 0.11 g (0.68 mmol) 2-hydroxymethyl-3-methylpyrrolo [2,3-b]pyridine and 0.13 g (7 mmol) (2-bromoethyl)benzene in 5 ml acetonitril was refluxed for 24 h. The solvent was evaporated. Chromatography on silica gel eluting with methylene chloride and methanol (10:1) gave the desired product. (0.03 g 13%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][OH:63]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:60][CH2:61][CH2:62][OH:63])=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxy pyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 100 mg, 0.28 mmol) and HATU (128 mg, 0.336 mmol) was added DIEA (0.146 mL, 0.840 mmol) at ambient temperature, followed by a solution of 2-aminoethanol (20.5 mg, 0.336 mmol) in minimal amount of DMF dropwise at 0° C. The reaction was warmed up to ambient temperature and stirred for 30 minutes, then directly purified by reverse-phase column chromatography (0 to 70% acetonitrile/water) to yield the product as white solid (95 mg, 85% yield). MS (apci pos) m/z=401.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21](=[O:36])[NH:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[H-].[Na+].[CH3:40]I.O>CN(C)C=O>[Cl:1][C:2]1[C:20]([C:21](=[O:36])[N:22]([CH3:40])[CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]3[C:29]2=[O:30])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)NCCN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N(C)CCN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-(2-phthalimidoethyl)carbamoyl]benzyloxy]-2-methylquinoline (390 mg) in N,N-dimethylformamide (4 ml) was added sodium hydride (32.1 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. Methyl iodide (114 mg) was added thereto under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (chloroform:ethyl acetate=3:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-(2-phthalimidoethyl)carbamoyl]benzyloxy]-2-methylquinoline (360 mg) as colorless amorphous.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[CH3:24][C:25]1[CH2:26][C:27](=[O:40])[N:28]([C:30]2[CH:39]=[CH:38][C:37]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[CH:31]=2)[N:29]=1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[OH:19][C:4]1[C:3]([NH:2][N:20]=[C:26]2[C:27](=[O:40])[N:28]([C:30]3[CH:39]=[CH:38][C:37]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=4[CH:31]=3)[N:29]=[C:25]2[CH3:24])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1
Reactant: O=N[O-]
Reactant: Cc1cc(N)c(O)c(-c2cccc(C(=O)O)c2)c1
Reactant: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1=NNc1cc(C)cc(-c2cccc(C(=O)O)c2)c1O
Yield: 40 %

Procedure:
3′-Amino-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid hydrochloride 11f (272 mg, 0.97 mmol) was dissolved in hydrochloric acid (3.3 mL, 1 mol/L) followed by dropwise addition of 1.3 mL of aqueous sodium nitrite (74 mg, 1.07 mmol) upon cooling by an ice-water bath. After the mixture was reacted for 20 minutes, 5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 3i (200 mg, 0.88 mmol), sodium bicarbonate (1.22 g, 14.6 mmol) and 2.1 mL of ethanol were added successively. The reaction mixture was reacted at room temperature for 4 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with 20 mL of water and then dissolved in 20 mL of water. Upon cooling by an ice-water bath, the mixture was adjusted to pH<5 with concentrated hydrochloric acid, filtered and dried to obtain the title compound 2′-hydroxy-5′-methyl-3′-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-biphenyl-3-carboxylic acid 11 (170 mg, yield 40.2%) as a red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][N:16]1C(=O)C2=CC=CC=C2C1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CN>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CN
Solvent: CCO
Solvent: C1CCOC1
Product: NOCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of N-[3-(benzyloxycarbonylamino)-1-propoxy]phthalimide (1.42 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). The solution was stirred at room temperature for 1 h. The solvent was evaporated and the residue passed through silica gel (3:1 ethyl acetate: hexane to ethyl acetate) to give the title compound as a white solid (870 mg, 97%). 1H-NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 5.38 (br s, 2H), 5.09 (s, 2H), 5.08 (br s, 1H), 3.73 (t, J=5.9 Hz, 2H), 3.29 (q, J=6.2 Hz, 2H), 1.79 (pentet, J=6.2 Hz, 2H).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([NH2:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:27]([CH2:31][C:32](Cl)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.O>ClCCl>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([NH:23][C:32](=[O:33])[CH2:31][C:27]([CH3:30])([CH3:29])[CH3:28])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)(C)C)cc1)C(C)(C)O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)(C)C)cc1)C(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride obtained in Reference Example 76 (400 mg, 1.16 mmol) and tert-butylacetyl chloride (0.17 mL, 1.22 mmol) in dichloromethane (10 mL) was added triethylamine (0.35 mL, 2.50 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 1 N hydrochloric acid and an aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain 110 mg (yield: 41%) of the title compound. Amorphous substance.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C>ClCCl>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:23][S:2]([NH:5][C:6](=[O:7])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Chlorosulfonyl isocyanate (0.063 mL) and t-butanol (0.07 mL) were mixed in dichloromethane. After 10 min a solution of (4-nitrophenyl)methanamine (100 mg, 0.657 mmol) in dichloromethane was added at 50° C. After stirring for 30 min the mixture was cooled to room temperature and triethylamine (0.11 mL) was added. The mixture was stirred for 3 h, extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave tert-butyl N-(4-nitrobenzyl)sulfamoylcarbamate (112 mg, 51%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[H][H].Cl[CH2:11][CH2:12][CH:13]1[CH2:19][N:18]([CH3:20])[C:17](=[S:21])[C:16]2[CH:22]=[CH:23][CH:24]=[N:25][C:15]=2[O:14]1>CN(C)C=O>[CH3:20][N:18]1[C:17](=[S:21])[C:16]2[CH:22]=[CH:23][CH:24]=[N:25][C:15]=2[O:14][CH:13]([CH2:12][CH2:11][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH2:19]1
Reactant: c1cn[nH]c1
Reactant: [H][H]
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(CCn2cccn2)Oc2ncccc2C1=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2.16 g (0.054 mole) of sodium hydride in 20 ml of dimethylformamide was added dropwise a solution of 2.92 g (0.043 mole) of pyrazole in 10 ml of dimethylformamide. There was a slight exotherm at this point with some evolution of hydrogen gas. The resulting solution was then added dropwise to a solution of 10.0 g (0.039 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione in 30 ml of dimethylformamide. The reaction flask was sealed and stirred overnight at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=1.ClC1C=CC=CC=1C1C2C(=CC=CC=2)C=C(C)N=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH:18]=[O:19])[N:9]=1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Agent: Cc1cc2ccccc2c(-c2ccccc2Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cc2ccccc2c(-c2ccccc2Cl)n1
Temperature: 25 °C

