Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=C.II>CO>[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)OC
Agent: II
Solvent: CO
Product: COC(=O)C=Cc1ccccc1

Procedure:
On the other hand, it is known that the reaction of benzoyl chloride with methyl acrylate in the presence of stoichiometric amounts of a nickel(O) catalyst leads to the formation of methyl trans-3-benzoyl acrylate if the reaction mixture is subsequently treated with iodine in methanol. Methyl cinnamate is formed as a by-product in this reaction. Methyl cinnamate is obtained as the main product and methyl benzoyl acrylate as a by-product by reacting a complex formed from benzoyl-palladium chloride and triphenylphosphine with methyl acrylate at 70° to 85° C. in the presence of triethylamine. If only catalytic amounts of the palladium and the triphenylphosphine are employed, the equilibrium of the reaction is shifted in favour of the formation of methyl benzoyl acrylate (the ratio by weight of methyl benzoyl acrylate:methyl cinnamate is approx. 8.3:1) [cf. Transition Met. Chem. 2, 270 (1977) and 4, 298 (1979)]. Finally, it is known from Synthesis, 777 (1977), that the reaction of aromatic acid halides with 1-alkines, catalysed by Pd, leads to alkinyl ketones without decarbonylation.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.O.[NH2:14][NH2:15]>C(O)C>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:14][NH2:15])=[O:8])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(CO)cc1
Reaction time: 2 h

Procedure:
To a solution of 1.66 g (10.0 mmol) of methyl 4-hydroxymethylbenzoate (19) in 20 ml of ethanol was added 3.0 g (60 mmol) of hydrazine hydrate. The mixture was stirred for 2 h, an additional 3.0 g hydrazine hydrate was added and the mixture was allowed to stand overnight. The precipitate was filtered, washed twice with ethanol and dried in vacuo to yield 20 as a white powder. (Literature references for compound: Yaroshenko, V. V.; Grekov, A. P.; Tkach, V. P.; Yakovenko, A. G. Inst. Khim. Vysokomol. Soedin. Sint. Fiz.-Khim. Polim. 1975, 17 97; and Galiano, R.; Joaquin, A.; Soria, A. (Instituto de Investigacion y Desarrollo Quimico Biologico, S. A., Spain). Span. (1993), 24 pp. CODEN: SPXXAD ES 2039161 A1 19930816)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][CH3:36])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:36]
Reactant: CCc1ccccc1COc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 460 mg of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(2-ethylbenzyl)oxy]thiophene-2-carboxamide in 30 ml THF is cooled to 0° C. At 0° C. 0.32 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for one hour.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:8]2[CH2:9][CH2:10][C:11](=[O:12])[N:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:22])=[CH:16][CH:15]=1
Reactant: O=C1CCNN1c1ccccc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C1CCN(C(=S)Nc2ccc(Cl)cc2)N1c1ccccc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of 2.11 grams (0.013 mole) of 2-phenyl-3-pyrazolidinone, 2.21 grams (0.013 mole) of 4-chlorophenyl isothiocyanate and 0.5 ml of pyridine in 15 ml of toluene was heated at reflux for 9 hours. The reaction mixture was allowed to cool to room temperature forming a crystalline precipitate. The crystalline precipitate was collected by filtration to yield 3.92 grams of 1-(4-chlorophenylthiocarbamoyl)-2-phenyl-3-pyrazolidinone (mp 136°-139° C.).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:19][CH:20]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:10][N:11]([C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[C@@H:20]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])[CH2:19]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)cc1C(O)C[C@H](CNC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: -5 °C
Yield: 57.38 %

Procedure:
To a solution of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate (4.810 g, 10.84 mmol) in CH2Cl2 (108 mL) at −60° C. was added TEA (4.534 mL, 32.53 mmol) followed by methanesulfonyl chloride (0.9231 mL, 11.93 mmol). The resulting mixture was slowly warmed to −5° C. and poured into a mixture of ice and saturated aqueous NaHCO3 (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica column chromatography, eluting with 2-10% MeOH/DCM to afford (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate (assumed to be a mixture of cis and trans isomers; 2.648 g, 57.38% yield). LC/MS (ES+APCI) m/z=326.1 (M+H-Boc).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=1/[CH:14]=[CH:15]/[C:16]([OH:18])=O)(=[O:3])[CH3:2].[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][N:25]2[CH2:30][C@H:29]([CH3:31])[NH:28][CH2:27][C@H:26]2[CH3:32])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C>[Cl:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][C:6](/[CH:14]=[CH:15]/[C:16]([N:28]2[CH2:27][C@H:26]([CH3:32])[N:25]([CH2:24][C:23]3[CH:33]=[CH:34][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:30][C@H:29]2[CH3:31])=[O:18])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: COc1cc(/C=C/C(=O)O)c(NC(C)=O)cc1Cl
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(NC(C)=O)cc1Cl
Yield: 55.3 %

