Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:26][C:27](Br)=[O:28].[CH2:30]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36])[CH3:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:26][C:27]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[O:32][CH2:30][CH3:31])=[O:28]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1Br
Reactant: O=C(Br)CBr
Reactant: CCOc1ccccc1CN
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(Br)c1

Procedure:
prepared by reaction of 1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzylamine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([C:16]([O:18]CC)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+].O.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccccc2C(=O)O)c(Cl)c1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 82.1 %

Procedure:
Ethyl 2′-chloro-4′-methoxybiphenyl-2-carboxylate (67.7 g) was dissolved in ethanol (100 ml), 4N aqueous sodium hydroxide (100 ml) was added, and the mixture was stirred at an oil bath temperature of 110° C. for 4.5 hr. The reaction mixture was cooled to room temperature, water (200 ml) and toluene (100 ml) were added, and the mixture was stirred overnight. To the reaction mixture was added activated carbon (3.6 g), and the mixture was further stirred for 1 hr. The insoluble material was filtered off through celite, and the insoluble material was washed with toluene (30 ml) and water (300 ml). The obtained filtrates were combined to allow for layer separation. The obtained aqueous layer was washed with toluene (100 ml), the aqueous layer was acidified with concentrated hydrochloric acid (40 ml), and stirred at room temperature for 1 hr. The precipitated solid was collected by filtration. The obtained solid was air-dried for 3 hr, and dried under reduced pressure at 60° C. overnight to give the title compound (50.2 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29].[Cl:41][CH2:42][C:43](Cl)=[O:44].C(N(CC)CC)C>O1CCCC1.O>[Cl:41][CH2:42][C:43]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])=[O:44]
Reactant: NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of (2S,4S)-2-aminomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (7.78 g) in a mixture of tetrahydrofuran (120 ml) and water (40 ml) was added dropwise chloroacetyl chloride (1.23 ml) with stirring under ice-cooling, keeping the pH 8-10 with triethylamine. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was evaporated in vacuo to remove the organic layer. The resulting residue was extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4S)-2-(chloroacetylamino)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (7.35 g).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14]2)[C@H:10]([CH2:24][OH:25])[CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[C:20]([O:19][C:17]([NH:16][C:13]1([C@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[CH2:24][OH:25])[CH2:14][CH2:15]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2CO)CC1
Reaction time: 24 h
Yield: 95 %

Procedure:
Cis-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-hydroxymethylpyrrolidine (820.1 mg, 2.376 mmol) was dissolved in methanol (50 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 750 mg) and stirred for one day under a hydrogen pressure of 4.5 kg/cm2. After removing the catalyst by celite filtration (methanol washing), the resulting filtrate was concentrated under reduced pressure to obtain 578.8 mg (91%) of the title compound as a white amorphous substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH:11]([CH3:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[Si:31]([O:1][C:2]1[CH:3]=[C:4]([C:8]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH:11]([CH3:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1CC(c2ccccc2)(c2cccc(O)c2)C(=O)N1C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC1CC(c2ccccc2)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Product of Step 6 (4.9 g) was dissolved in dichloromethane (200 mL). To this, imidazole (5 g) and tertiarybutyldimethylsilyl chloride (5 g) was added. The reaction mixture was stirred at 25° C. for 16 hrs. Then, the reaction mixture was extracted with water (200 mL) and the organic layer was dried on anhydrous magnesium sulfate. The organic layer was filtered and concentrated under vacuum. The crude product was loaded on a SNAP cartridge containing 340 g silica gel and eluted with a gradient of ethyl acetate and hexane using the BIOTAGE® AB ISOLERA™ flash chromatography system. Fractions containing product were pooled and evaporated to obtain product of Step 7 as a viscous, colorless oil. Yield of purified product: 2.75 g. 1H NMR (CDCl3): 0.1 δ (6H, —Si—(CH3)2), 0.9 δ (9H, (—CH3)3 of tertiary butyl), 1.3 δ (3H, —CH—CH3 of isopropyl), 2.8 δ (3H, —N—(CH3)), 2.25, 3.1, 3.5 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=396 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12)[CH2:16][CH2:17][CH3:18]
Reactant: CCn1ncc2c(Cl)c(CO)cnc21
Reactant: CCCCN
Product: CCCCNc1c(CO)cnc2c1cnn2CC
Yield: 87 %