Procedure:
Then 1-(2-clorophenyl)-3-isoquinolinecarboxylic acid 81 is formed by the following process. A mixture of 1-(2-clorophenyl)-3-methylisoquinoline 77 (6.68 g, 19.88 mmol), N-bromo-succinimide (NBS) (8.896 g, 19.98 mmol), and benzoyl peroxide (BPO) (0.57 g) in CCl4 was heated to reflux while being illuminated by a flood lamp for 5 hours. The reaction was cooled to room temperature and filtered. The filtrate was washed with saturated NaHCO3 (1×40 mL), dried with Na3SO4, filtered and concentrated in vacuo. The crude dibromide yellow product 79 was used in the next step. To a refluxing solution of the crude dibromide 79. (10.13 g) in EtOH (140 mL) and THF (70 mL) was added dropwise a solution of AgNO3 (10.595 g) in H2O (6 mL). The mixture was refluxed for 1 hour and filtered hot. The filter cake was washed with hot THF (2×20). The combined filtrate was concentrated in vacuo to give crude 1-(2-clorophenyl)-3-isoquinolinecarboxaldehyde as a dark yellow oil. (9 g) This oil was used without purification. To a solution of the crude aldehyde in absolute EtOH (100 mL) was slowly added a solution of AgNO3 (11.11 g) in 10 mL H2O. to this stirred solution was added dropwise a solution of NaOH (9.43 g) in H2O (140 mL). The resulting black slurry was stirred at room temperature for 2 hours. The solution was then filtered through a Celite column. The filter cake was washed with ether. The ether was evaporated and the aqueous solution was made slightly acidic with concentrated HCl. The precipitate was collected by filtration, then washed with H2O. It was then recrystallized from CH3CN affording pale yellow crystals (2.63 g, 35%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]2[CH3:39])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[N:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:40])[NH:22][C:9]4[CH:10]=[C:11]([C:14]#[C:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccccc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2cccc(C3=Nc4ccc(C#Cc5ccccc5)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (2-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example K60) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (57 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][N:37]([CH3:42])[CH:38]1[CH2:41][NH:40][CH2:39]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:40]3[CH2:41][CH:38]([N:37]([CH3:42])[CH3:36])[CH2:39]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(C)C1CNC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (360 mg, 0.91 mmol) and triethylamine (370 mg, 3.65 mmol) in ethanol (5 ml) was treated with N,N-dimethyl-3-azetidinamine (J.Med.Chem.;36; 801; 1993) (300 mg, 0.91 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was partitioned between ethyl acetate (150 ml) and saturated aqueous ammonium chloride solution (150 ml). The organic layer was washed with saturated ammonium chloride solution (150 ml), water (150 ml) and brine (150 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate:diethylamine (87.5:12.5:0.25) gradually changing to pentane:ethyl acetate:diethylamine (50:50:1) to afford the title compound as a colourless oil (355 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C1C=CC=CC=1>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCC(c2ccccc2)CC1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCN1CCC(c2ccccc2)CC1