Procedure:
(E)-3-(2-Acetylamino-4-chloro-5-methoxyphenyl)-acrylic acid (100 mg; 0.37 mmol), (2R,5S)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (Mavunkel, Babu J. et al., WO 00/71535) (83 mg; 0.37 mmol) and EDCl.HCl (85 mg, 0.44 mmol) were dissolved in DMF (3 ml) and stirred over night. The reaction mixture was evaporated, taken up in 2N Na2CO3 and extracted with EtOAc three times. The combined organic phases were evaporated and purified via chromatography (SiO2 acetone/hexanes 3/7 to 4/6) to yield the title compound as colorless crystals (97 mg; 55%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19]3=[CH:23][CH:24]=[N:25][N:18]3[CH2:17][CH2:16][C:15]=2[C:14]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19]3=[CH:23][CH:24]=[N:25][N:18]3[CH2:17][CH2:16][C:15]=2[C:14]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:11])=[O:10])[CH3:31]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CCn1nccc1-2
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCn1nccc1-2
Temperature: 80 °C
Yield: 60.7 %

Procedure:
A mixture of methyl 8-(2-bromo-4-fluorobenzenesulfonylamino)-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 21, 0.088 g), N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.222 g), tris-(dibenzylideneacetone)dipalladium (0) (0.020 g) and tri-tert-butylphosphonium tetrafluoroborate (0.01 g) in dioxane (3 mL) was de-gassed and purged with nitrogen and then heated to 80° C. in a sealed vessel for 2 hours. The resultant mixture was cooled, filtered through Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10% to give methyl 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.057 g) as a glass.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][N:18]([CH3:30])[C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[N:23][C:22]=2Cl)=[O:20])[N:16]=1)=[O:10].[CH3:34][Al](C)C.CO>O1CCOCC1.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>[F:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][NH:8][C:9](=[O:10])[NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][N:18]([CH3:30])[C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[N:23][C:22]=2[CH3:34])=[O:20])[N:16]=1
Reactant: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(Cl)nn1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(C)nn1
Yield: 52 %

Procedure:
N2 was bubbled for 15 minutes through a solution of 1-(3-fluorobenzyl)-3-(4-((3-chloro-6-methoxy-N-methylpyridazine-4-carboxamido)methyl)-thiazol-2-yl)urea (118 mg, 0.25 mmol) in 1,4-dioxane. Pd(PPh3)4 (15 mg, 13 μmol) was added followed by AlMe3 (250 μl, 2 M in toluene, 0.51 mmol). The mixture was refluxed for 4 hours and MeOH was added. Silica (300 mg) was added and the volatiles were removed in vacuo. The residue was brought on a column and purified by chromatography (CH2Cl2+5% 7N NH3 in MeOH) to afford the title product (60 mg, 0.13 mmol) as an off-white solid in 52% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:20])CC)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][F:20])[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCCCc1cccc(Br)c1
Solvent: O
Solvent: ClCCl
Product: FCCCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 5-(3-bromophenyl)pentan-1-ol (0.63 g, 2.6 mmol) in methylene chloride at −78° C. was treated with a solution of diethylamino sulfur trifluoride (DAST) (0.7 mL, 5.2 mmol) in methylene chloride, allowed to warm to room temperature, stirred for 0.5 h at room temperature, poured into water and extracted with ether. The extracts were combined washed sequentially with saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel, 40:1 hexane/ethyl acetate as eluent to give 1-bromo-3-(5-fluoropentyl)benzene as a pale yellow oil, 0.4 g (63% yield); 1H NMR (DMSO-d6) δ 1.3 (m, 2H); 1.6 (m, 4H); 2.5 (t, 2 H); 4.4 (dxt, 2H); 7.2 (m, 2 H); 7.4 (m, 2 H); MS [(+)ESI] m/z=245 [M−H]+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([CH2:12][C:13](=[NH:17])OCC)[C:8]=2[CH:18]=1.[CH2:19](N)[CH2:20][NH2:21].Cl>C(O)C>[ClH:1].[NH:21]1[CH2:20][CH2:19][N:17]=[C:13]1[CH2:12][C:9]1[C:8]2[CH:18]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=2[O:11][N:10]=1
Reactant: CCOC(=N)Cc1noc2ccc(OC)cc12
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: COc1ccc2onc(CC3=NCCN3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.4 %