Procedure:
51 g. of 4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-methanol (0.24 mol.) and 300 ml. of n-butylamine are heated at 100° in an autoclave for seven hours. After cooling, the surplus butylamine is removed by distillation in vacuo and the residue is treated with a total amount of 200 ml. of ether. The etheral solution is evaporated, yielding 51.9 g (87%) of the alcohol, m.p. 60°-72°. Recrystallization with hexane provides the pure 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-methanol, m.p. 85°-86°.
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([OH:17])=O)=[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:27][C:28]1[S:29][CH2:30][CH2:31][N:32]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([N:32]2[CH2:31][CH2:30][S:29][C:28]2=[S:27])=[O:17])=[C:10]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SC1=NCCS1
Reactant: Cc1cc(C(=O)O)c(OCc2ccccc2)c(=O)n1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(=O)n1Cc1ccccc1
Reaction time: 1 h
Yield: 74 %

Procedure:
1-benzyl-3-benzyloxy-4-carboxy-6-methyl-2(1H)-pyridinone (5.36 g, 15.3 mmol) was dissolved in CH2Cl2 (100 ml) under an atmosphere of nitrogen. Then 2-mercaptothiazoline (1.88 g, 16.1 mmol) and dimethylaminopyridine (DMAP, 0.16 g, 1.0 mmol) were added and the solution stirred for 1 h. Dicyclohexylcarbodiimide (DCC, 3.45 g, 16.9 mmol) was then added in small portions and the reaction mixture stirred for 16 h, and then allowed to stand for 24 h at 0° C. The reaction mixture was filtered and the solvent removed by evaporation. EtOAc (10 ml) was added, and the solution filtered. This last step was repeated 3 times in order to remove the dicyclohexylurea (DCU), yielding a yellow oil. The product was purified by flash column chromatography (silica, CH2Cl2 as eluent). The solvents were removed by rotary evaporation, yielding a viscous yellow oil, which was recrystallized from acetone to give a yellow crystalline solid (Yield: 5.10 g, 74%). 1H NMR (CDCl3, 400 MHz): δ=7.12-7.49 (m, 10H, Bn), 5.98 (s, 1H, HOPO), 5.38 (s, 2H, Bn-CH2), 5.34 (s, 2H, Bn-CH2), 4.59 (t, J=7.3 Hz, 2H, thiaz), 2.90 (t, 2H, J=7.3 Hz, thiaz), 2.27 (s, 3H, HOPO CH3) ppm. Anal. Calcd (Found) for C24H22N2O3S2: C, 63.98 (64.04); H, 4.92 (5.02); N, 6.22 (6.03). FAB-MS (+): m/z: 451 [M+H]+.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:29][CH3:30])=[C:16]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([N:22]2[CH2:23][CH2:24][CH:25]([OH:28])[CH2:26][CH2:27]2)[C:15]([O:29][CH3:30])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1N1CCC(O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (5 mg, 0.03 mmol), 1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]piperidin-4-ol (7 mg, 0.02 mmol), and N,N-diisopropylethylamine (0.0082 mL, 0.047 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H26ClN6O2 (M+H)+: m/z=417.2. found: 417.1.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:32]2[CH:31]=[C:30](B(O)O)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.COC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:31]4[C:32]5[C:23]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=6[CH:30]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: COC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc5ccccc5c5ccccc45)cc3CC[C@@H]12
Yield: 30.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 9-phenanthreneboronic acid (173 mg, 0.78 mmol), triethylamine (0.2 mL, 1.3 mmol), and 2 mL of dimethyl ether, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 80 mg (30%) of the title compound as a white solid. mp 218°-220°. FDMS: m/e=405. α[D]589 =+63.01 (c=0.98, chloroform).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.[I-].[K+].[CH3:30][NH2:31].O1CCCC1>C(OCC)(=O)C>[CH3:30][NH:31][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1
Reactant: CN
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 2-(chloromethyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (0.30 g, 0.76 mmol), potassium iodide (0.13 g, 0.76 mmol) and 2M methylamine-tetrahydrofuran solution (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=7/3) and recrystallized from hexane/diisopropyl ether to give the title compound (0.20 g, yield 67%) as colorless crystals.
Reaction SMILES: B([O:3][O-:4])=O.O.[Na+].[Na].[C:8]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:8]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:3][OH:4])=[O:23])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=BO[O-]
Reactant: O=C(O)CCCCCNC(=O)c1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(CCCCCNC(=O)c1ccccc1)OO

