Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[I-].[Na+].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=1>C(O)(C)C>[I:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:30][CH:31]=1
Reactant: BrCCOc1ccc(I)cc1
Reactant: CCCCCCCCCCCCN
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of dodecylamine (30 g, 162 mmol), diisopropylethylamine (22 ml, 128 mmol), sodium iodide (1.3 g, 8.5 mmol), 1-[2-bromoethoxy]-4-iodobenzene (13.9 g, 42.5 mmol) and isopropanol (250 ml) was stirred and refluxed for 24 h. After cooling to r.t., the mixture was filtered, washed with dichloromethane and concentrated in vacuo . The residue was chromatographed on silica gel (dichloromethane/methanol 50:1 to 20:1) to afford the title compound (15 g, 82%) as a white solid.
Reaction SMILES: C(C([NH:12][C:13]([C:15]1[C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([CH3:29])[N:18]=[C:17]([CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][C:46]([CH:49]([O:51]COC)[CH3:50])=[CH:45][N:44]=4)=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[N:16]=1)=[O:14])C([O-])=O)C1C=CC=CC=1.Cl.O1CCOCC1.[CH3:62][CH2:63][CH2:64][CH2:65][CH2:66]C.[C:68]([O:71][CH2:72][CH3:73])(=[O:70])[CH3:69]>>[CH2:22]([O:21][C:20]1[C:15]([C:13]([NH:12][CH2:69][C:68]([O:71][CH2:72][C:73]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:70])=[O:14])=[N:16][C:17]([CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][C:46]([CH:49]([OH:51])[CH3:50])=[CH:45][N:44]=4)=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)=[N:18][C:19]=1[CH3:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCOC(C)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(OCc5ccccc5)c(C(=O)NC(Cc5ccccc5)C(=O)[O-])n4)CC3)cc2)nc1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(C(C)O)cn4)cc3)CC2)nc(C(=O)NCC(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
Benzyl({[5-(benzyloxy)-2-{[1-(4-{5-[1-(methoxymethoxy)ethyl]pyridin-2-yl}phenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.80 g, 1.1 mmol) was dissolved in ethyl acetate (6 mL), and a solution of hydrogen chloride in dioxane (4 M, 1.5 mL, 6.0 mmol) was added, followed by stirring at room temperature for 1.5 hours. After hexane was added to the reaction solution, the deposited solid was collected by filtration using hexane. To this, was added a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.30 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.32 g, 0.49 mmol) as a yellow solid (yield 44%).
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1)=[CH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=O)=[CH:6][CH:5]=1.[C:25](Cl)(=[O:32])C1C=CC=CC=1.[K].C(Cl)(=O)[C:36](Cl)=[O:37].[N+](=C)=[N-]>[Ag]=O.CO>[CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1)=[CH:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:36]([O:32][CH3:25])=[O:37])=[CH:6][CH:5]=1
Reactant: CC(C)=CCOc1ccc(C(C)=Cc2ccc(C(=O)O)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=[Ag]
Agent: C=[N+]=[N-]
Agent: [K]
Solvent: CO
Product: COC(=O)Cc1ccc(C=C(C)c2ccc(OCC=C(C)C)cc2)cc1

Procedure:
4-(2-Methyl-2-(4-(3-methyl-2-butenoxy)phenyl) ethenyl)benzoic acid is converted to the corresponding benzoyl chloride by treating the potassium salt of the acid with oxalyl chloride as described in Example 12. The benzoyl chloride is reacted with diazomethane and the resulting diazoketone is decomposed using silver oxide catalyst in methanol to give methyl 4-(2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethenyl)phenylacetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[CH:13][S:14][C:10]=2[CH:9]=1.Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C(OCC)(=O)C.O>[S:14]1[C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)[CH:16]=[CH:15][C:11]=2[CH:12]=[CH:13]1
Reactant: OC1CNC1
Reactant: ClCCCOCCc1ccc2ccsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OC1CN(CCCOCCc2ccc3ccsc3c2)C1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 24.5 %