Procedure:
In ethanol (20 ml) was dissolved ethyl 5-methoxy-1,2-benzisoxazole-3-acetimidate hydrochloride (2.1 g) and thereto was added ethylenediamine (0.59 g) at room temperature. The mixture was stirred at room temperature for 3 hours and then kept in refrigerator overnight. To the mixture was added ethanol (10 ml) containing 20 % hydrochloric acid, and the precipitated crystallines were separated by filtration, washed with ether, dried and recrystallized from ethanol to give the desired compound (2.5 g). m.p. 240° to 252°C (decomp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1
Reactant: OCc1cccc(Cl)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cccc(COc2cncc(Cl)n2)c1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of 3-chlorobenyl alcohol (9.57 g, 67.1 mmol) in toluene (134 ml) at 23° C. under a nitrogen atmosphere was treated with NaH (60% dispersion in oil, 2.5 g, 67.1 mmol). The resulting suspension was heated to reflux for 30 min and cooled to room temperature. The mixture was treated with 2,6-dichloropyrazine (10.0 g, 67.1 mmol) and heated to reflux for 18 h. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic phase was washed with brine, dried over MgSO4 (anhydrous), filtered and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2-hexanes 3:7) to afford 10.0 g of the title compound (I-3l) as a clear oil (58%).
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.Cl.O1CCOCC1>C1(C)C=CC=CC=1.O.C(O)C>[C:2]1([C:1]2[CH:9]=[C:10]([OH:11])[C:20]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[N:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl benzoylacetate (10.00 g, 52.0 mmol., 1 eq) and m-anisidine (7.05 g, 57.2 mmol., 1.1 eq) in toluene (85 mL) was added 4M HCl in dioxane (0.520 mL, 2.08 mmol., 0.04 eq) drop wise. The reaction mixture was refluxed over night while ethanol and water were collected in a Dean and Stark's apparatus. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was suspended in diphenyl ether (28 mL) and the mixture was heated for 2 h at 240° C. The reaction mixture was then left to cool to ambient temperature and dichloromethane (55 mL) was added, leading to the precipitation of a yellow solid. Stirring was continued at ambient temperature for a further 30 min and the solid collected by filtration, rinsing the cake with a small amount of dichloromethane. The solid was transferred to a 100 ml round bottom flask and stirred with dichloromethane (50 mL) for another 45 min at ambient temperature. After filtration and drying under high vacuum, the title compound, 2-phenyl-4-hydroxy-7-methoxy-quinoline, was isolated as a pale yellow solid. Yield: 2.85 g (22%). 1H NMR (250 MHz, DMSO-d6) δ 11.54 (s, 1 H), 7.99 (d, J=8.91 Hz, 1 H), 7.73-7.90 (m, 2 H), 7.48-7.64 (m, 3H), 7.20 (d, J=2.32 Hz, 1 H), 6.94 (dd, J=2.34, 8.97 Hz, 1 H), 6.26 (s, 1 H), 3.86 (s, 3 H). LC-MS: purity 97% (ELS) 98% (UV), tR 1.52 min, m/z [M+1]+ 252.10.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11](=[O:15])[CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1.[F:16][B-](F)(F)F.N#[O+].ClC1C=CC=CC=1Cl>C(Cl)Cl>[Cl:14][CH2:13][CH2:12][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:16])[CH:10]=2)[CH2:6][CH2:7]1)=[O:15]
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2c(c1)N(C(=O)CCCl)CC2
Agent: N#[O+]
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 10 °C
Yield: 19.5 %

Procedure:
260 mg (2.2 mmol) of 6-amino-1-(3-chloropropionyl)indoline (prepared as described in Preparation 6) were dissolved in 10 ml of methylene chloride, and 450 mg (2.0 mmol) of nitrosonium tetrafluoroborate were added to the resulting solution while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 30 minutes. At the end of this time, 10 ml of 1,2-dichlorobenzene were added to the mixture, and the mixture was stirred at 90° C. for 1 hour. The solvent was then removed from the reaction mixture by distillation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 97 mg (0.39 mmol) of the title compound as crystals (yield: 20%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].C(N(CC)C(C)C)(C)C.[I-].[Na+].[O:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>C(#N)C.CS(C)=O>[CH3:23][C@H:19]([O:18][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:14]([O:15][CH3:16])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][NH:41][CH:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[C:11]([NH2:17])[N:10]=1)[CH2:20][CH2:21][CH3:22]
Reactant: NC1CCOCC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CS(C)=O
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Temperature: 70 °C
Yield: 36.4 %

