Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([NH2:12])[CH2:9][C:10]#[CH:11].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>O.C1COCC1>[CH2:8]([NH:12][S:22]([CH2:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1)(=[O:24])=[O:23])[CH2:9][C:10]#[CH:11]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: C#CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCCNS(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a mixture of potassium carbonate (40.2 g, 296 mmol) in water (50 mL) and THF (50 mL) at 15–20° C. was added but-3-ynylamine hydrogen chloride (10.4 g, 98.5 mmol). Then, (3,4-dichlorophenyl)methanesulfonyl chloride (5, 30.7 g, 118 mmol) was added in portions during of a period of 30 min. The mixture was stirred for 4 h at rt. THF is evaporated. The mixture is extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4. The solvent is evaporated to give a white solid (20.5 g, 71%). 1H NMR (CDCl3): δ7.53 (d, 1H, J=2.0 Hz), 7.47 (d, 1H, J=4.2 Hz), 7.27 (m, 1H), 4.52 (t, 1H, J=6.2 Hz), 4.22 (s, 2H), 3.17 (dd, 2H, J=6.2 Hz, 12.5 Hz), 2.41 (m, 2H), 2.07 (m, 1H)
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#N)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[OH2:16]>C(O)C>[C:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:4]([Cl:3])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])([OH:16])=[O:1]
Reactant: [OH-]
Reactant: O
Reactant: N#CCc1ccc(Cl)c(C(=O)O)c1
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccc(Cl)c(C(=O)O)c1

Procedure:
Potassium hydroxide (0.969 g) in water (10 mL) was added to a solution of 2-chloro-5-(cyanomethyl)benzoic acid [Aromatic Intermediate 7, step a] (1.25 g) in ethanol (10 mL) and the resulting mixture was heated at reflux for 2.25 hours, then allowed to cool. The mixture was concentrated in vacuo to remove the ethanol and then diluted with water and washed twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the subtitled compound as a brown gum. Yield 1.38 g.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>Cl>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Agent: Cl
Product: CC(C)C(=O)NC1CCc2[nH]c3ccc(Br)cc3c2C1
Yield: 76.7 %

Procedure:
Combine p-bromophenylhydrazine hydrochloride (10.0 g, 44.7 mmol) and N-(4-oxo-cyclohexyl)isobutyramide (8.20g, 44.7 mmol) in saturated ethanolic HCl (180 mL) and heat at reflux under nitrogen for 18 h. Concentrate in vacuo to remove about ½ of the EtOH, then dilute with water (300 mL). Collect the resulting solid, slurry in EtOAc and recollect to give 11.5 g (77%) of a beige solid. MS (ES): 335 (M+1), 337 (M+H+2). 1H NMR(DMSO-d6): δ 10.93 (s, 1H, NH), 7.80 (d, 1H, J=7.9 Hz), 7.48 (s, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.07 (d, 1H, J=8.4 Hz), 4.00 (m, 1H), 2.86 (dd, 1H, J=15.2, 5.1 Hz), 2.77 (m, 2H), 2.46-2.32 (m, 2H), 1.93 (m, 1H), 1.75 (m, 1H), 0.99 (d, 6H, J=6.6 Hz).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[C:12](#[N:14])[CH3:13]>C1CCCCC1.O>[CH3:10][C:7]([CH3:8])([CH3:9])[C:6](=[O:11])[CH2:13][C:12]#[N:14]
Reactant: CCOC(=O)C(C)(C)C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)(C)C(=O)CC#N
Temperature: 80 °C