Procedure:
1.00 g of 6-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in 5 ml of dimethyl sulfoxide. Thereafter, 0.86 g of 3-azetidinol hydrochloride and 1.63 g of potassium carbonate were added to the obtained solution, and the obtained mixture was stirred at 75° C. for 2.5 hours, and then at 95° C. for 1.5 hours. Thereafter, the reaction solution was cooled, and thereafter, water and ethyl acetate were added to the reaction mixture. The pH of the obtained mixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric acid, and a water layer was then separated. Ethyl acetate was added to the water layer, and the pH of the obtained mixture was adjusted to pH 10 by addition of a 2 mol/l aqueous sodium hydroxide solution, followed by separation of an organic layer. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=30:1 to 5:1), so as to obtain 0.28 g of an achromatic oil product, 1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol.
Reaction SMILES: CC1C=C([C:9]2(C3C=CC(N)=C(C)C=3)[C:21]3[CH:20]=[C:19](C#C[Si](C)(C)C)[CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][C:12]([C:28]#[C:29][Si](C)(C)C)=[CH:13][CH:14]=3)C=CC=1N.C[Si]([C:46]#[CH:47])(C)C.CC(O)(C#C)C.CC1C=C(C2(C3C=CC(N)=C(C)C=3)C3C=C(CC(O)(C)C#C)C=CC=3C3C2=CC(CC(C)(O)C#C)=CC=3)C=CC=1N>>[C:28]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][C:10]=2[C:11]=1[C:46]#[CH:47])#[CH:29]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(C2(c3ccc(N)c(C)c3)c3cc(C#C[Si](C)(C)C)ccc3-c3ccc(C#C[Si](C)(C)C)cc32)ccc1N
Agent: C#CC(C)(C)O
Agent: C#CC(C)(O)Cc1ccc2c(c1)C(c1ccc(N)c(C)c1)(c1ccc(N)c(C)c1)c1cc(CC(C)(O)C#C)ccc1-2
Product: C#Cc1ccc2c(c1C#C)Cc1ccccc1-2

Procedure:
Diethynylfluorene was synthesized by the same method as in the synthesis method of 9,9-bis(3-methyl-4-aminophenyl)-2,7-bis(trimethylsilylethynyl)fluorene represented by Example 1 except that trimethylsilylacetylene was replaced with 2-methyl-3-butyne-2-ol. The obtained compound was measured by the NMR and then the compound was 9,9-bis(3-methyl-4-aminophenyl)-2,7-bis(2-hydroxy-2-methyl-3-butynyl)fluorene represented by the following formula (3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1>C(O)C>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:12][CH2:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: SCCc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(CSCCc2ccc3c(c2)OCO3)ccn1
Temperature: 70 °C
Yield: 59.8 %

Procedure:
3.30 g of 2-(1,3-benzodioxol-5-yl)ethanethiol was dissolved in 30 ml of ethanol. 1.65 g of sodium hydroxide and then 2.70 g of 4-picolyl chloride hydrochloride were added to the solution and the mixture was heated under reflux at 70° C. for 30 min. The solvent was distilled off and water was added to the residue. After extraction with ethyl acetate, 1N hydrochloric acid was added to the extract. The aqueous layer was acidified, taken up and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 8 with potassium carbonate. After extraction with ethyl acetate, the extract was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified according to silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain 2.69 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1.C(O)(=O)C>C1COCC1.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: Nc1ccccn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccccn2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 13.3 %

Procedure:
To 0.224 g (2.38 mmol) of 2-aminopyridine in THF (3 mL) was added 2.5 mL of lithium bis(trimethylsilyl)amide (1 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.204 g (0.56 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (4 mL) was added and the mixture was stirred for 1 hr. The resulting mixture was neutralized with acetic acid, diluted with water and extracted with EtOAc. The organic layer was washed with water and aqueous NH3, and dried. After removal of the solvent, the residue was purified by chromatography on alumina, eluting with CH2Cl2/EtOAc (1:5) to give an orange powder. Recrystallization from EtOH/CH2Cl2 gave 31.5 mg (13% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyridinyl)-1,3,5-triazin-2-amine: mp 230-232° C.; 1H NMR (CDCl3) δ 8.41-8.37 (m, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.12 (br s, 1H), 7.91-7.89 (m, 1H), 7.75 (td, J=7.5, 1.8 Hz, 1H), 7.60 (t, JHF=53.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.05 (ddd, J=7.3, 4.9, 0.9 Hz, 1H), 3.96-3.94 (m, 4H), 3.85-3.82 (m, 4H); HRMS (FAB+) MNa+ Calcd. for C20H18F2N8NaO: m/z 447.1466. Found: m/z 447.1464.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.N1CCCC1.CC(O[C:20]([NH:22][C@@H:23]([C:27]([OH:29])=O)[CH:24]1[CH2:26][CH2:25]1)=[O:21])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH2:46]([N:48]1[CH:52]=[C:51]([C:53]2[N:58]=[C:57]3[C:59](C(O)=O)=[CH:60][N:61](COCC[Si](C)(C)C)[C:56]3=[N:55][CH:54]=2)[CH:50]=[N:49]1)[CH3:47].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1>>[CH:24]1([C@@H:23]([NH:22][C:20]([C:59]2[C:57]3[C:56](=[N:55][CH:54]=[C:53]([C:51]4[CH:50]=[N:49][N:48]([CH2:46][CH3:47])[CH:52]=4)[N:58]=3)[NH:61][CH:60]=2)=[O:21])[C:27]([N:6]2[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]2)=[O:29])[CH2:25][CH2:26]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: C1CCNC1
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(F)(F)CC4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 4,4-difluoropiperidine hydrochloride for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. MS: (M+H)+=458.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:23]=[CH:22][C:13]2[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][O:16][C:12]=2[CH:11]=1>CN(C)C=O.O>[CH3:1][O:9][C:10]1[CH:23]=[CH:22][C:13]2[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][O:16][C:12]=2[CH:11]=1
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1noc2cc(OC)ccc12
Temperature: 25 °C
Yield: 19 %