Procedure:
Perhydrolysis of the above phenolsulfonate ester to yield 6-benzoylaminoperoxycaproic acid was accomplished according to the following procedure. To 4 L of 95° F. city water was added 5.00 g (1250 ppm) of an alkaline detergent granule, 0.36 g (90 ppm) of sodium perborate monohydrate and 0.46 g (115 ppm) of the sodium salt of the phenolsulfonate ester of 6-benzoylaminocaproic acid (0.67 g of the 69% mixture described above). Perhydrolysis of the ester to form 6-benzoylamino-peroxycaproic acid was followed by analysis of the solution for available oxygen (AvO) using a conventional iodometric titration. Complete conversion of the ester to the peroxyacid would result in the formation of 4.5 ppm AvO. The results obtained for AvO versus time are tabulated below.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:9]1[S:13][C:12](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(C=O)s1
Reactant: O=C(O)CC(=O)O
Product: CCCCCCC#Cc1ccc(/C=C/C(=O)O)s1
Yield: 93.5 %

Procedure:
Reaction of 5-(1-octynyl)-2-thiophene carboxaldehyde (880 mg, 4 mmole) with malonic acid as described in Example 2 yielded 0.98 g (93.5%) of the title compound after recrystallization from hexane mp 79° C.; νmax (mull) 2600 (broad), 1690, 1670, 1610, 940, 845, 800; δ(CDCl3) 0.90(3H, t, J=6 Hz), 1.50(8H, m), 2.40(2H, t, J=6 Hz), 6.15(1H, d, J=15 Hz), 7.05(1H, d, J=4.5 Hz), 7.13(1H, d, J=4.5 Hz), 7.85(1H, d, J=15 Hz), 11.3(1H, bs). M+ 262.1022 C15H15O2S requires 262.1027. Found; C, 68.96; H, 7.14; C15H15O2S requires; C, 68.68; H, 6.92.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=NC=[CH:17][CH:18]=2)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4].N[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(CC(=O)CCC=C)#N.C(Cl)Cl>CO>[CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=[C:20]3[C:21](=[CH:17][CH:18]=2)[N:22]=[CH:23][CH:24]=[CH:25]3)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Nc1cccnc1
Reactant: C=CCCC1=NN=C(N)C1=NNc1cccnc1
Agent: C=CCCC(=O)CC#N
Solvent: CO
Solvent: ClCCl
Product: C=CCCC1=NN=C(N)C1=NNc1ccc2ncccc2c1
Yield: 54 %