Procedure:
To a refluxed solution of sodium hydride (33.18 g, 553.03 mmol) in 275 mL of cyclohexane is added a mixture of 2,2-dimethyl-propionic acid ethyl ester (30 g, 230.43 mmol) in 79 mL acetonitrile (553.03 mmol) in 25 mL of cyclohexane. The mixture is maintained at 80° C. overnight. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organics are washed with water, dried over sodium sulfate, filtered and concentrated to afford title compound which was used crude in subsequent reaction. ESI m/z 124=MH−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[CH:48][C:49]([CH2:52]O)=[N:50][CH:51]=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:52][C:49]4[CH:48]=[CH:47][C:46]([C:45]([F:54])([F:44])[F:55])=[CH:51][N:50]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(C(F)(F)F)cn2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.28 mmol), prepared as described in Example 1, Ph3P (220 mg, 0.84 mmol) and (5-trifluoromethyl-pyridin-2-yl)methanol (50 mg, 0.28 mmol) in THF (2.0 mL) was added 40 wt % diethyl azodicarboxylate (DEAD) solution in toluene (0.33 mL, 0.84 mmol) at RT under argon. The reaction was stirred at RT for 30 min. Water (5.0 mL) was then added and the resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) followed by saturated aqueous NaCl (2×5 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product. This crude product was purified using reverse phase preparative HPLC to give the title compound 7,8-bis(4-chlorophenyl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (69.2 mg, 48%) as a yellow solid. MS (M+H)=516; 1H NMR (CDCl3): δ 8.83 (1H, s), 8.20 (1H, s), 7.93 (1H, d, J=8.2 Hz), 7.40 (1H, d, J=10.0 Hz), 7.26-7.34 (6H, m), 7.11 (2H, d, J=10.0 Hz), 5.47 (2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[O:17])[CH:13]=[C:12]([C:23]([O:25]CC)=[O:24])[CH:11]=1)#[N:2].[OH-].[Na+].C(#N)C.Cl>O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[O:17])[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[CH:11]=1)#[N:2]
Reactant: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with ethyl 2′-cyano-5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylate (25 mg, 0.066 mmol), sodium hydroxide (10 mg, 0.25 mmol), acetonitrile (2 mL) and water (2 mL). The mixture was stirred at room temperature overnight. 1N aq. HCl (3 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with CH2Cl2, and the CH2Cl2 layer was concentrated to dryness to afford the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][OH:15].O>C1(C)C=CC=CC=1>[CH2:14]1[O:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)[O:7][CH2:13]1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(C2OCCO2)ccc1O

Procedure:
25 g of 4-hydroxy-3-nitrobenzaldehyde is mixed in toluene with 1.1 equivalents of ethylene glycol and 370 mg of paratoluenesulfonic acid. It is boiled for 4 hours in a water separator. The mixture is poured onto sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is washed with brine, dried with magnesium sulfate and concentrated by evaporation. 23.6 g of crude product, which is suitable for further reactions, results.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:33][CH2:32][CH:30]1[O:29][N:28]=[C:27]([C:25]2[S:26][C:22]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][C@H:11]([CH2:13][N:14]5[CH:18]=[CH:17][N:16]=[N:15]5)[O:10][C:9]4=[O:19])=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)[CH2:31]1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)cc1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)cc1
Temperature: 90 °C
Yield: 40.7 %

Procedure:
(5R)-3-(4-Iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (214 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (100 mg).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=3[C:13]=2[N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:15]2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Na+]>C(OCC)C.O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=3[C:13]=2[N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][CH2:19]2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCC(=O)N1CCN(c2c(-c3ccc(Cl)cc3)oc3ccccc23)CC1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCN1CCN(c2c(-c3ccc(Cl)cc3)oc3ccccc23)CC1
Product: Cl
Temperature: 0 °C

Procedure:
To the suspension of 9.3 g of lithium aluminumhydride in 200 ml of diethyl ether (anhydr.) is added dropwise the solution of 73.3 g of 1-(2-p-chlorophenyl-3-benzofuryl)-4-pelargonylpiperazine in the mixture of 500 ml of diethyl ether and 200 ml of tetrahydrofuran while stirring at 0°. After addition, the suspension is stirred at ambient temperature for 15 hours, then cooled again to 0° and successively combined with 9.3 ml of water, 9.3 ml of 15% aqueous sodium hydroxide and 27.9 ml of water. The suspension is stirred in the ice-bath for 1 hour, filtered and the residue washed with diethyl ether. The filtrate is dried, evaporated, the residue taken up in the minimum amount of isopropanol and the solution acidified with ethereal hydrogen chloride, to yield the 1-(2-p-chlorophenyl-3-benzofuryl)-4-n-nonylpiperazine hydrochloride melting at 268°-270° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[O:32][C:31]([C:33]([O:35]CC)=[O:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[O:32][C:31]([C:33]([OH:35])=[O:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCOC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.2 %