Procedure:
Potassium carbonate (9.42 mmol) and iodomethane (8.45 mmol) were added to a solution of crude ethyl 6-hydroxybenzo[d]isoxazole-3-carboxylate (2.42 mmol) in N,N-dimethylformamide (30 mL) and the reaction mixture was maintained for 48 h at rt in the dark. The reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (3×100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (30/1 petroleum ether/ethyl acetate) to provide ethyl 6-methoxybenzo[d]isoxazole-3-carboxylate in 19% yield as a yellow solid.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:14][C:15]1[C:19](C#N)=[C:18]([CH2:22][CH3:23])[NH:17][N:16]=1>C(O)(=O)C>[CH2:22]([C:18]1[C:19]([C:15]#[N:14])=[C:13]2[N:2]=[CH:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:16]2[N:17]=1)[CH3:23]
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: CCc1[nH]nc(N)c1C#N
Solvent: CC(=O)O
Product: CCc1nn2c(-c3ccccc3)ccnc2c1C#N

Procedure:
A mixture of 0.71 g. of 3-dimethylaminoacrylophenone, 15 ml. of glacial acetic acid and 0.55 g. of 3-amino-5-ethylpyrazole-4-carbonitrile is refluxed for 16 hours and then evaporated. The residue is treated as described in Example 1, giving the desired product, m.p. 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([C:19](O)=[O:20])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:19](=[O:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(=O)c1ccccc1
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1-c1ccccc1
Yield: 87.6 %

Procedure:
A mixture of 528 mg (2.98 mmol) of 4,5-dichloro-1,2-phenylenediamine and 448 mg (2.98 mmol) of benzoylformic acid in 8 mL of ethanol was refluxed overnight. It was filtered, washed by water, and dried to leave 760 mg (87%) of solid. 1H NMR (DMSO-d6), 7.465-7.536 (m, 4), 8.088 (s, 1), 8.256-8.282 (m, 2) 12.683 (s, 1).
Reaction SMILES: [C:1]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][C:9]=2[S:8][C:7]=1[N:16]=[C:17](OCC)[CH3:18])([O:3]CC)=O.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:27][CH2:26]1>C(O)C>[CH3:18][C:17]1[N:22]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH2:29][CH2:30]2)[C:1](=[O:3])[C:6]2[C:14]3[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][C:9]=3[S:8][C:7]=2[N:16]=1
Reactant: CCOC(=O)c1c(N=C(C)OCC)sc2c1CCN(C)C2
Reactant: COc1ccccc1N1CCN(CCN)CC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2c(C)nc3sc4c(c3c2=O)CCN(C)C4)CC1
Yield: 28.4 %

Procedure:
1.9 g (6.2 mmol) of ethyl N-(3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ethanimidate in 30 ml of ethanol were mixed with 1.5 g (6.2 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine and refluxed for 7 h. The mixture was then concentrated in a rotary evaporator, and the residue was taken up in 20 ml of ethyl acetate. 2.1 g of crude product crystallized out overnight and were filtered off with suction and purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 92/8). 0.8 g (29%) of product was isolated.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C.O>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)(=[O:18])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCCCNc2nc(Cl)ncc2Br)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1.2 g (5.3 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 30 ml of acetonitrile is added to a solution of 1.5 g (5.2 mmol) of N-(5-amino-pentyl)-3-nitro-benzenesulfonamide in 50 ml of acetonitrile. The reaction mixture is mixed with 1.0 ml (7.2 mmol) of triethylamine and stirred for 17 hours at room temperature. After water (50 ml) is added, it is extracted (2×) with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 2:1, Flashmaster II). 1.5 g (3.1 mmol, corresponding to 60% of theory) of the product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH3:22])[CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH:32]1([SH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.N1CCCCC1.[K+].[Br-]>C(O)(=O)C>[CH:32]1([S:38][CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3]2[C:4](=[O:23])[O:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[C:10]([CH3:22])[CH:9]=3)=[CH:7][C:2]=2[OH:1])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=Cc1ccccc1
Reactant: SC1CCCCC1
Reactant: Cc1cc(-c2cc(O)cc(=O)o2)ccc1OCc1cccnc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1cc(-c2cc(O)c(C(SC3CCCCC3)c3ccccc3)c(=O)o2)ccc1OCc1cccnc1