Procedure:
In a similar manner, 5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine was prepared from 3-aminopyridine (113 mg, 1.2 mmole) and 1-cyano-5-hexen-2-one (123 mg, 1 mmole). The crude material was pruified by preparative TLC (CH2Cl2:MeOH=21:1) to yield 131 mg (54%) of the title compound as an orange powder. MS (m/z, ES+): 243 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.68 (br s, 1H), 8.89 (s, 1H), 8.46 (m, 1H), 7.96 (d, 1H), 7.46 (dd, 1H), 7.19 (brs, 2H), 5.87 (m, 1H), 5.07 (dd, 1H), 4.96 (d, 1H), 2.84 (br m, 2H), 2.46 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)=O>ClCCl>[C:2]1([NH:1][C@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)Nc1ccccc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a stirred solution of aniline (4.55 mL, 50 mmol) and triethylamine (7 mL, 50 mmol) in anhydrous dichloromethane (120 mL) was added a solution of ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}propanoate (12.5 g, 50 mmol) in dichloromethane (60 mL) at 0° C. (Ice bath) over a period of 30 minutes under nitrogen. The ice bath was then removed and the reaction mixture was stirred at 35° C. for 2 h. The reaction mixture was cooled to rt, washed with water, dried over sodium sulfate, and evaporated to give desired product as oil (8.9 g, 92%) which was used as such for the next step. 1HNMR (300 MHz, CDCl3): δ 1.19-1.67 (m, 6H), 4.17-4.38 (m, 3H), 6.65-6.80 (m, 3H), 7.20-7.35 (m, 2H).
Reaction SMILES: COC1C=CC(C[N:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:10]3[N:11]([CH:25]=[CH:26][N:27]=3)[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][N:21]=[C:20]([NH2:23])[C:19]=4[CH:24]=3)[CH:14]=2)=CC=1.CCOC1C=CC(N)=CC=1.C(O)(C(F)(F)F)=O>>[NH2:23][C:20]1[C:19]2[CH:24]=[C:15]([C:13]3[CH:14]=[C:9]([NH:8][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:10]4[N:11]([CH:25]=[CH:26][N:27]=4)[N:12]=3)[CH:16]=[CH:17][C:18]=2[O:22][N:21]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc4onc(N)c4c3)nn3ccnc23)cc1
Agent: CCOc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1noc2ccc(-c3cc(Nc4ccccc4)c4nccn4n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d]isoxazol-3-amine from (1c) was added TFA (1 mL) and the solution stirred at RT for 1 hour. The reaction solution was concentrated in vacuo, diluted with methanol and purified by preparative HPLC to provide the titled compound (13.20 mg, 70%). 1H NMR (500 MHz, CD3OD) δ ppm 8.3 (1H, s), 8.21 (1H, d=2.2 Hz), 8.11 (1H, m), 7.97 (1H, m), 7.52 (4H, m), 7.3 (1H, m), 7.1 (1H, m), 7.07 (1H, d, J=8.8 Hz). LC/MS, m/e 343 (M+1). HPLC Rt, 2.63 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:17]#[N:18]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:15]=[C:16]([C:17]#[N:18])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[CH:9]=1
Reactant: N#Cc1cc(Cl)cc(CBr)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: N#Cc1cc(Cl)cc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 22.8 %

Procedure:
(Step 4) To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-(bromomethyl)-5-chlorobenzonitrile (0.29 g) obtained in Step 3, and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (80 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9](B(O)O)=[C:8]([O:17][CH3:18])[CH:7]=1.[CH3:19][O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](OS(C(F)(F)F)(=O)=O)=[CH:37][CH:36]=1)[NH:23][C:24](=[O:33])[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32]>>[CH3:19][O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:9]2[C:10]([O:12][CH3:13])=[CH:11][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:7][C:8]=2[O:17][CH3:18])=[CH:39][CH:40]=1)[NH:23][C:24](=[O:33])[C:25]1[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1cc(C2OCCO2)cc(OC)c1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cc(C3OCCO3)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
4-(1,3-Dioxolan-2-yl)-2,6-dimethoxybenzeneboronic acid was reacted with N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester in a similar manner as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4-[4-(1,3-dioxolan-2-yl)-2,6-dimethoxyphenyl]-L-phenylalanine methyl ester.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:32][I:33]>>[I-:33].[CH3:32][P+:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:8][CH:7]=1)([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1ccc(P(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)cc1
Reactant: CI
Product: C[P+](c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Product: [I-]
Yield: 89.4 %

Procedure:
Starting from 5.01 g (10.7 mmol) of tris(4-trifluoromethylphenyl)phosphine and 3.22 g (22.7 mmol, 2.11 eq) of methyl iodide, 5.82 g (9.57 mmol, 89.4%) of methyltris(4-trifluoromethylphenyl)phosphonium iodide was obtained: mp>250°.