Procedure:
To a solution of ethyl 5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-2-furoate (280 mg) in a mixed solvent of tetrahydrofuran (1.34 mL) and ethanol (1.34 mL) was added 1N aqueous sodium hydroxide solution (1.34 mL) and the mixture was stirred at room temperature for 14 hrs. 1N Hydrochloric acid (1.34 mL) and water (10 mL) were added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL×3) and diisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) to give the title compound (178 mg) as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[C:16]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:30]=2)[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1csc(COc2ccc(-c3cccc(-c4ccccc4)c3)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 71 mg, 0.2 mmol) in dioxane (3.5 mL) was added to a reaction tube containing biphenyl-3-boronic acid (available from Lancaster Synthesis Ltd., Morecambe, UK; 119 mg, 0.6 mmol). A solution of potassium carbonate (74 mg, 0.5 mmol) in water (0.4 mL) was added and the mixture was degassed. A solution of bis(tricyclohexylphosphine)-palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) in dioxane (0.5 mL) was added and the tube was heated in a microwave oven at 170 degrees for 25 min. Concentrated hydrochloric acid (0.1 mL) was added and the mixture was passed through a silica gel column (1 g of silica), and washed with dimethylacetamide (2×1 mL). The filtrate was evaporated to dryness and the resulting gum was triturated twice with 50% aqueous methanol to give 2-([1,1′;3′,1″]terphenyl-4-yloxymethyl) -thiazole-4-carboxylic acid. Mass spectrum MH+=388
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][C:22]([CH3:49])([CH3:48])[C:23]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][C:35]3=[O:47])=[N:28]1)=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:21][C:22]([CH3:49])([CH3:48])[C:23]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:38][CH2:39][N:40]([C:9]([C:7]4[CH:6]=[C:5]([O:12][CH3:13])[C:4]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[C:3]([O:2][CH3:1])[CH:8]=4)=[O:11])[CH2:41][CH2:42]2)[CH2:36][C:35]3=[O:47])=[N:28]1)=[O:24]
Reactant: COc1cc(C(=O)O)cc(OC)c1-c1ccccc1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn(COC(=O)C(C)(C)C)n4)ccc2O3)cc(OC)c1-c1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.23 mL) and water (2.0 mL) were added to a DMF (6.0 mL) solution of 2,6-dimethoxy-biphenyl-4-carboxylic acid (258 mg), [5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)-tetrazol-2-yl]methyl 2,2-dimethylpropanoate hydrochloride (500 mg), WSC (288 mg) and HOBT (202 mg), and stirred at 90° C. for 1 hour. Water was added to it at room temperature, and a white precipitate was thus obtained. This was dried under reduced pressure to obtain the title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.40 (1H, d, J=2.2 Hz), 8.26 (1H, dd, J=8.8, 2.2 Hz), 7.38-7.18 (6H, m), 6.75 (2H, s), 6.64 (2H, s), 4.35-4.21 (1H, m), 3.68 (6H, s), 3.65-3.39 (2H, m), 3.29-3.25 (1H, m), 2.98 (2H, s), 2.14-1.92 (2H, m), 1.89-1.78 (2H, m), 1.14 (9H, s). MS [M+H]+=640.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:27][NH2:28].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:28][OH:27])[CH2:7][CH2:8][N:9]2[C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(C(=O)c2ccc(Cl)cc2Cl)c2cc(Cl)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(Cl)cc1Cl)N1CCC(=NO)c2ccc(Cl)cc21
Yield: 87.7 %