Procedure:
The title compound was prepared by Method C using 4-hydroxy-6-[3-methyl-4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one (0.5 g, 1.62 mmol), benzaldehyde (0.189 g, 1.78 mmol), cyclohexylmercaptan (0.489 g, 4.212 mmol), piperidine, (0.5 mL), acetic acid (0.5 mL). m.p. 84-87° C. (d); IR (KBr) 3059, 2930, 2853, 1676, 1601, 1449, 1260, 1134, 700 cm-1 ; MS (CI) m/e 446 (2), 331 (9), 226 (61), 205 (24), 135 (44).
Reaction SMILES: [CH3:1][C@@:2]([NH:15][NH2:16])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.O.C(=O)(O)[O-].[Na+].O.[CH2:24]([O:31][C:32](ON1[C:39](=O)[CH2:38][CH2:37][C:36]1=[O:41])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(OC)(C)C.C1COCC1>[CH2:24]([O:31][C:32]([NH:16][NH:15][C@@:2]([CH3:1])([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1)[C:12]([OH:14])=[O:13])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:37]1[CH2:36][O:41][CH2:39][CH2:38]1
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@](Cc1ccc(O)c(O)c1)(NNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
A slurry of carbidopa monohydrate (20.0 g, 82 mmol), sodium bicarbonate (7.57 g, 90 mmol), water (200 mL), and THF (100 mL) was cooled to 5° C. to 10° C. and N-(benzyloxycarbonyloxy)succinimide (20.4 g, 82 mmol) was added. The mixture was warmed to ambient temperature and became a nearly homogeneous solution over 5 hours, when LC-MS showed nearly complete reaction. The solution was diluted with MTBE (100 mL), the layers separated, and organic layer extracted with saturated aqueous NaHCO3 (100 mL). The aqueous layers were acidified with 2 N HCl (160 mL) and the acidic aqueous layer was extracted with MTBE (2×100 mL). During the second back-extraction, a small amount of product began to precipitate. The combined organic layers were washed with brine (20 mL) and residual solid rinsed out of the separatory funnel with MTBE (20 mL). The resulting mixture was concentrated to 43 g total mass and 10% THF/MTBE (60 mL) was added. The mixture was too thick to stir, so additional MTBE (60 mL to 6 vol 5% THF/MTBE) was added. The resulting white slurry was then heated to 50° C. The slurry was cooled to ambient temperature over one hour and then stirred for 14 hours. The white solid was filtered, washed with 5% THF/MTBE (20 mL), and dried in a vacuum oven (50° C.), giving (S)-2-(2-((benzyloxy)carbonyl)-hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound with THF (4:3) (31.1 g, 71.9 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=9.0 Hz, 2H), 8.18 (br s, 1H), 7.49-7.17 (m, 5H), 6.59 (dd, J=5.0, 3.0 Hz, 2H), 6.44 (dd, J=8.0, 2.0 Hz, 1H), 5.04 (s, 2H), 2.73 (d, J=13.4 Hz, 1H), 2.59 (d, J=13.3 Hz, 1H), 1.07 (s, 3H); MS (ESI) m/z 361 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 58.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.30 g, 0.66 mmol) obtained in step 2 and ethanesulfonamide (0.35 g, 3.30 mmol), the title compound (0.21 g, 58%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCC>O1CCCC1>[Br:20][CH:8]([C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1cc(Cl)cc(-c2ccc(C#N)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(Br)c1cc(Cl)cc(-c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (±)-3′-chloro-5′-(1-hydroxyethyl)biphenyl-4-carbonitrile (171 mg, 0.664 mmol) and carbon tetrabromide (264 mg, 0.796 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (209 mg, 0.796 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with ca. 2 volumes of pentane and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (3%→8% ethyl acetate/hexanes) to give 201 mg (94%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.74 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.47 (s, 2H), 5.18 (q, J=6.7 Hz, 1H), 2.06 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.1, 143.8, 141.5, 135.4, 132.8, 127.9, 127.3, 127.1, 124.2, 118.6, 112.1, 47.4, 26.8.