Procedure:
A mixture of m-nitrobenzaldehyde (0.66 g), 2-(4-phenylpiperidino)ethyl acetoacetate (1.2 g), piperidine (0.1 ml) and benzene (20 ml) was refluxed overnight, during which time the water produced was removed azeotropically. The solvent was then distilled off and the residue was chromatographed on silica gel (50 g) [ethyl acetate-hexane (1:1, v/v)] to give 2-(4-phenylpiperidino)-ethyl 2-(3-nitrobenzylidene)acetoacetate as an oil. Yield 0.80 g (45.7%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>ClCCl.CN(C)C=O>[CH3:5][C:6]([CH3:32])([CH2:7][C:8]([N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)=[O:10])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31]
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Reactant: CN1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(C(=O)CC(C)(C)CC(=O)Nc2ccc(OC(=O)N(C)c3ccccc3)nc2)CC1
Reaction time: 2 h
Yield: 51 %

Procedure:
Thionyl chloride (56 microL, 0.78 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.15 g, 0.39 mmol) in dichloromethane (5 mL) and 2 drops of dimethylformamide. After stirring for 10 minutes N-methylpiperazine (1 mL) was added and stirring was continued for 2 hours. The solvent was evaporated in vacuo. The residue was redissolved in dichloromethane and extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by filtration over a short column (SiO2, ethyl acetate followed by acetone) yielding the title compound (93 mg, 51% yield) as a thick oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38]CC)=[O:37])=[CH:32][CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:48])=[O:18])[CH:27]=2)=[O:29])=[CH:35][CH:34]=1)([OH:38])=[O:37]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC)cc2)ccc1OCCCCCBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3ccc(C(=O)O)cc3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 54.4 %

Procedure:
Starting with 0.157 g (0.76 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.391 g (0.75 mmol) of 2-[(5-bromopentyl)oxy]-5-[[4-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.240 g; 63.6% overall yield) was obtained as a white solid, mp 175°-177° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[C:24](#N)[CH3:25].F[B-](F)(F)F.[O:32]=[N+]=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[C:24]([NH:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5])(=[O:32])[CH3:25]
Reactant: CC#N
Reactant: O=[N+]=O
Reactant: Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
To a mixture of 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-67 (50 mg, 0.15 mmol), acetonitrile (5 mL) and tetrahydrofuran (2 mL) was added nitronium tetrafluoroborate (0.50M sulfolane solution, 0.46 mL, 0.23 mmol) on an ice bath, and the solution was stirred overnight at room temperature. Water, ethyl acetate, tetrahydrofuran and an aqueous solution of saturated sodium bicarbonate were added to the reaction solution for extraction, washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=1:30), and the title compound (1.3 mg, 0.0035 mmol, 2.3%) was obtained as a white solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1C=CC=CC=1>[Br-:20].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Yield: 95 %

Procedure:
Triphenylphosphine and benzene were added to 4-bromobenzyl bromide, and then the mixture was refluxed for 12 hours, resulting in 4-bromobenzyltriphenylphosphonium bromide (G) (yield: 95%).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[S:13][C:12](=[S:23])[N:11]=2)=[CH:6][CH:5]=1.[CH2:24]1[O:26][CH2:25]1.O>C(O)C.C(Cl)Cl>[OH:26][CH2:25][CH2:24][S:23][C:12]1[S:13][C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: C1CO1
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
0.23 g of sodium are dissolved in 30 ml of ethanol under nitrogen. The solution is allowed to cool to room temperature, while stirring 3 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are added and, once dissolution is complete, ethylene oxide is introduced, the reaction temperature being maintained at 25°-30° by gentle cooling. After introducing the ethylene oxide for 30 minutes, it should not be possible to detect any more thione by thin layer chromatography. 10 ml of 2 N-ammonium chloride are then added, the ethanol is removed by distillation under reduced pressure, and the residue obtained by concentration by evaporation is shaken with a mixture of 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, then shaken with methylene chloride, dried over magnesium sulphate and concentrated to dryness by evaporation. The oily crude product is caused to crystallise by triturating with 20 ml of diethyl ether and dried under reduced pressure. 2-(2-Hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 82°-83° is obtained.