Procedure:
9-(4-Chlorobutyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine (70 mg, 0.205 mmol) was mixed with N,N-diisopropylethylamine (0.179 ml, 1.024 mmol), sodium iodide (30.7 mg, 0.205 mmol) and tetrahydro-2H-pyran-4-amine (62.1 mg, 0.614 mmol) in acetonitrile (1.5 ml) and heated at 70° C. under nitrogen overnight and then left at ambient temperature over the weekend. The acetonitrile was evaporated under nitrogen and the residue partitioned between aqueous sodium bicarbonate and dichloromethane. The aqueous phase was re-extracted with dichloromethane and the combined organic extracts were passed through a hydrophobic frit and evaporated under nitrogen to give an amber oil. This material was dissolved in 1:1 DMSO:MeOH (2×1 ml) and purified in two injections by Mass Directed AutoPrep (Method A). Product containing fractions were combined evaporated under nitrogen in a blowdown unit to give the title compound as a colourless oil (30.35 mg).
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8](=O)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.B>C1COCC1>[CH:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCOc2ccccc2N1
Agent: B
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCCO2
Temperature: 70 °C
Reaction time: 2 h
Yield: 125.7 %

Procedure:
6,7-Dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one (0.13 g, 0.8 mmol) was dissolved in THF and to this solution was added a 1M solution of borane in THF (1.59 mL, 1.6 mmol). The mixture was heated at 70° C. for 2 hrs. At this time a further portion of borane solution (1.59 mL, 1.6 mmol) was added and heating was continued for another 2 hrs. The solvent was evaporated at this point and the residue was dissolved in ethyl acetate. Extraction of the solution with 1M sodium hydroxide solution and then brine afforded an organic layer that was dried over anhydrous sodium sulfate. The filtrate was evaporated to afford 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene 2-4 (0.15 g, 100%) that was used without further purification. MS: 150.0 (M+H)+; tR=0.57 min (method 1).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[N:20]=2)=[CH:15][CH:14]=1)/[C:7]([O:9]CC)=[O:8])[CH3:4].C(O)(=O)C.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[N:20]=2)=[CH:15][CH:14]=1)/[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cc2)n1
Temperature: 68 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
0.93 mL (0.93 mmol) of aqueous 1 M lithium hydroxide solution is added to a solution of 0.29 g (0.62 mmol) of ethyl (Z)-2-ethoxy-3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}acrylate in 8 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 18 hours. After cooling, the reaction is worked up by addition of 0.93 mL (0.93 mmol) of aqueous 1 M acetic acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. After filtration, the solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture to give 0.10 g (37%) of (Z)-2-ethoxy-3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}acrylic acid in the form of a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][S:5]/[C:4]/1=[N:14]\[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][S:5]/[C:4]/1=[N:14]\[C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1)[CH3:2]
Reactant: CCn1c(-c2ccccc2)cs/c1=N\c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(-c2ccccc2)cs/c1=N\c1ccc(C(=O)O)cc1
Temperature: 80 °C

Procedure:
To a solution of (Z)-methyl 4-(3-ethyl-4-phenylthiazol-2(3H)-ylideneamino)benzoate (2-4) (50 mg, 0.19 mmol) in MeOH (1 mL) is added a solution of NaOH (1.0 mL of 1N aqueous solution, 1.0 mmol) and MeOH (0.5 mL). The mixture is heated at 80° C. for 1 hour and the solvent is removed. The residue is purified by preparative LC/MS to provide (Z)-4-(3-ethyl-4-phenylthiazol-2(3H)-ylideneamino)benzoic acid (2-5). HPLC-MS calculated for C18H16N2O2S (M+H+) 325.1. found 325.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=O.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][C:20]([NH2:25])=[C:21]([NH2:24])[CH:22]=2)[NH:17][C:16](=[O:26])[CH2:15]1>>[CH3:13][C:14]1([CH3:27])[C:23]2[CH:22]=[C:21]3[NH:24][C:10]([C:2]4[NH:1][C:9]5[C:4]([CH:3]=4)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[N:25][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:26])[CH2:15]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Product: CC1(C)CC(=O)Nc2cc3nc(-c4cc5ccccc5[nH]4)[nH]c3cc21
Yield: 45 %

Procedure:
In a manner analogous to that described in Example 2, from indole-2-carboxylic acid chloride and 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2one (see Example 13 a)), after column chromatography, there was obtained a yield of 45% of theory of the title compound; m.p. 264 -267° C.