Procedure:
To a mixture of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone (17.5 g), obtained in example 5, and ethanol (250 ml) were added hydroxyl amine hydrochloride (7 g) and pyridine (8.5 g), and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into 1000 ml of water, and precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime (yield 16 g) as white crystal.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[N:15][C:16]([OH:21])=[CH:17][C:18]=3[CH3:20])[NH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1.[F:22][C:23]([F:34])([F:33])[CH:24]1[CH2:29][CH2:28][N:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH3:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[N:15][C:16]([OH:21])=[CH:17][C:18]=3[CH3:20])[N:13]([C:30]([N:27]3[CH2:26][CH2:25][CH:24]([C:23]([F:33])([F:22])[F:34])[CH2:29][CH2:28]3)=[O:31])[N:12]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: Cc1cc(O)nc2[nH]nc(OC(=O)N3CCC(C)CC3)c12
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Product: Cc1cc(O)nc2c1c(OC(=O)N1CCC(C)CC1)nn2C(=O)N1CCC(C(F)(F)F)CC1

Procedure:
In analogy to example 12, 99.87 mg (0.344 mmol) of 6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl 4-methylpiperidine-1-carboxylate were reacted with 83.4 mg (0.52 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 16 mg (10%), M+H+: 470.20.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6](Cl)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2Cl
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A slurry of 8,11-dichloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridine (3.79 g, 13.43 mmol) in THF (25 ml) was added dropwise to piperazine (3.53 g, 157 mmol) in THF (50 ml) over 45 minutes. The mixture was stirred at room temperature for 5 hours and the reaction was then quenched with the slow addition of NaOH (200 ml, 2.5N) and extracted with CH2Cl2 (400 ml and 4×100 ml). The combined organic layers were washed with brine, dried (Na2SO4), decanted and concentrated; the crude product was purified by flash chromatography (10%acetone/CH2Cl2 to 10%MeOH/CH2Cl2 /NH4OH) and obtained as a white solid (4.08 g, 91%); MS (FAB, M+H)=332; found: C, 61.73; H, .5.60; N, 12.40; C17H18ClN3S requires: C, 61.53; H, 5.47; N, 12.66.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]O>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc(F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(F)c2)c1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.24 (2H, s), 5.73 (1H, d, J=2.0 Hz), 7.03-7.05 (1H, m), 7.07-7.21 (2H, m), 7.36-7.38 (1H, m), 7.40-7.42 (1H, m), 7.57 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=4.2 Hz). [M+H] Calc'd for C16H11FN4O, 295. Found, 295.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][CH:22]=[CH2:23])=[C:19]=[O:20]>>[CH2:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1)=[O:20])[CH:22]=[CH2:23]
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
Example 10 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 3-isocyanatoprop-1-ene (12.0 μl) to give the title compound (0.027 g). LC-MS (System A): Rt 1.93 mins, Mass Spectrum m/z 358 [MH+].
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([CH2:17][C:18]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=O.[C:32]1([CH3:45])[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[C:32]1([CH3:45])[CH:33]=[CH:34][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([CH2:15][CH2:17][C:18]3([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:41][CH2:40]2)=[CH:36][CH:37]=1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: O=CCC1(CCN2CCOCC2)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Cc1ccc(NC2CCN(CCC3(CCN4CCOCC4)CCCCC3)CC2)cc1
Reaction time: 3 h
Yield: 46 %

Procedure:
After adding sodium triacetoxyborohydride (579 mg, 2.73 mmol) to a solution of 4-[2-[1-(formylmethyl)cyclohexyl]ethyl]morpholine (625 mg, ca. 1.82 mmol), 4-(p-toluidino)piperidine (519 mg, 2.73 mmol) and acetic acid (0.21 mL, 3.64 mmol) in 1,2-dichloroethane (10 mL), the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was washed with saturated brine and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (30 g Merck Art 9385, chloroform:methanol=1:0-10:1) to obtain the title compound as a colorless oil (346 mg) (48% yield).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:19])=[O:9])=[O:2]
Reactant: Cc1cc(C)c(C(=O)O)cc1C=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C=O)c(C)cc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask, was placed 5-formyl-2,4-dimethylbenzoic acid (compound 83.1, 2.00 g, 11.2 mmol) and methanol (50 mL). Concentrated sulfuric acid (2 mL) was carefully added drop-wise and the resulting solution was stirred for 2 h at 80° C., then cooled and the volatiles were removed under reduced pressure. The pH of the residue was adjusted to 9 with sodium bicarbonate (sat.), then the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 2.0 g (crude) of the title compound as yellow oil. The crude product was used in next step without further purification.